Abstracts

Clinical Trials and Pharmacology

1

The UP study ‐ Ursodeoxycholic Acid (UDCA) as Neuroprotective Treatment for Parkinson's Disease

Thomas Payne (Sheffield, United Kingdom), Matthew Appleby (London, United Kingdom), Ellen Buckley (Sheffield, United Kingdom), Thomas Jenkins (Sheffield, United Kingdom), Thomas Foltynie (London, United Kingdom), Oliver Bandmann (Sheffield, United Kingdom)

Objective: To determine the safety and tolerability of ursodeoxycholic acid (UDCA) in Parkinson's disease (PD) and explore its neuroprotective potential.

Background: We previously undertook the first‐ever drug screen in PD patient tissue and identified UDCA as a promising neuroprotective compound for PD [1,2]. UDCA has been in clinical use for > 30 yr as treatment for primary biliary cholangitis (PBC).

Methods: We designed a phase IIa, randomised, placebo‐controlled clinical trial to assess UDCA in PD (the UP study). A total of 30 patients will be recruited. Key inclusion criteria are < 3 yr since diagnosis and definite response to dopaminergic medication. 20 patients will be started on a slowly increasing dose of UDCA until they reach the final dose of 30 mg/kg, 10 patients will take placebo. All research participants will take the study drug for 48 weeks and are then re‐assessed after an 8 week washout period. The primary outcome will be safety and tolerability of UDCA. Secondary outcomes include MDS‐UPDRS assessment in the practically defined Off, 31P‐MR spectroscopy and sensor‐based objective quantification of motor impairment.

Results: Recruitment across two study sites (Sheffield Teaching Hospitals and University College London Hospitals) started in January 2019. All patients will be randomised by October 2019. There were two screen failures due to unexpectedly low MoCA scores. Only 1/27 patients randomised to date had to stop taking the medication. This was due to swallowing problems rather than due to side effects of the medication as such. Mild, self‐limiting diarrhoea for < 24h is the only treatment‐related side‐effect observed so far. 25/27 patients underwent 31P‐MR spectroscopy. Compliance with the use of motion sensors was excellent.

Conclusions: The UP study provides a successful example of academically led drug development, reflecting the “bench‐to‐bedside” philosophy. The two independent objective readouts included in the UP study (31P‐MRS and sensor‐based objective quantification of motor impairment) could also be applied to assess the neuroprotective potential of other compounds and may be particularly promising for any drugs with a postulated rescue effect on mitochondrial function.

References: 1. Mortiboys H, Aasly J, Bandmann O (2013): Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson's disease. Brain;136:3038‐50. 2. Mortiboys H, Furmston R, Bronstad G, Aasly J, Elliott C, Bandmann O (2015): UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo. Neurology 85:846‐52.

2

The Effectiveness of Caffeine for Management of Motor and Non‐Motor Symptoms of Parkinson's Disease

Doniyorbek Daminov (Tashkent, Uzbekistan), Gulnara Sattarovna (Tashkent, Uzbekistan), Shakhnoza Mukhiddin Qizi (Tashkent, Uzbekistan)

Objective: The aim of this study to evaluate efficacy of caffeine for managing motor and non‐motor symptoms of Parkinson disease.

Background: Caffeine is potential neuroprotective agent as nonselective adenosine A2A receptors antagonist. Epidemiological studies established the inverse relationship between the consumption of caffeine and the risk of developing PD. Coffee has been shown to increase the effectiveness of L‐DOPA and a combination treatment would require less L‐DOPA administration for the same desired effect and the benefit of delaying or preventing the development of L‐DOPA induced‐dyskinesia.

Methods: The study involved 36 patients with PD (20 men and 16 women mean age of 56.6 ± 2.8 years, the average duration of the disease 6.9 ± 2.5 years. First group (18 patient) received Levodopa/carbodopa and caffeine 100 mg twice a day for 4 weeks, after 200 mg twice a day during 4 weeks. Second group (control group) took Levodopa/carbidopa without caffeine. Non‐ motor symptoms especially sleep disturbances assessed with Excessive Sleep Scale (ESS), Motor severity, assessed with the Unified Parkinson's Disease Rating Scale (UPDRS).

Results: The study showed that caffeine significantly decrease daytime somnolence. On the primary stage of analysis at 6 weeks, ESS was reduced (1.71 points) in the caffeine group compared to control group. On examination, UPDRS III scores at week 6 were reduced (2.65 points; 5.5, 0.8) in the caffeine group compared to control. The overall UPDRS was reduced 4.69 points in the caffeine group (CI 7.7, 1.6) at week 6, without significant differences in UPDRS parts I or II.

Conclusions: Caffeine may provide not only reduce daytime somnolence in PD, but improved objective motor measures

References: Altman RD, Lang AE, Postuma RB. Caffeine in Parkinson's disease: a pilot open‐label, dose‐escalation study.Mov Disord 2011;26:2427–2431.

3

Rapid Uptake and Stable Serum Levodopa Levels with Continuous S.C. Infudopa (Levodopa/Carbidopa) Administration

Filip Bergquist (Goteborg, Sweden), Mats Ehrnebo (Uppsala, Sweden), Leif Bring (Vimmerby, Sweden), Elias Eriksson (Goteborg, Sweden), Nil Dizdar Segrell (Linkoping, Sweden)

Objective: Pharmacokinetic characterisation of a novel online‐buffered levodopa/carbidopa (LD/CD) solution.

Background: LD/CD intestinal gel infusion has superior efficacy in advanced PD compared to oral treatment but requires surgery. S.c. infusion therapy would be more accessible but has previously not been feasible because of low solubility of levodopa at physiological pH.

Methods: Infudopa, a high concentration levodopa/carbidopa solution which is buffered on‐line, was infused i.v. or s.c. over 16h and compared with intestinal LD/CD gel (LCIG) regarding pharmacokinetic profile in a phase I, open‐label, randomized, crossover study (NCT03419806).

Results: Interim analysis of the first five patients (all male, age 58‐76, daily pre‐study LCIG levodopa dose 877‐2876 mg) demonstrated that levodopa bioavailability (AUC0‐16h) was 94.7±5.9% with s.c. Infudopa and 82.4±8.9% with LCIG. The coefficient of variation for levodopa bioavailability was 5.5% with Infudopa and 10.6% with LCIG. Carbidopabioavailability was complete with s.c. Infudopa but only 12% with LCIG. All patients reported mild to moderate pain at initiation of s.c. infusion and 4/5 patients reported mild to moderate discomfort at initiation of i.v. infusion, both lasting throughout the high‐speed bolus infusion period (<11 minutes). In three cases, mild pain at s.c. site persisted for 1‐8h. Three patients developed hematoma after >8h s.c. infusion.

Conclusions: Online buffering is a feasible method for continuous subcutaneous or intravenous infusion of a highly concentrated levodopa/carbidopa solution to PD patients. The drug formulation has been modified to reduce skin reactions in the remaining study.

4

Withdrawn by Author

5

Personality and Parkinson's disease

Aynur Ragimova (Moscow, Russia), Marina Samushiya (Moscow, Russia), Irina Smolentseva (Moscow, Russia)

Objective: To clarify premorbid features in patients with Parkinson's disease (PD) and assess its influence on complacence to therapy.

Background: Parkinson's disease (PD) is a systemic neurodegenerative disease with typical premorbid features. According to literature the traits of patients with PD include reduced novelty seeking, fear of damage, anxiety and rigidity [1,2].

Methods: Questionnaires as well as clinical interview and neurological examination

Results: The mean age of the patients was 70.4 years, the first motor symptoms appeared at the age of 68.1 and non‐motor symptoms at the age of 61.2; mean disease duration was 2.5 years, dopaminergic treatment was taken over a period of 1.5 years, 20 patients (69%) were classified as stage 2 (Hoehn‐Yahr), and 9 patients (31%) – as stage 2.5.According to SCID‐II, among the patients with PD there were no patients with clinically significant personality disorders, but all of them had some leading characteristic features: in 4 patients (13.7%) prevailed histrionic traits, 11(37%) ‐ obsessive‐compulsive, 3 (10.3%) ‐ dependent, 3(10.3%) ‐ paranoid, 3 (10.3%) ‐ schizoid and 5 (17.2%) ‐ schizotypal.According to Minimult questionnaire “correction of answers” was typical for all patients: they focused on public opinion and social norms; 20 (69%) had low results on psychopathy scale (tendency to maintain the existing lifestyle, rigidity), 23 (79.3%) were distrustful and suspicious. According to TAS n=25 (86.2%) patients suffered from alexithymia: either sub clinical (n=10; 34.4%) or prominent (n=15; 51.7%). «Somatotony» during lifetime was revealed in 20 patients (68.9%), cumulation of episodes of somatization of depressive phases (headache, GI diseases, blood pressure increase) in 17 patients (58.6%) ? 100% of patients had high anxiety according to HADS and 14 patients (48.2%) had depression; however according to HAD‐M depression was evident in 19 patients (65.5%). The widespread of alexithymia could be the cause of such difference. Patients with hysteric (n=4; 13.7%) and schizotypal traits (n=2; 6,8%) were the least compliant to terapy. These patients didn't follow medical recommendations, felt the difference between on/off states and misused dopaminergic drugs.

Conclusions: PD patients are typically focused on public opinion, prone to conflicts, had low impulsiveness, high rigidity and alexithymia. Somatization of affective diseases is typical. Patients with schizotypal and hysteric traits showed non‐compliance and abuse on therapy.

References: 1. Rosen, J.B., Brand, M., Polzer, C., Ebersbach, G., Kalbe, E., 2013. Moral decision‐making and theory of mind in patients with idiopathic Parkinson's disease. Neuropsychology 27, 562–572. doi:10.1037/a0033595 2. Sullivan, K.L., Mortimer, J.A., Wang, W., Zesiewicz, T.A., Brownlee, H., Borenstein, A.R., 2015. Occupational Characteristics and Patterns as Risk Factors for Parkinson's Disease: A Case Control Study. Journal of Parkinsons Disease 5, 813–820. doi:10.3233/jpd‐150635

6

The Effectiveness of Melatonin in Sleep Disorders in Patients with Parkinson's Disease

Shakhnozakhon Rakhimova (Tashkent, Uzbekistan)

Objective: The aim of this study to evaluate efficacy of melatonin in sleep disorders in patients with PD.

Background: Sleep problems may be an early sign of Parkinson's disease, even before motor symptoms have begun. Emerging evidences suggest that secretion of endogenous melatonin significantly decrease in patients with PD .Inadequate secretion of melatonin may main cause of sleep disturbances in PD.

Methods: The study included 43 patients with mean age (60 ±7.7) with a diagnosis of PD without dementia. The average duration of BP is 7.5 years. Patients made up two observation groups. In 23 patients of group I (study group) it was recommended to take Levodopa/carbodopa with melatonin (Melaxen 3 mg). In group II (comparison group), there were 20 patients who took only Levodopa/carbidopa. Sleep disturbance was measured using the Parkinson Disease Severity Scale (PDSS) rating scale, Euphoria sleepiness ‐ Excessive Sleep Scale (ESS), the cognitive function rating scale for PD‐SCales for Outcomes for Parkinsons diseases Cognition (SCOPA‐Cog) a quality of life questionnaire under the PD ‐ Parkinson's Disease Quality of Life (PDQ‐39).

Results: Sleep disorders was observed in 64.3% of patients, in a third of them almost daily. The study showed the effectiveness of synthetic melatonin (Melaxen, 3 mg tablets) in patients with PD. Against the background of daily intake of Melaxen at a dose of 3 mg / day at bedtime for 6 weeks, there was an improvement in sleep on the PDSS scale (p <0.005) by 27% in I group, a decrease in daytime sleepiness on the ESS scale by 8.7%, in 78% of patients the increased duration of sleep for 1.5 ± 0.5 hours; in most patients (72%), the number of nocturnal awakenings decreased by 50%, the time of falling asleep by 56%, the frequency of insomnia episodes decreased from 3 to 1 times a week (61%).

Conclusions: Our clinical research demonstrate that a long time administration of synthetic forms melatonin may improve sleep architecture in Parkinson's disease. On the other hand Melatonin cannot reduce daytime sleepiness significantly.

Clinicopathological Correlations

50

Serum Neurofilament Light Chain Levels and Disability Milestones in Lewy Body Diseases

Alberto Imarisio (Brescia, Italy), Andrea Pilotto (Brescia, Italy), Francesca Conforti (Brescia, Italy), Alessandro Lupini (Brescia, Italy), Giuliana Gianni (Brescia, Italy), Stefano Gipponi (Brescia, Italy), Elisabetta Cottini (Brescia, Italy), Andrea Scalvini (Brescia, Italy), Stefano Masciocchi (Brescia, Italy), Sara Nocivelli (Brescia, Italy), Rosanna Turrone (Brescia, Italy), Laura Bonanni (Chieti Scalo, Italy), Maria Cristina Rizzetti (Trescore Balneario (BG), Italy), Marina Pizzi (Brescia, Italy), Arianna Bellucci (Brescia, Italy), Emirena Garrafa (Brescia, Italy), Henrik Zetterberg (Uppsala, Sweden), Abdul Hye (London, United Kingdom), Nicholas Ashton (London, United Kingdom), Alessandro Padovani (Brescia, Italy)

Objective: Serum and CSF neurofilament light chain (NfL) levels have been proposed as markers of neurodegeneration. Several studies showed as NfL levels could be used to discriminate between Parkinson's disease and atypical parkinsonism. However, the relationship between serum NfL levels, motor and non‐motor functions in Lewy body diseases is still theme of discussion.

Methods: Serum NfL was assessed in a cross‐sectional study including patients with Parkinson's disease (PD, n=92) and dementia with Lewy bodies (DLB, n=27). We evaluate the correlation between NfL levels and motor, non‐motor symptoms, cognitive and behavioral abnormalities in PD and DLB. All analyses are corrected for age, sex and disease duration.

Results: Serum NfL correlated with age and age at onset in the cohort; PD showed lower NfL levels compared with DLB patients (p=0.001) . In PD, higher NfL levels correlated with hyposmia (p=0.01), total UPDRS‐II and UPDRS‐III scores (0.001), gait speed (0.04) and several disability milestones, including cognitive impairment (0.001), symptomatic dysautonomia (0.001), loss of independency in activities of daily living (p=0.01) and instrumental daily living (p=0.001). In DLB, NfL correlated with disease duration, hyposmia and neuropsychiatric symptoms, but not with motor function assessed by UPDRS‐III.

Conclusions: Elevated serum NfL levels are associated with disability milestones in PD patients and neuropsychiatric abnormalities in DLB. Further longitudinal investigations are warranted in order to evaluate NfL as a predictive biomarker of disability progression in Lewy bodies disorders.

51

CSF Inflammatory Cytokines and Correlation with Clinical Features in Early, Untreated PD Patients

Nicola Modugno (Rome, Italy)

Objective: The aims of the present study were to investigate the concentrations of inflammatory cytokines in the cerebrospinal fluid (CSF) of drug‐naïve PD patients and to investigate correlations between NMS and cytokines in PD patients.

Background: The presence of depression and anxiety has been reported in several neurodegenerative conditions, not only in Parkinson's disease (PD). However, the incidence seems higher in PD than in other chronic diseases and the onset of mood disturbances may even precede the motor symptoms. Non‐motor symptoms (NMS) in PD are associated with a variety of poor outcomes. Research and clinical data suggest that the etiology of PD and of NMS is multifactorial. Even if the pathophysiological mechanisms behind NMS, mood disorders in particular, are poorly understood, recent advance in neuroinflammation have provide a better knowledge of these symptoms. The inflammatory hypothesis states that mood disturbances are caused by an activation of the inflammatory system, increasing production of cytokines that promote changes in neuroendocrine, neurochemical processes and in the metabolic pathway of serotonin. Neuroinflammation may be involved in the pathophysiology of PD and specifically in the initiation and/or maintenance of NMS in PD. Based on this hypothesis, immune and inflammatory biomarkers have been largely investigated in PD patients. The levels of inflammatory cytokines in peripheral blood tend to be higher in PD patients. Studies of brains from patients and animal models have provide several evidence for neuroinflammation involvement in PD. However, at present, the influence of inflammation on NMS in PD remains unclear.

Methods: CSF was collected in new diagnosed, drug‐naïve PD patients. Exclusion criteria were autoimmune or inflammatory diseases, anti‐inflammatory or antidepressant medication, evidence of an inflammatory process at the time of CSF withdrawal or blood‐tinged CSF. Cytokines were assessed using a Bio‐Plex multiplex assay. Motor disability was evaluated using UPDRS part‐III. Cognitive status and quality of life were assessed by MoCA test and PDQ‐8. Depression and anxiety were investigated with the Beck Depression Inventory (BDI)‐II and the State‐Trait Anxiety Inventory (STAI‐Y). The sleep quality and the daytime sleepiness were assessed using the PD Sleep Scale (PDSS‐2) and the Epworth Sleepiness Scale (ESS) respectively.

Results: The study population comprised 28 patients with a median of disease duration of 12 months. Disease duration, UPDRS‐III, MoCA, PDSS‐2 and ESS scores did not correlate significantly with CSF cytokines levels. BDI‐II score correlated significantly and positively with IL‐6 (Spearman's Rho = 0.52, p = 0.005) and IL‐10 (Spearman's Rho = 0.44, p = 0.01). STAI‐st score correlated significantly and positively with IL‐6 (Spearman's Rho = 0.58, p = 0.001) and IL‐10 (Spearman's Rho = 0.43, p = 0.02). STAI‐tr score correlated significantly and positively with IL‐6 (Spearman's Rho = 0.54, p = 0.003) and IL‐10 (Spearman's Rho = 0.44, p = 0.02). These correlations remain significant also after controlling for disease duration, motor impairment and age.

Conclusions: We suggest that NMS in PD patients, such as depression and anxiety, might be generated via inflammatory mechanisms. These data are consistent with a growing body of literature that implicates inflammatory cytokines in neural and behavioral processes and further suggests that cytokines may be involved in NMS in PD. Our results are, however, based on a small sample and without a healthy control group for comparison. For all these reasons these results are clearly exploratory and preliminary. Further studies are required to study the role of these cytokines in different type of PD and to correlate inflammatory mediators with clinical features and neuroimaging measures.

References: Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology 2010;129(2):154‐69.Barnum CJ, Tansey MG.Neuroinflammation and non‐motor symptoms: the dark passenger of Parkinson's disease? Curr Neurol Neurosci Rep 2012;12(4):350‐8.Brodacki B, Staszewski J, Toczylowska B, Kozlowska E, Drela N, Chalimoniuk M, Stepien A. Serum interleukin (IL‐2, IL‐10, IL‐6, IL‐4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett 2008;441(2):158‐62.Maes M, Berk M, Goehler L, Song C, Anderson G, Galecki P, Leonard B. Depression and sickness behavior are Janus‐faced responses to shared inflammatory pathways. BMC Med 2012;10:66. McGeer PL, McGeer EG. Inflammation and neurodegeneration in Parkinson's disease. Parkinsonism Relat Disord 2004;10 Suppl 1:S3‐7.Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Bienfait K, et al. The role of inflammatory cytokines in cognition and other non‐motor symptoms of Parkinson's disease. Psychosomatics 2010;51(6):474‐9.

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Every cloud has a silver lining? A case report of midbrain hemorrhage in patient with Parkinson's disease

Paulina Papier (Wroclaw, Poland), Katarzyna Markowska (Wroclaw, Poland), Joanna Bladowska (Wroclaw, Poland), Ewa Koziorowska‐Gawron (Wroclaw, Poland), Slawomir Budrewicz (Wroclaw, Poland)

Objective: To present unusual and rare clinical presentation of midbrain hemorrhage caused by a developmental venous anomalies (DVA) in Parkinson's disease (PD) patient.

Background: The results of previous epidemiological studies of the relationship between Parkinson's disease and stroke varied. Some of them showed a reduced risk of haemorrhagic stroke and others indicated an increased likelihood of stroke [1]. Although there have been reports in the literature showing cases of stroke‐induced parkinsonism [2‐3], recovery of symptoms after midbrain hemorrhage has not been demonstrated.

Methods: 63‐year‐old patient with a 10‐year history of Parkinson's disease presented with acute onset of transient diplopia. After two weeks neurological examination showed the absence of tremor. Further improvement of gait and balance was also observed. A history of comorbid factors, included insulin resistance, obesity and ischemic heart disease.

Results: Magnetic resonance imaging (MRI) revealed further evolution of the brainstem hematoma located on the border of the pons and midbrain. Several years before angio‐CT scans revealed the presence of congenital venous malformation at exact location. The 63‐year‐old patient with long‐term Parkinson's disease who complained of tremor and freezing of gait was diagnosed with hemorrhagic stroke. The MDS‐UPDRS Part III subscore was reduced after stroke by 36 points (>50%, from 66 to 30).

Conclusions: Our report shows that focal midbrain hemorrhage can have at least positive impact on parkinsonism.

References: 1. Mastaglia FL, Johnsen RD, Kakulas BA (2002) Prevalence of stroke in Parkinson's disease: a postmortem study. Mov Disord 17:772–774. 2. Harik SI, Al‐Hinti JT, Archer RL, Angtuaco EJC. Hemiparkinsonism after unilateral traumatic midbrain hemorrhage in a young woman. Neurol Clin Pract. 2013;3(1):4–7. doi:10.1212/CPJ.0b013e318283fef6. 3. Siniscalchi A, Gallelli L, Labate A, Malferrari G, Palleria C, Sarro GD. Post‐stroke Movement Disorders: Clinical Manifestations and Pharmacological Management. Curr Neuropharmacol. 2012;10(3):254–262. doi:10.2174/157015912803217341

Cognitive Disturbances and Dementia

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The relationship between asymmetric dopamine loss, cognition and brain structural changes in early Parkinson's disease from PPMI study

Roberta Biundo (Venice‐Lido, Italy), Eleonora Fiorenzato (Venice, Italy), Luca Weis (Venice‐Lido, Italy), Elisabetta Gasparoli (Venezia Lido, Italy), Angelo Antonini (Padua, Italy)

Objective: To explore the distribution and the degree of asymmetric putaminal dopamine transporter availability in early right‐handed Parkinson's disease (PD) patients, its underlying anatomical changes and its association with cognitive symptoms.

Background: PD is characterized by asymmetric motor onset that is linked to strong asymmetric nigro‐striatal dopaminergic dysfunction. However, if right or left asymmetry contributes differently to cognitive performance and the extent of the anatomical changes associated with this asymmetry remain still controversial.

Methods: From a sample of 612 PD patients and 238 HC, which had [123I]FP‐CIT SPECT (DaTscan) from the PPMI, we observed 378 PD with marked putaminal asymmetry index greater than 20% at the baseline visit and 196 HC with negative [123I]FP‐CIT and MoCA>26. We identified 249 right‐handed de novo PD, with left (n=106) vs. right (n=143) putaminal asymmetry (PD‐LPA vs. PD‐RPA) (see Figure 1) and analyzed clinical and neuropsychological data available in PPMI dataset for PD and HC. We measure brain cortical thickness, cortical folding and subcortical volumes in a subsample of PD patients, as structural T1‐MRI data was available for 103 PD‐LPA and 70 PD‐RPA. MRI differences were assessed by means of ANCOVA with age, gender and estimated total intracranial volume as covariates. Striatal binding ratio (SBR) was calculated for the left and right caudate and putamen separately, using the occipital lobe as a reference region.

Results: There were no significant differences between the overall asymmetric PD subgroups (n=249) and HC (n=196), but PD showed poorer cognitive performance in all cognitive tests, except for the LNS and Benton JLO (see Table 1). PD‐RPA and PD‐LPA did not differ in terms of demographics variables. However, PD‐RPA showed significant higher MDS‐UPDRS‐III scores than PD‐LPA, while PD‐LPA showed a worse performance in SDMT task (p=0.029) compared to the other group. Further in PD‐LPA group, we found a significant cortical thinning in the left inferior parietal and inferior temporal cortices. Regarding sulcal indices, significant local reductions were shown in the bilateral cuneus and left paracentral lobule in PD‐LPA. Subcortical analyses reveal a significant reduction in the left amygdala, nucleus accumbens and thalamus of the PD‐LPA group.

Conclusions: Cognitive alterations can be present in de novo PD compared to aging population. We found that side of onset of motor symptoms, in these patients, affects cognition. Namely, in PD left putaminal dopaminergic degeneration seems to be associated with visuospatial‐attention dysfunctions. Moreover, PD‐LPA patients were characterized by cortical thinning and folding reduction of posterior regions as well as by a reduction of specific subcortical volumes. Interestingly, these anatomical changes were located in the left hemisphere, possibly suggesting alterations in the ipsilateral networks of the putaminal asymmetry and involving posterior regions which are linked with attentive and visuospatial processes. Prospective longitudinal studies are needed to clarify whether visuo‐spatial‐attention deficits might be added to the prodromal non‐motor symptoms that may precede or be concurrent with PD motor manifestations.

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Clinical characteristics of pain in Parkinson's disease dementia

Bogdan Ciopleias (Brasov, Romania), Stefania Diaconu (Brasov, Romania), Ramona Chiperi (Brasov, Romania), Cristian Falup‐Pecurariu (Brasov, Romania)

Objective: The aim of this study was to assess the prevalence of pain in Parkinson's disease dementia, its clinical characteristics and the correlations with motor features and with severity of dementia.

Background: Pain in Parkinson's disease dementia (PDD) is an underrecognized and undertreated non‐motor symptom. The assessment of pain in advanced PDD is challenging due to the reduced capacity of self‐reporting.

Methods: Prospective study on 31 PDD patients. We used a standardized questionnaire, Pain Assessment in advanced dementia (PAINAD) Scale, Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC‐II), and Functional Assessment Staging (FAST).

Results: There were 11 mild, 8 moderate and 12 severe dementia cases. In patients with advanced dementia we were focusing especially on the facial expressions, verbalizations, body movements, interpersonal interactions, and mental status changes.The overall prevalence of pain was 26/31 (83.97%). According to the subgroups, pain was present in 8/11 in the mild, 7/8 in the moderate and 11/12 in the advanced cases. The most frequent type of pain was the musculoskeletal one, followed by genital pain (especially in patients with genitourinary infection). Pain severity was correlated with severity of dementia and motor disability. Pain was associated with agitation and hallucinations. Patients reporting more pain had significant more sleep disruption. Out of 26 PDD patients with pain, 12 did not disclose it to the neurologists.

Conclusions: Pain has a high prevalence in PDD patients. In severe cases, active screening for pain is needed, best using non‐verbal assessment.

References: 1. Lautenbacher S, Kunz M. Facial Pain Expression in Dementia: A Review of the Experimental and Clinical Evidence. Curr Alzheimer Res. 2017;14(5):501‐505. doi: 10.2174/1567205013666160603010455. 2. Choi SM et al. Impact of pain and pain subtypes on the quality of life of patients with Parkinson's disease. J Clin Neurosci. 2017 Nov;45:105‐109. doi: 10.1016/j.jocn.2017.08.002. 3. de Tommaso M et al. Pain in Neurodegenerative Disease: Current Knowledge and Future Perspectives. Behav Neurol. 2016;2016:7576292. doi: 10.1155/2016/7576292

55

Brain amyloid contribution to cognitive deficits in Lewy bodies disorders: A pilot study

Eleonora Fiorenzato (Venice, Italy), Roberta Biundo (Venice‐Lido, Italy), Diego Cecchin (Padua, Italy), Angelo Antonini (Padua, Italy)

Objective: To investigate regional [18F]florbetapir binding to beta amyloid (Aß) and its contribution to cognitive alterations in Lewy bodies disorders (LBD).

Background: LBD like Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are synucleinopathies, but accumulation of Aß has been frequently reported [1,2]. Clarifying the relationships of Aß and a‐syn in LBD can possible yield insights on the contributions of comorbid Aß‐pathology to dementia progression.

Methods: Five DLB, 21 PD [3 PD with normal cognition, 11 PD with mild cognitive impairment, 7 PDD] underwent [18F]florbetapir positron emission tomography (PET) scanning. Clinical features, including demographic characteristics cognitive testing, motor severity and motor phenotypes (tremor dominant vs. postural instability gait disorder) were assessed. For the purpose of this study, we analyzed various neuropsychological tests assessing all cognitive functions and allowing Level‐II cognitive diagnosis. Non‐ parametric analyses were run due to the small sample size.

Results: Ten out of 26 patients (38.5%) were amyloid positive (Aß+) at visual assessment. The two groups (Aß+ vs. Aß‐) agreed in terms of demographics variables. We found Aß+ had a worse performance than Aß‐ patients on global cognition, as assessed by Montreal Cognitive Assessment (MoCA) (p=0.029) and there was a trend toward Mini‐Mental State Examination (p=0.061). Further, the Aß+ group showed a poorer performance in the WAIS‐IV subtests Digit Span Sequencing (DSS) (p=0.03) and Similarities (p=0.05). On the contrary we found Aß‐ patients performed worse in the Stroop test‐ time than the other group (p=0.012), although there was a tendency for the Aß+ group to make more errors (Stroop test ‐errors) (p=0.186). Of note, the two groups did not differ in terms of other clinical or motor variables, as MDS‐UPDRS‐III or motor phenotypes.

Conclusions: Our results corroborate evidence of additional Aß contribution to worse global cognitive profile in Lewy body disorders [3], attentive/working memory abilities (as assessed by DSS) as well language conceptualization, verbal abstraction, and analogical verbal reasoning (as assessed by Similarities). Further studies will be necessary to investigate whether these WAIS‐IV‐subtests can be considered sensitive cognitive tools in detecting amyloid‐related cognitive deficits. Finally, we found an opposite pattern for the Stroop test, wherein Aß+ were faster in completing the task compared to Aß‐ group, parallelled by a tendency of Aß+ patients in making more errors during the execution of Stroop test. Overall, these findings need to be confirmed in a larger cohort but seem to support the therapeutic potential of anti‐Aß interventions in patients with LBD with positive [18F]florbetapir PET.

References: 1. Petrou M, Dwamena BA, Foerster BR, MacEachern MP, Bohnen NI, Muller ML, Albin RL, Frey KA (2015) Amyloid deposition in Parkinson's disease and cognitive impairment: a systematic review. Mov Disord 30:928‐935. 2. Gomperts SN, Rentz DM, Moran E, Becker JA, Locascio JJ, Klunk WE, Mathis CA, Elmaleh DR, Shoup T, Fischman AJ, Hyman BT, Growdon JH, Johnson KA (2008) Imaging amyloid deposition in Lewy body diseases. Neurology 71:903‐910. 3. Fiorenzato E, Biundo R, Cecchin D, Frigo AC, Kim J, Weis L, Strafella AP, Antonini A, Cagnin A (2018) Brain Amyloid Contribution to Cognitive Dysfunction in Early‐Stage Parkinson's Disease: The PPMI Dataset. Journal of Alzheimer's Disease 66:229‐237

56

Category‐Exemplars language test (CATEX). Italian validation and its application on a Parkinson's disease population

Tommaso Gandolfi (Padova, Italy), Stefano Vicentin (Vicenza, Italy), Giorgio Arcara (Padova, Italy), Charlotte Jacquemot (Paris, France), Carlo Semenza (Padova, Italy), Angelo Antonini (Padua, Italy), Roberta Biundo (Venice‐Lido, Italy)

Objective: This study aims to explore if Catex sensitivity to detect cognitive deficits in Huntington patients, even at the asymptomatic stage [7], can be also applied to PD Italian population.

Background: Evidence on PD language deficits is heterogeneous, mostly associated with attentive/executive deficits [1‐2]. Catex is a tool developed and validated in France, which investigates categorization abilities controlling for executive loads.

Methods: For the Italian validation analyses, we recruited 108 healthy controls (HCs) with MMSE score>25 and no cardiovascular or psychiatric comorbidities. Frequency on Categorical (CAT) and exemplar (EX) picture (93 items) were collected and naming agreement (NA) and entropy (E) was performed to identify the most accurate items which were homogeneously distributed between CAT and EX (similar frequency of the word (F), syllables (S) and phonemes (P)). Overall, 25 CAT and 25 EX were chosen and cut values extracted. Moreover, further 172 participants were collected, 76 healthy controls (HC), 20 with MCI (MCI); 48 PD with normal cognition (PD‐NC), and 28 PD with mild cognitive impairment (PD‐MCI).

Results: 25 EX and 25 CAT were chosen with a cumulative NA>0.5, E<2.0 and accordingly to F, S, P homogeneity criteria (p=,83; p=1; p=,53). One‐way ANOVA test (Bonferroni corrected) was used for statistical analysis. Age and education were balanced between groups (p=.094; p=.188). A significant difference is present between groups in both CAT and EX (p<,001). Post‐hoc analysis showed significant differences in CAT scores for HC vs. MCI (p<,001); HC vs. PD‐MCI (p<,001); PD‐NC vs. MCI (p=,006); PD‐NC vs. PD‐MCI (p<,001). Also, EX significant score differences between groups have been found for: HC vs MCI (p<,001); HC vs PD‐MCI (p<,001); PD‐NC vs PD‐MCI (p=,015).

Conclusions: Matching items according to NA and E (>0,7; <2,0) altogether with homogeneous linguistic properties (p>0,5) made Catex a valid test in Italian language, showing sensitivity in detecting MCI status [4]. Compared to the French version applied on Huntington chorea patients, which resulted as a good biomarker for the pathology, this version on Parkinson's disease showed no such difference (p=1). However, its high usability, easy administration and peculiarity in identifying the MCI status, makes it a good clinical and neuropsychological instrument. Future investigation should check possible correlations with neuropsychological tests of different cognitive domains and with MRI data.

References: [1] Hoffman, P., Jefferies, E., Lambon Ralph, M.A. (2011). Explaining semantic short‐ term memory deficits: Evidence for the critical role of semantic control. Neuropsychologia, 49, 368–381. ?[2] Moretti, R.,Torre, P., Antonello, R.M., Carraro, N., Cazzato, G., Bava, A. (2002). Complex Cognitive Disruption in Motor Neuron Disease.?Dementia and Geriatric Cognitive Disorders,14,141–150. ?[3] Jacquemot, C., Schramm C., Lavisse, S., Nazir, M. Sliwinski A., Gaura, V., Remy, P., Bachoud‐Lévi, A‐C. (in prep). Toward a cognitive marker for Huntington disease: coupling language and executive functions.[4] Litvan, Irene et al. (2012). «Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines». In: Move‐ ment disorders 27.3, pp. 349–356.

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Exploring cognitive aspect of linguistic prosody in Parkinson's disease

Caroline Moreau (Marcq En Baroeul, France), Anahtia Basirat (Lille, France), Serge Pinto (Aix‐en‐Provence, France), Kathy Dujardin (Lille, France), Luc Defebvre (Lille, France), David Devos (Lille, France)

Objective: To explore the correlation between linguistic prosody and cognition in Parkinson's disease.

Background: Around 90% of patients with Parkinson's disease (PD) report speech deficit. Prosody (i.e. melody of the language) is early affected in PD and assessed by the fundamental frequency (f0). We hypothesize that linguistic prosody is correlated with cognitive process, and a valuable biomarker.

Methods: Patients were investigated in ON drug condition: MDS UPDRS part 3, MoCA, Pulmonary functional testing, including maximal expiratory mouth pressure (MEP), maximal inspiratory mouth pressure (MIP), the sniff nasal inspiratory pressure (SNIP).F0 declination was calculated using the recordings of 4 declarative sentences read in French. For each sentence, the mean f0 of the first and the last vowel was measured using semitones. The slope of the straight line connecting the first and the last vowel has been calculated and averaged across sentences for each patient. Maximum phonation time (MPT) was measured on two sustained /a/ produced by each patient. All acoustic analyses were done using Praat.? Multiple regression analyses were performed on f0 declination and MPT to test whether cognitive performance (MoCA score) and respiratory muscle strength (MEP, MIP, SNIP values) were significantly associated with f0 declination and MPT.

Results: Fifteen parkinsonian patients (3 females; mean age ± SD: 65.1 ± 6.6 years; disease duration: 7.5 ± 2.1 years; UPDRS III: 17.9 ± 8) participated in this study. We demonstrated a mean negative slope for f0 declination: ‐1.56, 95% CI = [‐1.97 ‐1.16]. Results of the analysis on f0 declination showed significant effects of MoCA, MEP and SNIP. As expected no correlations were found between MPT and MoCA.

Conclusions: We observed that cognitive performance (MoCA score) on one hand and respiratory muscle strength on the other hand were significantly associated with f0 declination. This highlights that the respiratory muscle strength may impact the melody of the language. Equally the cognitive capacity is also influencing the prosody. We suggest that f0 declination would be an interesting acoustic parameter during the progression of disease, as a valuable biomarker of prosody but also of the interaction with cognition. Speech seems logically influenced by cognition even for basic aspects.

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Prevalence Study of Dementia with Lewy Bodies in a Parkinson Disease Reference Center: Clinical and Laboratory Analysis of a Rio de Janeiro/ Brazil Cohort

Vanderson Neri (Rio de Janeiro, Brazil), Ana Carolina Ribeiro (Campos Dos Goytacazes, Brazil), Carolina Rosas (Campos Dos Goytacazes, Brazil), Gabriela Pessanha (Campos Dos Goytacazes, Brazil), Thalita Oliveira Rocha (Campos Dos Goytacazes, Brazil), Thaina Lopes (Campos Dos Goytacazes, Brazil), Thais Melo (Campos Dos Goytacazes, Brazil), Yasmim Dias (Campos Dos Goytacazes, NC, Brazil), Thaynara Oliveira Marcilio (Campos Dos Goytacazes, Brazil), Danielle Viana (Campos Dos Goytacazes, Brazil), Glaucia Licassali (Campos Dos Goytacazes, Brazil)

Objective: To apply the diagnostic criteria for dementia with Lewy bodies (DLB) in a cohort of patients with parkinsonian syndromes in Rio de Janeiro; to estimate the prevalence of this syndrome; to analyze the clinical profile, pharmacological treatment and neuroimaging of this group of patients.

Background: DLB is an important differential diagnosis for Parkinson's Disease. There are few studies about prevalence in medical literature, as well as the diagnostic differentiation of this syndrome with other parkinsonisms.

Methods: Application of the diagnostic criteria for DLB (McKeith et al. 1996) in patients with parkinsonism and cognitive impairment (after brief neuropsychological assessment). Selection of patients who met criteria for DLB, clinical and laboratory evaluation of this group.

Results: In a cohort of 750 patients with parkinsonian syndromes (prospectively followed from May 2010 to June 2019), 22 patients met the criteria for diagnosing DLB (2.9% of the total). Average age was 78.36 (SD ± 7.9); 12 (54.5%) were men. Mean time neurological symptoms 1.77 years (± SD 0.81). MMSE: average 11.3 (SD ± 8.86), MOCA: average 9.43 (SD ± 7.2). The presentation of the domains applied for diagnosis are shown in Table 1. Most prevalent motor symptoms: bradykinesia (90.9% of cases) and bilateral muscle stiffness (90.9%)[ Table 2]. After clinical, laboratory and imaging evaluation, it was concluded that secondary causes were excluded. 100% of cases presented impairment in more than one domain of cognition, impacting their daily activities. Treatment: 18 (81.8%) used levodopa / benseraside, 4 (18%) pramipexole, 13 (59%) quetiapine, 8 (36.5%) donepezil, 3 (13.6%) rivastigmine and 1 (4, 5%) galantamine. Neuroimaging: MRI morphometric evaluation showed predominance of diffuse cerebral atrophy 21 (95.5%), dilated cerebral ventricles 15 (68.2%), and preservation of temporal lobe structures 17 (77.3%) [Table 3].

Conclusions: We observed a prevalence of 2.9/100 DLB patients in this cohort. Significant cognitive impairment with few years of evolution, predominance of rigidity and bradykinesia on neurological examination and clinical manifestation started in the seventh decade of life were more specific results found.

References: 1. MCKEITH, Ian G. et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology, v. 89, n. 1, p. 88‐100, 2017. 2.CHIBA, Yuhei et al. Retrospective survey of prodromal symptoms in dementia with Lewy bodies: comparison with Alzheimer's disease. Dementia and geriatric cognitive disorders, v. 33, n. 4, p. 273‐281, 2012. 3.CHIN, Kai Sin; TEODORCZUK, Andrew; WATSON, Rosie. Dementia with Lewy bodies: Challenges in the diagnosis and management. Australian & New Zealand Journal of Psychiatry, v. 53, n. 4, p. 291‐303, 2019.

59

Specific in using SCID‐II Minimult questionnaires questionnaire in patients with Parkinson's disease

Aynur Ragimova (Moscow, Russia), Marina Samushiya (Moscow, Russia), Irina Smolentseva (Moscow, Russia)

Objective: To clarify the validity of the use of the SCID‐II questionnaire in patients with Parkinson's disease (PD) at different stages of the disease.

Background: Parkinson's disease (PD) is a neurodegenerative disease with premorbid features such as: reduced novelty seeking, fear of damage, anxiety and rigidity [1,2].

Methods: 29 patients with recently diagnosed PD (1‐2,5 Hoehn‐Yahr) and 10 patients with 3 Hoehn‐Yahr stage of decease was examined with using SCID‐II and Minimult (short version of MMPI').

Results: Patients with stage 3 Hoehn‐Yahr showed in SCID‐II an increase in positive answers (average 32 «+» responses) compared with patients in the early stage of the disease (14.3 «+» answers). Such an increase probably occurs due to the repetitive positive answers, similar to “motor perseverations” and the appearance of positive responses about flirting and shopping from the rubric of “hysterical” personality traits that more likely describe lack of the frontal control function than premorbid personal characteristics. Among all patients more popular were following statements «Are you usually quiet when you meet new people?» (20 «+» answers (51,2%) for avoidant personality trait), «Do you have trouble throwing things out because they might come in handy some day?» (21 «+» answers (53,8%) for obsessive—compulsive personality trait), «Have other people told you that you are stubborn or rigid» (21 «+» answers (53,8%) for obsessive—compulsive personality trait), «Do you find that it is best not to let other people know much about you because they will use it against you?» (23 «+» answers (58,9%) for paranoid personality), «Are there really very few things that give you pleasure?» (20 «+» answers (51,2%) for schizoid personality trait. The obtained results of the dimensional analysis demonstrate the prevalence of cluster A and C personality traits reflecting premorbid rigidity of patients with difficulty interpreting other people's behavior and reducing the function of positive reinforcement. This result correlate with Minimult questionnaire in which “correction of answers” was typical for all patients: they focused on public opinion and social norms; 20 (69%) had low results on psychopathy scale (tendency to maintain the existing lifestyle, rigidity), 23 (79.3%) were distrustful and suspicious.

Conclusions: Personality questionnaires may be not useful in patients with advanced stage of PD due to motor perseverations and lack of frontal control function. It is also incorrect to interpret the results of the questionnaire in the way of certain personality traits: they can be considered as parts of the dimensional mosaic of premorbid characteristics in PD patients.

References: 1. Rosen, J.B., Brand, M., Polzer, C., Ebersbach, G., Kalbe, E., 2013. Moral decision‐making and theory of mind in patients with idiopathic Parkinson's disease. Neuropsychology 27, 562–572. doi:10.1037/a0033595 2. Sullivan, K.L., Mortimer, J.A., Wang, W., Zesiewicz, T.A., Brownlee, H., Borenstein, A.R., 2015. Occupational Characteristics and Patterns as Risk Factors for Parkinson's Disease: A Case Control Study. Journal of Parkinsons Disease 5, 813–820. doi:10.3233/jpd‐150635.

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Withdrawn by Author

61

Zonisamide improves motor symptoms in dementia with Lewy bodies from the analysis on phase 3 trial

Kazuko Hasegawa (Kanagawa, Japan), Toshinari Odawara (Kanagawa, Japan), Ritsuko Kajiwara (Tokyo, Japan), Hisao Takeuchi (Tokyo, Japan), Hidenori Maruyama (Tokyo, Japan), Masaaki Tagawa (Tokyo, Japan), Miho Murata (Tokyo, Japan), Kenji Kosaka (Kanagawa, Japan)

Objective: To clarify the motor improvement and safety of zonisamide (ZNS) for dementia with Lewy bodies (DLB).

Background: In Japan, ZNS is now available as an anti‐Parkinson drug. The results of phase 2 trial in DLB showed that ZNS improved parkinsonism and was well‐tolerated in DLB patients [1].

Methods: In the phase 3 trial, probable DLB outpatients were randomized into placebo, ZNS 25 or 50 mg/day groups and received any of drugs at fixed dose for 12 weeks in the double‐blind confirmatory phase. In the subsequent 40‐week open‐label extension phase, the patients received ZNS at an initial dose of 25mg/day over 2 weeks, and then at a flexible dose of 25 or 50 mg/day depending on patients' condition. The primary endpoint was a change from baseline in UPDRS part III total score at week (W) 12. In addition, UPDRS part III, individual motor symptoms (assessed using subitems of UPDRS part III), MMSE, NPI‐10 as well as safety were evaluated throughout the trial.

Results: Of 373 patients screened, 351 were randomized. Patients' background for primary endpoint was following, mean age, 77.2 years; mean durations of dementia and motor dysfunction, 3.6 and 2.7years; mean UPDRS part III total score, 31.2. At W12, the UPDRS part III total scores in both ZNS groups were significantly decreased compared with that in placebo (figure1). Subsequently, the UPDRS part III total scores were further decreased until W24‐28 by ZNS treatment and then were almost constant until W52 (figure2). Regarding individual motor symptoms, the scores of tremor, rigidity and bradykinesia were decreased by long‐term ZNS treatment. In contrast, the score decline in MMSE at W12 was greater in ZNS 50 mg than in placebo, but in term of long‐term evaluation, the scores of MMSE as well as NPI‐10 were not affected by ZNS treatment (figure3). Of 335 patients for long‐term evaluation, 230 completed the 52‐week treatment. There was no remarkable adverse event throughout the trial.

Conclusions: ZNS improves motor symptoms in DLB without deteriorating cognitive function or psychiatric symptoms. (A part of the results has been presented at several meetings such as MDS2018 [Oct 2018] and AAN2019 [May 2019]).

References: [1] Murata M, Odawara T, Hasegawa K, et al. Adjunct zonisamide to levodopa for DLB parkinsonism: a randomized, double‐blind phase 2 study. Neurology. 2018; 90: e664‐e672.

Dopaminergic Medications

7

Frequency and Risk Factors of Peripheral Edema as a Side Effect of Dopamine Agonist Treatment

Seda Bostan (Eskisehir, Turkey), Fatma Durmaz Celik (Odunpazari, Eskisehir, Turkey), Serhat Ozkan (Eskisehir, Turkey)

Objective: To determine the frequency and risk factors of peripheral edema (PE) development and whether discontinuation of the drug is enough for treatment.

Background: Non‐ergot dopamine agonists (DA) pramipexole and ropinirole, used for the treatment of Parkinson's disease (PD), are proven to be effective and well‐tolerated. PE is a rare side effect of DA's. It can be limited to ankles but can be more aggressive even interfering with the walk of the patient causing misinterpretation as off period and a raise in DA or levodopa dosage.

Methods: Data of PD patients using DAs admitted to our clinic between years 2000‐2019 was evaluated retrospectively. IBM SPSS Statics Data Editor was used for data analyses.

Results: From 370 patients using DA treatment, 73 patients (%19) developed PE, 45(%61,6) of them were women, in concordance with literature(1). Female gender is found to be an independent risk factor for PE (p=0,011). Mean disease duration was 9,23±5,0 years. Mean age was 65,6±10,3 years. Dopamine agonists equivalent dose (DAED) was 321,0±194,6. Disease duration, age and DAED were not associated with PE (p=0,82 ; p=0,13 and p=0,7 respectively). Mean time from treatment initiation to PE development was 4,0±3,3 years. Although statistically insignificant (p=0,06), %72,6 had been using DA for =2 years, suggesting that PE is seen more commonly after two years of usage(2). After DA treatment was ceased, the mean to resolving of PE was 3,2 months. Only two (%2,7) patients had persistent PE etiology remained unclear.

Conclusions: Peripheral edema is a relatively common side effect of DA treatment. Its formation is not dose‐dependent and resolves after DA discontinuation, suggesting an idiosyncratic reaction. Cessation of DA is almost always an effective treatment. Our study showed that women have a higher risk for PE development, also usage of DA =2 years may be a risk factor. To the best of our knowledge, our study has the highest number of cases with PE in literature. Our results can help understanding leg edema as a side effect of DA treatment.

References: 1. Kleiner‐Fisman G, Fisman DN. Risk Factors for the Development of Pedal Edema in Patients Using Pramipexole. Arch Neurol. 2007;64(6):820–824. 2. Biglan K. M, Holloway R.G, McDermott M.P, Richard I.H(2007). Risk factors for somnolence, edema and hallucinations in early Parkinson disease.Neurology,69(2),187–195.

Emerging and Experimental Therapeutics

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Withdrawn by Author

9

Effects of transcranial magnetic stimulation on hypokinetic dysarthria in Parkinson's disease

Irena Rektorova (Brno, Czech Republic), Lubos Brabenec (Brno, Czech Republic), Jiri Mekyska (Brno, Czech Republic)

Objective: To identify an optimal protocol for repetitive transcranial magnetic stimulation (rTMS) to improve hypokinetic dysarthria (HD) in PD. We investigated both short‐term and long‐term effects of rTMS using acoustic and perceptive analysis of speech.

Background: Hypokinetic dysarthria is common in PD. rTMS is a non‐invasive brain stimulation technique that can modulate brain function and connectivity.

Methods: In a single‐session cross‐over study, we used 1 Hz and 10 Hz rTMS applied over the left orofacial motor area, the right superior temporal gyrus (STG), and over the vertex (a control stimulation site) in 15 PD patients with HD. Resting state seed‐based functional connectivity (rs‐FC) with the seeds located in the stimulation sites was used as a readout of behavioural changes. Based on the results we investigated long‐term effects of 10 stimulation sessions using an optimal stimulation protocol and site.

Results: In the single‐session, both 1 Hz and 10 Hz rTMS of the right STG induced positive changes on HD, but only 1 Hz rTMS over the STG induced significant improvement of speech articulation when compared with the vertex stimulation. The stimulation significantly enhanced the STG rs‐FC with the parahippocampal gyrus. Preliminary results from our longitudinal multiple‐sessions study suggest improvement of speech intelligibility and acoustic parameters of speech in PD. The effects were still present 1 month after the stimulation completion.

Conclusions: We demonstrated that low frequency rTMS applied over the auditory feedback area may lead to improved articulation in PD. Preliminary results of the multiple sessions rTMS suggest long‐term aftereffects.

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Risk Assessment Study of Pharmaceutical Pollutants in Environment for Neurotoxicity and Movement Disorders

Nitin Verma (Baddi, India)

Objective: The objectives of the present study is to highlights toxicity, health risk and assessment of environmental hazards due to pharmaceutical pollutants especially for neurotoxicity and movement disorders.

Background: Diverse classes of pharmaceutical compounds like analgesic, antihypertensive, contraceptive, antibiotic, steroids, hormones and heavy metals etc. have been detected in water samples from ng/l to μg/l range. Though the detected amounts are very tiny but highly toxic for human, animal and aquatic lives. Traditional wastewater treatment methods, such as activated sludge, are not sufficient for the complete removal of active pharmaceutical ingredients and other wastewater constituents from these waters. Environment and health are directly or indirectly affected by pharmaceutical effluents especially in the vicinity of pharma industrial zones. The present study highlights such toxicity, health risk and assessment of environmental hazards due to pharmaceutical pollutants in environment in Baddi region, hub of major pharmaceutical hub in India.

Methods: We performed a cohort study among 300 workers in Pharmaceutical Industries, followed for up to 05 years, to examine the occurrence of Parkinson's disease and other basal ganglia and movement disorders compared with an age and geographical area matched general population comparison cohort.

Results: It has been conjectured that low grade exposure to pharmaceutical environmental polluents may increase the risk for Parkinson's disease and other basal ganglia and movement disorders. It has also been proposed that compounds released during manufacturing of pharmaceuticals may accelerate the onset of Parkinson's disease. Thus, a large number of populations be studied over a long time period in order to evaluate a potential occupational component to the development of Parkinson's disease and other basal ganglia and movement disorders.

Conclusions: Pharmaceutical pollutants in environment in Baddi region, may be the reason for Parkinson's disease and other basal ganglia and movement disorders. Considering the increasing numbers of environmental contaminants with potential neurotoxic potential, eco‐neurotoxicity should be also considered in risk assessment.

References: 1. Hellou J. Behavioural ecotoxicology, an “early warning” signal to assess environmental quality. Environ Sci Pollut Res Int. 2011;18:1–11. doi: 10.1007/s11356‐010‐0367‐2. 2. Basu N, Head J. Mammalian wildlife as complementary models in environmental neurotoxicology. Neurotoxicol Teratol. 2010;32:114–119. doi: 10.1016/j.ntt.2008.12.005.

Epidemiology

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Proportion of Parkinson's disease patients with an early‐onset: a systematic review and meta‐analysis

Gaurav Nepal (Kathmandu, Nepal)

Objective: To conduct a systematic review and meta‐analysis of all available evidence to quantify the proportion of Parkinson's Disease (PD) patients with an early onset.

Background: Early onset Parkinson's disease (EOPD) is relatively rare, but severely impacts patients, families, and healthcare systems given its severity and length of long‐term disability. In addition to motor, cognitive and autonomic symptoms, EOPD patients often have serious social and psychological complications. With the extent of physical and mental destruction seen in EOPD, the diagnosis holds a high economic, social, and psychological burden. Therefore, early diagnosis, treatment, and psychiatric support are critical in EOPD. Currently, no data exists regarding the proportion of EOPD cases in patients diagnosed with Parkinson's disease (PD). Epidemiological data affirming the percentage of EOPD cases is of interest for determining the potential role race and geographic location have on disease onset. In addition, this data analysis can be used to inform physicians of the populations at risk and guide effective healthcare management of medical services.

Methods: Systematic searches were performed using Medline, EMBASE and Google Scholar to identify population and record based studies that reported number of EOPD and PD patients. The primary outcome was the proportion of patients with EOPD. We conducted a proportion meta‐analysis and presented a summary estimate with 95% CI.

Results: Our analysis included 23 studies. There were 10,854 PD patients and 632 EOPD patients. After a meta‐analysis, the pooled proportion of EOPD was found to be 5.9 % [95% CI: 4.1 ‐8.5, I2 = 93.97%]. In individual studies, the proportion ranged from 0.6 % to 16.3 %. The proportion fluctuated according to the study country, the diagnostic criteria for PD, the age limit for EOPD, the method of patient recruitment, and the quality of the research methodology.

Conclusions: The pooled proportion of EOPD was found to be 5.9 %. The proportion of EOPD may vary among different countries which can be due to various factors like race, genetics, environment and life time expectancy. Since EOPD can initially be diagnosed as secondary Parkinsonism, young patients with Parkinsonism should be regularly reassessed regularly during follow‐up.

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Predictors of dysphagia in early Parkinson's disease: The role of excessive daytime sleepiness

Francesco Motolese (Roma, Italy), Deepak Gupta (Burlington, VT, USA), Mariagrazia Rossi (Rome, Italy), Vincenzo Di Lazzaro (Rome, Italy), Massimo Marano (Rome, Italy)

Objective: The aim of the present study is to investigate potential predictors of self‐reported dysphagia by a retrospective analysis of the Parkinson's Progression Marker Initiative (PPMI) data [1].

Background: Dysphagia is a highly relevant symptom in Parkinson's disease (PD) as well as a predictor of poor prognosis [2]. Since no specific treatment for dysphagia exists, it is important to recognize and treat as early as possible potential predisposing factors.

Methods: PD patients from PPMI database who reported a baseline score = 1 at MDS UPDRS “item 2.3” and at SCOPA‐AUT “question 1” (i.e. the items exploring the presence of swallowing impairment) were classified as dysphagic and their clinical features, including questionnaires' scores and neuroimaging findings, were compared to non‐dysphagic patients. Distinctive features of non‐dysphagic PD patients at baseline were investigated as predictors of the development of dysphagia within the PPMI year 3 visit. For this aim, we performed univariate and then multivariate logistic regressions, after checking for multicollinearity.

Results: Patients with dysphagia at baseline (~10% of the sample) differed from non‐dysphagic patients according to several non‐motor features including REM sleep behavior questionnaire, Epworth sleepiness scale (ESS), MDS UPDRS I “sleep problems”, caudate [123I]FP‐CIT uptake parameters and BMI. The cumulative 3 years incidence of dysphagia grows as high as ~20%. At a univariate regression ESS, RBDQ, the presence of pathologic daytime sleepiness and possible RBD related to the development of dysphagia. In particular, excessive daytime sleepiness (EDS) was independently related to the development of dysphagia at year 3 in a regression model including RBD (OR~3). No correlation with the use of dopamine replacement therapy (DRT) was found.

Conclusions: Dysphagia appears in PD earlier than previously thought [3] and EDS has been identified as a putative predictor. Dysphagia in PD lacks specific rating scales and its evaluation relies on ENT techniques, while EDS is easily detected through questionnaires (e.g. ESS). It is possible to speculate that EDS and dysphagia share, at least partially, a common pathophysiological background (i.e. degeneration of reticular formation) [4]. Despite the relevance of EDS, modafinil (a milestone of narcolepsy treatment) has an insufficient level of evidences in PD and deserves further investigations [5]. Latter or “ad hoc” trials are warranted to evaluate the role of wake‐promoting agents in dysphagia.

References: 1. Parkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol. 2011 Dec;95(4):629‐35. 2. Suttrup I, Warnecke T. Dysphagia in Parkinson's Disease. Dysphagia. 31 (2016) 24‐32. 3. Polychronis S, Dervenoulas G, Yousaf T, Niccolini F, Pagano G, Politis M. Dysphagia is associated with presynaptic dopaminergic dysfunction and greater non‐motor symptom burden in early drug‐naïve Parkinson's patients. PLoS One. 2019 Jul 25;14(7):e0214352. 4. Costa MMB. NEURAL CONTROL OF SWALLOWING. Arq Gastroenterol. 2018 Nov;55Suppl 1(Suppl 1):61‐75. 5. Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson's disease‐an evidence‐based medicine review. Mov Disord. 2019 Feb; 34 (2) : 180‐198.

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Management of the motor symptoms of Parkinson's disease in the low‐income country and environment of restricted medications

Bakhtiyor Mukhammedaminov (Tashkent, Uzbekistan), Mukhlisa Khanova (Tashkent, Uzbekistan), Gavhar Abdusattarova (Tashkent, Uzbekistan)

Objective: To inform the world community about the state situation on Parkinson's disease in Uzbekistan.

Background: Uzbekistan has 35 million population, largest in the region, but the diversity of the medications and treatment options are too low. In addition, the knowledge of neurologists about movement disorders leaves much to be desired.List of available medications: MAO inhibitor: Rasagilinum. DOPA agonists: Pramipexolum, Ropinirolum. L‐DOPA: Nakom, Madopar, Tidomed. Surgery: No DBS because of absence of stereotactic frame, no L‐DOPA pump.

Methods: 73 Patients with Parkinson's disease was examined and diagnosis confirmed by single specialist.Average age of patients ‐ 64,3 (±17,4). Sex: Male ‐ 33 (46%), Female ‐ 40 (54%). Average Anamnesis ‐ 7,1 years (1‐26 years ). Unfortunately mostly of neurologists still uses a Trihexyphenidyl (Cyclodolum). 21 patient was only in L‐DOPA. 10 Cyclodolum. 41 Cyclodolum + L‐DOPA. 3 Rasagilinum + L‐DOPA. 4 Cyclodolum+ Rasagilinum + L‐DOPA. 2 Pramipexolum + L‐DOPA. 1 no medications.47 patient was a under dosage of L‐DOPA, 32 of them was taking less than 300mg a day.

Results: Patients taking Pramipexolum + L‐DOPA has better motor conditions. Cyclodolum has been reduced than cancelled in all patients. Recommendations: 1 patient Rasagilinum only. 10 Rasagilinum + Pramipexolum.62 L‐DOPA + other medications dosage and taking time was correlated.1 to 6 month follow up showed moderate to high Improvement of motor symptoms by UPDRS II – III in 69 patients, 4 patients showed low improvement, probably atypical Parkinsonism, need to be observed.

Conclusions: The results of this study showed that the in low‐income countries most of the patients suffer from the motor and other symptoms of the Parkinson's disease. Moreover, situation with the restricted diversity of the medications worsen general condition, and the absence of stereotactic frame does not lead situation to the positive point. Patients have only 1 to 6 month follow‐up, they need to be observed further for get more data.

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Development of a Registry for Parkinson's Disease in Utah

Paolo Moretti (Salt Lake City, UT, USA), Allyn Nakashima (Salt Lake City, USA), Kathy Paras (Salt Lake City, USA), Bernie LaSalle (Salt Lake City, USA), Meghan Zorn (Salt Lake City, UT, USA), Sara Woltz (Salt Lake City, USA), Ludovica Farese (Salt Lake City, USA), Lisa Cannon‐Albright (Salt Lake City, UT, USA), Stefan Pulst (Salt Lake City, UT, USA)

Objective: To report the progress made in establishing the Utah Parkinson Disease Registry (http://UPDR.org).

Background: Precise epidemiological information about Parkinson's disease (PD) and related conditions is difficult to obtain. This information is important for research, clinical care and resource planning. Nebraska became the first state in the United States (US) to establish a statewide registry for PD. Utah followed Nebraska in 2015 and became the first web‐based registry in the US.

Methods: In 2011, one of us (SMP) approached the Utah Department of Health (UDoH) and the Utah Medical Association with a plan to establish a PD registry. In 2013, the Utah State Legislature passed a resolution urging UDOH to make PD a reportable condition and in 2015, UDOH modified its reporting rules requiring that health care providers report cases of PD and related movement disorders. UPDR is an electronic registry run by the UDOH through a contract with the Department of Neurology at the University of Utah School of Medicine (with bioinformatics support from the Utah Center for Clinical and Translational Science) to collect and manage the data. UDOH retains ownership and all rights to the records in the Registry and manages the access to these data. Physicians, hospitals, clinics, pathology laboratories licensed in the state, nursing homes, and other facilities and health care providers are required to report to the Registry. In addition, there is voluntary self‐reporting by patients. The reporting of cases of PD or related movement disorder that are diagnosed or treated in Utah is done through a website or by mail, within a year of the date of diagnosis.

Results: As of September 2019, the UPDR contains 4,319 registered cases, corresponding to 3,864 unique registrants living in Utah in 23 counties. The male/female ratio is 1.7 (63% males vs 37 % females). The age distribution is as follows: <50 years = 3.6%; 50‐59 y = 7.1%; 60‐69 y = 20.7%; 70‐79 y = 36.4%; 80+ y = 32.1%. The analysis of PD mortality shows that, between 1999 and 2017, the age‐adjusted death rate per 100,000 was higher in Utah compared to the rest of the US.

Conclusions: The available data, although preliminary, suggest that collection of data in this population will be important to further our understanding of the epidemiologic factors associated with PD in Utah. The UPDR can map PD prevalence on a county‐ and zip code‐ level grid and has the potential to correlate prevalence with environmental data. The next steps would be to evaluate and improve the completeness of reporting and the quality of the data in the Registry.

References: Tysnes OB, Storstein A. Epidemiology of Parkinson's disease. J Neural Transm (Vienna). 2017 Aug;124(8):901‐905. Bertoni JM, Sprenkle PM, Strickland D, Noedel N. Evaluation of Parkinson's disease in entrants on the Nnebraska state Parkinson's disease registry. Mov Disord 2006; 21: 1623–1626. Xu K, Alnaji N, Zhao J, Bertoni JM, Chen L‐W, Bhatti D, Qu M. Comorbid Conditions in Parkinson's Disease: A Population‐Based Study of Statewide Parkinson's Disease Registry. Neuroepidemiology 2018;50:7–17.

Genetics

46

Identification of Parkinson's disease predisposition genes in high‐risk pedigrees

Paolo Moretti (Salt Lake City, UT, USA), Karla Figueroa (Salt Lake City, USA), Stefan Pulst (Salt Lake City, UT, USA), Lisa Cannon‐Albright (Salt Lake City, UT, USA)

Objective: To identify families with an increased risk of Parkinson's disease (PD) and the gene variants associated with such increased disease risk studying large multi‐generation pedigrees.

Background: Several monogenic forms of PD and many genetic factors increasing risk for the disease have been identified, but together they account for only ~ 30% of familial, and 3‐5% of sporadic PD. Analysis of multi‐generation families with an excess of disease has been shown to be a powerful approach to the identification of disease predisposition genes. This approach was previously used in Utah to identify several cancer predisposition genes.

Methods: To identify pedigrees with high‐risk of PD, we used the Utah Population Database (UPDB), a unique resource linking extensive genealogy information with medical data. The UPDB now includes information in 3 million individuals who are representative of US and Northern European populations and have a low rate of inbreeding. Currently, the UPDB contains over 4,000 PD cases identified from death certificates who also have 3+ generations of genealogy data.

Results: We identified all clusters of related PD cases in the UPDB, and determined which of these clusters represent a significant excess of PD among pedigree members. 2,357 clusters/pedigrees of PD cases were identified, including from 2 to 43 individuals with PD‐related death. Of these, 379 pedigrees including from 2 to 37 PD cases were identified as high‐risk (p<0.05). More than 80% of the identified clusters of related PD cases were therefore excluded from further consideration for not having a significant excess of PD among the pedigree members. We then used two existing biorepositories to identify DNA samples from pairs of related cases in each PD pedigree. 182 clusters with genealogy data and 2‐7 sampled cases were identified; 25 of the pedigrees had a significant excess of PD cases and at least one pair of related cases. Whole Exome Sequencing and bioinformatics analysis of sequence data in a subset of these samples is currently underway.

Conclusions: From a total of 2,357 PD pedigrees in the Utah population, we have identified 379 with a statistically significant excess of PD‐related deaths. From this group, we selected 25 pedigrees with DNA samples from at least one pair of related cases. The identification of gene variants associated with PD risk in these families is currently underway.

References: Miki Y, Swensen J, Shattuck‐Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen‐Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon‐Albright LA, Goldgar D, Wiseman R, Kamb A, Skolnick MH. (1994). A Strong Candidate for the Breast and Ovarian Cancer susceptibility Gene BRCA 1. Science, 266, 66‐71.Savica R, Cannon‐Albright LA, Pulst S. Familial aggregation of Parkinson disease in Utah: A population‐ based analysis using death certificates. Neurol Genet 2016. Mar 22;2(2):e65. PMID: 27123483.

47

Sex‐specific neuroprotection by inhibition of the Y‐chromosome gene, SRY, in experimental Parkinson's disease

Joohyung Lee (Clayton, VIC, Australia), Paulo Pinares‐Garcia (Clayton, VIC, Australia), Hannah Loke (Clayton, VIC, Australia), Seungmin Ham (Clayton, VIC, Australia), Eric Vilain (Los Angeles, CA, USA), Vincent Harley (Clayton, Australia)

Objective: Given the presence and function of SRY in male DA (dopamine) neurons, we hypothesised that dysregulation of SRY may contribute to male susceptibility to PD (Parkinson's disease).

Background: PD is a debilitating neurodegenerative disorder caused by the loss of midbrain DA neurons. Male sex is a strong risk factor. Aside from the protective actions of sex hormones in females, emerging evidence suggests that sex‐chromosome genes contribute to the male bias in PD. We previously showed that the Y‐chromosome gene, SRY, directly regulates adult brain function in males independent of gonadal hormone influence. SRY protein colocalizes with DA neurons in the male substantia nigra, where it regulates DA biosynthesis and voluntary movement.

Methods: Human cell culture and toxin‐induced rat models of PD were combined with repeated Sry antisense oligonucleotide (ASO) infusions. Motor behaviours, histological and molecular analyses were undertaken.

Results: Nigral SRY expression is highly and persistently up‐regulated in animal and human cell culture models of PD. Lowering nigral SRY expression with ASO in male rats diminished motor deficits and nigral DA cell loss in toxin‐induced rat models of PD. The protective effect of the Sry ASO was associated with male‐specific attenuation of DNA damage, mitochondrial degradation, and neuroinflammation in the toxin‐induced rat models of PD [1]. New data addressing the mechanism of ODN (oligodeoxynucleotide) induced neuroprotection by SRY will be discussed.

Conclusions: SRY directs a previously unrecognized male‐specific mechanism of DA cell death and suggests that suppressing nigral Sry synthesis represents a sex‐specific strategy to slow or prevent DA cell loss in PD.

References: [1] Lee J, Pinares‐Garcia P, Loke H, Ham S, Vilain E, Harley VR (2019). Sex‐specific neuroprotection by inhibition of the Y‐chromosome gene, SRY, in experimental Parkinson's disease. PNAS, 116(33), 16577‐16583. doi: 10.1073/pnas.1900406116.

48

Is it possible to treat GBA associated Parkinson's disease?

Alena Kopytova (Saint‐Petersburg, Russia), Mikhail Nikolaev (Gatchina, Russia), Konstantin Senkevich (Saint‐Petersburg, Russia), Galina Baydakova (Moscow, Russia), Olga Bolshakova (Gatchina, Russia), Svetlana Sarantseva (Gatchina, Russia), Irina Miliukhina (Saint‐Petersburg, Russia), Ekaterina Zakharova (Moscow, Russia), Sofya Pchelina (Saint‐Petersburg, Russia), Anton Emelyanov (Saint‐Petersburg, Russia)

Objective: The aim was to explored the effectiveness of pharmacological chaperone ABX on lipid metabolism and restoration of GCase activity in primary macrophages from GD and GBA‐PD patients.

Background: Gaucher disease (GD), caused by GBA mutations, encodes lysosomal enzyme glucocerebrosidase (GCase). Pharmacological chaperones could potentially enhance GCase activity and treat GD and PD linked to mutations in the GBA gene (GBA‐PD). One of such molecules is ambroxol (ABX). ABX was identified as a potent stabilizer of GCase and characterized as a pH‐dependent, mixed inhibitor of the enzyme.

Methods: Peripheral blood mononuclear cells from GD (n=8) and GBA‐PD (n=6) patients were isolated using Ficoll gradient. Macrophages were differentiated from purified monocytes using M‐CSF (10ng/ml) in RPMI1640 medium, supplemented with 10% FBS. Differentiation medium was refreshed every other day and macrophages were harvested on day eight. GCase activity and concertation of lysosphingolipids (hexosylsphingosine (HexSph)) were measured by LC‐MS/MS. The translocation of GCase (Alexa Fluor 488) to lysosomes (marker LAMP2 (Cy3)) was demonstrated in patient macrophages. Z‐stack images were acquired using a Leica TCS‐SP5 confocal microscope.

Results: Using ABX as pharmacological chaperone for macrophages derived from GD and GBA‐PD patients we observed significantly enhanced GCase activity and decrease of HexSph concentration (Table 1). In GD macrophages we observed increase colocalization of GCase with LAMP2 by determining Pearson's coefficient in areas of colocalization.

Conclusions: ABX treatment enchanted GCase activity and decrease lysoscphingolipids concentration not only in primary macrophages derived from GD patients but also in primary macrophages from GBA‐PD patients. Our work supports the proposition that ABX should be further investigated as a potential novel disease‐modifying therapy for treatment of PD and neuronopathic GD to increase GCase activity.

The study was supported by RSF № 17‐75‐20159.

Table 1. GCase activity and HexSph concentration in macrophages derived from GD and GBA‐PD patients.

	GD ABX ‐	GD ABX +	p value	GBA‐PD ABX‐	GBA‐PD ABX+	p value
GCase activity, mmol/l/h	0,62 (0,16‐1,82)	2,09 (0,60‐5,04)	<0.001	19,52 (8,30‐27,67)	56,80 (29,35 – 115,14)	<0.001
HexSph, ng/ml	60,12 (39,92‐219,97)	22,74 (15,38‐165,36)	<0.001	48,26 (32,15 – 86,66)	31,68 (19,73 – 37,92)	0.015

49

Genetic mutations in Parkinson's disease: screening of a selected population from Northeastern Italy

Giulia Bonato (Padova, Italy), Manuela Pilleri (Vicenza, Italy), Michele Mainardi (Genova, PA, Italy), Lisa Lerjefors (Padova, Italy), Silvia Andretta (Padova, Italy), Federica Garri (Padova, Italy), Ivan De Tomasi (Padova, Italy), Leonardo Salviati (Padova, Italy), Miryam Carecchio (Padua, Italy), Angelo Antonini (Padua, Italy)

Objective: To assess the prevalence of pathogenic variants in Parkinson's disease‐related genes in a selected cohort of PD patients enrolled in Northeastern Italy and to characterize their clinical phenotype.

Background: Monogenic forms of PD account for 5‐10% of all PD patients, but the wide‐spread use of Next‐Generation Sequencing Techniques in clinical practice is likely to increase these figures in selected cohorts of patients.

Methods: 63 patients from two specialized centers (University of Padua; Vicenza Villa Margherita) were selected to undergo genetic testing according to the presence of at least one of following criteria: 1) age of onset under 50 years; 2) reported positive family history of PD; 3) early development of cognitive decline or postural instability and falls. After extraction from peripheral blood cells, DNA was analysed by a customized panel (Illumina platform) including 80 genes related to movement disorders, 14 specifically associated with PD. Later data‐analysis, literature revision and publicly available database search were performed in order to determine variants pathogenicity. Clinical and neuropsychological assessment was performed.

Results: 26 out of 63 patients (41%) carried at least one pathogenic or likely pathogenic variant in one PD‐related gene, for a total of 31 different mutations in 12 genes (GBA, PARK2, LRRK2, CSMD1, VPS13C, ATP13A2, DNAJC6, NPC1, PDE8B, DHX30, NKX2‐1, PINK 1). 10 (38%) of the identified variants had evidence of pathogenicity, whereas 6 had an uncertain significance (VUS). A definite genetic diagnosis was formulated in 15 subjects (24% of the cohort). Average age of onset was 45 vs 49 years old in gene negative. 38.5% of patients carried a pathogenic variant in the GBA gene and 6 of them underwent Deep Brain Stimulation of the Subthalamic nucleus.

Conclusions: Pathogenic variants in PD‐related genes are common in our cohort of patients from Northeastern Italy, confirming that a positive family history of PD, early age at onset and the presence of atypical signs and symptoms are useful predictors of an underlying genetic etiology. Definition of specific selection criteria for genetic testing in PD will allow better allocation of financial resources and increase the probability to find pathogenic variants and fully delineate the mutational spectrum of known PD‐related genes.

Health Professional (Non‐Physician) Focus

30

Living with Parkinson's disease: Beyond the disease symptomatology

Leire Ambrosio (Mondragón, Spain), Pablo Martinez‐Martin (Madrid, Spain), Carmen Rodriguez Blazquez (Madrid, Spain), Jose Manuel Rojo (Madrid, Spain), Mari Carmen Portillo (Southampton, United Kingdom)

Objective: To identify the key components when living with Parkinson's disease (PD).

Background: Living with PD is a complex, dynamic, cyclic and multifactorial process influenced by several factors. Healthcare professionals need to be aware and adopt a comprehensive approach so that all aspects of the patients are individually addressed. Identifying and understanding which are the components that could make the person have a positive Living with PD or not is necessary to provide care according to the patient individual and unique needs.

Methods: An international study with an observation and cross‐sectional design which took place in five countries (Spain, Argentina, Ecuador, Mexico, Cuba) was carried out in 324 patients with PD. Multiple linear regression analysis was carried out to identify associations between living with PD and the following concepts: duration of disease, motor symptoms, non‐motor symptoms, psychosocial function, satisfaction with life, social support, and home economical situation.

Results: Living with PD was strongly associated with concepts related to the persons daily living: social support (ß = 0.51), satisfaction with life (ß = 0.26) and home economical situation (ß = ‐0.16). PD duration or symptoms did not present significant association in the daily living with PD.

Conclusions: It is necessary to incorporate multidisciplinary and individualized interventions in nowadays health services, focusing on the components that directly influence in living with PD, as for social support, satisfaction and economical status. Consequently, possible negative aspects of the daily living with PD as lack of support, loneliness or dissatisfaction with life could be prevented and a more positive living achieved.

References: 1) Navarta‐Sánchez, M.V., Caparrós, N., Riverol, M., Díaz de Cerio, S., Ursúa, M.E., & Portillo, M.C., 2017. Core elements to understand and improve coping with Parkinson's disease in patients and family carers: A focus group study. Journal of Advanced Nursing, 73(11), 2609‐2621.

Infusion Therapy

11

Pros and Cons of Nasojejunal Testing Prior to Levodopa Carbidopa Intestinal Gel Treatment: Preliminary Results of a Case Series

Yildiz Degirmenci (Duzce, Turkey), Serkan Torun (Duzce, Turkey)

Objective: To evaluate the pros and cons of nasojejunal (NJ) testing before continuous levodopa‐carbidopa (LDCD) intestinal gel infusion in patients with Parkinson's disease (pwPD), and to document the data of drop offs following NJ testing.

Background: Continuous LDCD intestinal gel infusion is one of the device‐aided therapy options in selected pwPD who are suffering from motor, non‐motor fluctuations and complications, dyskinesia despite optimal oral and/or transdermal dopaminergic therapy [1, 2].

Methods: Data was retrospectively collected over a 16‐months period from June 2018 to September 2019 in our clinic. Sociodemographic features and disease characteristics of pwPD were recorded. All pwPD underwent nasojejunal (NJ) testing prior to percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG‐J). LDCD intestinal gel test doses were titrated following NJ tube insertion. The patients who showed significant improvements with NJ testing underwent PEG‐J placement. Treatment with LDCD intestinal gel was initiated, and their data were recorded. However, the data of pwPD who had to drop off due to following NJ testing were also recorded.

Results: Fourteen pwPD with mean age of 71 ± 5.39 years old were enrolled the study. All were suffering from motor fluctuations, complications with dyskinesia under optimum dopaminergic treatment. NJ tube and PEG‐J tube insertions in patients who showed improvement to test doses were performed in the endoscopy unit under sedation anaesthesia in the same day. During NJ testing, two patients experienced hallucinations, daydreaming, excessive sleepiness which persisted despite dose titration. Jejunal tumour was found during the NJ test tube insertion in one patient. Patients who showed significant improvement after NJ testing and underwent LCD gel infusion treatment following PEG‐J tube insertion are under control with regular follow‐ups.

Conclusions: NJ testing can be omissible in pwPD who are well‐known in terms of the levodopa response of parkinsonian symptoms and complications. However, NJ test phase allows to monitor the response to treatment, as well as to predict the possible side‐effects and tolerability to treatment. Thus, NJ test phase may allow to establish a familiarity in pwPD as well as their caregivers that can reduce the possible drop offs from the treatment following PEG‐J phase.

References: 1. Udd M, Lyytinen J, Eerola Rautio J, Kenttämies A, Lindström O, Kylänpää L, Pekkonen E. Problems related to levodopa‐carbidopa intestinal gel treatment in advanced Parkinson's disease. Brain and Behavior. 2017;7 (7):e00737. 10.1002/brb3.737. 2. Karlsborg M, Korbo L, Regeur L, Glad A. Duodopa pump treatment in patients with advanced Parkinson's disease. Dan Med Bull. 2010 Jun;57(6):A4155.

12

The effect of continual subcutaneous infusions of apomorphine on axial deformities in Parkinson's disease

Katerina Mensikova (Olomouc, Czech Republic), Michaela Kaiserova (Vracov, Czech Republic), Miroslav Vaštík (Olomouc, Czech Republic), Martin Nevrly (Olomouc, Czech Republic), Sandra Kurcová (Vrutky, Slovakia), Petr Kanovsky (Olomouc, Czech Republic)

Objective: To assess the long‐term efficacy and safety of treatment with continuous subcutaneous infusions of apomorphine on camptocormia in patients with Parkinson's disease (PD).

Background: Axial deformities in PD such as camptocormia or Pissa syndrom respond very poorly to botulinum toxin injections, manipulation with oral dopaminergic treatment or deep brain stimulation. The results of our previous pilot study showed good effect of apomorphine infusions in a small cohort of patients.

Methods: Patients with advanced fluctuating PD who developed camptocormia were treated with apomorphine infusions, based on a positive clinical response and good apomorphine tolerance during apomorphine testing. The daily dose of apomorphine was gradually increased according to clinical effect and tolerance. Patients were monitored regularly, at monthly intervals, over a 24‐month follow‐up period. The clinical effect of treatment was assessed using the UPDRS‐III, UDysRS, and GCI‐I scales.

Results: Treatment was initiated in a total of 11 patients. The effective daily doses of apomorphine varied according to clinical effect and tolerance in the range of 40‐70 mg. Improvement of camptocormia was observed in all patients approximately after four weeks of continuous apomorphine treatment, and this effect remained stable over the whole follow‐up period in 10 patients. One patient was discontinued after one year due to loss of effect; later, MSA‐P phenotype developed in this case. The treatment was well tolerated by all patients, the side effects were rare and, if present, not serious.

Conclusions: Apomorphine infusion therapy may have a beneficial effect on this very unpleasant manifestation of the disease. This effect can be explained by the sustained stimulation of the ventrolateral striatal D1 receptors, alleviating this type of dystonia.

Supported by: grant from the Ministry of Health, Czech Republic – conceptual development of research organization – MH CZ – DRO (FNOL, 00098892) 2019.

13

A new type of highly soluble L‐DOPA ester for continuous subcutaneous application in Parkinson's disease

Ralf Wyrwa (Jena, Germany), Christoph Völkel (Berlin, Germany), Dirk Palla (Zossen, Germany), Matthias Bräutigam (Berlin, Germany), Thorsten Laube (Jena, Germany), Matthias Schnabelrauch (Jena, Germany), Johannes Tack (Berlin, Germany)

Objective: To experimentally evaluate GlyDopa with respect to synthesis, solubility, stability in water and rate and extent of enzymatic cleavage under ex vivo conditions. First data have been generated with respect to skin tolerability after 24h subcutaneous (SC) infusion in mini‐pigs.

Background: Therapies based on continuous dopaminergic stimulation (CDS) have been proposed for L‐DOPA for many years to be a superior therapy of PD but with present oral approaches it was quite difficult to evaluate this concept due to high variability of L‐DOPA's oral PK. SC infusion of L‐DOPA itself is not a valid option due to its low water solubility. Simple alcohol ester derivatives of L‐DOPA (from methanol, ethanol) have limited stability and solubility in water as well, which may contribute to their known skin problems (oedema, erythema). GlyDopa (L‐DOPA glycerol ester) is a newly synthesized L‐DOPA ester of a group of new esters using glycerol and other polyalkanols for SC infusion in early and advanced PD patients.

Methods: We have synthesized GlyDopa and determined its solubility and hydrolytic stability. Enzymatic cleavage and conversion into L‐DOPA was examined in human plasma ex vivo. Local skin tolerance was tested in mini‐pigs after SC infusion lasting 24h.

Results: GlyDopa can be synthesized specifically by several routes; a preferred one is to convert N‐, ‐O3, O4‐ protected L‐DOPA into L‐DOPA glycerol ester hydrochloride (HCl) by using glycidol and subsequent removal of the protecting groups (Patent EP3277660 is granted). Compared to the known L‐DOPA ethyl ester (LDEE) GlyDopa exhibits significant higher solubility in water up to 2 g/ml and improved stability in water, specifically at lower pH‐values, to support SC application over 24h. In human plasma GlyDopa is converted into L‐DOPA at the same rate and extent as LDEE under similar ex vivo conditions. GlyDopa tested in mini‐pigs as 24h SC infusion with 250 and 500 mg L‐DOPA equivalent doses/day resulted in good skin tolerance.

Conclusions: GlyDopa is a highly soluble and stable ester prodrug of L‐DOPA which is designed to be converted rapidly and completely into L‐DOPA after SC infusion by enzymatic cleavage in the systemic circulation. With good skin tolerance demonstrated in mini‐pigs GlyDopa SC infusion appears to be a promising drug development to achieve CDS for the treatment of PD.

Levodopa

14

Withdrawn by Author

15

Examining connection between level of hemoglobin and medical treatment efficacy in patients with Parkinson's disease

Shokhijakhon Shokhimardonov (Tashkent, Uzbekistan), Hilola Daminova (Tashkent, Uzbekistan), Shaimardan Khudjanov (Tashkent, Uzbekistan)

Objective: 1. Is there a correlation between the concentration of hemoglobin in the blood and the effectiveness of drug treatment for Parkinson's disease? 2. Is it possible to increase the effectiveness of levodopa in combination therapy with iron preparations?

Background: Despite the fact that hemoglobin is considered the most widespread source of peripheral iron and an extremely often diagnosed test, the relationship between the level of hemoglobin in the blood and the severity of Parkinson's disease is still poorly understood.(1) This report will address issues related to the use of iron preparations in the treatment of brain neurodegeneration. The relationship between the level of hemoglobin in the blood and the effectiveness of drug treatment will also be examined.

Methods: We observed medical records from the neurology department of the TMA clinic for the period 2012–2019. The medical records of patients with PD in the amount of 92 patients were studied, of which 53 (57.6%) were women in the age group 57–75 and 39 cases (42.4%) were men in the age group 61–83 years. General blood tests were analyzed to determine the level of hemoglobin, all subjects were divided into two groups according to the level of hemoglobin in the blood. The first group of patients with diagnosed anemia (according to WHO criteria) and the second group of patients with normal blood hemoglobin concentration. Their data about the course of the disease were compared among themselves.

Results: The amount of hemoglobin decreased significantly with age. In the first group (with a low hemoglobin content), to obtain effective corrections of motor impairment almost twice the superior dosage of the preparations was required compared with the second group (with normal concentration of hemoglobin in blood) (p <0.001) [table 1]. During the data collection it was found that a high level of hemoglobin in age groups and the severity of Parkinson's disease have a directly proportional tendency to increase. A more severe course of the disease was observed in people with low hemoglobin levels.

Conclusions: Although hemoglobin levels decline with age, evidence suggests that a marked decrease in hemoglobin levels in the elderly is associated with an increased risk of severe Parkinson's disease and the development of therapeutic resistance.

References: 1. Disorders Journal. Supplement 2. October 2019. Examining level of hemoglobin in patients with parkinson's disease and the role of hemoglobin level in the disease courseS.h. Shohimardonov, K. Daminova (Tashkent, Uzbekistan)

Motor Fluctuations and Dyskinesia

82

PDMonitor: A novel system for objective monitoring of Parkinson's disease symptoms ‐ efficacy and usability study

Nikolaos Kostikis (Ioannina, Greece), Georgios Rigas (Ioannina, Greece), Spyridon Konitsiotis (Ioannina, Greece), Dimitrios Fotiadis (Ioannina, Greece)

Objective: The efficacy and usability of a novel Parkinson's disease (PD) motor symptom monitoring system, the PDMonitor, is presented.

Background: Parkinson's disease (PD) management and treatment are largely based on healthcare professionals' experience and training. During clinical examination, scale‐based, subjective symptom rating is the “gold standard”, whereas patient diaries are relied upon to obtain information concerning the disease progression. This paradigm requires experienced physicians, it is cumbersome to follow during advanced therapies' eligibility assessment and calibration, and it can be particularly problematic when patients suffer from cognitive impairment. To optimize medication titration, increase cost efficiency and address low expert‐per‐patient ratio and low quality of information conveyed by the patients, there is an increasing interest for validated, objective measures of PD symptoms, with a potential for remote use[1]. Various approaches for objective monitoring and remote PD management have been proposed, mainly based on wearable sensors and smart technologies. The PDMonitor is a wearable system consisting of five movement monitoring devices to be worn on specific body parts, i.e., wrists, shanks and waist, and a smart base to take care of data processing and communication. PDMonitor can evaluate the main motor symptoms which are presented as clinical meaningful reports to treating physician by a web application The symptoms monitored are tremor, bradykinesia, dyskinesia, gait impairment, FoG, postural instability and also off time is estimated.

Methods: Thirty patients with PD were recruited in a multisite clinical study conducted in Greece and Italy (Table 1). All patients were fitted with the five wearable sensors of the PDMonitor system and were kept at the clinic for an average duration of 3 hours. During this time, they were assessed by a PD expert physician every half hour, according to the motor evaluation (Part III) of the Unified Parkinson's Disease Rating Scale and the Abnormal Involuntary Movement Scale (AIMS) for presence of dyskinesia. Patients who were able to wear the devices themselves, were first given instructions and then told to put them on while patients with increased impairment, were assisted by their caregiver or a nurse. Both the fitting process and the clinical assessments were videotaped. To assess the device usability, 10 patients and 19 healthy volunteers were given PDMonitor devices to wear at home for 3‐5 days each for a total of 900 hours and filled a comfort rating scale questionnaire containing questions on a 0‐20 scale (0: best, 20: worst) regarding the user's emotion, attachment, harm, perceived change, movement, and anxiety.

Results: The PDMonitor symptom quantification algorithms were used on the collected data, calculating equivalent UPDRS scores, and the results were compared with the UPDRS scores assigned by the expert physician and averaged over all half‐hour assessments. The device accurately detected and estimated the severity of the major motor symptoms including arm bradykinesia (R2=0.46 with UPDRS items 23, 24, 25), dyskinesia (accuracy 90% compared to AIMS score), gait Impairment (R2=0.6 with UPDRS item 29), wrist tremor (accuracy 89% and R2=0.67 with UPDRS item 20), leg tremor (accuracy 93%) and FoG (accuracy 93% compared to UPDRS item 14). Regarding wearability, the average time required to mount the sensors with the help of a caregiver or nurse was 3 minutes, whereas patients with slight or mild cognitive impairment needed 4 minutes to wear the device by themselves. The results from the 900‐hour wearability study were very good indicating that the users found it relatively easy to wear the device (score=3.3).

Conclusions: An objective measurement wearable system like the PDMonitor can be used to monitor PD motor symptoms accurately and remotely. PD patients are able to effectively use a device with 5 sensors and require minimum effort to put it on. Adherence in a longitudinal use of any similar device is still an open issue, and can be significantly improved by using proper patient notification and empowerment methods.

References: [1] Odin P, Chaudhuri KR, Volkmann J, et al. Viewpoint and practical recommendations from a movement disorder specialist panel on objective measurement in the clinical management of Parkinson's disease. NPJ Parkinsons Dis. 2018. 4:14.

Table 1. Patient statistics

Number of patients: 30Number of male subjects: 15Number of female subjects: 15
Sex	Age [mean/std]	Years from first PD diagnosis [mean/std]	Average UPDRS Part III score over all half‐hour assessments [mean/std]	Average AIMS score over all half hour assessments [mean/std]
Male	64.5/10.8	7.9/4.9	21.7/13.5	2.1/3.7
Female	65.5/8.2	10.4/5.0	20.3/20.9	3.0/3.25
Total	65.0/9.5	9.1/5.0	21.0/17.2	2.56/3.36

Neurodegeneration

62

Interleukin‐4 and interleukin‐13 contribute to degeneration of dopamine neurons in the 6‐OHDA‐treated striatum in vivo

Rayul Wi (Seoul, South Korea), Won‐Ho Shin (Daejon, South Korea), Young Cheul Chung (Seoul, South Korea), Byung Kwan Jin (Seoul, South Korea)

Objective: The present study investigated the effects of interleukin (IL)‐4 and IL‐13 on midbrain dopamine (DA) neurons in 6‐hydroxydopamine (6‐OHDA)‐treated rat.

Background: Even various role of IL‐4 and IL‐13 are purposed in many neurodegenerative disease animal models, their role are little known under Parkinoson's disease condition.

Methods: To understand the role of IL‐4 and IL‐13 in 6‐OHDA rat model of PD, we performed stereotoxic surgery, immunohistochemistry, double fluorescent imaging and diverse image analysis.

Results: Tyrosine hydroxylase immunohistochemistry showed a significant loss of DA neurons in the substantia nigra and their fibers in the striatum at 7 and 14 day post‐6‐OHDA. In parallel, IL‐4 and IL‐13 immunoreactivity were upregulated as early as 3 day, reached a peak at 7 day and sustained at 14 day post‐6‐OHDA. IL‐4 and IL‐13 immunoreactivity were exclusively detected in microglia, not neurons and astrocytes. Neutralizing antibody (NA) for IL‐4 and IL‐13 protects DA neurons and fibers against 6‐OHDA‐induced neurotoxicity. Moreover, IL‐4NA and IL‐13NA increased the production of neurotrophic factors in the reactive astrocytes in 6‐OHDA‐treated striatum in vivo.

Conclusions: The detailed neuroprotective mechanism of IL‐4 and IL‐13 will be discussed, which may be especially related to regulate production of astrocyte‐derived neurotrophic factors in 6‐OHDA rat model of PD.

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Interleukin‐4 and interleukin‐13 aggravated neuronal death in the lipopolysaccharide‐injected striatum in vivo

Ah‐Reum Hong (Seoul, South Korea), Jae Gune Jang (Seoul, South Korea), Kyung In Kim (Seoul, South Korea), Jae Young Jung (Seoul, South Korea), Won‐Ho Shin (Daejon, South Korea), Young Cheul Chung (Seoul, South Korea), Byung Kwan Jin (Seoul, South Korea)

Objective: The present study investigated the effects of interleukin (IL)‐4 and IL‐13 on striatal neurons in lipopolysaccharide (LPS)‐injected rat striatum.

Background: Even IL‐4 and IL‐13 are well‐known cytokine in periphery immune responses, their role are little known under neuroinflammatory condition.

Methods: To understand the role of IL‐4 and IL‐13 in LPS‐injected STR, we performed stereotoxic surgery, immunohistochemistry, double fluorescent imaging and diverse image analysis.

Results: NeuN immunohistochemistry showed a significant loss of striatal neurons at 3 and 7 days post‐LPS. In parallel, IL‐4 and IL‐13 immunoreactivity were upregulated as early as 1 day, reached a peak at 3 day and remained at 7 days post‐LPS. Increased levels of IL‐4 and IL‐13 immunoreactivity were exclusively detected in microglia. Neutralizing antibody (NA) for IL‐4 and IL‐13 significantly protects striatal neurons against LPS‐induced neurotoxicity in vivo. Moreover, IL‐4NA and IL‐13NA reduces the size of LPS damaged core area by the recovery of blood brain barriers in the striatum in vivo.

Conclusions: The detailed neuroprotective mechanisms of IL‐4 and IL‐13 will be discussed in LPS‐injected rat striatum in vivo.

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Sexual dysfunction in PD

Majlinda Shyti (Tirana, Albania)

Objective: The primary objective of this study was to evaluate the sexual dysfunction in PD patients in stage II‐ III Hoehn&Yahr of the disease.

Background: Nonmotor symptoms, among them sexual dysfunction, are common in Parkinson's disease patients and play a major role in the deterioration of quality of life of patients and their partners. Loss of desire and dissatisfaction with their sexual life is encountered in both genders. Loss of dopamine in the brain is often the primary cause of decreased libido. Because dopamine acts as a “pleasure molecule”, any reduction can make it harder for men and women to experience sexual pleasure or achieve orgasm. Lower testosterone levels, commonly seen in men with parkinsonism, can also contribute.

Methods: We included 53 ambulatory patients which were classified in the second or third stage of Hoehn and Yahr. They were asked about their interest in sexual activity (hiper or hypo sexuality) and if they had difficulty during sexual activity. In this study the patient were random, during consultations in Neurology department from January until July 2019. Patients who had other comorbidity which can influence sexual activity were excluded from this study. Statistical analysis was done using chi square test.

Results: Mean age of patients were 69.1± 8.5 (? 68.87± 7.546 ? 69.46± 9.742). Analyzing our data we found that 75.5 % of the patients expressed alteration of sexual interest, among men 73.3% and among women 78.3%. Difficulty during sexual activity was found in 92.5% of all patients, 93.3% of all men and 91.3% of all women.

Conclusions: Using chi square test we found that there is not any significant statistical difference between genders about sexual interest (p=0.679) or difficulty during sexual activity (p=0.782).

References: International multicenter pilot study of the first comprehensive self‐completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study.Chaudhuri KR1, Martinez‐Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, Brown RG, Koller W, Barone P, MacPhee G, Kelly L, Rabey M, MacMahon D, Thomas S, Ondo W, Rye D, Forbes A, Tluk S, Dhawan V, Bowron A, Williams AJ, Olanow CW.

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Botulinum toxin treatment of freezing of gait in Parkinson's disease patients reflected in functional magnetic resonance imaging of leg movement supported by the investigation of grey matter atrophy using surface –based algorithm, open, longitudinal, signle‐centre study

Miroslav Vaštík (Olomouc, Czech Republic), Pavel Hok (Olomouc, Czech Republic), Petr Hluštík (Olomouc, Czech Republic), Pavel Otruba (Olomouc, Czech Republic), Petr Kaňovský (Olomouc, Czech Republic), Zdeněk Tüdös (Olomouc, Czech Republic)

Objective: We investigated the clinical effect and changes of the activity of the sensorimotor system using repeated functional MRI (fMRI) before and after application of botulinum toxin in Parkinson's disease patients with FOG.

Background: Freezing of gait (FOG) is a common disabling symptom in Parkinson's disease (PD). The mechanism of FOG in not clearly understood. We investigated the clinical effect and changes of the activity of the sensorimotor system using repeated functional MRI (fMRI) before and after application of botulinum toxin in Parkinson's disease patients with FOG and the relationship between the progression of the regional cortical atrophy, neuropsychological profile and FOG severity progression.

Methods: We investigated 21 patients with PD, 11 with FOG and 10 without FOG. PD patients with FOG were treated with intramuscular application of botulinum toxin type A into the tensor fasciae latae muscle bilaterally. The clinical effect of treatment was assessed using FOG questionnaire, “Time up and go” test, UPDRS, Hoehn and Yahr staging, Clinical global impression scale and the neuropsychological examinations (Beck Depression and Anxiety Inventory, Hamilton Depression and Anxiety Rating Scales and Sheehan Anxiety Scale) were done in all subjects. Activation of the sensorimotor system was studied using BOLD fMRI of the whole brain during repetitive abduction – adduction of each leg interleaved with rest. The clinical (in the FOG group) and imaging (in both groups) examination was repeated after a four‐week interval. Surface‐based method implemented in FreeSurfer was used to quantify the GM atrophy. To assess the significance of differences between both groups, vertex‐wise and ROI comparison of spatially normalized subject data and the Wilcoxon rank sum test were done.

Results: In the FOG group, the FOG questionnaire has shown a decline of scores after application of botulinum toxin that suggests possible effect of botulinum toxin on freezing of gait. In fMRI results, both groups manifested reduction of the sensorimotor network activated with leg movement, however, the FOG group also showed increased activation in cerebellar vermis and nuclei, in dorsal pons and in medulla after treatment. The strong and statistically significant correlation between the grey matter reduction, level of anxiety and severity (or worsening) of FOG were present in the group of PD freezers when compared to PD non‐freezers. The most prominent grey matter changes were present in the supplementary motor area, cingulate cortex, anterior temporal cortex and frontal operculum.

Conclusions: Alleviation of the FOG in PD patients by botulinum toxin seems to be reflected in the functional participation of the cerebellum and its projections as seen by fMRI.

Conclusions: The results of the study support the initial hypothesis that FOG is significantly driven by the emotional stress and anxiety, and that there is a significant correlation between the atrophy of the non‐motor cortical areas and the severity and progression of FOG. Alleviation of the FOG in PD patients by botulinum toxin seems to be reflected in the functional participation of the cerebellum and its projections as seen by fMRI.

References: 1. Astur, R.S., Talylor, L.B, et Human with hippocampus damage display sever spatial memory impairments in a virtual Morris water task. Behavioural Brain Research 2002, 132:77‐84. 2. Bartles AL, de Jong BM, Giladi N Striatal dopa and glucose metabolism in PD patients with freezing of gait. Mov Disord, 2006 21, 1326‐1332. 3. Beckmann, C.F., Jenkinson, M., Smith, S.M. General multilevel linear modeling for group analysis in FMRI. NeuroImage 2003 20, 1052–1063. doi:10.1016/S1053‐8119(03)00435‐X. 4. Behzadi, Y., Restom, K., Liau, J., Liu, T.T. A Component Based Noise Correction Method (CompCor) for BOLD and Perfusion Based fMRI. Neuroimage 37, 90–101. doi:10.1016/j.neuroimage.2007.04.042. 5. La Fougère C1, Zwergal A, Rominger A, Förster S, Fesl G, Dieterich M, Brandt T, Strupp M,Bartenstein P, Jahn K. Real versus imagined locomotion: a [18F]‐FDG PET‐fMRI comparison. Neuroimage. 2010 May 1;50(4):1589‐98. doi: 10.1016/j.neuroimage.2009.12.060. Epub 2009 Dec 23. 6. Giladi N, Meer J, Kidan C, Greenberg E, Gross B, Honigman S. Interventional neurology: botulinum toxin as a potent symptomatic treatment in neurology. Isr J Med Sci 1994, 30: 816‐819. 7. Groenewegen, The basal ganglia and motor control, Neural plasticity 2003, Volume 10, NO.1‐2. 8. Guverich, T., Peretz, Ch., Moore, O., Weizmann, N., Giladi, N.,The effect of injecting botulinum toxin type A into the calf muscles on freezing of gaitn in Parkinson's disease: A double blind placebo‐controlled pilot study. Movement disorders, Vol.22, No.6, 2007. 9. Hanakawa T1, Katsumi Y, Fukuyama H, Honda M, Hayashi T, Kimura J, Shibasaki H. Mechanisms underlying gait disturbance in Parkinson's disease: a single photon emission computed tomography study. Brain. 1999 Jul;122 ( Pt 7):1271‐82. 10. Herman T, Rosenberg ‐ Katz K, Jacob Y, Giladi N, Hausdorff JM Gray matter athrophy and freezing of gait in Parkinson's disease.Mov Disord 2014, 29, 134‐139. 11. Jenkinson, M., Beckmann, C.F., Behrens, T.E.J., Woolrich, M.W., Smith, S.M., 2012. FSL. Neuroimage 62, 782–790. doi:10.1016/j.neuroimage.2011.09.015. 12. Jenkinson M, Bannister P, Brady M, Smith S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 2002;17:825–41. 13. Jenkinson M, Smith S. A global optimisation method for robust af fi ne registration of brain images. Med Image Anal 2001;5:143–56. 14. Logothetis NK (2008). What we can do and what we cannot dowith fMRI. Nature. 453: 869–878. 15. Lyoo CH, Aalto S, Rinne JO, Lee KO, Oh SH, Chang JW, Lee MS. Different cerebral cortical areas influence the effect of subthalamic nucleus stimulation on parkinsonian motor deficits and freezing of gait. Mov Disord. 2007 Nov 15;22(15):2176‐82. 16. Martens KAE, CG Ellard, QJ Almeida. Does anxiety cause freezing of gait in Parkinson's disease?PLoS ONE . Sep2014, Vol. 9 Issue 9, p1‐10. 10p. 17. Phan KL, Wager T, Taylor SF, Liberzon I. Functional neuroanatomy of emotion: a meta‐analysis of emotion activation studies in PET and fMRI. Neuroimage. 2002 Jun;16(2):331‐48. 18. Reiman EM1, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ, Yun LS, Chen K. Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry. 1997 Jul;154(7):918‐25. 19. Shine JM, Matar E, Ward PB, Frank MJ, Moustafa AA, Pearson M, Naismith SL, Lewis SJ. Freezing of gait in Parkinson's disease is associated with functional decoupling between the cognitive control network and the basal ganglia. Brain. 2013 Dec;136(Pt 12):3671‐81. doi: 10.1093/brain/awt272. Epub 2013 Oct 18. 20. Smith SM. Fast robust automated brain extraction. Hum Brain Mapp 2002;17:143–55. 21. Schweder PM, Joint C, Hansen PC, Green AL, Quaghebeur G (2010).Chronic pedunculopontine nucleus stimulation restores functional connectivity.Neuroreport, 21, 1065‐1068. 22. Ueno E, Yanagisava N, Takami M. Gait disorders in parkinsonism. A study with floor reaction forces and EMG. Adv Neurol 1993, 60:414 – 418. 23. Vriend C, Boedhoe PS, Rutten S, Berendse HW, van der Werf YD, van den Heuvel OA.J Neurol Neurosurg Psychiatry. 2015 May 18. pii: jnnp‐2015‐310383. doi: 10.1136/jnnp‐2015‐310383A smaller amygdala is associated with anxiety in Parkinson's disease: a combined FreeSurfer‐VBM study. 24. White, N.M., McDonald, R.J. Multiple parallel memory systems in the brain of the rat. Neurobiology of Learning and Memory 2002, 77:15‐184. 25. Woolrich, M.W., Behrens, T.E.J., Beckmann, C.F., Jenkinson, M., Smith, S.M., 2004. Multilevel linear modelling for FMRI group analysis using Bayesian inference. NeuroImage 21, 1732–1747. doi:10.1016/j.neuroimage.2003.12.023 26. Woolrich MW, Ripley BD, Brady M, Smith SM. Temporal autocorrelation in univariate linear modeling of FMRI data. Neuroimage 2001;14:1370–86. 27. Worsley, K.J., 2001. Statistical analysis of activation images, in: Jezzard, P., Matthews, P.M., Smith, S.M. (Eds.), Functional MRI: An Introduction to Methods. Oxford University Press, Oxford [England]; New York.

Neuroimaging and neurophysiology

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Pain syndrome in Parkinson's disease: neurophysiological and morphometric features

Olga Alenikova (Minsk, Belarus), Ivan Goursky (Minsk, Belarus), Nikita Alenikov (Minsk, Belarus), Tatiana Svinkouskaya (Minsk, Belarus)

Objective: Investigation of the neurophysiological disorders and identify their structural correlates in the brain by MRI studies with using voxel‐based morphometry to investigate subtle changes in gray matter volume in PD patients with pain syndromes.

Background: Pain syndromes (PS) in Parkinson's disease (PD) are complex pathology in the somatosensory and autonomic systems leading to disorders in the subcortical‐brainstem‐spinal systems functions in which specific brain structural changes may also occur.

Methods: We used short‐latency somatosensory evoked potentials (SEPs), blink reflex (BR) investigation which provides information about the afferent pathways and can assess the functional integrity of supraspinal structures and their descending influence on the brainstem. MRI scanning was conducted on a 3T scanner and neuroimaging data were processed using the FreeSurfer 6.0 software.52 patients with PD were examined in the age range of 40‐70 years: 22 with PS (1st group) and 20 ‐without PS (2nd group). 25 age‐match healthy individuals were included in the control group. The 1st group included individuals with unexplained PS that corresponded to the side of motor manifestations, or pain in the perineum, face, mouth; PS changed with levodopa.

Results: In PD patients with PS it was revealed neurophysiological sign of sensitization processes at the level of brainstem and thalamocortical projections according to the SEP. A significant decrease in the latency and increase in amplitudes of the second BR components indicate polysynaptic BR hyperexcitability. In PD patients, caudate nucleus and precentral gyrus volumes from both sides were diminished as compared to the control group, which may reflect the general neurodegeneration associated with PD. 3rd and 4th ventricles were markedly dilated and volumes in the postcentral gyrus were significantly lower in PD patients with PS. There was significant increase in the thalamus grey matter volume in 1st group as compared with 2nd group.

Conclusions: Disturbances of somatosensory processes at the different level of the brain with specific disorder in the brainstem reflexes was revealed in PD patients with PS. The presence of a significant increase in the volume of gray matter of the thalamus simultaneously with dilatation of the 3rd and 4th ventricles can be considered as a distinctive morphometric feature in these individuals. Identified by mean voxel‐based analysis of MTR images the structural changes in certain brain structures probably have association with functional neurophysiologic abnormalities in PD patients with PS.

References: 1. Geng, D. Y., Li, Y. X. & Zee, C. S. (2006). “Magnetic resonance imaging–based volumetric analysis of basal ganglia nuclei and substantia nigra in patients with parkinson's disease.” Neurosurgery 58:256–62. doi: 10.1159/000070676.2. Heinricher, M. M., Tavares, I., Leith, J. L. & Lumb, B. M. (2009). “Descending control of nociception: specificity, recruitment and plasticity.” Brain Res Rev, 60, 214–25.

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REM Sleep Behavior Disorder in the General Population: A case‐control structural imaging study

Roberta Biundo (Venice‐Lido, Italy), Robert Jech (Prague 7, Czech Republic), Luca Weis (Venice‐Lido, Italy), Elisabetta Gasparoli (Venezia Lido, Italy), Evzen Ruzicka (Prague, Czech Republic), Angelo Antonini (Padua, Italy)

Objective: The aim of this study is to investigate clinical‐neuropsychological and neuroanatomical characteristics of patients with idiopathic rapid eye movement Behavior Disorder (iRBD) compared to healthy controls (HCs).

Background: RBD is a parasomnia associated with neurodegenerative synucleinopathies. Long‐term studies have shown that the majority of persons with onset of iRBD in mid‐life are actually in prodromal stages of neurodegeneration [1‐3].

Methods: Forty‐six patients with iRBD and twenty‐two age matched HCs were enrolled by the Neurology Department of the Charles University in Prague. All participants underwent MRI neurological and neuropsychological assessment. Full video‐polysomnographic data were collected for RBD diagnosis, according to ICSD‐3 criteria [4]. Participants with vascular, neurologic, psychiatric problems, Stroke, apnea–hypopnea index [AHI] >30, and drug addiction were excluded. Chi‐square test for the categorical and Mann‐Whitney test for the continuous variables were used for comparisons between groups. General lineal model was run to analyse volume differences with age and eTIV as covariates. Freesurfer‐software was used to carry on a surface‐based analysis.

Results: iRBD patients were older, scored significantly higher in all the UPDRS sessions, and obtained a significantly lower MoCA score than HCs (see Table 1).Cortical thinning was found in iRBD patients vs. HCs in the left pre‐central gyrus and temporal sulcus. Moreover, increased cortical volumes were evident in the left primary motor cortex, in the left superior parietal lobule and in the left insula. Conversely, atrophy was detected in the left inferior occipital gyrus and in the right inferior temporal gyrus. Finally, the dorsal portions of both caudate nuclei and the mid‐posterior corpus callosum showed hypertrophy in patients as opposed to HCs. Six out of 46 iRBD patients converted to parkinsonisms around 10 years later RBD onset (see Table 2).

Conclusions: The brain morphometry alterations highlighted in this study mirrors the underlying early neurodegenerative process active in iRBD. Interestingly, the worst cognitive performance together with volumetric alterations in the occipital, parietal and temporal lobes, possible suits cognitive decline patterns typical of LBD. Finally, insular lobe was hypertrophic, which could be related to the emotional overload experienced by iRBD patients during their frequent nightmares. Further studies will be necessary to better localize the involved areas and hopefully halt the pathological stream ranging from the physiological setting, through iRBD, to that of overt parkinsonism.

References: 1. Schenck CH, et al. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diag‐nosed with idiopathic rapid eye movement sleep behavior disorder: a 16‐year update on a previously reported series. Sleep Med. 2013;14(8):744–748. 2. Iranzo A, et al. Neurodegenerative disorder risk in idi‐opathic REM sleep behavior disorder: study in 174 patients. PLoS One. 2014;9(2):e89741. 3. Postuma RB, et al. Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neu‐rology. 2015;84(11):1104–1113. 4. Sateia MJ. International Classification of Sleep Disorders‐Third Edition. Chest. 2014. doi:10.1378/chest.14‐0970

Table 1. Clinics and demographics characteristics of the sample

	HC (N=22)	iRBD (N=46)	Mann Whitney U
	Media (SD)	Media (SD)	p‐value
Age	60.27 (7.35)	65.26 (8.92)	0.0092
Time from iRBD onset (ys)		8.86 (6.94)
Gender (% male)	86%	91%	0.8409
Education (primary; high school, degree)	2; 10; 10	9; 18; 19	0.54*
UPDRS‐MDS I	2.39 (2.38)	7.31 (4.04)	< 0,0001
UPDRS‐MDS II	0.09 (0.43)	2.55 (3.12)	< 0,0001
UPDRS –MDS III	3.44 (4.74)	5.31 (5.24)	0,067
MoCA	24.95 (2.13)	23.63 (3.02)	0,037
RBDSQ	1,64 (1,43)	9,72 (2,10)	< 0,0001

*:Chi‐square. UPDRS‐MDS=Unified Parkinson Disease Rating Scale‐Movement Disorders Society; MoCA=Montreal Cognitive Assessment; RBDSQ=RBD Screening Questionnaire.

Table 2. Characteristics of the converted iRBD sample

	iRBD pts(N=46)
iRBD converted to parkinsonisms (N; %)	6; 13%;
Gender distribution among converted iRDB patients (% male)	100%
Time to convertion from iRBD symtoms (mean; SD)	9,83 (5,56)
Diagnoses post convertion (N; %)	PD: 5; 83,3%
	DLB: 1; 16,6%

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Inertial‐sensor based full‐body kinematics reveals an unstable gait with increased variability in patients with evidence of dopaminergic denervation with 123I‐FP‐CIT SPECT

Marcelo Mendonça (Lisboa, Portugal), Joaquim Silva (Lisbon, Portugal), Francisco Oliveira (Lisboa, Portugal), Albino Oliveira‐Maia (Lisbon, Portugal), Joaquim Ferreira (Torres Vedras, Portugal), Durval Costa (Lisboa, Portugal), Rui Costa (Lisbon, Portugal), Ricardo Matias (Castanheira Do Ribatejo, Portugal)

Objective: To assess the role of inertial‐sensor full body kinematics (FBK) in the distinction of patients with and without dopaminergic denervation (as assessed by 123I‐FP‐CIT SPECT – DaTscan).

Background: The differential diagnosis of Parkinson's disease (PD) remains challenging with frequent mis and underdiagnosis. DaTscan has been a useful technique for assessing the integrity of the nigrostriatal pathway loss in PD and differentiating true parkinsonism from mimics as essential tremor or iatrogenic parkinsonism. However, DaTscan remains unavailable in most non‐specialized clinical centres, making imperative the search for other easy and low‐cost solutions.

Methods: We invited all subjects referred for DaTscan in our nuclear medicine unit for participation. Patients were excluded if they were found to have any peripheral disorder that may influence walking or if they use a walking aid. A set of 15 inertial sensors was used to collect FBK from each participant while walking in a 30 meters corridor. Clinical assessment with the MDS‐UPDRS III was also performed.

Results: Twenty subjects were recruited, from which 10 were found to have a positive DaTscan (evidence of dopaminergic denervation). Both groups had 7 women, there were no age differences (68.4 ± 7.8 vs. 66.6 ± 7.4 years, p=0.809), and the denervated group scored higher in the MDS‐UPDRS III (29.0 ± 16.2 vs. 15.3 ± 10.3, p=0.031). Spatiotemporal kinematic variables (gait speed, step and stride length, width, time and gait phases) were similar between groups. No differences were also detected in joint angular velocities (with the exception being the hip rotation range of motion being significantly lower in denervated subjects: 10.52º ± 2.64º vs. 14.20º ± 3.46º, p=0.016). However, non‐linear gait variability metrics were found to be significantly different between groups. The anterior‐posterior harmonic ratio, a gait‐stability metric, was reduced in the denervated subjects (1.89 ± 1.07 vs. 3.1 ± 1.78, p=0.049), with an accompanying increase in the width of the main frequency in the same axis (0.26 ± 0.04 vs. 0.23 ± 0.01, p=0.015), representing a gait variability increase.

Conclusions: In this ongoing study, our preliminary analysis has revealed that subjects with evidence of dopaminergic denervation have a significantly higher gait variability than those without dopaminergic denervation. Besides identifying kinematic metrics that may have a role distinguishing PD from its mimics, it could help identify metrics with a role in early detection of Parkinson's disease.

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Parkinson's patients at Hoehn and Yahr stage 1 show deficits in reactive but not proactive inhibitory control

Nicola Modugno (Rome, Italy)

Objective: We wanted to assess whether i) PD patients at HY1 show a global or a selective impairment in inhibitory control; and whether ii) LPD patients have a greater deficit in inhibiting a pending action than RPD.

Background: It is well known that Parkinson's patients suffer from a deficit in inhibitory control [1,2], however this is not a unitary construct and it is unclear whether Parkinson's patients at early stage of the disease (Hoehn and Yahr stage 1, HY1) exhibit a deficit in outright stopping (reactive inhibition), a deficit in the ability to shape their motor strategy in anticipation of known task demands (proactive inhibition), or both. In addition, as it has been suggested that inhibition relies upon a right‐lateralized pathway, we tested whether left‐dominant Parkinson's disease (LPD) patients suffered from a more severe deficit in this key executive function than right‐dominant PD patients (RPD).

Methods: Via a reaching stop signal task [1,3,4,5], we assessed both proactive and reactive inhibition in 15 LPD, 15 RPD patients, and in 23 healthy subjects.

Results: We found that reactive inhibition was more impaired in PD patients than in healthy subjects. However, proactive inhibition [4,5] was not affected. Furthermore, we did found no differences between LPD and RPD patients. Importantly, we confirmed these negative findings using not only inferential statistics, but also the Bayesian statistic [6].

Conclusions: For the very first time, we found evidence for a deficit of reactive inhibition in the earliest stages of PD in the absence of evidence for deficits in proactive inhibition. These findings have clinical relevance as they provide key insights on the time‐course of the disease. In addition, we confirmed on a different population of PD patients our previous results [4,5] showing that the onset of the disease does not affect inhibition.

References: [1] Mirabella et al., 2017 Neuropsychologia; [2] Gauggel et al; 2004 J Neurol Neurosurg Psychiatry; [3] Mirabella et al 2012 Cerebral Cortex, [4] Mirabella et al 2013, Plos One; [5] Mancini et al 2019 Frontiers in Neurology; [6] Rouder et al 2009 Psychon Bull Rev.

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Intrinsic functional connectivity correlates of RBD in cognitively unimpaired drug‐naive Parkinson's disease patients

Sara Satolli (San Nicola La Strada, CE, Italy), Rosa De Micco (Naples, Italy), Mattia Siciliano (Napoli, Italy), Federica Di Nardo (Napoli, Italy), Francesco Bonifacio (Castellammare Di Stabia (Naples), Italy), Giuseppina Caiazzo (Naples, Italy), Fabrizio Esposito (Baronissi (SA), Italy), Gioacchino Tedeschi (Napoli, Italy), Alessandro Tessitore (Napoli, Italy)

Objective: To investigate intrinsic brain intra and inter‐network connectivity correlates of REM Behavioural Disorder (RBD) in a cohort of cognitively unimpaired drug‐naive Parkinson's disease (PD) patients and to correlate neuroimaging findings to clinical and cognitive measures.

Background: RBD is characterized by lack of skeletal muscle atonia during REM sleep. RBD develops in around 50% of PD patients and appears before motor symptoms in about half of them. PD patients with RBD present an increased risk of worse motor progression and dementia over the disease course.

Methods: 3T MRI images of 56 drug‐naive PD patients (25 PD‐RBD and 31 PD‐no‐RBD) were acquired. RBD presence and severity was assessed by means of a clinical interview and the RBD Screening questionnaire (RBDSQ). Single‐subject and group‐level independent component analysis was used to investigate intra and inter‐network functional connectivity differences within the default mode (DMN), fronto‐parietal (FPN), salience (SN) and executive control (ECN) networks between patients sub‐groups. Finally, linear regression analysis was used to investigate correlations between imaging and clinical data.

Results: Compared to PD‐no‐RBD patients, PD‐RBD showed an increased connectivity in the anterior cingulate cortex within the SN as well as an increased connectivity in the medial frontal gyrus within the ECN. Within the DMN, PD‐RBD exhibit an increased connectivity in the middle temporal gyrus as well as a decreased connectivity in the posterior cingulate cortex compared to PD‐no‐RBD. Finally, PD‐RBD patients showed a decreased connectivity in the middle temporal gyrus within the FPN compared to PD‐no‐RBD. Moreover, we observed significant group differences in functional coupling between the ECN and the DMN between PD‐RBD and PD‐no‐RBD. This imaging pattern was found to be correlated with both RBD severity and cognitive outcomes in PD patients.

Conclusions: Our findings demonstrated that an abnormal intrinsic brain connectivity within and between the major neurocognitive networks may represent a potential neural correlates of RBD symptoms and severity in early PD patients. This aberrant connectivity is correlated with cognitive outcomes even in the absence of cognitive impairment and may potentially be proposed to develop a sensitive and early biomarker of dementia in PD.

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Functional brain connectome in drug‐naive Parkinson's disease patients

Rosa De Micco (Naples, Italy), Federica Agosta (Milan, Italy), Silvia Basaia (Milan, Italy), Mattia Siciliano (Naples, Italy), Camilla Cividini (Milan, Italy), Gioacchino Tedeschi (Napoli, Italy), Alessandro Tessitore (Napoli, Italy), Massimo Filippi (Milan, Italy)

Objective: To investigate whole‐brain network topologic organization in a large cohort of drug‐naive Parkinson's disease (PD) patients using resting‐state functional MRI (rs‐fMRI); and to determine whether early functional connectivity measures may predict disease progression overtime.

Background: 147 drug‐naive PD patients were consecutively enrolled. Motor, non‐motor and neuropsychological assessments as well as rs‐fMRI were performed at baseline. 38 age‐ and sex‐matched controls were also enrolled in the study. Non‐hierarchical cluster analysis using motor, non‐motor and neuropsychological data were applied to stratify PD patients in two subtypes: 77 patients were grouped as “early/mild” and 70 as “early/severe”. After the baseline assessments, all patients started a dopaminergic replacement therapy accordingly to current international guidelines and were followed for an observation period, lasting a maximum of 24 months, with a clinical follow‐up every 12‐months.

Methods: Graph analysis and connectomics were used to assess global and local topological network properties and regional functional connectivity (FC) at baseline in both PD patients and controls. Multivariate linear and logistic regressions investigated whether functional imaging data at baseline were predictors of motor impairment and levodopa requirement over a 2‐year period.

Results: At baseline, “early/mild” PD patients showed a preserved global functional brain architecture compared to controls. “Early/severe” PD patients showed altered functional topological properties within the basal ganglia network compared to “early/mild” PD patients. Widespread FC abnormalities were detected in several networks encompassing basal ganglia, sensorimotor and occipital areas in PD patients compared to controls. Decreased FC involving mainly striato‐frontal, striato‐temporal and limbic connections differentiated “early‐mild” from “early‐severe” PD patients. FC abnormalities at baseline were found to be an independent predictor of levodopa requirement over 2‐years.

Conclusions: Our findings revealed that a specific subtype of PD patients, characterized by severe motor and non‐motor burden as well as widespread FC abnormalities, may be identified at the time of diagnosis. We hypothesize that this FC pattern may reflect the presence of more diffuse neuropathological changes. Combined clinical and neuroimaging tools are promising to stratify risk of PD progression overtime.

This abstract was presented at the 2019 International Congress of Parkinson's Disease and Movement Disorders in September 2019.

Neuropharmacology

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Adherence to Drug Treatment in Patients with Parkinson's Disease: evaluation of a Brazilian cohort

Vanderson Neri (Rio de Janeiro, Brazil), Ayne Sepulveda (Campos Dos Goytacazes, RJ, Brazil), Marina Barreto (Macaé, Brazil), Thaina Lopes (Campos Dos Goytacazes, Brazil), Luiz Soares Figueiredo (Campos Dos Goytacazes, Brazil), Glaucia Licassali (Campos Dos Goytacazes, Brazil), Kamilla Rodrigues (Campos Dos Goytacazes, Brazil)

Objective: To verify adherence to treatment and to identify intervening factors related to treatment abandonment or non‐compliance with therapeutic guidelines among patients with Parkinson's disease (PD).

Background: Adherence to drug treatment is the basis for the control of PD motor and non‐motor symptoms; however, this specific approach in PD is limited, since few studies prioritize this subject.

Methods: Descriptive, quantitative, observational epidemiological study Interview and application of questionnaires in patients with PD attended between January 2019 and July 2019 at a Movement Disorders Reference Center in Rio de Janeiro / Brazil; review of medical records. The social and cultural profile, motor aspects related to the disease (Hoehn & Yahr and Schwab‐England Scale) and knowledge and degree of adherence to drug therapy: Morisky and Green (1986) and Evaluation instrument for medication intake (validated for Brazil) were evaluated. Considered adherent according to Morisky score between 6 and 8 [Figure 1]. We used the Kruskal‐Wallis H Test and Pearson's ?2 Test and Fisher's exact test for statistical analysis.

Results: Eighty‐nine patients were interviewed, mean age was 68.8 years (SD ? 10,2), 50,6% were women. Regarding schooling, 47,2% had up to 4 years of training, 36% up to 12 years, 13,5% with more than 12 years and 2,2% with no schooling. All the interviewees were using antiparkinsonian drugs. All of them used Levodopa / benzeraside, the most common formulation being 400/100mg / day (53,9%); 28% used Pramipexole, 32,5% Amantadine, 8% Rasagiline (1mg/day) and 4% Selegiline (10mg/day). 48,3% of the patients used two to three drugs [Figure 2]. According to the Morisky Score were considered adherents to treatment 40 (44,9%) [Table 1]. According to the Evaluation instrument for medication intake, 19 (21,3%) have positive attitudes to maintain their treatment. There was a significant relationship between drug adherence and patient age (p = 0.02) and treatment time (p = 0.01). Demographic aspects such as gender, education, social security status and more committed stages in the Hoehn & Yahr and Schwab‐England Scale were also not related to drug adherence (p> 0.05).

Conclusions: Most PD patients in this study did not fully adhere to the drug treatment. Patients with the lowest adhesion rate were those with greater age and longer disease duration. Social and family aspects and the motor impairment of the disease did not influence the treatment.

References: 1‐Daley DJ, et al. Systematic review on factors associated with medication non‐adherence in Parkinson's disease. Parkinsonism Relat Disord. 2012 Dec;18(10):1053‐61.2‐ Postuma RB, et al. The new definition and diagnostic criteria of Parkinson's disease. Lancet Neurol. 2016 May; 15(6):546‐8.3‐ Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet. 2009 Jun 13;373(9680):2055‐66.

19

The influence of selected polymorphisms in COMT, DAT (SLC6A3), DRD2 and ANKK1 genes on the onset of dyskinesias and hallucinations in individuals with idiopathic Parkinson's disease

Branislava Radojevic (Belgrade, Serbia), Natasa Dragasevic‐Miskovic (Belgrade, Serbia), Ana Marjanovic (Belgrade, Serbia), Valerija Dobricic (Belgrade, Serbia), Igor Petrovic (Belgrade, Serbia), Miroslav Savic (Belgrade, Serbia), Ivan Jancic (Belgrade, Serbia), Marina Svetel (Belgrade, Serbia), Vladimir Kostic (Belgrade, Serbia)

Objective: The aim of our study was to determine the correlation between polymorphisms in COMT, DAT (SL6A3), DRD2, and ANKK1 genes and treatment complications such as motor fluctuations, dyskinesias and hallucinations in a large group of patients with idiopathic Parkinson's disease.

Background: Long‐term use of levodopa leads to the development of motor fluctuations, dyskinesias, hallucinations, psychosis. Recent studies described connection between polymorphisms in genes related to dopamine metabolism with complications of long‐term levodopa treatment.

Methods: The study included 230 patients with PD who were treated with levodopa for at least two years. Demographic and clinical data were obtained through the use of a detailed, specially designed questionnaire for this study. Each patient underwent comprehensive neurological examination, assessment of depression and anxiety and cognitive screening. Genotyping of rs4680 in COMT, rs2283265, rs1076560, and rs6277 in DRD2, rs1800497 and rs2734849 in ANKK1 genes was performed using TaqMan SNP genotyping assays on the ABI Prism 7500 Fast Real‐Time PCR System. Variable number of tandem repeats polymorphism in the DAT gene was detected by PCR and subsequent agarose gel electrophoresis.

Results: The overall percentage of patients who developed motor fluctuations during illness was 74%, dyskinesia developed in 51%, whereas hallucinations appeared in 44%. The prevalence of dyskinesias and hallucinations increased significantly with the duration of Parkinson's disease. Patients with hallucinations were more likely to have motor complications in the form of dyskinesia and fluctuations in the motor response (p?0.01). No significant associations between dyskinesia and polymorphisms in COMT, DAT (SL6A3), DRD2, and ANKK1 genes were observed. In addition, patients with A‐allele of rs2283265 (DRD2) and A‐allele of rs2734849 (ANKK1) had significantly lower risk for development of hallucinations (p?0,05).

Conclusions: The results of this study suggest that variants in the DRD2 and ANKK1 gene may have a protective impact for the development of hallucinations. Therefore, pharmacogenomics approaches could be used to personalized treatment of patients with Parkinson's disease. This study highlights the importance of genotyping of relevant SNPs prior to therapeutic decisions.

References: 1. Jankovic J. Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations. Mov Disord. 2005; 20 Suppl 11:S11‐6. 2. Fox SH, Lang AE. Levodopa‐related motor complications‐ phenomenology. Mov Disord. 2008; 23 Suppl 3:S509‐14. 3. Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson's disease. A community‐based study. Brain 2000; 123(11): 2297–2305. 4. Fénelon G, Mahieux F, Huon R, Ziégler M. Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors. Brain 2000; 123:733‐745. 5. Kurzawski M, Bialecka M, Drozdzik M, Pharmacogenetic considerations in the treatment of Parkinson's disease. Neurodegener. Dis. Manag. 2015; 5(1): 27‐35. 6. Drozdzik M, Bialecka M, Kurzawski M. Pharmacogenetics of Parkinson's Disease ‐ Through Mechanism of Drug Actions. Current Genomics 2013; 14 (8). 7. de Lau LM, Verbaan D, Marinus J, Heutink P, van Hilten JJ. Catechol‐O‐methyltransferase Val 158 Met and the risk of dyskinesias in Parkinson's disease. Mov Disord 2012; 27 (1): 132‐135. 8. Moreau C. et al. Polymorphism of the dopamine transporter type I gene modifies the treatment response in Parkinson's disease. Brain 2015; 138: 1271‐128 3 9. Tunbridge EM, Harrison PJ, Weinberger DR Catechol‐o‐methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 2006;60:141‐51. 10. Kaiser R, Hofer A, Grapengiesser A et al. L‐dopa‐induced adverse effects in PD and dopamine transporter gene polymorphism. Neurology 2003; 60 (11): 1750‐1755. 11. Kaplan N, Vituri A, Korczyn AD et al. Sequence variants in SLC6A3, DRD2, and BDNF genes and time to levodopa‐induced dyskinesias in Parkinson's disease. J Mol Neurosci. 2014; 53(2):183‐188. 12. Contin M, Matinelli P, Mochi M et al. Dopamine Transporter Gene Polymorphism, SPECT Imaging, and Levodopa Response in Patients with Parkinson Disease. Clin Neuropharmacol. 2004; 27 (3): 111‐115. 13. Rieck M, Schumacher‐Schuh AF, Altmann V et al. DRD2 haplotype is associated with dyskinesia induced by levodopa therapy in Parkonson's disease patients. Pharmacogenomics. 2012; 13(15): 1701‐1710.ts the importance of genotyping of relevant SNPs prior to therapeutic decisions.

20

Attenuation of mitochondrial dysfunction mediated death of Dopaminergic neurons by Chlorogenic acid in MPTP intoxicated Parkinsonian mouse model

Saumitra Singh (Varanasi, India), Surya Singh (Varanasi, India)

Objective: To investigate the effect of Chlorogenic acid in MPTP induced mitochondrial dysfunction mediated apoptotic death of Dopaminergic neurons in Parkinsonian mouse model.

Background: The progressive loss of dopaminergic neurons of substantia nigra results in Parkinson's disease, marked by disabling motor abnormalities. The exact mechanism underlying PD pathogenesis is yet to be understood; however, it is attributed that mitochondrial malfunction may play a key pathogenic component in PD. Various toxins involved in the characteristic symptoms of PD and genes associated with familial PD induce mitochondrial dysfunction. For that reason, treatments focusing on effective restoring of mitochondrial function may be useful in preventing the progression of PD.

Methods: For drug treatments, animals were randomly divided into four groups (eight mice in each group). The first group served as control. The Second group was intraperitoneally injected with MPTP (20 mg/kg body weight, 5 doses). The third group received oral treatment with Chlorogenic acid (CGA, 50 mg/kg body weight) in conjunction with MPTP. Whereas, the fourth group animals were only administered with CGA. All the drug treatments were given every day for a period of 24 days.

Results: The results indicated that CGA treatment subsequent to MPTP intoxication partially prevented the decline in activity of mitochondrial Complexes‐I, and –IV, along with improving the mitochondrial GSH level as well as SOD activity. Furthermore, CGA attenuated the MPP+ induced decrease in ATP synthase activity indicating increased energy available for dopamine biosynthesis. CGA was also reported to improve mitochondrial membrane potential (MMP) in the striatum as compared to the MPTP intoxicated group, indicating restoration of mitochondrial function. Moreover, it was demonstrated that CGA may have reversed the changes in expression of Bcl‐2, Bax and caspase‐3 in the substantia nigra pars compacta (SNpc) of mice, in addition to significantly improving the TH expression in SNpc.

Conclusions: Overall, our results suggested that CGA administration reduced MPTP induced mitochondrial dysfunction and apoptotic death of DA neurons, indicating its therapeutic effects in MPTP‐induced PD model.

References: 1. Singh SS, Rai SN, Birla H, Zahra W, Kumar G, Gedda MR, Tiwari N, Patnaik R, Singh RK, Singh SP: Effect of Chlorogenic Acid Supplementation in MPTP‐Intoxicated Mouse. Frontiers in pharmacology 2018, 9. 2. Lee E, Park HR, Ji ST, Lee Y, Lee J: Baicalein attenuates astroglial activation in the 1‐methyl‐4‐phenyl‐1, 2, 3, 4‐tetrahydropyridine‐induced Parkinson's disease model by downregulating the activations of nuclear factor‐?B, ERK, and JNK. Journal of neuroscience research 2014, 92(1):130‐139.

21

Neuroprotective propensity of marmelosin against 6‐OHDA‐induced cognitive impairment and apoptosis via upregulation of PI3K/Akt pathway

Ekta Yadav (Prayagraj, India)

Objective: Deficit in dopamenergic neuron and neuro‐inflammation are known as major pathological hallmark of Parkinson's disease (PD). Marmelosin, a natural furanocoumarin bioactive constituent of Indian traditional medicinal plant, Aegle marmelos, has been clinically utilized for treatment of various neurodegenerative diseases as it possess strong antioxidant and anti‐inflammatory activities.

Background: Current study was designed to explore the neuroprotective effect of Marmelosin against apoptosis caused by 6‐hydroxydopamine (6‐OHDA) by upregulating the phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt) signaling pathway.

Methods: Twenty four rats were utilized for the study and they were treated unilaterally with 6‐OHDA injection into the mid brain's substantia nigra at a dose level of 5?μg/2?μL. Rats were randomly divided into four groups‐ Marmelosin (10, 20 and 40?mg/kg) and Control (vehicle) and treated with their respective treatment for consecutive 30 days. The severity of damaging effects induced by 6‐OHDA was measured by behavioral tests (open field test and locomotor activity) performance. In addition, underlying mechanism concerning with PI3K/Akt upregulating pathway was further undertaken via Western blotting method and immunohistochemical detection.

Results: Results revealed that Marmelosin (20 and 40 mg/kg; p< 0.05,p< 0.01, respectively) ameliorated the damaging effects induced by 6‐OHDA by significantly improving the cognitive function as well as elevation in level of dopaminergic neurons and, p‐Akt Ser473, PI3K‐110a expression and pro‐caspase‐3 as compared with control group. Additionally, a significant reduction in the concentration of activated caspase‐3 and ratio of Bax/Bcl‐2 was observed in Marmelosin (20 and 40 mg/kg) administered group.

Conclusions: The results suggest that Marmelosin significantly reversed 6‐OHDA‐induced cognitive impairment and apoptosis by regulating the PI3K/Akt pathway. Thus, it could be utilized as a promising neuroprotective agent for treatment of PD.

References: Ding, G., Zhao, J., Jiang, D., 2016. Allicin inhibits oxidative stress‐induced mitochondrial dysfunction and apoptosis by promoting PI3K/AKT and CREB/ERK signaling in osteoblast cells. Exp. Ther. Med. 11, 2553–2560. Liu, H., Mao, P., Wang, J., Wang, T., Xie, C.H., 2015. Allicin protects PC12 cells against 6‐ OHDA‐induced oxidative stress and mitochondrial dysfunction via regulating mitochondrial dynamics. Cell. Physiol. Biochem. 36, 966–979

Non‐Motor Symptoms

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Localization of deep brain stimulation electrodes within subthalamic nucleus has different impact on non‐motor symptoms in patients with Parkinson's disease

Jan Bardon (Olomouc, Czech Republic), Sandra Kurcova (Olomouc, Czech Republic), Pavel Otruba (Olomouc, Czech Republic), Martin Nevrly (Olomouc, Czech Republic), David Krahulik (Olomouc, Czech Republic), Jana Zapletalova (Olomouc, Czech Republic), Petr Kanovsky (Olomouc, Czech Republic)

Objective: To evaluate the impact of precise localization of DBS electrodes within the STN on the improvement of NMS, when the anatomical segmentation of subthalamic nucleus has been explored.

Background: Recently, the work of Kurcova et al (1) studied the initial effects of subthalamic nucleus deep brain stimulation (STN‐DBS) on non‐motor and motor symptoms in patients suffering from Parkinson's disease (PD). Results of this study showed that STN‐DBS in patients with advanced PD clearly improves not only motor symptoms (MS), but also several domains of non‐motor symptoms (NMS), namely sleep, autonomic functions and quality of life.

Methods: Data from pre‐surgery planning MR scans and post‐surgery CT scans of 24 patients who underwent bilateral STN ‐ DBS were uploaded into the SureTune3® (Medtronic, Inc.) system and merged; this provided direct visualization and exact localization of the tip and each contact of the electrode within both STN, which were virtually divided into parts by perpendicular transversal lines. The electrodes were divided into groups according to the precise localization of their active contacts. Non‐motor and motor symptom have been evaluated before using validated scales and questionnaires. The data were collected preoperatively (M0), one month after implantation, just before the adjustment of initial stimulation parameters (M1) and three months after the stimulation parameters were adjusted (M4). The correlation between precise position of the active contact within the given STN segment and change in the values of NMS and MS scales for each side was calculated.

Results: From 37 evaluated electrodes, 13 electrodes were located in the ventromedial part and 24 electrodes were located in the dorsolateral part of STN. 28 active contacts were located in medial part of STN and 9 contacts were located in dorsolateral part. On the left side greater improvement was found in the dorsolateral localization of electrode (p = 0,045) in MNSS at M4. There were no other significant differences between the different electrode localisations in regard to the improvement on NMS.

Conclusions: Our study showed greater improvement in the MNSS in dorsolateral localization of DBS electrode on the left side. Otherwise we have not proven correlation between position of the active contact of the electrode and change of NMS, which could be due to relatively large stimulation field and also differences in STN subdivision 2); further research must be carried out.

References: 1. Kurcova S, Bardon J, Vastik M er al. Bilateral subthalamic deep brain stimulation initial impact on nonmotor and motor symptoms in Parkinson's disease. Medicine (Baltimore). 2018 Feb; 97(5): e9750. 2. Dafsari HS, et al., Non‐motor outcomes of subthalamic stimulation in Parkinson's disease depend on location of active contacts, Brain Stimulation (2018;, 11: 904 ‐ 912

70

Influence of peripheral immune system on non motor symptoms in Parkinson's disease

Luca Magistrelli (Novara, Italy), Elisa Storelli (Varese, Italy), Anna Vera Milner (Novara, Italy), Emanuela Rasini (Varese, Italy), Franca Marino (Varese, Italy), Marco Cosentino (Varese, Italy), Cristoforo Comi (Novara, Italy)

Objective: To describe the suitable role of peripheral immune system on non motor symptoms in PD patients.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease. It is clinically characterized by bradykinesia, rest tremor and rigidity. Recent papers highlight the emerging role of peripheral immune system in the pathophysiology of PD. Kustrumovic et al demonstrated that patients display a pro‐inflammatory immune phenotype (increase of Th1 and decrease of Th2 lymphocytes), increased levels of pro‐inflammatory cityokines and lymphocytes transcription factors leading to the Th1 phenotype. How the immune system may influence motor and non motor symptoms in PD patients is not yet fully understood.

Methods: Patients were recruited at the Movement Disorders Center of Novara. Subjects with autoimmune diseases, on or with past history of immune therapy were excluded. All subjects underwent a neurological assessment using specific scales (UPDRS III and H&Y) and peripheral venous blood samples were collected. Non motor scales included Zung score (total and percentage) for anxiety, Epworth for daytime sleepiness, BDI II for depression, Questionnaire for Impulsive‐Compulsive Disorders in Parkinson's Disease‐Rating Scale (QUIP‐RS), The REM Sleep Behavior Disorder Screening Questionnaire, Non‐Motor Symptom assessment scale for Parkinson's Disease, Compass 31 for the autonomic symptoms. Lymphocytes sub populations (Th1, Th2, Th17) were evaluated with flow cytometry.

Results: 42 PD patients were enrolled (12 female and 30 male). Mean age was 68.9±8.4; mean age at disease onset was 65.2±7.9. Mean Zung total score was 34.8±7.04; mean BDI‐II score was 11.08±9.7 and mean Epworth total was 5.17±4.07. Regarding QUIP‐RS total score was 13.6±14.9, with the highest sub‐score in hobby with a total of 4.11±5.58. Total score of non motor Symptoms (NMS) assessment scale was 31.5±21.7. More in details, a significant positive correlation was detected between NMS urinary sub‐score and Th2 total number (p=0.04; r2=0.12) and between NMS cardiovascular sub‐score and Th1 total number (p=0.004; r2=0.23). Mean RBD score was 4.8±2.9; moreover a positive correlation was found for RBD total score and Th2 total number (p=0.003; r2=0.24). Compass 31 total score was 15.3±8.8.

Conclusions: In this study we point out a possible role of peripheral immune system in the development of non motor symptoms in a cohort of PD patients. To the best of our knowledge this is the first study to investigate the suitable role of immunity in non motor symptoms in PD patients. Further studies are needed to confirm these data.

71

Blue light therapy glasses in Parkinson's disease: Patients' experience and effectiveness

Katarzyna Smilowska (Katowice, Poland), Daniel Van Wamelen (London, United Kingdom), Antonius Schoutens (Tilburg, Netherlands), Marjan Meinders (Nijmegen, Netherlands), Bastiaan Bloem (Nijmegen, Netherlands)

Objective: We aimed to assess how patients experience the use of blue light glasses, aiming to optimise compliance in upcoming clinical trials where these glasses will be tested for efficacy.

Background: Blue light glasses have been introduced as a possible new treatment option to treat sleep disturbances in patients with Parkinson's disease (PD). Assessing patient attitudes represents a key step in the road towards formal testing and introduction into clinical practice.

Methods: We invited 58 PD patients who had used the blue light glasses for at least one week on a daily basis to complete an online survey about their experiences and self‐reported impact. For this purpose, the System Usability Scale was used, supplemented with additional questions about (side) effects. A total of 31 patients (53%) replied.

Results: 74% of respondents reported subjective improvements in night‐time sleep, daytime sleepiness, depressive symptoms, motor functioning, or a combination thereof. The median score for the System Usability Scale (SUS; 0‐100 range, higher scores indicating better performance) was 70.0. A total of 26 patients (84%) had an overall positive attitude towards the technique, patients rating the glasses with an average score of 6.9 ± 2.0 [SD] out of 10. Except for one patient, all responders would like to continue using the glasses, mostly because they considered it a useful aid.

Conclusions: Blue light therapy appears to have a positive effect on sleep, mood and motor symptoms in PD. PD patients had an overall positive attitude towards blue light glasses as treatment for sleep disorders.

References: 1. Gelb, D.J., E. Oliver, and S. Gilman, Diagnostic criteria for Parkinson disease. Arch Neurol, 1999. 56(1): p. 33‐9. 2. Lees, A.J., N.A. Blackburn, and V.L. Campbell, The nighttime problems of Parkinson's disease. Clin Neuropharmacol, 1988. 11(6): p. 512‐9. 3. Tandberg, E., et al., Risk factors for depression in Parkinson disease. Arch Neurol, 1997. 54(5): p. 625‐30. 4. Videnovic, A. and G.L. Willis, Circadian system ‐ A novel diagnostic and therapeutic target in Parkinson's disease? Mov Disord, 2016. 31(3): p. 260‐9.

This abstract was presented at the 2019 International Congress of Parkinson's Disease and Movement Disorders in September 2019.

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Short term and long term effect of Deep brain stimulation and Continuous infusion of levodopa‐carbidopa intestinal therapy on non‐motor symptoms in patients with advance Parkinson's disease

Vladimira Vuletic (Zagreb, Croatia)

Objective: Our aim was to see short term and long term effects of deep brain stimulation (DBS) and continuous infusion of levodopa‐carbidopa intestinal gel (LCIG) on non‐motor symptoms in advanced Parkinson's disease (APD).

Background: The modern holistic management of PD is patient‐oriented and must include non‐motor symptoms.

Methods: We tested 70 patients treated with DBS and 20 patients treated with LCIG, before implementation and in period of 3 months, 6 months, 1 year and 3 years after. The investigation was conducted with anamnesis and treatments' data, Non‐motor Symptom Scale (NMSS), Non Motor Symptoms Questionnaire (NMSQ), Visual Analogue Scale (VAS), McGill questionnaire and Hospital Anxiety and Depression Scale (HADS), Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE), Parkinson's disease sleep scale (PDSS), Unified Parkinson's Disease Rating Scale‐ part II (activities of daily living‐ADL), part III (motor examination ‐ME), Parkinson's Disease Questionnaire‐ 39 (PDQ‐39) and levodopa dosage. Statistical analysis was done.

Results: Mean age was 70.09±0.9 (man 56%; women 44%). Mean disease duration was 14.0±0.6. We found statistically significant improvement in non‐motor symptoms (NMSS total score and NMSQ), motor symptoms and PDQ‐39 in both methods that was persistent and stable in all examined period. Considering subdomains, we found significant beneficial effect on gastrointestinal, cardiovascular and urological symptoms in both methods, but better improvement in pain, sleep and sexual function in DBS and mood and apathy section in LCIG patients (p<0.05).

Conclusions: We found short term and long term beneficial and stable effects with both invasive methods (DBS and LCIG) on non‐motor symptoms and quality of life. Non‐motor effects of these methods can help us to decide on advanced therapy for individual patients.

References: 1. Hariz GM, Hamberg K. Perceptions of living with a device‐based treatment: an account of patients treated with deep brain stimulation for Parkinson's disease. Neuromodulation 2014;17:272–8. 2. Reich M, Chaudhuri K, Ashkan K, et al: Changes in the non‐motor symptom scale in Parkinson's disease after deep brain stimulation. Basal Ganglia 2011, 1:131–133.

This abstract was presented at the 2019 International Congress of Parkinson's Disease and Movement Disorders in September 2019.

Other

84

Association between risk factors and sleep benefit in patients with Parkinson disease: A systematic literature review and meta‐analysis of observational studies

Mohammad Adil (New Delhi, India), Pinaki Ghosh (Pune, India), Manju Sharma (New Delhi, India)

Objective: This systematic literature review and meta‐analysis designed to find out association between possible risk factors and sleep benefit in Parkinson's disease (PD) patients.

Background: Sleep benefit in PD refers that patient's wake up in the morning with improved motor function. Association between sleep benefit and PD has been explored in various previous studies, but results are still equivocal.

Methods: A systematic literature search on PubMed/Medline and Embase was performed to identify observational studies in PD patients. Studies considering possible risk factors for the association with sleep benefit in patients with PD were included. We calculated mean difference (MD) with 95% confidence interval (CI) with fixed/random effect model based on heterogeneity (I2). Meta‐analysis was performed by using RevMan 5.3 software. Quality of the included studies were assessed by using Newcastle Ottawa Scale (NOS).

Results: Off 136 studies, total 6 observational studies with 1042 PD patients met the inclusion criteria. One each study performed in China, Australia and Norway, and 3 studies performed in Holland. Most of the studies (n=5) included Caucasian race. Results from pooled meta‐analysis suggested that duration of PD and on‐state MDS‐UPDRS‐III total score were significantly associated (MD 1.22; 95% CI: 0.21‐2.23; I2: 65%; P=0.02; and MD 3.05; 95% CI: 0.53‐5.57; I2: 0%; P=0.02) with sleep benefit when compared to no sleep benefit in PD patients. On the other hand, results from meta‐analysis showed that total sleep duration, Hoehn‐Yahr scale and PSQI total score were not significantly associated (MD ‐0.15; 95% CI: ‐0.53‐0.24; I2=64%; P=0.46; MD 0.10; 95% CI: ‐0.07‐0.28; I2=0%; P= 0.25 and MD 0.39; 95% CI: ‐0.22‐1.00; I2=0%; P=0.21) with sleep benefit when compared to no sleep benefit group in PD patients. Quality score of the included studies were ranged from 6‐8 according to NOS scale.

Conclusions: Current systematic literature review and meta‐analysis highlighted role of risk factors associated with sleep benefit in PD patients. Two risk factors (MDS‐UPDRS‐III total score and duration of PD) were associated with sleep benefit in PD patients. However due to differences in heterogeneity and lower population size, further research are warranted to confirm present findings.

85

Determining the stage of Parkinson's disease on the scale of Hoehn and Yahr

Assel Aralbayeva (Almaty, Kazakhstan), Saltanat Kamenova (Almaty, Kazakhstan), Karlygash Kuzhibaeva (Almaty, Kazakhstan), Aida Kondybaeva (Almaty, Kazakhstan)

Objective: Objective: to identify stage of Parkinson's disease on the scale of Hoehn and Yahr.

Background: Parkinson's disease is a severe, progressive disease of the nervous system, the main manifestations of which are impaired motor function. Depending on the severity of symptoms, there are five main stages of the disease. In this case, the progression of the disease can be fast, moderate or slow.

Methods: 56 people were examined, of whom 9 were newly diagnosed patients with early stages of Parkinson's disease who had not previously received antiparkinsonian therapy. Among patients with PD, there were 20 males (35.71%) and 36 females (64.28%), the age of the subjects was from 44 to 85 years old (average age 63.06 + 7.24 years). According to the anamnesis, the average age of onset of the disease (the moment from which patients began to notice the symptoms of PD) was 56.23 years. To determine the stage of Parkinson's disease, the Hoehn and Yah scale was used.

Results: Among 56 patients when evaluated on a scale of Hoehn and Yahr 1 stage 4 patients (7%), 1.5 stage 6 patients (10%), 2 stage 9 patients (16%), 2.5 stage 10 patients (17%), 3 stage 17 patients (30%), 4 stage 8 patients (14%), 5 stage 2 (3%) patients.As a result of a clinical study in patients with PD on the Hen and Yar scale, the third stage was most often found in 17 patients (30%).

Conclusions: As a result of a clinical study in patients with PD on the Hoehn and Yahr scale, the third stage was most often found in 17 patients (30%).

References: 1. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh‐Sorensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8‐year prospective study. Arch Neurol. 2003;60:387–392. 2. Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies of dementia in Parkinson's disease. Mov Disord. 2005;20:1255–1263.

86

The role of microRNA in Parkinson's disease

Assel Aralbayeva (Almaty, Kazakhstan), Saltanat Kamenova (Almaty, Kazakhstan), Karlygash Kuzhibaeva (Almaty, Kazakhstan), Aida Kondybaeva (Almaty, Kazakhstan)

Objective: to identify biological markers, which allow to increase the effectiveness of diagnosis of PD at an early stage of the disease.

Background: Parkinson's disease is a chronic neurological disease characterized by a progressive impairment of motor function, as well as the development of autonomic and psychiatric disorders. At present, PD is diagnosed only if there are motor disorders. In this regard, there is an urgent need to develop objective and measurable biological markers, which allow to increase the effectiveness of diagnosis of PD at an early stage of the disease, when the patient has not yet appeared signs of dysfunction of the musculoskeletal system.

Methods: 18 women and 14 men with Parkinson's disease were examined. The age of patients varies from 60 to 75 years. The comparison group was comparable in age and sex, without CNS (central nervous system) diseases. All patients underwent general expression of the microRNA molecules in the blood plasma.

Results: According to the survey, thirteen of the most differentially expressed mRNA molecules that are supposed to become biomarkers that could help identify patients with PD are identified.

Conclusions: The research is at the stage of further study. In the next stage of the study, the quantitative polymerase chain reaction (qRT‐PCR) method will be used to validate and evaluate the effectiveness of these biomarkers on the samples.

References: 1. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology. 2001;57:456–462.

87

Nutrient patterns in Parkinson's disease: a case‐control study

Stefania Diaconu (Brasov, Romania), Andrada Maceasa (Brasov, Romania), Bogdan Ciopleias (Brasov, Romania), Raluca‐Maria Stroescu (Brasov, Romania), Cristian Falup‐Pecurariu (Brasov, Romania)

Objective: The aim of this study is to evaluate dietary habits and food preferences of PD patients versus healthy controls.

Background: Currently, there is a growing body of evidence suggesting that nutritional habits might be related with the progression and management of Parkinson's disease (PD).

Methods: In this case‐control study we assessed nutrient intakes in 82 PD patients and 60 controls. We used a standardized questionnaire that included extensive food assessment and nutrient intakes, and dietary preferences.

Results: There were 56 men (68%), mean age 68,23±14,38 years [range 53‐ 84 years]. Among the non‐motor features in the PD patients group, the most common were nocturia and gastro‐intestinal symptoms. Overall PD patients had lower BMI and lower daily food intake than healthy controls. Comparing with controls, PD patients reported a higher daily intake of the following nutrients: iron (13.4mg/day vs. 11.2mg/day), potassium (4123mg vs. 3456mg), carotene (4124μg vs. 3897μg), and folate (345μg vs 342μg). PD patients have a lower daily intake of vitamin E (15.4 mg vs. 17.6mg) comparing with healthy controls. PD patients consumed less alcohol and fewer calories. PD patients with dysphagia had softer food intake and used to drink less fluid per day. Regarding the diet style, the PD patients showed preferences for aliments belonging of Mediterranean diet. Protein intake was correlated with motor fluctuations.

Conclusions: Dietary compounds might pay an important role in patients with PD, and nutritional habits are important, especially in advanced stages.

References: 1. Mischley LK, Lau RC, Bennett RD. Role of Diet and Nutritional Supplements in Parkinson's Disease Progression. Oxid Med Cell Longev. 2017;2017:6405278. doi: 10.1155/2017/6405278. 2. Erro R et al. Nutritional habits, risk, and progression of Parkinson disease. J Neurol. 2018 Jan;265(1):12‐23. doi: 10.1007/s00415‐017‐8639‐0. 3. Cassani E et al. Dietary habits in Parkinson's disease: Adherence to Mediterranean diet. Parkinsonism Relat Disord. 2017 Sep;42:40‐46. doi: 10.1016/j.parkreldis.2017.06.007.

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Development of a Home Based Care Pathway for people with Parkinson's

Emma Edwards (Plymouth, United Kingdom), Rebecca Partridge (Sheffield, United Kingdom), Ursula Ankeny (Sheffield, United Kingdom), Joe Langley (Sheffield, United Kingdom), Sue Whipps (Plymouth, United Kingdom), John Whipps (Plymouth, United Kingdom), Jane Rideout (Plymouth, United Kingdom), Fiona Murphy (USA), Emma Pearson (Plymouth, United Kingdom), Kevin Triscott (Plymouth, United Kingdom), Alyson Evans (Plymouth, United Kingdom), Sue Bentley (Plymouth, United Kingdom), Helen Matthews (London, United Kingdom), Neil Stevens (London, United Kingdom), Rupa Chilvers (Exeter, United Kingdom), Thea Dominey (Devon, United Kingdom), Camille Carroll (Yelverton, United Kingdom)

Objective: To design a home based care pathway for people with Parkinson's disease (PD) which promotes self‐management, supported by digital technology. The aim is to reduce unnecessary appointments, crisis interventions and unplanned admissions, while improving patient quality of life and staff wellbeing.

Background: Healthcare provision for people with PD varies globally, but commonly involves a service led pathway, or patient review precipitated by a health crisis. This leads to missed opportunities for more effective patient care and is frustrating and stressful for patients and staff. We were keen to explore whether a move away from a traditional clinic‐based care model to a pathway that promotes self‐management and patient initiated healthcare contacts supported by digital technology was more effective. Here we report the development of our Home Based Care pathway.

Methods: A series of 8 workshops were held over 18 months [figure 1]; participants included patients and their partners, PD practitioners from a range of disciplines, as well as digital health representatives. The workshops were facilitated by healthcare design engineers. The goals for these workshops were to explore and devise supportive self‐management and educational materials, and to ascertain which clinical tools would be most helpful for home‐based monitoring.

Results: Three major themes with associated support materials were developed: (1) education and support, including an introductory booklet explaining the pathway, a slide set for an initial training event for pathway enrolment, symptom and activity tracking cards [figure 2] to promote a better understanding of needs, written and online information, and a social media group for patients to access peer support; (2) clear information on when and how to trigger a healthcare contact; (3) home‐based monitoring of motor function via the Parkinson's KinetigraphTM (PKG) watch [figure 3] and non‐motor symptoms via regular completion of validated questionnaires. A dedicated telephone and email support was created for patients to seek further advice or assistance. In addition, process and evaluation measures for patients and staff were agreed and developed.

Conclusions: The outcome of the workshops has formed the structure of the Home Based Care Pathway. A pilot of pathway implementation will begin in October 2019.

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Unhealthy Traits and Risk of Parkinson's Disease: A Mendelian Randomization Study

Melanie Jensen (London, United Kingdom), Karl Heilbron (Sunnyvale, CA, United States), Pierre Fontanillas (Sunnyvale, CA, United States), Karl Heilborn (Sunnyvale, CA, United States), Paul Cannon (Sunnyvale, CA, United States), Alastair Noyce (London, United Kingdom)

Objective: Using Mendelian randomisation (MR), this study sought to determine the causal relationship between three generally recognized unhealthy traits, tobacco smoking, alcohol intake, and high body mass index (BMI), and Parkinson's disease (PD) risk.

Background: Observational studies have flagged smoking and alcohol as potential protective factors against developing PD; associations that merit careful verification given their detrimental effects on most other health outcomes. Low BMI appears to be associated with higher PD risk in some case‐control studies, albeit inconsistently. Because of the possibility of residual confounding and reverse causation, it is unclear whether such epidemiological associations are truly causal. MR uses genetic variants to explore causal effects of exposures or traits on outcomes, thus minimising these sources of bias.

Methods: We performed genome‐wide association studies to identify single nucleotide polymorphisms (SNPs) associated with the traits of interest. MR analysis of the relationship between each trait and PD was undertaken using a split‐sample design. The inverse weighted (IVW) method was used to combine the SNP‐specific effect estimates to determine the effect of each trait on PD. Two additional MR methods, MR‐Egger and a weighted mean‐based approach, were used to check for bias in the IVW estimate, arising through violations of MR assumptions.

Results: In the IVW analysis, ever‐smoking caused a significant reduction in PD risk (OR 0.96; 95% confidence interval [CI] 0.92‐0.99; p=0.01). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. Alcohol intake and was causally linked with increased risk of PD (OR 1.13, 95% CI 1.03‐1.24; p=0.01) and a 1 kg/m2 increase in BMI was causally linked with reduced risk of PD (OR 0.99, 95% CI 0.98‐1.00; p=0.01).

Conclusions: Using split‐sample MR in a cohort of over 2.4 million participants, we observed a protective effect of smoking on risk of PD. Although the mechanisms underlying this apparent protective effect remain speculative, these findings warrant the prioritisation of related therapeutic targets, such as nicotine agonists, in clinical trials. Conversely, alcohol consumption appeared to causally increase risk of PD. In keeping with previous studies, higher BMI had a protective effect on PD, but the effect was marginal.

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Body composition and sarcopenia in ischemic stroke patients and patients with Parkinson's disease

Sonja Mandjikoska (Maribor, Slovenia), Gordana H. Pinteric (Maribor, Slovenia), Katja Karnicnik (Maribor, Slovenia), Jure Potocnik (Radovljica, Slovenia)

Objective: This prospective single‐centre clinical trial was designed to evaluate the body composition and the prevalence of sarcopenia in ischemic stroke (IS) patients and patients with Parkinson's disease (PD).

Background: Approximately 30% of hospitalized patients are malnourished.1 Sarcopenia is a condition characterized by a progressive generalized loss of skeletal muscle mass and strength. The most common nutritional problem that predisposes a stroke is sarcopenia. In PD, sarcopenia may represent the common downstream pathway that, from motor and non‐motor symptoms leads to the progressive loss of resilience, frailty, and disability.

Methods: Clinical tests and bioimpedance analyses were used to recognize malnourished patients. We chose the Jansen's formula to calculate the total skeletal muscle mass index (TSMMi)2 and Cruz‐Jentoft's cut‐off values3 to identify sarcopenia.

Results: The nutritional status was performed on 123 patients, of which 72 were with moderate IS in acute phase and 51 with PD, 47% were women and 53% were men. Their average age was 71.6 years. The average BMI was 27.6 kg/m2 (21.0–35.4) in women and 27.9 kg/m2 (20.8–44.4) in men with IS, and 24.0 kg/m2 (18.0‐34.1 kg/m2) in women and 26.4 kg/m2 (20.2‐31.5 kg/m2) in men with PD. Among the 72 participants with moderate IS, the prevalence of sarcopenia was 71.9% in men and 23.7% in women. The prevalence of sarcopenia in patients with PD was 22.6% in men and 15% in women. In older women, the upper limit for normal fat composition is set at 41%. The average fat percentage in our study in patient with IS was 41.2%, and half of the female patients (50.0%) exceeded the upper limit. For men, the upper limit is set at 29%, and the average fat percentage value in our study patient with IS was 28.0% (9.5–41.6), thus only 35.3% of male patients exceeded the upper limit. In contrast, the average fat percentage in female patients with PD was 34.1%, and 10% exceeded the upper limit. In male patients with PD the average fat percentage was 21.7%, and only 3.2% exceeded the upper limit for normal fat [table 1.].

Conclusions: Sarcopenia is a common and unrecognized problem in stroke patients and patients with Parkinson's disease. Thus, BMI is no longer a sufficient tool for recognizing malnourished patients. Bioimpedance analysis is becoming a golden standard for individual nutritional interventions, which provide a solid basis for an efficient rehabilitation.

References: 1. McWhirter JP, Pennington CR. Incidence and recognition of malnutrition in hospitals. BMJ. 1994; 308: 945–8. 2. Janssen I, Heymsfield SB, Baumgartner RN, Ross R. Estimation of skeletal muscle mass by bioelectrical impedance analysis. J Appl Physiol. 2000; 89(2): 465–71. 3. Cruz‐Jentoft AJ, Baeyens JP, Bauer JM, Boirire Y, Cederrholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis. Age Ageing. 2010; 39(4): 412–23

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Inertial sensor‐based kinematics in the differential diagnosis of Parkinson's Disease and Atypical Parkinsonisms

Marcelo Mendonça (Lisboa, Portugal), Pedro Ferreira (Lisbon, Portugal), Raquel Barbosa (Lisboa, Portugal), Bruna Meira (Lisboa, Portugal), Joaquim Silva (Lisbon, Portugal), Rui Costa (Lisbon, Portugal), Ricardo Matias (Castanheira Do Ribatejo, Portugal)

Objective: To study the role of a multidimensional inertial sensor‐based phenotyping of patients in the differential diagnosis of parkinsonism.

Background: The use of wearable devices to study human movement has been progressively expanding in the filed of movement disorders. However, the role of these tools on differential diagnosis of movement disorders remains unclarified. Additionally, multimodal gait, posture and finger movements assessment could provide us a better phenotyping and therefore a deeper understanding of movement disorders physiology and progression.

Methods: From a neurology outpatient clinic, we've recruited 32 subjects with a diagnosis of Parkinson's disease (PD), 11 subjects with an Atypical Parkinsonism (AP) and 33 age matched controls. Subjects were evaluated on state subjectively reported as a “good on”. Using a set of 7 inertial sensors, leveraged by biomechanical models, we've assessed subject lower‐limb kinematics and posture during a 3x20 meters walk and stance. With a small inertial sensor in the finger, we've recorded the kinematics of a finger‐tapping test.

Results: PD and AP subjects presents significantly smaller (stride length: 0.92 ± 0.18 m vs 1.1 ± 0.14 m p < 0.001) and slower (gait speed: 0.77 ± 0.20 m/s vs 1.00 ± 0.19 m/s) movements when compared to control subjects. Using 162 gait‐related metrics (including 43 traditional gait parameters, 66 angular parameters, 18 non‐linear parameters and 35 asymmetry coefficients) a random forest model with 10‐fold cross validation yielded a classification accuracy of 82.9% predicting Parkinsonism/Non‐Parkinsonism. AP patients differed from the PD cohort with lower ranges of motions in the ankle joints (22.12º ± 6.47º vs 29.83º ± 6.59º, p<0.001) with higher velocity asymmetries in hip and ankle joints (AP: 0.656 ± 0.563 m/s vs PD 0.268 ± 0.177 m/s, p=0.002, AP: 1.586 ± 1.227 m/s, PD 0.636 ± 0.537 m/s, p=0.002) with the opposite in the knee joint (AP: 0.656 ± 0.563 m/s PD: 0.919 ± 0.710 m/s, p=0.001).Classification models are currently being improved to include finger‐tapping and postural sway data.

Conclusions: With a fast and standardized movement assessment protocol (< 5 minutes/patient) we were able to extract and identify kinematic differences between parkinsonian and healthy subjects. Expanding and optimizing these results across different stages of PD and AP could provide important insights and be a potential tool for differential diagnosis and clinical assessment.

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Adherence to Pharmacotherapy in Serbian Patients with Idiopathic Parkinson's Disease: A Cross‐Sectional Study

Andona Milovanovic (Belgrade, Serbia), Natasa Dragasevic‐Miskovic (Belgrade, Serbia), Branislava Radojevic (Belgrade, Serbia), Marina Svetel (Belgrade, Serbia), Igor Petrovic (Belgrade, Serbia), Aleksandra Tomic (Belgrade, Serbia), Vladimir Kostic (Belgrade, Serbia)

Objective: The aim of this study is to explore patient's adherence to antiparkinsonian medication and to determine factors that influence therapy adherence among Serbian patients with Parkinson's disease (PD).

Background: Adherence to therapy for PD is important for achieving effective management of the illness. Several previous studies showed that main predictors of low adherence are severity of the disease, number of daily doses, cognitive status and depression.

Methods: The study was conducted as a cross‐sectional study that included 150 outpatients with PD diagnosed according to the United Kingdom Brain Bank criteria. Patients were treated with at least one antiparkinsonian drug for at least two years. Patient's adherence was assessed through Eight‐Item Morisky Medication Adherence Scale (MMAS‐8). Each patient underwent neurological examination, assessment of depression and anxiety and cognitive screening. The following scales were used: UPDRS, H&Y PD staging scale, HDRS, HARS and Non‐Motor Symptoms Questionnaire for Parkinson's disease.

Results: Of the total number of participants 63 patients (42%) reported low adherence to their medication, 62 (41.3%) reported medium adherence and the remaining 25 patients (16.7%) reported high adherence. We found no significant relationship between adherence and sex, age, level of education, duration of PD, number of drugs taken and levodopa average doses. Low adherence was associated with higher UPDRS I scores (p<0,01), HDRS and HARS total scores (p<0.05). Freezing, falls and non‐motor symptoms of PD were more frequent in the group with low adherence.

Conclusions: This study suggests that low medication adherence is common among studied Serbian PD patients. We showed that the main predictors for low adherence were severity of the disease, depression, presence of freezing and non‐motor symptoms. The recognition of non‐adherence and consideration of medication‐taking behavior is crucial for improving management and clinical outcomes of PD patients. Treatment of depression and non‐motor symptoms are important for improving adherence to therapy in PD patients.

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Connected wearable insoles to monitor gait in Parkinson's disease (PD): validation protocol

Caroline Moreau (Marcq En Baroeul, France), Leila Farid (Paris, France), Anne‐Sophie Rolland (Paris, France), Guillaume Baille (Lille, France), Damien Jacobs (Paris, France), Erwan Bezard (Bordeaux, France), Luc Defebvre (Lille, France), Arnaud Delval (Alle Cedex, France), David Devos (Lille, France), Dominique Guehl (Bordeaux, France)

Objective: To develop and validate a new connected device to monitor gait in ecological condition in PD patients.

Background: Gait impairments are among the most disabling symptoms of Parkinson's disease occurring early in the disease course and leading to major handicap after several years. There is an urgent unmet need to monitor gait in real‐life condition that can be achieved with Feetme Monitor® insoles.

Methods: First, spatio‐temporal kinematic gait parameters (speed, variability and asymmetry) of Feetme® insoles were compared to the gold standard opto‐electronic device (VICON®, UK) in ON and OFF drug condition in 17 PD during the task of 7 meters with half turn 3 two‐ways at normal speed and 3 two‐ways on tiptoe on the bars of a ladder drawn on the ground. Secondly patients were assessed at home for 5 days to evaluate the insoles' sensitivity to the on/off fluctuations by comparing it with drug intakes. Metrics were stride length, cadence, velocity, stride ‐ swing ‐ stance ‐ and double support ‐ duration. Student‐tests were performed to identify significant differences between conditions on the median, the mean, the 95th percentile.

Results: 17 PD patients (4 women, mean age: 56 years old, mean disease duration: 7.2 years, mean UPDRS 3 dopa‐sensitivity: 67%). With all strides of ON and OFF dopa from each patient, four different statistical parameters have been used: mean, median, the 95 percentile and step by step (without statistical parameters) to describe both populations. For each t‐tests, significant differences were systematically observed for the velocity, the stride length and the swing duration (p‐values of mean parameter were respectively equal to 3e‐4, 9.14e‐5 and 0.039). No significant differences were observed for stride duration and stance duration excepted without statistical parameters.

Conclusions: The two first steps of validation of the Feetme Monitor® insoles are fulfilled. The sensitivity to the ON‐Off drug effect on gait were validated as compared with the gold standard (VICON) and at home in ecological conditions. The significant differentiation between ON and OFF‐dopa condition high‐lights the dopa‐sensitivity of stride length, velocity and swing duration. Now, those parameters will be used to build a classifier of ON and OFF‐dopa condition which could be apply on gait analysis during daily activities. Assessments on large prospective cohorts are planned to develop new ecological end‐points for clinical trials and new prognosis biomarkers of gait disorders in real life condition.

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Electrophysiological Markers of Early Diagnostics of Parkinson's Disease

Diyorakhon Okhunova (Tashkent, Uzbekistan), Abdukayum Babokhujaev (Tashkent, Uzbekistan)

Objective: It is known that in the early stages of Parkinson's disease, despite the onset of degeneration of dopaminergic neurons, clinical symptoms are absent for a long time. It is assumed that at the preclinical stage of Parkinson's disease, plasticity mechanisms are included that provide compensation for the arising violations. An urgent task is to search for markers of preclinical and the earliest clinical stages of Parkinson's disease. EEG analysis is an accessible and informative method for studying brain pathology. Our studies also showed a decrease in the main EEG frequency in patients with advanced Parkinson's disease. At the same time, there are practically no special works devoted to the analysis of EEG at an early stage of Parkinson's disease.

Background: The aim of this work was to study the features of EEG in patients with Parkinson's disease at the earliest stage of the disease (stage 1 on the Hoehn and Yahr scale).

Methods: In the work, EEG was analyzed in the 21st patient of the 1st stage of Parkinson's disease who were being treated in the neurological department of the 1st clinic of the Tashkent Medical Academy. Patients with a shaky‐rigid form of the disease prevailed. All of them underwent examination in our clinic, where they recorded electroencephalography. The electrodes were arranged in a standard 10x20 pattern. When analyzing the data obtained, patients were divided into two age groups: young (19‐30 years old, n = 5) and elderly (over 45 years old, n = 16). The control group included 5 young and 5 elderly, practically healthy volunteers. The wavelet transform was used to analyze the EEG. The staff of our clinic developed programs for the quantitative assessment of data obtained by wavelet analysis.

Results: The paper presents data on the features of the dominant alpha range (frequency from 8 to 12 Hz). In the group of young patients with stage 1 Parkinson's disease, the dominant EEG frequency was approximately 2 Hz higher than in young healthy volunteers (average values were 12.23 ± 0.17 Hz and 10.07 ± 0.04 Hz, respectively). In elderly patients with Stage 1 Parkinson's disease, an increase in frequency compared with the norm was also observed. On average throughout the group, the frequency was 11.05 ± 0.14 Hz, i.e. lower than in the group of young patients. The average frequency for the elderly norm was 9.82 ± 0.41 Hz. It turned out that elderly patients can be divided into 2 subgroups: in 12 of them, as well as in young patients, the average frequency of the dominant EEG rhythm was 11.88 ± 0.11 Hz, i.e. there was a significant excess of the elderly norm over the EEG frequency, and in 4 patients a decrease in the frequency to 8.57 ± 0.11 Hz was observed.

Conclusions: The analysis revealed that in the early stages of Parkinson's disease there is an increase in the frequency of the dominant EEG rhythm in young patients and in most elderly patients, in contrast to the later stages of the disease, which are characterized by a decrease in the frequency of the dominant rhythm. Possibly, an increase in the frequency of EEG reflects some aspects of compensatory plastic.

References: Okhunova Diyorakhon Alisher kiziBabokhujaev Abduqayum Srojiddin ogli

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Multiple sclerosis and parkinsonism: Coincidence or causation?

Rania Zouari (Tunis, Tunisia), Bedoui Ines (Nabeul, Tunisia), Hajer Derbali (Tunis, Tunisia), Mariem Messelmani (Tunis, Tunisia), Anis Riahi (Tunis, Tunisia), Jamel Zaouali (Tunis, Tunisia), Malek Mansour (Tunis, Tunisia), Ridha Mrissa (Tunis, Tunisia)

Objective: To describe cases of early‐onset parkinsonian syndrome occurring in the context of multiple sclerosis (MS) in order to discuss the possible mechanisms of such association.

Background: MS is a common demyelinating disease characterized by plaques in the white matter but also basal ganglia and the brainstem. A variety of movement disorders (MD) have been described associated with MS. Tremors were the most frequent ones, however, parkinsonism seems to be the rarest among other MD. In such cases, it remains difficult to determine whether MS is responsible for the extra‐pyramidal symptoms or the association with Parkinson's disease (PD) is just a coincidence.

Methods: This retrospective study was carried out on Tunisian MS patients who attended our Neurology department between 2000 and 2019. We included among them those who had parkinsonian symptoms in order to investigate their clinical and radiological features.

Results: We identified 4 patients (2 males, 2 females) who presented with MS and PD. The mean age at onset of MS was 36.5 years (range: 32‐40) with an average disease course of 11.75 years (range: 4‐18). The mean age at onset of parkinsonism was 33.5 years (range: 30‐38). In all patients, parkinsonism preceded MS and parkinsonism occurred at a very disabling stage of the disease (Expanded Disability Status Scale > 5). Parkinsonian symptoms developed within a mean duration of 9.5 years (range: 2‐17) after MS. Neurological examination revealed abnormal bradykinesia in all patients, asymmetric rest tremor in the upper limbs in 3 patients and mild rigidity in 2 patients. Brain magnetic resonance imaging revealed demyelinating lesions of the central nervous system consistent with MS, as well as plaques within the thalamus (50%), the brainstem (75%), the cerebellum (75%) and capsula interna (25%). Seventy‐five percent of patients showed no significant improvement with levodopa, while 2 patients manifested good recovery with intravenous methylprednisolone.

Conclusions: Parkinsonism due to MS is rare. Usually, in these cases, MS manifests first with a typical clinical presentation, and parkinsonism develops later in the course of the disease. In MS‐induced parkinsonism, parkinsonian symptoms generally have a good response to intravenous methylprednisolone treatment.

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Parkinson's disease and dermatomyositis: an unusual association

Rania Zouari (Tunis, Tunisia), Bedoui Ines (Nabeul, Tunisia), Hajer Derbali (Tunis, Tunisia), Mariem Messelmani (Tunis, Tunisia), Anis Riahi (Tunis, Tunisia), Jamel Zaouali (Tunis, Tunisia), Malek Mansour (Tunis, Tunisia), Ridha Mrissa (Tunis, Tunisia)

Objective: To report a rare case of Parkinson's disease associated with dermatomyositis and anti‐mitochondria antibodies.

Background: Lately, several autoimmune disorders were discovered to be closely associated with Parkinson's disease (PD) such as systemic lupus erythematosus and Sjögren's syndrome. However, PD occurring with autoimmune rheumatic disease, as dermatomyositis is rarely encountered. The mechanisms of PD remains poorly understood, even less is known about the pathophysiology of such association.

Methods: A case report.

Results: A 59 years‐old Tunisian man, from non‐consanguineous parents, manifested for 3 years with an asymmetric rest tremor of the left arm. He had a history of diabetes, hypertension, and dyslipidemia. On examination (at an age of 57 years old), he had an asymmetric resting tremor and rigidity predominating on the left, bradykinesia and hypomimia. He had a slow shuffling and unsteady gait with a reduced swing of the left arm. Brain MRI showed no abnormalities. Standard metabolic workup and ophthalmologic evaluation were normal. His parkinsonism was mildly responsive to levodopa therapy but non‐responsive neither to amantadine nor to piribedil. In the follow‐up, 2 years later, he developed general edema and erythema of the face, as well as photosensitivity. He had no difficulty in swallowing and no muscular weakness. His parkinsonian symptoms abnormally worsened, with severe bradykinesia poorly responsive to levodopa. Electromyography showed no muscular impairment. Laboratory investigations revealed normal creatine kinase level, negative tumor markers but positive autoimmune markers with positive anti‐mitochondria antibodies. The diagnosis of autoimmune amyopathic dermatomyositis was made and the patient was effectively treated with oral steroids and hydroxychloroquine, with an improvement of his skin lesions as well as his parkinsonism.

Conclusions: Although previously it was believed that PD and autoimmunity are not associated, evidence accumulated over the past years concerning immune alterations in PD increased the awareness of the possible role of the immune system in PD's etiopathogenesis. The occurrence of parkinsonism in autoimmune rheumatic diseases is just an example of this potential association.

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Role of Neurodegeneration in Motor Complications Induced by Levodopa Therapy

A.V. Milner, L. Magistrelli, E. Contaldi, C. Comi, R. Cantello (Novara, Italy)

Objective: Our aim is to analyze the influence of neurodegeneration on motor fluctuations and dyskinesias induced by Levodopa, reporting a paradigmatic case.

Background: Levodopa‐induced dyskinesia and motor fluctuations have been described for decades, but the underlying pathophysiology has not been fully understood, yet.

Methods: Clinical observation and neuroimaging (MRI scan and DaTscan) were essential. Genetic testing is still ongoing.

Results: We report a case of a young female who developed difficulty in walking when she was 9‐year‐old, becoming severly disabled over the following decade. A diagnosis of conversive disorder was previously made. At age 19, she suffered from generalized dystonia and parkinsonism. The patient was started on levodopa/benserazide therapy (150/37.5 mg/die) and she gradually improved within few days. After a week, when the total dosage was slightly increased to 200/50 mg/die, she developed disabling peak‐dose dyskinesia and experienced wearing‐off phenomenon. Meanwhile, a DaTscan was performed showing dramatic bilateral nigro‐striatal dopaminergic neurodegeneration.

Conclusions: Motor complications induced by levodopa therapy have been considered for many years long‐term side effects of pharmacological therapy itself. Nonetheless, recent evidence suggests that disease duration may represent the key to explaining their pathophysiology. Regardless of the final diagnosis, this case strongly suggests that motor complications eventually depend on disease duration and on the severity of the loss of dopamine innervation of the striatum, rather than on therapy. To the best of our knowledge, this is the first paradigmatic case describing motor complications induced by levodopa therapy after only a week of treatment.

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Late Onset Man in the Barrel Syndrome: A Case Report

Y. Güzey Aras, Ö. Kaya, T. Acar, S.S. Gül (Sakarya, Turkey)

Objective: The presence of brachial diplegia despite the normal muscular strength of the lower extremities is called the man‐in‐the‐barrel syndrome (MIBS). Although this rare syndrome often occurs due to the bilateral supratentorial brain lesions, it may also rarely occur as a result of infratentorial causes.

Background: Brachial diplegia with normal leg strength can presents symptom of cervical cord lesions such as infarction and trauma. Cervical cord injuries as presenting with brachial diplegia without lower limb weakness have been reported. Here, however, we present a patient with a cervical trauma who presented with MBS.

Methods: Case Report: A 73‐year‐old male patient presented to our clinic with complaints of progressive weakness on both upper limbs and shoulders. It started insidiously two years ago and gradually increased. Motor compromise was characterized by shoulder abductors 1/5; elbow flexors 1/5; elbow extensors 3/5; wrist extensors 4+/5; finger flexors; and abductors 4+/5 (Medical Research Council grading scale) bilaterally. Deep tendon reflexes were 1+ in both upper and lower extremities, and were accompanied by bilateral Babinski's and Hoffmann's signs without clonus.

Results: Cervical MRI showed multipl disc bulging between C3 – C7 segments and spinal cord compression with myelopathy of the spinal cord. It was learned from the history that a serious traffic accident happened 15 years ago which caused neck injury. The patient was consulted to neurosurgery and it was suggested surgery by them, but patient did not accept.

Conclusions: In this report, we describe a case presenting with MIBS of which etiological underlying cause was servical injury probably secondarily to 15 years ago trauma.

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AMBLED ‐ A Randomized, Double‐Blind, Placebo‐Controlled Phase II Study of the Efficacy, Safety and Tolerability of Foliglurax in Parkinson's Disease: Study Design and Baseline Characteristics

D. Meulien, C. Baayen, O. Rascol (Valby, Denmark)

Objective: To describe the study design of AMBLED (NCT03162874), and baseline characteristics of patients.

Background: Agents targeting the metabotropic glutamate receptor 4 (mGlu4) have emerged as a potentially attractive new class of drugs for the treatment of Parkinson's disease (PD). Foliglurax is a mGlu4 positive allosteric modulator in phase II clinical development.

Methods: The AMBLED study was designed to assess the efficacy of 10 and 30 mg of foliglurax twice daily versus placebo adjunct to levodopa in reduction of OFF time and dyskinesia in approximately 165 patients with PD. The primary endpoint was reduction in daily OFF time from baseline to Day 28. Safety and tolerability was also assessed. The study is conducted at 46 investigational sites in 6 countries across Europe.Eligible patients had PD for ≥3 years; 35‐85 years of age; a Hoehn and Yahr (H&Y) score of 2‐4; stable levodopa therapy (≤1600 mg/day). Further, patients had motor fluctuations ≥3 months prior to randomization, with both daily OFF time and daily ON time with dyskinesia (troublesome and/or non‐troublesome) of ≥2 h/24 h, while awake. A ≥28 days screening period (to assess and confirm eligibility as well as to perform Hauser diary completion training and concordance testing) was followed by a 28‐day treatment period and a safety follow‐up period. Key efficacy assessments Hauser diary data entries, Movement Disorder Society Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale [UDysRS] were performed at baseline and repeated on Days 14 and 28. Safety and tolerability was assessed throughout the study.

Results: At the cut‐off date (26‐Nov‐2019), 141 patients (61 female [43.3%]; 80 males [56.7%]) had baseline Hauser diary data. Data presented are mean (standard deviation). Age: 66.7 (9) years. H&Y score: 2.3 (0.7). UDysRS total score: 36.5 (10.1). OFF time: 4.9 (2.2) h; ON time without dyskinesia: 3.8 (2.6) h; ON time with troublesome dyskinesia: 2.5 (2.4) h; ON time with non‐troublesome dyskinesia: 4.9 (2.5) h; ON time without troublesome dyskinesia: 8.7 (2.6) h.

Conclusions: Patients enrolled in AMBLED have motor complications, i.e. are experiencing OFF time and dyskinesia. The study is ongoing. The poster will include baseline characteristics of the full population.

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Parkinson's Disease Developed While Imiglucerase Treatment in a Patient with Gaucher Disease

H. Apaydin, A. Çam (İstanbul, Turkey)

Objective: A patient with Gaucher disease (GD) type1 on β‐glucocerebrosidase (GBA) enzyme replacement therapy (ERT) with imiglucerase (Cerezyme), developped Parkinson's disease (PD) on the 7th year of ERT while all the symptoms of GD were returned to normal.

Background: Gaucher disease (GD) is an autosomal recessive, lysosomal storage disorder and caused by homozygous mutations in the GBA gene which are the most important risk factor yet discovered for Parkinson's disease (PD). GBA‐ERT with imiglucerase is the standard of care for patients with GD.

Methods: The present patient is a 53 year‐old man who was diagnosed as GD at the age of five. His sister had GD as well; she passed away as a result of cirrhosis at the age of 18. Both had organomegaly as the first prominent symptom. The index patient diagnosis was genetically confirmed as GD‐type1 in 2010 and since then he is under GBA‐ERT with imiglucerase (Cerezyme) that he receives 60 U/kg, total 4000 U, every 2 weeks. During this treatment, liver and spleen returned to normal size and diffuse loss of medullar intensity on cranium, clivus and cervical vertebrae suggesting myelodysplastic syndrome was disappeared as demonstrated on control MRI studies. The bone density became normal and anemia recovered. The persistent abnormal signs are low platelet number and hyperferritinemia which is two times higher than normal.

Results: At the age of 52 his wife noticed reduced arm swing while he was walking. Then he admitted to our outpatient clinic for medical advice. He reported slowness at meal‐times and difficulty while he was shaving. His neurological examination revealed right sided bradykinesia, bradymimia and synkinetic rigidity together with loss of associated arm swing movements during gait. Olfaction, sleep, mood and cognition were normal. He was at stage 1 of Hoehn‐Yahr scale. He was given levodopa‐benserazide 125 mg, t.i.d.. Finger movements became near normal at one month of levodopa treatment.

Conclusions: ERT is the standard of care for patients with GD as well as for my patient but it doesn't prevent neurological manifestations of GD. In the presented patient, PD developed at the 7th year of ERT when the majority of systemic signs of GD were regressed. PD symptoms responded to levodopa treatment and remained stable for last 3 years.

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GBA Mutation in Parkinson's Disease: Toward a Definition of Peculiar Clinical and Biochemical Markers

M. Avenali, S. Cerri, G. Ongari, E.M. Valente, C. Pacchetti, C. Tassorelli, F. Blandini (Pavia, Italy)

Objective: In this study we investigated the presence of peculiar clinical and biochemical features able to differentiate GBA‐PD subjects from iPD patients.

Background: Heterozygous mutations in the GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the main risk factor for Parkinson's disease (PD). GBA associated PD (GBA‐PD) is clinically indistinguishable from idiopathic PD (iPD) except for earlier and more prevalent cognitive impairment and non‐motor features. The identification of a genotype‐phenotype correlation could be important for both predicting disease progression and identifying target pathways for personalized medicine intervention.

Methods: We enrolled 15 GBA‐PD patients, 30 iPD, and 30 healthy subjects (HC). All participants have been examined with a structured clinical work‐up that comprises cognitive performance, olfactory function, sleep behavior disorders, autonomic dysfunction and depression. Moreover, we evaluated lysosomal alterations in peripheral blood lymphocytes by analyzing the GCase enzymatic activity and the expression of the main GCase‐related proteins.

Results: We observed a prevalence of non‐motor features, such as cognitive impairment and hyposmia, in GBA‐PD group compared to iPD. Regarding biochemical features, GCase enzymatic activity was significantly lower in GBA‐PD subjects compared both to iPD and HC, and was accompanied by a significant increase in a‐synuclein (a‐syn) protein levels. The GBA‐PD group also displayed lower Saposin C levels – an essential activator for GCase ‐ compared to the iPD group. Stratifying GBA‐PD by mutation severity, we observed that in patients with severe mutation, GCase activity was lower and a‐syn was higher than in patients carrying mild mutation. In GBA‐PD subjects, hyposmia, cognitive and sleep disorders were also correlated with higher levels of a‐syn and lower level of GCase.

Conclusions: This study confirms the presence of distinctive lysosomal alterations related to GCase enzyme deficiency in GBA‐PD group compared to iPD. The increase of intracellular levels of α‐syn is related with GCase deficiency in PD‐GBA. Moreover, we showed a correlation between biochemical alterations and non‐motor features in these subjects. These results provided new evidences about the mechanisms potentially related to the development of PD in subjects carrying GBA mutations, and also identified biomarkers correlated with genotype and clinical profile that could be used to identify subjects at higher risk of rapid progression and new potential therapeutic targets for GBA‐PD.

Quality of Life/Caregiver Burden

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Psychosocial Adjustment to Illness Scale in family carers of patients with Parkinson's disease: Spanish validation

Leire Ambrosio (Mondragón, Spain), Mari Carmen Portillo (Southampton, United Kingdom), Maria Victoria Navarta‐Sanchez (Madrid, Spain), Raquel Martin‐Lanas (Pamplona, Spain), Mario Riverol Fernandez (Pamplona, Spain)

Objective: To analyse the psychometric properties of the Spanish version of the Psychosocial Adjustment to Illness Scale (PAIS) in family carers of patients with Parkinson's disease (PD).

Background: Family carers, as informal caregivers, face multiple challenges that require a significant effort in terms of psychosocial adjustment, which must be considered by healthcare professionals in order to provide a holistic care.

Methods: An open, national cross‐sectional study with one point in time evaluation was carried out. Family carers of patients with PD from twenty‐five patient associations that belong to the Spanish Parkinson Federation were included. In addition to PAIS a health‐related quality of life scale (SF‐36) was also used.

Results: A total of 450 family carers of patients with PD were included. 76% of the sample was women, 87.1% were married and 74.4% was the spouse of the patient with PD. The confirmatory factor analysis showed that the ratio of the Chi‐squared coefficient with its degrees of freedom were slightly greater than 2. The root mean square error of approximation presented a satisfactory fit value below 0.06. The comparative fit index and Tucker‐Lewis index showed values slightly below the criteria established for a good fit (0.86 and 0.85, respectively). The factor loads of the items in the expected factors were satisfactory. In terms of internal consistency, ordinal alpha coefficients were high (> 0.80) for the total PAIS score and for the seven domains, except for Domain I. Health care orientation, for which the alpha coefficient was 0.70.Convergent validity showed that more than half of the correlations (64%) between the PAIS and the eight domains of the SF‐36 were moderate or strong. All correlations were positive and in the expected direction (higher psychosocial adjustment to illness was associated with better health‐related quality of life).

Conclusions: The psychometric analysis results showed that the Spanish version of the PAIS‐SR for family carers presents adequate indicators of reliability, internal and external validity, and is structured according to the seven‐domain model proposed by the original author of the instrument.

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Multidisciplinary movement disorders clinical daycare, customized care for Parkinson patients

Camelia Bogaert (Gent, Belgium), Christiaan Van Der Linden (Ghent, Belgium)

Objective: The aim is to evaluate the patient‐perceived usefulness of the multidisciplinary movement disorders clinical daycare in the approach of somatic and non‐somatic needs in patients with movement disorders, e.g. with Parkinson's disease (PD).

Background: Despite optimal medical guidance, PD patients become progressively disabled, with profound impact on their quality of life. There is increasing evidence that effective care should involve a multidisciplinary team of healthcare professionals.

Methods: The clinical daycare started in 2016. With approval of the Ethics Comity we created a 8 items questionnaire with scaled answer possibilities. We included 80 PD patients (Montreal Cognitive Assessment = 25; n = 60 with Deep Brain Stimulation, DBS). To avoid carry over and response shift effects in this survey each patient was asked to fill in the questionnaire only once, following the first visit on the daycare.

Results: 86 % of the PD patients perceived the daycare as beneficial. They considered multidisciplinarity as an added value. 74 % of the patients with DBS found it preferable to undergo neurostimulation adjustments on the daycare when compared to ambulatory setting.

Conclusions: According to our 3 year experience, multidisciplinary care approach in a clinical daycare is considered by PD patients as beneficial. Our future objective is to continue this project, try to quantify long term effects and retention of the reported benefits. We also intend to work on the hypothesis that for non – end stage PD patients multidisciplinary clinical daycare is superior to standard care i. e. hospital admissions.

References: M.A. van der Marck, J.G. Kalf, I.H.W.M. Sturkenboom, M.J. Nijkrake, M. Munneke, B.R. Bloem, Multidisciplinary care for patients with Parkinson's disease, Parkinsonism and Rel. Dis., 2009, 219 – 223.

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Quality of Life of Patients Living with Parkinson's Disease in Dakar‐Senegal

Maouly Fall (Dakar, Senegal), Mariane Sarr (Dakar, Senegal)

Objective: The objective is to assess the quality of life of patients living with Parkinson's disease in a resource‐limited country where the only therapeutic options remain medical and oral.

Background: Parkinson's disease is a neurodegenerative disease with an incidence generally between 10 and 50/100 000 people per year and its prevalence between 100 and 300/100 000 people. In Africa, the problem remains unresolved due to the therapeutic gap linked to the inaccessibility of the latest generation treatments and surgical treatments. This therapeutic gap affects the quality of life of patients.

Methods: This is a descriptive and cross‐sectional prospective study on the quality of life of patients living with Parkinson's disease in Dakar from 01 February 2017 to 31 August 2018. The data were collected with the help of a questionnaire. The MDS‐UPRS III score, the Schwab and England scale, the apathy inventory and the Beck Depression Inventory were used.

Results: Twenty‐three cases were collected with male predominance (sex ratio 1.8). The average age was 63 with extremes ranging from 46 to 81 years old. Seven patients were under 55 years old. At the professional level, three of the 10 cases that were active at the time of diagnosis, 3 had to stop work and 4 faced a change of position. At the clinic, the akineto‐rigid and shaking form was predominantly 95.6%. 7 patients reported dysarthria and 10 disorders of writing. The MDS‐UPDRS score ranged between 21 and 87. According to SCHAWB and ENGLAND's daily activity scale, 34.8% of patients had 100%, 17.4% of patients had a score of 80 to 90%, 30.4% of patients had a score of between 40 and 60%, 17.4% of patients had a score between 20 and 40%. Most of our patients were on dopamine plus or minus an older generation dopamine agonist. The evolution was favorable at 52%, stationary at 39% and unfavorable at 9%.

Conclusions: The quality of life of patients living with Parkinson's disease depends largely on non‐motor signs that need to be diagnosed early and well managed, especially in resource‐limited settings where access to treatment is still a major problem.

References: ‐ Von Campenhausen S, Bornschein B, Wick R, Botzel K, Sampaio C, Poewe W, et al. Prevalence and incidence of Parkinson's disease in Europe. Eur Neuropsychopharmacol 2005; 15(4): 473‐490.‐ Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinson's disease: a systematic review and meta‐analysis. Mov Disord 2014; 29(13): 1583‐1590‐ Reichmann H, Schneider C, Lohle M. Non motor features of Parkinson's disease:Depression and dementia. Parkinsonism Relat Disord. Dec 2009; 15 Suppl 3: S87‐92.‐ Haudhuri KR, Odin P. The challenge of non‐motor symptoms in Parkinson's disease. Prog Brain Res. 2010; 184: 325‐41‐ Chaudhuri K R, Martinez‐Martin P, Schapira A H et al. International multicenter pilot study of the first comprehensive self completed no motor symptoms questionnaire for Parkinson's disease. Movement Disorders 2006; 21: 916‐23‐ Daniel D. Truong A, Roongroj B, Wolters E. Management of non‐motor symptoms in advanced Parkinson disease. Journal of the Neurological Sciences 2008; 266: 216‐28.

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Optimising resources and systems of support in the community for people with PD and family carers: A multisectoral approach

Mari Carmen Portillo (Southampton, United Kingdom), Claire Reidy (Southampton, United Kingdom), Helen Roberts (Southampton, United Kingdom)

Objective: To develop understanding of available community resources and systems of support for family carers of people with PD, and discuss strategies that could foster multisectoral action and approximate interests of stakeholders, professionals, voluntary groups, patients and families.

Background: The impact of PD on patients' and family‐carers' quality of life and daily functioning is well reported. Sustainable person centred approaches in the community are essential to design and implement care pathways, integrating a parallel system of support for people living with PD.

Methods: This is the exploratory stage of a feasibility trial in 4 European countries (Denmark, Norway, Spain, UK). For this stage UK data were collected through semi‐structured interviews, networks mapping and sociodemographic forms with 10 family carers of people with PD and 11 stakeholders involved in strategic roles related to PD care. With a special interest in less advantaged areas in UK we focused on available community resources and systems of support for PD and knowledge, attitudes towards them; and roles, working relationships, partnerships and tensions between sectors for the promotion of positive living with PD. Thematic analysis of the interviews took place.

Results: Carers had a mean age and caring experience of 60/12.71 years respectively. Their caring experience and support needs were discussed and strategies to improve care through navigation of social prescribing and better links to and across services. Stakeholders had roles as researchers, Chairs of community networking groups and local PD groups, and commissioners at a national level. They highlighted the need for changing care models encouraging organisations to share best practice, working with carers and people with PD to change services and build capacity. The poor support or cooperation from both health and social care services emerged and the lack of centralised/national priorities in the provision of Parkinson's care.

Conclusions: This project represents a step forward in a strategic research agenda, in relation to positive living with PD, optimisation of community resources, and implementation and evaluation of multisectoral action. The next step of the project, the feasibility trial and testing of a multisectoral care pathway across Europe, will benefit different sectors by learning from ‘good practice’ across European countries.

References: Navarta‐Sanchez MV, Senosiain Garcia JM, Riverol M, Ursua Sesma ME, Diaz de Cerio Ayesa S, Anaut Bravo S, et al. Factors influencing psychosocial adjustment and quality of life in Parkinson patients and informal caregivers. Qual Life Res 2016; 25: 1959‐1968. DOI: http://10.1007/s11136-015-1220-3.Nolte E, Knai C, Saltman RB. Assessing Chronic Disease Management in European Health Systems. Concepts and Approaches World Health Organisation, on Behalf of the European Observatory on Health Systems and Policies 2014. http://www.euro.who.int/en/publications/abstracts/assessing-chronic-disease-management-in-european-health-systems-concepts-and-approaches-2014/2015 (accessed 27 September 2019). Peel C, Thomas S, Worth P. Developing an integrated care pathway: the process and its application to neurological conditions. Br J Neurosc Nurs 2013; 9. https://doi.org/10.12968/bjnn.2013.9.6.292World Health Organisation Regional office for Europe. Noncommunicable

diseases prevention and control in the South‐easter Europe Health Network. An analysis of intersectoral collaboration. 2012. http://www.euro.who.int/en/publications/abstracts/noncommunicable-diseases-prevention-and-control-in-the-south-eastern-europe-health-network.-an-analysis-of-intersectoral-collaboration-2012 (accessed 27 September 2019).

35

Age and motor experiences of daily living at surgery predict handicap reduction after 5 years of DBS‐STN in Parkinson's disease

Daniela Silva (Lisbon, Portugal), Margherita Fabbri (Lisbon, Portugal), Leonor Guedes (Lisbon, Portugal), Ana Caldas (Lisbon, Portugal), Patrícia Lobo (Lisbon, Portugal), Begoña Cattoni (Lisbon, Portugal), Herculano Carvalho (Lisbon, Portugal), António Ferreira (Lisbon, Portugal), Mario Rosa (Lisboa, Portugal), Joaquim Ferreira (Torres Vedras, Portugal), Miguel Coelho (Oeiras, Portugal)

Objective: To characterize the handicap after 4.8 years of DBS‐STN and to compare with pre‐surgery data.

Background: The London Handicap Scale (LHS) was studied in PD in different disease stages. Its sensitivity to identify the handicap determinants was demonstrated, which makes it a good measure of perceived‐health status in PD.

Methods: 33 PD patients submitted to DBS‐STN were evaluated after a mean of 4.8 years of surgery in 4 conditions (stimOFF/medOFF, stimON/medOFF, stimOFF/medON, stimON/medON), using MDS‐UPDRS, HY and S&E. Nonmotor symptoms (NMSS, NPI, MMSE, GDS), QoL (PDQ‐8, EQ‐5D) and handicap (LHS: maximum handicap=0 and minimum handicap=1) were also evaluated. Pre‐surgery data were collected.

Results: Mean age and age at DBS were 64.3(±9.9) and 59.4(±9.6) years, respectively. Mean LHS score after 4.8 years of DBS‐STN was 0.707(±0.207) and the most affected domains were Occupation, Mobility and Social Integration. Functional independence (S&E)(r=0.562), gait assistance (r=‐0.600) and depression (GDS)(r=‐0.491)(all p<0.05) were the post‐DBS independent handicap predictors (adjusted R2=0.600; p=0.010). LHS was evaluated before and 4.8 years after surgery in 18 of the 33 patients. Handicap significantly improved after DBS ??LHS 0.213(±0.185); p=0.002)?. The improvement correlated with age at disease onset, age and UPDRS‐II (med on) at DBS (r=‐0.598, r=‐0.473 and r=‐0.556 respectively; p<0.05). Age and UPDRS‐II at DBS were independent predictors of ?LHS (adjusted R2=0.552; p=0.025), and also of post‐DBS LHS (adjusted R2=0.465; p=0.022).

Conclusions: PD patients submitted to DBS‐STN were only mild handicapped 5 years after surgery, which was determined by functional and gait independency, and depression. The affected subdomains were Occupation, Mobility and Social integration. Handicap improvement persisted after 5 years of surgery, and its main determinants were age at DBS and motor experiences of daily living “on” medication before surgery. LHS seems to be an instrument sensitive to change in health status of these patients.

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Passive monitored daily motor behavior significantly relates to quality of life in individuals with early Parkinson's disease

Alessandra Thomann (Basel, Switzerland), Kirsten Taylor (Basel, Switzerland), Florian Lipsmeier (Basel, Switzerland), Ekaterina Volkova‐Volkmar (Basel, Switzerland), Ron Postuma (Montreal, QC, Canada), Wei‐Yi Cheng (New York, United States), Ben Van Lier (Basel, Switzerland), Dylan Trundell (Welwyn Garden City, United Kingdom), Wagner Zago (South San Francisco, United States), Anne Boulay (Basel, Switzerland), Gennaro Pagano (Basel, Switzerland), Christian Gossens (Basel, Switzerland), Michael Lindemann (Basel, Switzerland)

Objective: The purpose of this study was to investigate whether passively acquired measures of gait (via smartphone) and gestures (via smartwatch) are associated with quality of life (QoL; PDQ‐39) and health‐state (EQ‐5D‐5L) in early Parkinson's disease (PD).

Background: The severity of motor impairment among individuals with Parkinson's disease (PD) impacts their perceived QoL. Smartphone‐ and smartwatch‐based sensors appear to represent a reliable and valid means to estimate motor impairment in daily life.

Methods: Data were collected from 248 individuals with early PD (<2y) participating in a Phase II study of prasinezumab (PASADENA). Two‐week averaged sensor data were compared to QoL and health‐state using regression analysis and Spearman's rank order correlations.

Results: Gesture data were related to PDQ‐39 communication and mobility scores and all EQ‐5D‐5L domains. Gait features predicted mobility and bodily discomfort scores (PDQ‐39); self‐care, usual activities, anxiety/depression, and pain/discomfort (EQ‐5D‐5L).

Conclusions: Passively acquired sensor data from individuals with PDs daily lives were related to self‐reported QoL and health status. These findings may inform future endeavors to develop digital outcome scores that assess meaningful, QoL‐affecting impairment in motor function.

Rating scales

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Passively measuring motor behavior in daily life: preliminary reliability and validity in individuals recently diagnosed with Parkinson's disease

Florian Lipsmeier (Basel, Switzerland), Kirsten Taylor (Basel, Switzerland), Alessandra Thomann (Basel, Switzerland), Ron Postuma (Montreal, QC, Canada), Wei‐Yi Cheng (New York, United States), Ben Van Lier (Basel, Switzerland), Ekaterina Volkova‐Volkmar (Basel, Switzerland), Dylan Trundell (Welwyn Garden City, United Kingdom), Wagner Zago (South San Francisco, United States), Anne Boulay (Basel, Switzerland), Gennaro Pagano (Basel, Switzerland), Christian Gossens (Basel, Switzerland), Michael Lindemann (Basel, Switzerland)

Objective: The purpose of this study was to determine the reliability and clinical validity of smartphone‐ and smartwatch‐based, passively acquired measures of motor behavior in daily life of individuals with recently diagnosed Parkinson's disease (PD).

Background: Motor functioning in daily life is the most ecologically valid reflection of motor disease severity, but is difficult to quantify objectively. Smartphone‐ and smartwatch‐based sensors may represent a passive and objective means to this aim.

Methods: Data from 248 individuals with early PD (<2y) in a Phase II study (PASADENA) were analyzed. Two‐week averaged sensor data were compared to MDS‐UPDRS scores (Mann‐Whitney tests, Spearman's rank order correlations). ICC were calculated on consecutive intervals.

Results: Strong evidence of test‐retest reliability was demonstrated (ICC>.7). Arm gesture features significantly correlated with MDS‐UPDRS total, bradykinesia, rigidity, and apathy scores. Measures of gait were related to bradykinesia, gait, and self‐reported motor and posture problems.

Conclusions: These findings provide support for the reliability and validity of (passively) monitored daily motor behavior with the Roche PD Mobile Application v2; which is notable in the context of the overall low levels of impairment in this PD population.

Rehabilitation

37

Impacts of classical music and dancing on cognitive functions in Parkinson's disease

Dilyora Akmaljonova (Tashkent, Uzbekistan), Shokhijakhon Shokhimardonov (Tashkent, Uzbekistan), Marhamat Yakubova (Tashkent, Uzbekistan)

Objective: To study changes in the cognitive plan among patients with Parkinson's disease after conducting dance classes and listening to classical music based on rehabilitation therapy under the TMA program, evaluate the dynamics of changes in such cognitive functions, memory, speech, attention, etc. according to MMSE and MoCa rating scales.

Background: In the modern world, Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease ‐ about 120 cases per 100 thousand people. In the complex treatment of Parkinson's disease, in addition to drugs (including the “gold standard” of treatment ‐ levodopa), speech therapy, neuropsychological support, physical activity, competent dietary support, a variety of non‐pharmacological methods and technologies occupy an important place rehabilitation.

Methods: In the modern world, Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease ‐ about 120 cases per 100 thousand people. In the complex treatment of Parkinson's disease, in addition to drugs (including the “gold standard” of treatment ‐ levodopa), speech therapy, neuropsychological support, physical activity, competent dietary support, a variety of non‐pharmacological methods and technologies occupy an important place rehabilitation.

Results: Comparison of the results showed that the cognitive functions of patients such as verbal training (= 28%), delay (= 28%), recall delay (= 20%), memory capacity for verbal material (= 12%) improved in relation to the control group (p <0.05).

Conclusions: Rehabilitation with the help of dance lessons and classical music have a clear benefit from psychological symptoms, preservation and optimization of cognitive function. Long‐term studies are necessary to confirm the persistence of these effects.

References: Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–386. Tolosa E, Compta Y, Gaig C. The premotor phase of Parkinson's disease. Parkinsonism Relat Disord. 2007;13 Suppl:S2–S7. Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL. The effectiveness of exercise interventions for people with Parkinson's disease: a systematic review and meta‐analysis. Mov Disord. 2008;23(5):631–640.

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Withdrawn by Author

39

Comparative evaluation of the effectiveness of group cognitive rehabilitation and relaxation therapy in patients with Parkinson's disease

Shakhnoza Kuzieva (Tashkent, Uzbekistan), Shaimardan Khudjanov (Tashkent, Uzbekistan)

Objective: Compare the effectiveness of group cognitive rehabilitation and relaxation therapy in patients with Parkinson's disease (PD).

Background: Today there are a number of methods among non‐pharmacological approaches for the prevention and compensation of cognitive impairment in Parkinson's disease and cognitive rehabilitation (CR) is one of them. The main objective of cognitive rehabilitation can safely be considered a delay in the onset of cognitive changes. Due to the frequent loss of cognitive function in PD, such as impaired executive function, attention and working memory, work on therapeutic strategies for their treatment is extremely important.

Methods: We examined 20 patients with Parkinson's disease and conducted a prospective, single‐blind, randomized clinical trial. Participants passed tests to evaluate cognitive function to assess the presence of mild cognitive impairment or dementia in Parkinson's disease. All patients were divided into two groups by the group of cognitive rehabilitation (CRG) and relaxation therapy group (RTG) in random order. CRG participants (n = 12) trained cognitive functions in the perspective of household life. This group focused on strategies for restoring, compensating, and optimizing cognitive brain function. Patients of the second group (n = 8) also performed home training. They underwent music therapy and art therapy. All trainings were 2 times a week for 10 weeks.

Results: The results of the study of the obtained statistical data (p = 0.05) showed a significant improvement in CRG demonstrated in verbal learning (by = 28%), retention (by = 28%), delayed recall (by = 20%), memory capacity for verbal material (by=12%). There were significant improvements in the WG that were demonstrated in verbal learning (by = 36%) deferred recall (by = 40%), the amount of memory for verbal material (by = 12%), and the total amount of recall in non‐verbal memory (by = 36%).

Conclusions: Based on the results obtained, it can be concluded that CR does not have a specific effect on short‐term memory performance in patients with PD. These requests require further research in the long term because other types of interventions may also be effective in relation to the cognitive functions of patients with PD.

References: Therapeutic Advances in Neurological Disorders. 2016, 9(3), 153‐164. DOI: http://10.1177/1756285616628765. ISSN 1756‐2856. Dostupné také z: http://journals.sagepub.com/doi/10.1177/1756285616628765 HINDLE, John V., Tamlyn J. WATERMEYER, Julie ROBERTS, Andrew BRAND, Zoe HOARE, Anthony MARTYR a Linda CLARE. Goal‐orientated cognitive rehabilitation for dementias associated with Parkinson's disease—A pilot randomised controlled trial. International Journal of Geriatric Psychiatry. 2018, 33(5), 718‐728. DOI: http://10.1002/gps.4845. ISSN 08856230. Dostupné také z: http://doi.wiley.com/10.1002/gps.4845

40

Assessment of gait disorders in Parkinson's disease by video analysis and the rehabilitation

Anastasiia Kuzmina (Moscow, Russia), Natalia Amosova (Moscow, Russia), Irina Smolentseva (Moscow, Russia)

Objective: To develop effective rehabilitation strategies to improve gait in Parkinson's disease (PD).

Background: Gait disorders are significant motor disorder in PD patients. There are postural and cognitive impairment, phenomenon of freezing in the later stages, which often leads to disability.

Methods: 298 patients were examined (178 (59.7%) men and 120 (40.3%) women). The study included patients with II and III stages of Hoenh and Yahr (179 (60%)‐ stage II, 119 (40%) ‐stage III). Gait disorders were assessed by video analysis of movements in 57 patients. Brain perfusion was assessed by SPECT by Siemens after intravenous administration of the drug teoxim‐TS‐99m with 700 MBC activity in 39 patients with gait disorders (20 men and 19 women, average age – 59 y.o.) and 10 healthy volunteers (5 women and 3 men, average age – 59 y.o.) The obtained data were processed according to the Neurogam program. The rehabilitation program consisted of aerobic training on a treadmill, Nordic walking, virtual reality technology, gait training. Rehabilitation was carried out on an outpatient basis for 3 months.

Results: Method of video analysis of movements in PD patients revealed reliable change indices walk in the form of reduced step length, increased double support and step width, speed reduction transfer legs, frequency of steps per minute and step speed. According SPECT in patients with PD were identified hypoperfusion of the left frontal lobe in 55% of patients, the right frontal lobe in 40%, the left parietal lobe — 35%, the right parietal lobe — 55%, the left temporal lobe in 40%, right temporal lobe in 25%. The change in the walking pattern correlated mostly with the frontal lobes. After 3 months of rehabilitation significantly (p<0.05) revealed an increase in the length of the step when gait at a fast pace, increasing the frequency of steps per minute, the rate of transfer of the leg and the overall gait speed. The frequency of congestions and their severity significantly decreased after basic rehabilitation according to the results of the FOG‐q questionnaire.

Conclusions: The application of the developed rehabilitation program allowed to significantly improve the basic parameters of gait, reduce the frequency and severity of freezing.

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Cognitive and psychiatric symptoms are associated with walking difficulties in mild Parkinson's disease

Beata Lindholm (Malmo, Sweden), Christina Brogardh (Lund, Sweden), Peter Hagell (Kristianstad, Sweden), Christer Nilsson (Lund, Sweden)

Objective: To investigate the association of different aspects of cognitive impairment, depression and anxiety with walking difficulties in daily life in persons with mild Parkinson's disease (PD).

Background: Walking difficulties in daily life are common among persons with PD and may cause falls and near falls, limitations in activity, restrictions in participation and decrease in quality of life. Motor symptoms are often cited as a major reason for these difficulties while the association with cognitive and psychiatric symptoms is still poorly explored.

Methods: The study included cross‐sectional data from 73 persons with PD that visited a neurology outpatient clinic during 2012‐2017. Mean (SD) age was 69 (8.9) years, mean (SD) disease duration was 8 (4.3) years and mean (SD) “on” phase motor symptoms (Unified PD Rating Scale, UPDRS, part III) and cognition (Mini Mental State Examination, MMSE) were 16.4 (9.9) and 27.3 (2.6), respectively. Walking difficulties in daily life (the dependent variable) was investigated with the generic Walk‐12 (Walk‐12G). Multiple linear regression analysis (controlling for age and motor symptoms) included the following independent variables: cognition (MMSE), memory (Alzheimer's Disease Assessment Scale, ADAS, cognitive subscale), cognitive perception speed (A Quick Test of Cognitive Speed, AQT, part I‐III) frontal lobe/executive impairment (Frontal Assessment Battery, FAB) and depression and anxiety (Hospital Anxiety and Depression Scale, HADS).

Results: The median Walk‐12G scores was 11.5 (q1‐q3, 5.5‐25.5). Four significant independent variables were identified explaining 17% of the variance in the Walk‐12G scores. The strongest associated factor to walking difficulties in daily life was cognitive perception speed (AQT part I) (explaining 6%) followed by anxiety (5%), cognitive perception speed (AQT part II) (3%) and frontal lobe/executive impairment (3%).

Conclusions: Cognitive and psychiatric symptoms are associated with walking difficulties in persons with mild PD. By targeting cognitive perception speed, anxiety and frontal lobe/executive impairments in PD rehabilitation walking ability in daily life may improve.

Stem Cells

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Human induced pluripotent stem cells (iPSCs) as a model for the study of neural development in Parkinson's disease patients carrying GBA mutation (variant p.E326K)

Massimo Marano (Rome, Italy), Eris Bidollari (San Giovanni Rotondo, Italy), Francesco Motolese (Roma, Italy), Mariagrazia Rossi (Rome, Italy), Federica Consoli (San Giovanni Rotondo, Italy), Alessandro De Luca (San Giovanni Rotondo, Italy), Vincenzo Di Lazzaro (Rome, Italy), Angelo Vescovi (San Giovanni Rotondo, Italy), Jessica Rosati (San Giovanni Rotondo, Italy)

Objective: To study in vitro neural development of human induced pluripotent stem cells (iPSCs) [1] derived from fibroblasts of Parkinson's disease (PD) patients carrying glucocerebrosidase gene (GBA) mutation.

Background: iPSCs technology allows generating in vitro models that accurately reflect the human disease, through a source of patient's specific cells (i.e. fibroblasts) [2]. Mutations of the GBA gene are recognized as the most common risk factor for PD [3].

Methods: Dermal fibroblast derived from two PD patients carrying GBA mutation (variant p.E326K) [4] and two healthy donors were reprogrammed into iPSCs through virus‐free and feeder‐free protocol. All iPSCs clones, showing a uniform flat morphology, were characterized for their pluripotency, both in vitro through embryoid bodies formation and in vivo through teratoma formation assay. A new protocol was optimized to obtain iPSCs derived Neural Stem Cells (NSCs) able to spontaneously differentiate in neural cells such as astrocytes, oligodendrocytes and neurons.

Results: We successfully reprogrammed the fibroblasts into iPSCs. Neural stem cells were obtained from iPSCs lines. We analyzed these cell lines at morphological and molecular level to underline functional and biochemical differences possibly related to the mutation.

Conclusions: NSCs were obtained from two PD patients carrying GBA mutations and two healthy donors. These "induced" Neural Stem Cells had the same properties of brain derived NSCs and could differentiate in all of three neural lineages (neurons, astroglia and oligodendrocytes). Disease specific stem cells offer the unprecedented opportunity to study in vitro tissue formation and pave the way for the development of molecules reverting pathological phenotype. In this regard, since GBA mutations impair endolysosomal trafficking, likely favoring alpha‐synuclein accumulation, iPSCs could be used as models to better understand GBA mutations role in PD and to study targeted treatments aimed at counteracting disease progression [5].

References: 1. Rosati J, Ferrari D, Altieri F, et al. Establishment of stable iPS‐derived human neural stem cell lines suitable for cell therapies. Cell Death Dis. 2018 Sep 17;9(10):937. 2. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ. Disease‐specific induced pluripotent stem cells. Cell. 2008 Sep 5;134(5):877‐86. 3. Riboldi, G. M., & Di Fonzo, A. B. (2019). GBA, Gaucher Disease, and Parkinson's Disease: From Genetic to Clinic to New Therapeutic Approaches. Cells, 8(4), 364. 4. Berge‐Seidl V, Pihlstrøm L, Maple‐Grødem J, et al. The GBA variant E326K is associated with Parkinson's disease and explains a genome‐wide association signal. Neurosci Lett. 2017 Sep 29;658:48‐525.Sidransky, E., & Lopez, G. (2012). The link between the GBA gene and parkinsonism. The Lancet. Neurology, 11(11), 986–998. doi:10.1016/S1474‐4422(12)70190‐4

Surgical Therapy

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The Method of Simultaneous Implantation of 4 Electrodes for the Control of Motor Symptoms of Parkinson's Disease by DBS

Vladimir Alexeyevets (Minsk, Belarus), Anna Bunyak (Minsk, Belarus)

Objective: To increase the efficiency DBS for PD control by the method of simultaneous implantation 4 electrodes in STN and GPI.

Background: Introduction In the RSPC Neurology and Neurosurgery, stereotactic surgical treatment of patients with Parkinson's disease (PD) using DBS method since 2011 and currently 52 patients are under observation. It was noted that among patients with early non‐disabling drug dyskinesia, several years after the implantation of the electrodes in STN, dyskinesia acquired a disabling nature and were poorly controlled by neurostimulation and dose adjustment of antiparkinsonian therapy. Two such patients, 3 years after the implantation of the electrodes in the STN, re‐implanted the electrodes in GPI in order to control severe dyskinesia.

Methods: Before surgery, all patients were evaluated using the unified Parkinson's disease rating scale (UPDRS), Schwab & England daily activity scale, Mental Health Assessment Scale (MMSE), late‐stage depression screening scale GDS‐15, quality of life questionnaire Parkinson's disease patients (PDQ‐39).Electrodes, extension lines, and 16‐channel Activa PC / RC stimulator were used. Four or two electrodes were implanted through two bore holes.

Results: In four patients, the technique of simultaneous implantation of 4 electrodes (one pair in STN, the other pair in GPI) with the connection to one stimulator was used, while only one pair of electrodes could be active. Patients with four implanted electrodes were programmed with active contacts on the electrodes in STN. A pair of electrodes implanted in the GPI remained inactive and constituted a therapeutic reserve for disease progression and increased hyperkinesis. Electrical control showed the operability of all contacts from ‐4 electrodes and the ability to programmatically turn on the electrodes in pairs (either a STN pair or a GPI pair) by reprogramming a neurostimulator. One patient, due to severe dyskinesias, was reprogrammed to a pair of electrodes implanted with GPI with an increase in the dose of antiparkinsonian drugs without significant dynamics on the UPDRS and Schwab and England scales.

Conclusions: The simultaneous implantation of four electrodes in STN and GPI reduces the number of surgical interventions, improves the correction of motor manifestations of the disease, and increases the efficiency of DBS.

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Effect of Subthalamic Nucleus Deep Brain Stimulation on cognitive outcome in Parkinson's Disease: A Longitudinal Study

Roberta Biundo (Venice‐Lido, Italy), Luca Weis (Venice‐Lido, Italy), Asia Di Liberto (Padua, Italy), Elisabetta Gasparoli (Venezia Lido, Italy), Manuela Pilleri (Vicenza, Italy), Andrea Landi (Padua, Italy), Angelo Antonini (Padua, Italy)

Objective: To investigate the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) on different cognitive domains behavioral and clinical features in Parkinson's disease.

Background: STN‐DBS is an effective treatment of PD motor disabilities. Given STN functional division and its small size, the stimulation applied to the STN dorsolateral sensorimotor part can perhaps spread to adjacent regions involved in cognition, leading to modifications of cognitive functions.

Methods: Twenty‐eight PD patients (10 females and 18 males) who underwent STN‐DBS, were recruited at 3 Italian centers (Venice, Milan, Vicenza). They underwent a comprehensive clinical‐neuropsychological assessment prior to surgery and within a year follow‐up. Presence of apathy, depression, impulsivity, quality of life, anxiety and impulsive‐compulsive disorders was also investigated. Wilcoxon test was used to run within‐group comparisons. Cognitive tests ‘scores have been adjusted according to norms of age and education, and then transformed into z scores. Failure was considered when z score value was below 1.5, and the its frequency was provided. McNemar test has been applied to analyze differences among the % of failure.

Results: Within group‐comparison (pre vs. post STN‐DBS) showed a significant motor symptoms reduction [MDS‐UPDRS‐III: 27.1 (15.7) vs. 16.7 (10.3); p=0.004] paralleled by a significant decrease of the levodopa equivalent daily dose [1178.3 (486.2) vs. 538.9 (538.9) respectively; p=0.0001]. Moreover, at follow‐up evaluation, PD performance decreased on prose memory (immediate recall), semantic and phonemic fluency tasks significantly (p=0.002; p=0.016 and p=0.037, respectively). Further, patients were statistically significant less depressed, there was a tendency to be less anxious and showed less impulsive‐compulsive behaviors as compared to the baseline (p=0.0273, p=0.084 and p=0.0625, respectively).

Conclusions: STN‐DBS improves motor symptoms but was associated with worse cognitive performance on the immediate memory and verbal fluency recall. These defects can be possibly due to STN‐DBS per sé (via cortical microlesion at the entry point (DLPFC) or indirectly via STN) or be secondary to PD‐degenerative processes. In this regard, the dorsolateral‐striatum cognitive pathway is altered during the disease and is well‐known to be crucial for the executive functions. Overall evidence shows a relative cognitive safety of STN‐DBS using a wait‐listed PD control group. However, the underlying pathophysiology of cognitive changes post‐DBS and the identification of pathways underpinning declines will require further investigations.

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Objectification of changes in voluntary postural control in PD patients during Deep Brain Stimulation

Anna Buniak (Minsk, Belarus), Irina Maryenko (Minsk, Belarus), Vladimir Alexeyevets (Minsk, Belarus)

Objective: In PD patient the voluntary postural control (VPC) is impaired. Modern diagnostics of violations of VPC is based on the construction of a graph of center of pressure (CP) movement in time during voluntary movement with a deviation of the patient's CP to a given point and speed of returning to the starting position.

Background: To evaluate the changes of VPC during DBS in PD patients.

Methods: We examined 60 (39 with tremor, 21 with bradykinesia‐rigidity) PD patients. 31 male and 29 female, mean age 56,5±6,9 years, 41 patients–II stage of H&Y, 19–III. 48 patient with DBS STN, 9 ‐ DBS GPi, 3 ‐ DBS Vim. We used computer stabiloanalizator "Stabilan ‐ 01‐2" with biofeedback. The objective of the test was to hold the moving marker by deviation of the body. The results are presented as a diagram deployed in the directions of testing and indicators of statokineziogramm. Stability parameters were assessed: deviation forward (DF), mm, backward (DB), mm, to the sides left and right (DL, DR), mm, DF/ DB, displacement area (DA), mm2.[figure 1].

Results: Found the increase of DF (W, T=17, Z=2,817, p=0,0049), DF/ DB (W, T=31, Z=2,373, p=0,017621) a month later. Found the increase of DA (W, T=7,0, Z=2,312, p=0,020796) in a year. Changing the value of the index characterizes the increase in the stock patients sustainability in a forward direction, the balance between the increase in abnormalities forward and backward deviation of the observation period.

Conclusions: We can talk about the positive effect of the DBS on VPC in patients with PD in the form of an increase in the stability deviation in the forward direction and an increase in the balance between deviations with an increase in the DA.

References: Stabilographic studies. The user manual "Stabilan‐01‐2". ‐ Taganrog, ZAO OKB «RITM». (in Russian).

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Safety and research: LFP recordings in Parkinson's disease and infections

Lucia Feldmann (Berlin, Germany), Wolf‐Julian Neumann (Berlin, Germany), Katharina Faust (Berlin, Germany), Gerd‐Helge Schneider (Berlin, Germany), Andrea Kuehn (Berlin, Germany)

Objective: As research demand of long‐term electrophysiological recordings with post‐operatively externalized patients increases with the development of adaptive stimulation protocols (aDBS), one concern is the incidence of infections in DBS research. Here, we retrospectively analyzed all PD patients undergoing DBS in our center during the last 12 years, and compared patient groups with LFP recordings versus no LFP recording with regards to surgery‐related infection.

Background: As a major surgery‐related adverse event of DBS, infections are regularly reported in major studies [1‐7]. For the ethical justification of research with patients, the evaluation whether the incidence of infections increases with LFP recordings, is of crucial importance. To date, only one center has, to our knowledge documented that there is no increase in infection following LFP recordings in a smaller cohort [8].

Methods: We retrospectively analyzed the incidence and characteristics of infections in Parkinson's disease patients following deep brain stimulation surgery in our center from 2008‐2019 according to our database. Patients were included if there was at least one follow‐up appointment 3 months post‐OP until 1 year post‐OP.

Results: 301 PD patients received DBS surgery with externalization in our center between 2008 and 2019; 224 patients participated after informed consent in post‐operative LFP recordings (74.4%). There was no difference in the infection rates between patient groups with and without LFP recordings. In the non‐LFP group, the infection rate amounted to 1.3% (1/77) at three months and 2.6% (2/77) at 1 year after the surgical procedures, while in the LFP group 1.3% (3/224) presented with infections after 3 months, and 2.2% (5/224) after 1 year.

Conclusions: This study demonstrated in a representative and large cohort of PD patients that LFP recordings are a safe method and do not increase the risk of infection after DBS. Hence, further research in PD patients with externalized leads can be used for the development of innovative stimulation protocols and improvement of deep brain stimulation technology.

References: 1. Deep‐Brain Stimulation for Parkinson's Disease Study, G., et al., Deep‐brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. N Engl J Med, 2001. 345(13): p. 956‐63. 2. Deuschl, G., et al., A randomized trial of deep‐brain stimulation for Parkinson's disease. N Engl J Med, 2006. 355(9): p. 896‐908. 3. Follett, K.A., et al., Pallidal versus subthalamic deep‐brain stimulation for Parkinson's disease. N Engl J Med, 2010. 362(22): p. 2077‐91. 4. Odekerken, V.J., et al., Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial. Lancet Neurol, 2013. 12(1): p. 37‐44. 5. Okun, M.S., et al., Subthalamic deep brain stimulation with a constant‐current device in Parkinson's disease: an open‐label randomised controlled trial. Lancet Neurol, 2012. 11(2): p. 140‐9. 6. Timmermann, L., et al., Multiple‐source current steering in subthalamic nucleus deep brain stimulation for Parkinson's disease (the VANTAGE study): a non‐randomised, prospective, multicentre, open‐label study. Lancet Neurol, 2015. 14(7): p. 693‐701. 7. Williams, A., et al., Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson's disease (PD SURG trial): a randomised, open‐label trial. Lancet Neurol, 2010. 9(6): p. 581‐91. 8. Rosa, M., et al., Risk of Infection After Local Field Potential Recording from Externalized Deep Brain Stimulation Leads in Parkinson's Disease. World Neurosurg, 2017. 97: p. 64‐69.

27

MoCA score and education level predict DRS‐2 Total score in patients evaluated for deep brain stimulation surgery

Meghan Zorn (Salt Lake City, UT, United States), Kevin Duff (Salt Lake City, United States), John Rolston (Salt Lake City, UT, United States), Camila Aquino (Oakville, ON, Canada), James Ballard (Salt Lake City, UT, United States), Paolo Moretti (Salt Lake City, UT, United States)

Objective: To streamline the cognitive screening process of individuals considered for deep brain stimulation (DBS) surgery. We hypothesized that the Montreal Cognitive Assessment (MoCA) score is predictive of the Dementia Rating Scale‐2 (DRS‐2) score in the clinical evaluation of DBS candidates.

Background: Cognitive impairment can be one exclusionary criterion for DBS surgery, and the DRS‐2 Total score has frequently been used as an indicator of cognitive functioning for these subjects. The DRS‐2 is time‐consuming, and scores on briefer cognitive screening measures predictive of the DRS‐2 Total score could be clinically helpful.

Methods: In 46 individuals considered for DBS surgery (32 with PD, 9 with ET, 3 with dystonia, and 2 others), a stepwise multiple linear regression analysis was used to determine whether MoCA score, age, education, sex, and race were predictive of the DRS‐2 Total score.

Results: In the first step, MoCA scores significantly predicted DRS‐2 Total scores (R2 = 0.347, p < 0.001). In the second step, education significantly added to the prediction of DRS‐2 Total (R2 = 0.41, p < 0.001). None of the other variables added to this prediction. In the simplest model, adding 111 (y intercept) to the MoCA yielded a good estimate of the DRS‐2 Total score. Thus, a MoCA score of 25 would yield a DRS‐2 score of 136.

Conclusions: Such prediction equations can aid clinicians in the screening of candidates for DBS surgery. Although considering the entire clinical presentation remains important, a rapid screening tool may aid in the identification of the most likely DBS candidates.

References: Lang, A. E. and Widner, H. (2002), Deep brain stimulation for Parkinson's disease: Patient selection and evaluation. Mov. Disord., 17: S94‐S101. Massano J. and Garrett, C. Deep brain stimulation and cognitive decline in Parkinson's disease: a clinical review. Frontiers in Neurology. 2002;3:1–13.

This abstract was presented at the 2019 International Congress of Parkinson's Disease and Movement Disorders in September 2019.

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PREDISTIM: a French multi‐centric and multi‐modal longitudinal prospective cohort to predict STN DBS response in Parkinson's disease on quality of life in order to refine DBS indication

Anne‐Sophie Rolland (Paris, France), Caroline Moreau (Marcq En Baroeul, France), Stephane Thobois (Lyon, France), Alexandre Eusebio (Marseille, France), Elodie Hainque (Paris, France), Tiphaine Rouaud (Nantes Cedex 01, France), Jean‐Luc Houeto (POITIERS, France), Sophie Drapier (Rennes, France), Dominique Guehl (Bordeaux, France), David Maltete (, France), Christine Tranchant (Strasbourg, France), Caroline Giordana (Nice, France), Pierre Krystkowiak (Abu Dhabi, United Arab Emirates), Lucie Hopes (Nancy, France), Cecile Hubsch (Paris, France), Vadim Afanasiev (Paris, France), Franck Durif (Clermont‐Ferrand, France), Olivier Rascol (Toulouse, France), Jean‐Christophe Corvol (Paris, France), David Devos (Lille, France)

Objective: To determine predictive factors of quality of life, 1 and 5 years after Subthalamic Nucleus (STN) Deep Brain Stimulation (DBS) in order to refine DBS indication with multimodal parameters (clinical, radiological, biological, genetic).

Background: STN‐DBS improves quality of life (PDQ 39) with a mean of 20% at one year in patients with severe motor fluctuations. Some symptoms can worsen with STN‐DBS and early occurrence of dementia and severe axial disorders impede the benefit.

Methods: Since 2012, 17 French expert centers from the NS‐Park network have implemented a web‐based solution to prospectively collect clinical information from all PD patients' candidates to DBS. The protocol include 4 visits: at the time of inclusion (V0), at the time of the surgery (Vc), at 1 year post‐surgery (V1) and at 5 years post surgery (V5). Clinical data include demography, risk factors, medical and surgical history, general impact, motor and non‐motors symptoms, adverse event, stimulation parameters, treatments (related or not to the disease). In parallel, biological samples and a set of MRIs were performed to create a biobank and brain‐imaging bank. Inclusions ended in June 2019 and follow‐up will continue up to 2024.

Results: PREDISTIM cohort database has 702 advanced PD patients enrolled (33% of women, mean age of 60 years old). Numerous motor and non‐motor data are collected into an eCRF. A central biobank ensures the quality and conformity of all biological samples (DNA, plasma, serum, CSF). A central brain‐imaging bank harmonizes and ensure the quality of all MRIs sequences (3DT1, FLAIR, 3D T2*, 2D‐T2* GRE, T2 TSE, rsfMRI and DTI). Statistical approaches with joint latent class analyses, linear mix model analyses and machine learning will be used.

Conclusions: PREDISTIM is the largest prospective multi‐centric cohort of 702 PD patients at the stage of severe motor fluctuations from 17 PD centers. It will allow 1) to define weighted and multimodal predictors of STN DBS response on quality of life at 5 years 2) to refine new DBS inclusion criteria with a decisional tree including new parameters and 3) to offer to a large database to assess surrogate clinical, biological, radiological biomarkers of disease progression from advanced stage to late stage with dementia and severe axial disorders in order to stratify PD population for future trials on advanced disorders (dementia and severe gait disorders) contributing to the precise medicine.

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Asymmetric deep brain stimulation electrodes for Parkinson's disease: a pilot study of symptom‐tailored stimulation

Chencheng Zhang (Shanghai, Peoples Republic of China), Bomin Sun (Shanghai, China, Peoples Republic), Dianyou Li (Shanghai, China, Peoples Republic)

Objective: To evaluate the clinical efficacy and safety of unilateral STN and contralateral GPi in patients with advanced Parkinson's disease.

Background: Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus interna (GPi) are both effective in managing Parkinson's disease. As each target has its own clinical effects and risk profiles, we hypothesized that ipsilateral STN and contralateral GPi stimulation could exploit the clinical advantages of both targets for some patients, would also induce fewer stimulation related adverse effects.

Methods: We retrospectively reviewed 8 patients with idiopathic PD. Motor symptoms, non‐motor symptoms, and medication dose, were evulated before surgery and at 6‐ and 12‐month follow‐up under the following conditions: medication on and off, bilateral stimulation on and off, ipsilateral STN stimulation on.

Results: All patients showed a significant (43‐45%) improvement in motor symptoms, as measured by the UPDRS‐III while being off medication, at 6‐month and 12‐month follow‐up. At 1‐year follow‐up, 41% of levodopa equivalent daily dose was reduced, bilateral stimulation improved axial symptoms by 28.4% in the medication on condition. 3m TUG (Time‐Up Go test) improved by 41% at 6‐month follow‐up compared to baseline, which lasts for 1 year. 64% reduction was found between baseline and 1‐year follow‐up in gait and fall questionnaires. DBS treatment had no effect on non‐motor symptoms, including global cognitive function and emotional status. No adverse events other than stimulation related were observed.

Conclusions: These initial findings provide the first evidence indicating that ipsilateral STN and contralateral GPi DBS could offer an effective, personalized, and well‐tolerated, DBS treatment for certain patients with advanced PD. Long term studies are needed to verify the hypothesis.

References: Krack P, Martinez‐Fernandez R, del Alamo M, et al. Current applications and limitations of surgical treatments for movement disorders. Mov Disord 2017;32:36–52. doi:10.1002/mds.26890. Shemisa K, Hass CJ, Foote KD, et al. Unilateral deep brain stimulation surgery in Parkinson's disease improves ipsilateral symptoms regardless of laterality. Park Relat Disord 2011;17:745–8. doi:10.1016/j.parkreldis.2011.07.010