Available and future treatments for atypical parkinsonism. A systematic review

Abstract

Aims

Success in treating patients with atypical parkinsonian syndromes, namely progressive supranuclear palsy (PSP), cortico‐basal degeneration (CBD), multiple system atrophy (MSA), Parkinson's disease with dementia (PDD), and Lewy body dementia with (LBD), remains exceedingly low. The present work overviews the most influential research literature collected on MEDLINE, ISI Web of Science, Cochrane Library, and Scopus for available treatment in atypical parkinsonisms without time restriction.

Discussion

Transdermal rotigotine, autologous mesenchymal stem cells, tideglusib, and coenzyme Q10 along with donepezil, rivastigmine, memantine, and the deep brain stimulation have shown some benefits in alleviating symptoms in APS. Moreover, many new clinical trials are ongoing testing microtubule stabilizer, antitau monoclonal antibody, tau acetylation inhibition, cell replacement, selective serotonin reuptake inhibitor, active immunization, inhibition of toxic α‐synuclein oligomers formation, and inhibition of microglia.

Conclusion

A detailed knowledge of the pathological mechanism underlying the disorders is needed, and disease‐modifying therapies are required to offer better therapeutic options to physician and caregivers of APS patients.

1. INTRODUCTION

Atypical parkinsonian syndromes (APS) include progressive supranuclear palsy (PSP), cortico‐basal degeneration (CBD), multiple system atrophy (MSA), Parkinson's disease with dementia (PDD), and Lewy body dementia (LBD).1, 2, 3, 4, 5 Up to date, the therapeutic choices are still very restricted due to the lack of a clear etiology and because of overlapping clinicopathological correlations. Also, therapeutic attempts with levodopa (L‐dopa) and other dopaminergic agents in APS have not been as successful as they are in Parkinson's disease.6, 7 Several options have been recently investigated to find symptomatic treatment for atypical parkinsonisms both pharmacological (donepezil, rivastigmine, transdermal rotigotine, rasagiline, immunoglobulin, autologous mesenchymal stem cells, davunetide, lithium, and tideglusib)8, 9, 10 and surgical attempts such as pedunculopontine nucleus (PPN), deep brain stimulation (DBS) alone, or in association with DBS of the globus pallidus internus (Gpi).11 New clinical trials are implemented to test other alternative mechanisms to tackle the disease, such as antitau monoclonal antibody, tau acetylation inhibition, cell replacement, selective serotonin reuptake inhibitor, active immunization, and inhibition of toxic α‐synuclein oligomers formation.12, 13 In the current study, the latest research on the treatment options for APS is shown with a broad review of the past and the current clinical trials. The present review is structured as follows: For each APS, a clinic‐epidemiological description followed by a pharmacological section has been provided. The pharmacological section consists of a part dedicated to the current drug treatments, regarding both motor and non‐motor symptoms, and a part reserved for the ongoing clinical trials. Where appropriate, surgical approaches have been explained.

2. MATERIAL AND METHODS

Research for the review was conducted on the main medical databases (ie, MEDLINE, ISI Web of Science, Cochrane Library, and Scopus) to detect the available works on APS as a whole or each clinical syndrome without time limitation. The following keywords have been used progressive supranuclear palsy, cortico‐basal degeneration, multiple system atrophy, Parkinson's disease with dementia and Lewy body dementia, atypical parkinsonism, atypical parkinsonian syndromes, alone or in combination with therapy, treatment, or cure. To obtain extensive literature on the subject, we decide to include large trials (ie, randomized controlled trials, reviews, meta‐analyses, guidelines), as well as case reports, case‐control studies, and cohort studies. Previous seminal works and consensus criteria were followed to include patients with the diagnosis of APS.14, 15, 16, 17, 18, 19, 20

2.1. Progressive supranuclear palsy

PSP has a prevalence rate around 0.9 per 100 000 person‐years with a similar impact on women and men.21 The beginning is at about age 63, and the duration of disease is, on average, of 7 years. PSP is considered a mainly sporadic tauopathy. Few familial cases have been described, characterized by MAPT (microtubule‐associated protein tau) gene alterations.22

The clinical manifestations of PSP could be different. The 40%‐50% of cases have a clinical picture with a prevalent akinetic‐rigid syndrome, mainly affecting the axial musculature, not responsive to L‐dopa therapy. Typical symptoms are an early tendency to fall backward, and a vertical supranuclear gaze palsy (the so‐called Richardson's syndrome). From a cognitive point of view, impairment of executive functions associated with apathy, in the context of a frontal lobe syndrome, is also evident. In another 20%‐30%, the PSP onset is characterized by asymmetric parkinsonism (PSP‐P) associated with postural tremor and a moderate initial therapeutic response to L‐dopa for the first 2‐3 years.2

2.1.1. Current drug treatments for PSP

According to some case reports studies, the response to L‐dopa of the akinetic‐rigid symptoms response has a rate between 25% and 38% at a dosage of 1500 mg/day. The improvement of dopaminergic therapy is higher for the PSP–parkinsonism phenotype with a mild‐to‐moderate relief of symptoms.23 However, no information about the dosage, the precise therapy extent, and the duration of therapeutic effects had been supplied.

Mitochondrial chain complex I is dysfunctional in PSP. Coenzyme Q (10) (CoQ10) is a cofactor of respiratory chain complex I. A clinically modest improvement inside the PSP rating scale (PSPRS) and frontal assessment battery (FAB) has been determined in a double‐blind, placebo‐controlled, randomized trial administering CoQ10 for six months. An emulsion of CoQ10 had been delivered on the dose of 5 mg/kg body weight 3 times daily. CoQ10 was safe and well‐tolerated (Table 1).24

Table 1.

Synopsis of the past clinical trials for the treatment of atypical parkinsonism

Study	Syndrome	Study design	Subjects (active/placebo)	Experimental drug	Duration	Outcome measure	Dose	Administration	Results	ClinicalTrials.gov Identifier
Moretti et al (2014)	MSA‐PSP‐CBD‐LBD	Open‐label, single‐center, pilot trial	61	Rotigotine	24 mo	UPDRS III and NPI	4.9 mg on average/day	Transdermal	Significant reduction on UPDRS III and NPI scores	na
Low et al (2014)	MSA‐C, MSA‐P	Randomized, double‐blind, placebo‐controlled	50/50	Rifampicin	12 mo	UMSARS I score	600 mg/day	Oral	No changes from baseline	NCT01287221
Poewe et al (2012)	MSA	Randomized, placebo‐controlled	84/90	Rasagiline	48 wk	UMSARS total score	1 mg/day	Oral	No changes from baseline	NCT00977665
Stamelou et al (2008)	PSP	Double‐blind, randomized, placebo‐controlled, phase II trial	10/11	Coenzyme Q10	6 wk	PSPRS and FAB; change in ADP	15 mg/kg body weight/day	Liquid nanodispersion	Mild improvement in the PSPRS and FAB; increased occipital ADP	na
Nuebling et al (2016)	PSP	Randomized, double‐blind, placebo‐controlled trial	12/14	Rasagiline	12 mo	PSPRS, SEADL, MMSE, FAB	1 mg/day	Oral	No effects on primary and secondary outcomes	na
Emre et al (2004)	PPD	Randomized, double‐blind, placebo‐controlled trial	362/179	Rivastigmine	24 wk	ADAS‐Cog, CGIC	8,6 mg/day on average	Oral	Improvement in ADAS‐cog and CGIC	na
Bensimon et al (2009)	MSA‐PSP	Double‐blind, placebo‐controlled, stratified, parallel‐group trial	161/161 (MSA) 199/199 (PSP)	Riluzole	36 mo	Survival, disease progression	50‐200 mg/day	Oral	No significant effect on survival or rate of deterioration	na
Ikeda et al (2013)	LBD	Multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled	140	Donepezil	12 wk	MMSE NPI UPDRS III CIBIC‐plus NPI	3, 5, or 10 mg/day	Oral	Improvement in MMSE and CIBIC‐plus	na
McKeith et al (2000)	LBD	Randomized, double‐blind, placebo‐controlled multicentric	120	Rivastigmine	20 wk	CDR system	12 mg/day	Oral	Improvement in NPI and tests of attention, working memory, and episodic memory.	na
Emre et al (2010)	LBD	Randomized, double‐blind, placebo‐controlled trial	34/41	Memantine	24 wk	CGIC, NPI	20 mg/day	Oral	Improvement in CGIC and NPI scores	na
Lee et al (2012)	MSA‐C	Single‐center, double‐blind, randomized, placebo‐controlled	11/18	Autologous mesenchymal stem cells	12 mo	UMSARS total score and II	4 × 107/injection (100 mL)	Intra‐arterial and intravenous	Improvement in UMSARS total score and II	NCT00911365
Tolosa et al (2014)	PSP	Multinational, double‐blind, randomized, placebo‐controlled, phase II trial	60/55/31	Tideglusib	52 wk	PSPRS	600/800 mg/day	Oral	No changes from baseline	NCT01049399
Hoglinger et al (2012)	PSP	Multinational, double‐blind, randomized, placebo‐controlled, phase II trial	28/9	Tideglusib	52 wk	Progression of brain atrophy	600/800 mg/day	Oral	Reduced progression of atrophy	NCT01049399
Boxer et al (2014)	PSP	Multinational randomized, double‐blind, placebo‐controlled	156/157	Davunetide	52 wk	PSPRS and SEADL	60 mg/day	Intranasally	No changes from baseline	NCT01110720

MSA: multiple system atrophy; PSP: progressive supranuclear palsy; CBD: cortico‐basal degeneration; LBD: dementia with Lewy bodies; UPDRS: Unified Parkinson's Disease rating scale (part II and part III); NPI: neuropsychiatric inventory; UMSARS: Unified Multiple System Atrophy rating scale; PSPRS: Progressive Supranuclear Palsy rating scale; SEADL: Schwab and England Activities of Daily Living; FAB: frontal assessment battery; ADP: adenosine‐diphosphate; MMSE: Mini‐Mental State Examination; ADAS‐cog: Alzheimer's Disease Assessment Scale‐Cognitive Subscale; CGIC: Clinical Global Impression of Change Scale; CDR system: Cognitive Drug Research computerized assessment system.

Rasagiline, a monoamino oxidase B (MAO‐B) inhibitor, has been administered to 26 patients in the PROSPERA study (PROgressive Supranuclear Palsy and results of RAsagiline). In this double‐blind, placebo‐controlled trial, patients have been randomized to 1 mg/day rasagiline or placebo during a time of 1 year. The endpoints were symptoms impairment, assessed with PSPRS, and the need of L‐dopa as remedy drug. Schwab and England Activities of Daily Living (SEADL), Bernard Law Montgomery–Asberg Depression Rating Scale, Mini‐Mental State Examination (MMSE), FAB, and post‐urographic assessments had been evaluated as secondary endpoints. Rasagiline was safe (just a few adverse events like hallucinations and ventricular extrasystoles had been located). No difference was observed in SEADL, behavioral disorders, cognitive evaluations, and urographic tests.25 There were no effects on primary or secondary endpoints, probably because of the small sample size. Indeed, it has been suggested that a n = 51 would be needed if the PSP rating scale were to be used as the primary endpoint in future PSP trials26 (Table 1).

Davunetide, which has a neurotrophic activity based on growth factor leading to a stabilization of microtubule, had been administered to 313 individuals with PSP, at the dose of 30 mg davunetide twice every day for 52 months, in a multicentric, double‐blind, placebo‐controlled clinical trial. No significant results had been located on two rating scales, the PSPRS and the SEADL (Table 1).27

Tau phosphorylation is controlled to some extent by the GSK‐3β (glycogen synthase kinase‐3 beta) enzyme. Lithium, which is an inhibitor of glycogen synthase kinase‐III (GSK‐III), had been administered to 14 patients with PSP (and CBD) within a 28‐week, open‐label, non‐randomized trial. Most of the patients had been dropped away because of collateral events28 (Table 1).

Tideglusib, also a GSK‐III inhibitor, was orally administered (600 or 800 mg/day) in 142 patients with PSP in a multicentric, double‐blind, placebo‐controlled trial, for 12 months. The primary endpoint became the change from baseline to week 52 on the PSPRS scores. Tideglusib was safe, aside from a few asymptomatic, brief, and reversible growth of transaminase (mostly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of subjects, but outcomes revealed that there have not been significant improvements between the greater and the reduced dosage and comparing both dosages versus the placebo within the primary outcomes scores. In a substudy with MRI, volumetric evaluation of atrophy results highlighted lower cortical atrophy after 52‐week follow‐up just in patients assuming tideglusib (Table 1).29

Autologous bone marrow stromal mesenchymal cells (SMC) were administered into cerebral arteries of 5 PSP patients in a pilot, open‐label trial. One single administration was performed for each patient with clinical evaluation after one year. Impacts have been evaluated using the well‐known motor scales UPDRS, Hoehn and Yahr, and PSPRS. All treated patients maintained stable motor function for minimum of 6 months in a 1‐year follow‐up.30

Modification of GABAergic deficits in PSP has been investigated in a small, double‐blind, placebo‐controlled trial using zolpidem, a hypnotic non‐benzodiazepine belonging to the family of imidazopyridine, in 10 subjects which found temporary enhancements in eye moves and UPDRS scores over a period of hours.31 In a subsequent small, randomized, placebo‐controlled, investigator‐blinded trial, gabapentin, a gabaergic agent that binds voltage‐dependent calcium channels, administered for five days, found out enhancements during the inhibition of a voluntary saccade, an index of frontal inhibitory function.32 Some limitations affect these early medical studies such as the small‐size pattern and the mainly symptomatic target of remedy.

2.1.2. Ongoing medical trials in PSP

The following experimental drugs are presently under investigation for the remedy of PSP.

TPI 287: It binds to tubulin and stabilizes microtubules, leading to the inhibition of microtubule meeting/disassembly dynamics, mobile cycle arrest during the G2/M degree, and apoptosis (ClinicalTrials.Gov Identifier: NCT02133846; Table 2).

Table 2.

Synopsis of the ongoing clinical trials for the treatment of atypical parkinsonism

Experimental drug	Mechanism of action	Disease	Study design	Estimated enrollment (subjects)	Outcome measures	ClinicalTrials.gov Identifier
TPI‐287	Microtubule stabilizer	CBD, PSP	Randomized, double‐blind, placebo‐controlled	44	Maximum tolerated dose of TPI‐287; TPI‐287 levels in blood plasma and cerebrospinal fluid	NCT02133846
BMS‐986168	Antitau monoclonal antibody	PSP	Multicenter, open‐label, long‐term	48	Safety and tolerability measured by the incidence of adverse events	NCT02658916
C2N‐8E12	Antitau monoclonal antibody	PSP	Double‐blind, placebo‐controlled, single ascending dose	32	Safety and tolerability; immunogenicity as measured by antidrug antibodies developed	NCT02494024
Salsalate	Inhibiting tau acetylation	PSP	Multicenter, open‐label, Pilot Futility Clinical Trial	10	Number of patients experiencing drug‐limiting toxicity; changes in motor function, cognition, ADL, behavior	NCT02422485
Young plasma	Rejuvenation	PSP	Open‐label, Pilot Futility Clinical Trial	10	Number of patients experiencing drug‐limiting toxicity; changes in motor function, cognition, ADL, behavior	NCT02460731
Autologous mesenchymal stromal cells	Production of growth factors	PSP	Randomized, double‐blind, controlled clinical Trial	25	The incidence of adverse events; total and motor UPDRS scores, Hoehn and Yahr staging, SEADL score, CGI; SPECT/PET brain images	NCT01824121
Fluoxetine	Selective serotonin reuptake inhibitor	MSA	Double‐blind, placebo‐controlled randomized trial	87	Parts I and II of the UMSARS scale	NCT01146548
EGCG	Inhibition of toxic α‐synuclein oligomers formation	MSA	Double‐blind, randomized, placebo‐controlled parallel‐group study	92	UMSARS motor examination score; UMSARS total score	NCT02008721
AFFITOPE	Active immunization	MSA	Randomized, placebo‐controlled, parallel‐group, patient‐blind	30	Adverse events due to autoimmune reaction; immunological activity of AFFITOPE; UMSARS II, CGI	NCT02270489
AZD3241	Inhibition of microglia	MSA	Multicenter, randomized, parallel‐group study	64	Safety and tolerability of AZD3241; biomarker effects of AZD3241; pharmacokinetics of AZD3241; UMSARS	NCT02388295

MSA: multiple system atrophy; PSP: progressive supranuclear palsy; CBD: cortico‐basal degeneration.

BMS‐986168: It is a humanized IgG4 monoclonal antibody toward extracellular tau (ClinicalTrials.Gov Identifier: NCT02658916; Table 2).

C2N‐8E12: A fully human antibody focused on the tau protein found in neurofibrillary tangles within the brains of patients with tauopathies such as PSP (ClinicalTrials.Gov Identifier: NCT02494024; desk 2).

Salsalate is a non‐acetylated dimer of salicylic acid, inducing the tau acetylation inhibition (ClinicalTrials.Gov Identifier: NCT02422485; Table 2).

Young plasma transfusions: The rationale behind this treatment approach is that systemic factors present in young blood cross into the brain, where they counteract aging processes and neurodegeneration by modulating neuroinflammation, neurogenesis, and cognitive function. This approach attempts to rejuvenate the aging brain with infusions of plasma from young adults (ClinicalTrials.Gov Identifier: NCT02460731; Table 2).

Autologous mesenchymal stromal cells infusion of bone marrow mesenchymal stromal cells (MSC) has been demonstrated to reduce neuronal cell loss in neurodegenerative disorders (ClinicalTrials.Gov Identifier: NCT01824121; Table 2).

2.1.3. Surgical approach in PSP

Three patients with PSP underwent the deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN).11 Patients and caregivers reported a marked improvement of postural stability and a reduced number of falls after DBS. Overall, the patients had much better performance in daily living activities. Analysis regarding the PSPRS scores after one year reveals a noticeable difference of 26.3%. Better outcomes were found in a patient who had been additionally implanted in the globus pallidus pars interna (GPi), showing a reduction in the PSPRS score of 35.7%. The complexity of the clinico‐pathological features of PSP could explain the essential difference between clinically reported enhancement and the rating scales score. Furthermore, it ought to be considered that dystonic signs could possibly be ameliorated because of the GPi concomitant implantation. Of note, the high‐frequency stimulation might have a significant role given that the rise as much as 130 Hz has accomplished the higher results.

2.2. Cortico‐basal syndrome

Cortico‐basal syndrome (the CBD phenotype) often includes asymmetric rigid‐akinetic parkinsonism in addition to one or more cortical signs, such as motor apraxia, alien limb phenomenon, dystonia, visual agnosia, and cortical sensory loss. These signs and symptoms tend to be non‐responsive to dopaminergic therapy. A tremor, which is abnormal and unusual, may be overlapped to myoclonus.33, 34 The prevalence rate is not identified, but it is thought to be lesser than PSP or MSA, and male and female tend to be similarly affected. The course of sickness is, on average, 8 years. CBD is a tauopathy and typically is sporadic. CBD is described as extensive deposition of hyperphosphorylated tau protein (specifically, 4‐R) into the brain. The hallmark feature of CBD pathology is characteristic astrocytic plaques (tufted astrocytes) that differentiate CBD from various other 4R tauopathies such as PSP.20

2.2.1. Current drug treatments in CBD

Retrospective studies have shown minimal, if any, benefit of L‐dopa for the rigidity or bradykinesia of CBD.35, 36, 37 Intrasalivary gland botulinum toxin is helpful in treating sialorrhea while challenging dystonia, consisting of blepharospasm and apraxia of eyelid opening can be managed by intramuscular botulinum toxin.38, 39 Myoclonus could be handled with levetiracetam, a pyrrolidonic drug that acts on Ca ++ levels of neurons by reducing the release from intraneuronal deposit sites.40 Like PSP, disease‐modifying treatments and CBD have targeted tau pathology (Table 1).

2.2.2. Ongoing clinical trials in CBD

The intravenous (IV) infusions of a microtubule inhibitor called TPI 287, belonging to the taxane diterpenoid (taxoid) family, are under investigation. The goal of this research was to determine the safety and tolerability of TPI 287 administered once every 3 weeks for 9 weeks (for an overall total of 4 infusions) in patients with CBD as well as primary 4‐R tauopathies or PSP (Table 2).13

2.3. Multiple system atrophy

MSA has a clinical picture mainly characterized by parkinsonism, autonomic failure, and cerebellar signs. The incidence is 0.8 per 100.000 person‐years.21 Typical age at the beginning is 53 to 55 years.4 Women and men are equally affected, and mean survival time is 9 years from symptom onset. MSA is a sporadic α‐synucleinopathy. Nevertheless, a few mutations in COQ2 gene (vital for biosynthesis of Coenzyme Q10) have been described.41

Usually, MSA is categorized into one of three different phenotypes: MSA‐P (parkinsonism signs predominate; formerly known as "striato‐nigral degeneration"),42, 43 MSA‐C (cerebellar signs prevail; formerly known as olivo‐ponto‐cerebellar atrophy"),42, 43 or MSA‐A (autonomic signs predominate; formerly known as "Shy‐Drager syndrome).42, 43

2.3.1. Current drug treatments in MSA

Although less effective as compared to PD, L‐dopa replacement indicates the gold standard of antiparkinsonian remedy in MSA. Retrospective researches showed that 30%‐40% of MSA patients take benefit from L‐dopa in open‐label studies although transiently.44, 45, 46 Outcomes from dopamine agonists have been much more unsatisfactory due to the occurrence of psychiatric adverse events.47

174 patients affected by MSA‐P were administered with rasagiline (a monoamine oxidase‐B inhibitor) with a dosage of 1 mg/day or placebo in a randomized, placebo‐controlled multicentric clinical trial. At the end of 48 weeks, there were no significant differences in total UMSARS scores between rasagiline and placebo groups (Table 1).48

In another clinical trial, 7 MSA patients were administered infusions of intravenous immunoglobulin (0.4 gm/kg) once each month. Primary outcomes examined safety, and secondary outcomes evaluated the initial efficacy of intravenous immunoglobulin. UMSARS was assessed monthly. Outcomes showed better UMSARS part I (activities of everyday living) and II (motor signs) scores after 6‐month follow‐up. There were no severe adverse events.49 Anyway, it should be remarked that small, unblinded trials are extremely sensitive to the placebo effect.

Rifampicin, an antibiotic drug that has been proven to prevent the synthesis of α‐synuclein fibrils, has been tested in a 52‐week, double‐blind, placebo‐controlled clinical trial with 100 MSA patients (both MSA‐P and MSA‐C) as a neuroprotective agent (600 mg/day rifampicin versus placebo). All primary (Activities of Daily Living subscore of the UMSARS) and secondary outcome measures failed to reach improvement (Table 1).50

Paroxetine, a second‐generation selective serotonin reuptake inhibitor (SSRI), has been shown to provide some benefits in patients with MSA. Twenty patients received paroxetine at 30 mg daily dosage for two months in a placebo‐controlled, add‐on trial, indicating an improvement of dysarthria and parkinsonism.51

Sertraline, another SSRI, is one of the most encouraging therapeutic choices for MSA. Sertraline has been confirmed to stop the endocytic paths by which α‐synuclein is taken into oligodendroglia in a dose‐dependent manner and to inhibit α‐synuclein neuron‐to‐neuron transmission.52

The aggregation of α‐synuclein determines an inflammatory reaction in the central nervous system (CNS). This inflammatory reaction is mediated by using activated microglia. The enactment of microglia may additionally increase the neuronal damage.53 Minocycline is a broad‐spectrum antibiotic belonging to the class of second‐generation tetracyclines which crosses the blood‐brain barrier and inhibits microglial activity and secretion of pro‐inflammatory cytokines. Minocycline‐induced suppression of microglial activation also prevented the loss of nigral dopaminergic neurons as well as the loss of dopaminergic terminals in the striatum.54 Notwithstanding these empowering outcomes, 62 patients with MSA‐P enrolled in a multicenter, randomized, double‐blind, placebo‐controlled clinical trial did not show any significant improvement following 12 months of treatment with minocycline, even though microglial enactment, as surveyed by using PET, had been decreased.53

In a double‐blind, placebo‐controlled trial, 33 subjects with MSA‐C were randomly assigned to either autologous mesenchymal stem cells (MSCs) injections or placebo injections. The primary outcomes were the modification in total UMSARS ratings from baseline between groups throughout a 12‐month follow‐up duration. Additional outcomes were alterations within the UMSARS part II scores, cerebral glucose metabolism, gray matter thickness, and cognitive performance. The patients administered revealed only a smaller increase on both the total and the part II scores on UMSARS scale (Table 1).55

Droxidopa, a prodrug of norepinephrine, able to cross the blood‐brain barrier, has been examined as a symptomatic drug to treat orthostatic hypotension in MSA, which is one of the most clinically relevant symptoms in these patients leading to recurrent syncopes. Twenty‐six MSA patients (out of 162 patients affected by neurogenic orthostatic hypotension) were recruited, in an open‐label dose optimization to droxidopa (100‐600 mg three times a day), followed by a double‐blind phase. Treatment with droxidopa resulted in a significant reduction in orthostatic symptoms, measured by the change in the orthostatic hypotension questionnaire (OHQ) score.56 Some contrasting results about droxidopa were obtained by another trial, testing 30 patients with MSA inserted in a group of 101 patients with orthostatic hypotension of neurogenic origin. After a follow‐up of 2 weeks, this randomized, placebo‐controlled study failed in finding improvement in Item 1 of the Orthostatic Hypotension Symptom Assessment (OHSA) scale.57 Despite this, the US Food and Drug Administration has approved the use of droxidopa to treat symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure, including MSA.

The results of a 50 mg single dose of losartan, an antagonist of angiotensin II receptors (sartanic drugs), to treat supine hypertension in MSA patients had been examined in a randomized, placebo‐controlled crossover trial, showing its efficacy in decreasing overnight supine high blood pressure and nocturnal urinary sodium excretion without increasing orthostatic symptoms.58 As about supine hypertension, nebivolol, a selective beta‐blocker on β1‐adrenergic receptors, on a daily dosage of 5 mg has been proven superior to the metoprolol, another selective beta‐blocker on β1 adrenergic receptors, in 6 patients with MSA‐A.59 Two studies are ongoing with an association of antihypertensive drugs, losartan and captopril, an angiotensin‐converting enzyme (ACE) inhibitor, and with an agent blocking endothelin (BQ123).

2.3.2. Ongoing medical trials in MSA

Fluoxetine, an SSRI, has been seemed to enlarge glial cell–derived neurotrophic factor (GDNF) and brain‐derived neurotrophic factor (BDNF) in a transgenic (tg) mouse model expressing human α‐synuclein under the oligodendrocyte‐specific myelin basic protein promoter (MBP1‐hαsyn tg mice),60 to prevent elements of inflammation in microglial cells cultures, and to boost neurogenesis in the hippocampus (ClinicalTrials.Gov Identifier: NCT01146548; Table 2).

Epigallocatechin gallate (EGCG), a polyphenol observed in green tea, has been demonstrated to inhibit the toxic α‐synuclein formation and to modify toxic in non‐toxic α‐synuclein oligomers species (ClinicalTrials.Gov Identifier: NCT02008721; Table 2).

Anti‐α‐synuclein antibodies able to cross the blood‐brain barrier were evaluated in AFFITOPE study. Active vaccination with AFFITOPE ended in less burden of α‐synuclein (ClinicalTrials.Gov Identifier: NCT02270489; Table 2).

The AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. Myeloperoxidase is an enzyme generating reactive oxygen compounds within the microglia. Action mechanisms of AZD3241 are thought to decrease the oxidative stress and neuroinflammation (ClinicalTrials.Gov Identifier: NCT02388295; Table 2).

2.3.3. Surgical approach in MSA

The role of DBS in MSA has not been especially studied in controlled trials. Most of the literature describes case reports. A recent report reviewed records of MSA subjects which underwent bilateral subthalamic nucleus (STN) DBS treatment.61 Five patients, three women and two men, with a mean age at beginning of 42.2 ± 2.2 years, had been included within the research. All five patients had L‐dopa‐responsive parkinsonism, asymmetric beginning, motor fluctuations, and postural instability. Pre‐surgical and postsurgical UPDRS‐III have been assessed. Outcomes reveal that 6 months after surgery, three patients showed a decrease in dyskinesia. However, a reappearance and worsening of symptoms have been seen within 12 months from the surgery, especially in "off" state. Therefore, it was not possible to decrease the daily L‐dopa dosage. Various other clinical trials, in which MSA subjects who underwent DBS of STN had a higher mean age between 55 and 60, did not show different effects. Overall, these reports conclude that surgical treatment in MSA patients was not justified by clinical evidence.62

3. PARKINSON'S DISEASE DEMENTIA

Parkinson's disease (PD) incidence is growing with age, and PD impacts 1% of the population above 60 years.63 Measurements suggest that 10% of patients with PD progress in dementia each year63 although the occurrence of dementia is dependent upon existing age, age at PD onset, length of disease, and symptoms profile.64 Underlying pathology in PDD is heterogeneous with several contributing findings like Lewy bodies, neurofibrillary tangles, senile plaques, microvascular disease, and argyrophilic inclusions.65 The evidence suggests that Lewy‐related pathology is the most important factor in the development of cognitive impairment in PD. A synergistic effect between α‐synuclein and Alzheimer disease (AD) pathology could drive cognitive decline in PD.66 A recent study of 92 PDD and 48 nondemented PD found that the severity of cortical Lewy body pathology correlates most with dementia.67 A community‐based study of 872 autopsies reported 103 cases with neocortical Lewy body–related pathology, which was associated with increased odds for dementia and more rapid cognitive decline. It should also be noted that not all patients with cortical Lewy body–related pathology present with dementia.67 Anyway, most studies point to the importance of combination of Lewy body and AD pathology as the most robust finding correlating with dementia in PD.68 Therapeutic efforts in PDD are tightly related with the differential diagnosis with others APS. So, a brief review of the main differential motor, non‐motor, and cognitive‐behavioral aspects distinguishing PDD and APS is essential to understand the current drug treatment options.

3.1. Motor symptoms

The presence of bradykinesia is a prerequisite to diagnose parkinsonism.68 Classical bradykinesia is described as a progressive decrement in speed and amplitude of repeated movements. The beginning of manifestations in PD is asymmetrical. Even though these manifestations will become bilateral, this asymmetrical nature persists for all the length of the disease. In comparison, signs and symptoms are generally symmetrical in patients with APS. The distinction is not full, as patients with MSA can present with an asymmetrical clinical picture. Additionally, there is a critical exception to this controlling rule: The asymmetry in CBD is more evident compared with PD. An axial onset is very rare for PD and more suggestive of PSP.62

3.1.1. Tremor type

PD traditionally manifests with a rest, pill‐rolling type tremor (with associated participation of the thumb). Pill‐rolling tremor will not entirely exclude APS, as it can additionally take place in MSA, LBD, or PSP‐P although in APS the tremor is commonly much more bilateral and symmetrical. A tremor of a jerky type, perhaps because of polyminimyoclonus, is much more suggestive of MSA.

3.1.2. Myoclonus

Myoclonus is a rapid, brief, shocklike movement, because of muscle tissue contractions. Especially when myoclonus is severe and frequently repetitive, if not rhythmic, the differentiation from tremor could be difficult. Pronounced myoclonus, upon voluntary activity or perhaps in a reaction to physical stimuli, can present in LBD, CBD, and PSP. In CBD, the myoclonus is typically focal, and many times restricted to a single limb.62

3.1.3. Dysphagia/dysarthria

Dysphagia and dysarthria could be present both in PD and in APS. Nonetheless, severe dysphagia at the beginning of the disease is suggestive for PSP, CBD, and MSA. Likewise, the very early existence of severe dysarthria could suggest MSA or PSP as first diagnosis. A pseudobulbar type dysarthria reveals PSP, while cerebellar dysarthria suggests MSA.62

3.1.4. Dystonia

Dystonia may appear in both PD and APS. Foot dystonia manifests in patients with PD, particularly in individuals with young‐onset PD or among the autosomal recessive types of idiopathic PD. These forms can be dopamine‐responsive (especially the regular incidence early in the morning during a deep “off” stage). Segmental dystonia of trunk area, leading to latero‐flexion (Pisa sign) or antero‐flexion (camptocormia), may also appear in PD. Varieties of dystonia are present in patients with APS: retrocollis or blepharospasm in PSP, antecollis‐laterocollis in MSA, and an early, limb‐fixed dystonia in CBD.62

3.1.5. Gait and stability abnormalities

Impaired gait could manifest in every patient with parkinsonism. Nevertheless, the features differ between various conditions. Early gait abnormalities in PD are characterized by slowing of gait and an asymmetrically reduced swinging of the arms. With disease development, step height and size come to be smaller, and numerous patients begin start hesitation, festination, and freezing. Notably, gait is narrow‐based in PD, while it is frequently broad‐based in patients affected by the various types of APS, also at the very early stage of the disease. Ataxic gait is a crucial indication in MSA‐C but also can develop in subjects with PSP. Gait in CBD is normally suffering from asymmetrical and in most cases fixed foot dystonia. Stability is typically not affected at the beginning of PD, unlike APS. PD patients mainly fall forwards (due to freezing of gait), whereas many falls are backward (for explanations unidentified) in PSP. Typical for MSA may be the existence of straight (“drop down”) drops due to preceding syncope caused by an orthostatic hypotension, whereas this is unusual in PD.62

3.1.6. Eye movement problems

The investigation of eye movements is crucial for diagnosis, as PD and APS can demonstrate different abnormalities. PD patients show reduced natural blinking and hypometric saccades, but a preserved velocity associated with the saccades. Supranuclear vertical gaze palsy is pathognomonic for PSP. Subjects with MSA can present cerebellar signs, with nystagmus, square‐wave jerks, and dysmetria. In CBD, the start—although not the execution—of saccades is slowed in each of the horizontal and vertical line.62

3.2. Non‐motor symptoms

3.2.1. Autonomic symptoms

Evident dysautonomia in PD is generally moderate and not apparent in the first 12 months of the condition. Signs and symptoms of autonomic illness, especially orthostatic hypotension, erectile weakness, and urinary urge incontinence, are ordinarily early evident effects of MSA, usually manifesting before parkinsonian signs. Autonomic disorder does occur in LBD, including orthostatic hypotension, carotid sinus hypersensitivity causing syncope and transient loss of consciousness. Bladder control problems take place in PSP patients, although usually not so early.62

3.2.2. Sleeping problems

Daytime sleepiness frequently happens in PD and has a multifactorial source, including bad nighttime rest and negative effects of dopaminergic medicine. The current presence of rapid eye movements (REM)‐sleep behavior disorder reveals the presence of α‐synucleinopathy (PD, MSA, LBD). Restless legs and regular limb motions during rest happen regularly both in PD and APS. Nocturnal inspiratory stridor is typical of MSA.62

3.2.3. Dopaminergic drugs response

Patients with PD have a definite and unambiguous response to L‐dopa with a good toleration of the dopaminergic agents. Patients with APS tolerate dopaminergic medication less well, and many become nauseated whenever making use of L‐dopa. Roughly, one‐third of patients with MSA may reveal some benefit to L‐dopa, although a sustained response is unusual. Patients with PSP typically never show a beneficial, long‐duration response to L‐dopa. However, subjects with the PSP‐P phenotype (where parkinsonism is prevalent) can show some response.62

3.2.4. Cognitive and behavioral issues

As much as 25% of newly identified PD patients show impaired overall cognitive performance in at least three neuropsychological examinations. PD patients usually manifest reduced psychomotor speed, executive disorder, visuospatial disorder, and memory deficits. Nevertheless, the clear presence of extreme cognitive disability or serious dementia should suggest additional research, as numerous APS types (including PSP, LBD, and MSA) present damaged cognitive function early within the illness course. Apraxia, non‐fluent aphasia, and behavioral modifications can happen in PSP and, particularly, CBD patients. Apathy is common in PD, frequently associated with depression. In PSP patients, apathy can be typical, but often develops earlier and much more prominently in comparison with PD. Hallucinations and delusions in the paranoid spectrum are typical in LBD patients particularly before beginning dopaminergic treatment.62

3.2.5. Current drug treatments in PDD

L‐Dopa should be the drug chosen to treat parkinsonian motor features in PDD. It is well‐tolerated, although problems with confusion and hallucinations, and intestinal adverse events may occur.69

Non‐motor symptoms of PD tend to be resistant to therapy with L‐dopa, probably because they do not derive from the classic dopaminergic deficit.70 Significant loss of cholinergic forebrain neurons was demonstrated in PDD brain,71 and in vivo cholinergic deficits in PDD tend to be more extended than those in AD patients.72 This aspect supports the therapy with cholinesterase inhibitors in PDD,70 and good results have been obtained with rivastigmine and donepezil.73

3.2.6. Rivastigmine

Of note, rivastigmine, an acetylcholinesterase (AChE) inhibitor, is the only drug authorized by the Food and Drug Administration (FDA) to treat mild‐to‐moderate PDD. The effectiveness of rivastigmine in PDD has been demonstrated in a double‐blind, randomized, placebo‐controlled study, the EXPRESS study.74 In this research, 541 mild‐to‐moderate PDD participants had been assigned to get either rivastigmine (up to 12 mg/day) or placebo over 24 weeks. PDD patients treated with rivastigmine revealed improvements in each of the 2 major outcomes: the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐cog) together with Clinical Global Impression of Change Scale (CGIC). Improvements in secondary outcomes, including tests that assess attention and executive function, were also noticed.75 While not typical, an increased frequency of nausea, vomiting, and tremor has been associated with therapy when compared with placebo group. The observed improvement produced by rivastigmine lasted for as much as 48 months, though there was some decrease in efficacy in a longitudinal follow‐up regarding the original EXPRESS study.76 Nonetheless, no indicator of worsening of motor function had been seen during the period of 12‐month therapy.77

The rivastigmine transdermal patch also has been useful for the treating PDD. The long‐lasting protection in patients with mild to moderate severe PDD associated with the 9.5 mg/24 hours has been investigated in 288 patients compared with 295 patients assuming capsules78 in a 76‐week, open‐label research. The outcome revealed that even though the incidences of bradykinesia, muscle rigidity, and falls had been comparable among the two groups, the occurrence of tremor had been reduced in the patch group, when compared with the 6 mg, twice‐daily capsule group (9.7% versus 24.5%). There have been additionally reduced incidences of gastrointestinal side effects (vomiting, diarrhea, and nausea) in the patch group. Cognitive performance, as assessed by the Mattis Dementia Rating Scale (MDRS), showed improvements from baseline to week 52 in both groups. Such enhancement remained through week 76 only for the capsule group. However, the authors advised this decrease could be counterbalanced by a rise in the patch dosage.79

3.2.7. Donepezil

In a large double‐blind, randomized, placebo‐controlled study, 550 PDD patients had been randomized to get donepezil, another AChE inhibitor, at 5 mg (195), or 10 mg donepezil (182), or placebo (173) for 24 months. The primary outcomes measures of ADAS‐Cog and the Clinician's Interview‐Based Impression of Change Plus Caregiver Input (CIBIC‐Plus) scale showed statistically significant result only in the higher (10 mg) dosage group as compared to placebo. The occurrence of undesirable events (nausea, vomiting, and diarrhea) had been greater into the therapy compared to the placebo group, but such activities were of mild or moderate severity.80

3.2.8. Neuroleptic treatment

The treatment of hallucinations can be especially difficult because of the sensitivity to neuroleptic drugs showed by around 39% of patients with PDD81 and because of the danger of worsening motor parkinsonian signs. Hallucinations do not constantly need therapy, and the very first action is certainly to eliminate iatrogenic causes and treat concomitant infections.71 Discontinuation of PD drugs starts with anticholinergics, followed by amantadine, dopamine agonists, monoamine oxidase B inhibitors, catechol‐O‐methyltransferase inhibitors, and lastly, L‐dopa. Neuroleptics may be suggested if hallucinations still persist.71 Clozapine has proved powerful in treating psychotic symptoms in PD; it is infrequently connected with neuroleptic sensitivity, and it has a benign motor profile.82 Nevertheless, the chance for agranulocytosis restricts its usage.73 Many clinicians choose quetiapine, which includes a harmless motor profile among other neuroleptics.83 Recently, pimavanserin, a selective serotonin 5‐HT2A inverse agonist, demonstrated a good efficacy for the treatment of psychosis in PD at 40 mg daily dosage.84

3.2.9. Lewy Body Dementia

LBD rate of incidence is 5.9 per 100.000 person‐years,85 with a prevalence rate of 52/100.000.86 LBD is pathologically described as intraneuronal inclusion containing alpha‐synuclein in the brainstem, cholinergic nucleus basalis, substantia nigra, neocortex, and limbic areas. Besides dementia, the cardinal features of LBD include at least two of the following four features: REM sleep behavior disorder, fluctuating cognition, parkinsonism, and visual hallucinations.87 LBD and PDD are often distinguished because of the beginning of cognitive impairment along the course of disease. The diagnosis of LBD is made if cognitive impairment precedes motor involvement by at least 1 year. The medical picture is diagnosed as PDD if motor disability occurs prior to or at the same time of cognitive deficits.87

3.2.10. Current drug treatments in LBD

Dopaminergic treatment with L‐Dopa or dopamine agonists is administered with caution to avoid the impairment of hallucinosis.87 AChEIs represent the gold standard for the treatment as concerning the cognitive symptoms, principally because of a cholinergic deficit.87 Of note, donepezil and rivastigmine can be used for both the cognitive disability and the behavioral symptoms of the LBD.87

3.2.11. Donepezil

In a multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled trial, 140 patients with LBD had been assigned to assume placebo or 3, 5, or 10 mg of donepezil hydrochloride daily (number of patients 35, 35, 33, and 37, respectively) for 12 weeks. Impacts on cognitive aspects had been assessed with Mini‐Mental State Examination (MMSE) and many domain‐specific neuropsychological examinations. Alterations in behavior had been assessed applying the Neuropsychiatric Inventory (NPI). Clinical assessments were evaluated with the Unified Parkinson's Disease Rating Scale component III (UPDRS III) and global functioning by the CIBIC‐plus. Outcomes indicated that donepezil at 5 and 10 mg/day was significantly superior to placebo on both the MMSE and CIBIC‐plus. Considerable improvements had been discovered additionally in behavioral symptoms. Within the subsequent 52‐week, multicenter, open‐label expansion study, 108 patients had been enrolled. Cognitive and behavioral symptoms, including the typical fluctuations, had been improved following the beginning of donepezil therapy, and improvement had been preserved for 52 weeks.88

3.2.12. Rivastigmine

In a randomized, double‐blind, placebo‐controlled multicentric study, 120 subjects had been randomized to receive either rivastigmine or placebo (59 rivastigmine, 61 placebo). Patients received up to 12 mg rivastigmine daily or placebo for 20 weeks, accompanied by a rest of 3 weeks. Primary outcome were the behavioral modifications evaluated by the NPI, made at baseline, and at weeks 12, 20, and 23. Patients receiving rivastigmine had considerably less apathy, delusions, and hallucinations while on therapy than control subjects. Recognized adverse events of cholinesterase inhibitors (nausea, vomiting, anorexia) had been seen with major frequency with rivastigmine than with placebo, but with an overall good safety and tolerability.89 In the same study, a cognitive evaluation was performed with the Cognitive Drug Research computerized assessment system, and significant advantages were found for rivastigmine over placebo on tests of attention, working memory, and episodic memory. Three months after discontinuation of rivastigmine, many variables of cognitive performance returned to pre‐drug levels.90

3.2.13. Neuroleptic treatment

Atypical antipsychotics have been administered to manage psychiatric symptoms and visual hallucinations in LBD. In a large double‐blind, placebo‐controlled, randomized, parallel‐group study to treat psychosis in subjects with Alzheimer's disease (AD) with olanzapine, a second‐generation neuroleptic drug, a subgroup of patients with LBD was enrolled for a post hoc evaluation.91 Twenty‐nine patients showed the requirements for LBD; 10 patients have been randomized to placebo, five patients obtained 5 mg, seven patients 10 mg, and seven patients 15 mg of olanzapine. Psychosis was evaluated with the Neuropsychiatric Inventory/Nursing Home (NPI‐NH) variation together with Brief Psychiatric Rating Scale (BPRS). Extrapyramidal signs had been examined with the Simpson‐Angus scale. Patients with LBD treated with both with 5 and 10 mg of olanzapine showed a considerable reduction in the NPI‐NH delusion subscale rating. There was no exacerbation of parkinsonian features, nor decrement in Mini‐Mental State Examination results in any research group.

Quetiapine, another new‐generation neuroleptic drug, had been administered to 23 patients with LBD in a multicenter, double‐blind, placebo‐controlled, parallel‐group trial with a mean dose of 120 mg/day. The primary outcomes were assessed as improvement in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of treatment. The UPDRS motor section has been inspected for the safety on motor aspects. Quetiapine had been well‐tolerated and did not aggravate parkinsonism but failed to show any benefit on behavioral symptoms. However, the authors claim that results could be confounding because of the little sample size recruitment.92

3.2.14. Antiglutamatergic drugs for Atypical Parkinsonian Syndrome

Excitotoxicity caused by glutamate is a possible mechanism of neuronal death in MSA and PSP.93 Oligodendrocytes tend to be extremely sensible to glutamate‐delivered excitotoxicity. Oligodendrocytes are the cells active during the glutamate clearance.94 Under precise conditions, oligodendroglial glutamate transporters can cause glutamate production from oligodendrocytes,95 with a further Ca2+ flux increase.96 Ca2+ load inside mitochondria leads to the growth of proapoptotic elements, activation of nitric oxide synthase (NOS), production of reactive oxygen species (ROS) and peroxynitrite, which prolong oxidative stress destroying oligodendrocytes and neurons.97 Glutamate antagonists could avoid excitotoxicity with the inhibition of glutamate‐NMDA receptors binding. Amantadine and riluzole are the most investigated glutamate inhibitors in central nervous system diseases.52 Amantadine has N‐methyl‐D‐aspartate (NMDA) antagonist properties, promotes dopamine synthesis and release, and prevents dopamine reuptake along with a moderate anticholinergic impact.98, 99, 100 An early report about the open‐label use of amantadine proposed some amount of antiparkinsonian effectiveness in a subgroup of patients with MSA46 as well as a further study enrolling both MSA and PSP patients.101 Nonetheless, a subsequent open‐label trial of amantadine in APS, including MSA, revealed too little antiparkinsonian effectiveness.102 Additionally, a pionieristic retrospective research evaluating amantadine for PSP did not reveal considerable benefits.100

In a double‐blind, placebo‐controlled crossover trial of amantadine in MSA patients, eight subjects had been recruited for this study. Amantadine 200 mg two times daily or placebo for 3 weeks, followed by a washout of 1 week, accompanied by a subsequent alternative therapy for other 3 weeks was administered. Antiparkinsonian effects were tested with the UPDRS II (daily activities) and UPDRS‐III (motor evaluation) before and after the end of each therapy period. Results showed that, although a tendency toward a decrease in UPDRS‐III scores, it was not significant both in total score and in the single subscores for akinesia, stress, tremor, postural instability, and gait. To conclude, this controlled research showed that amantadine does not supply clinical considerable antiparkinsonian advantage to patients with MSA.103

Riluzole stops activity at potassium and sodium channels which blocks the stimulation of glutamate receptors.52 It has been shown to prevent basal ganglia degeneration in rodent and primate studies.93 Riluzole (100 mg two times daily) was administered in a placebo‐controlled crossover trial in 10 patients with MSA for 4 weeks, followed by a washout period of 4 weeks. Outcomes were assessed through the UPDRS II and III subscales prior to as well as at the termination of each therapy phase. Riluzole had been generally well accepted, but there have been no significant antiparkinsonian effects of riluzole examining the UPDRS values.104

In the Neuroprotection and Natural History in Parkinson Plus Syndrome (NNIPPS) study, a double‐blind, placebo‐controlled, stratified (by diagnosis of MSA or PSP), parallel‐group trial, patients were randomized to riluzole at daily variable dosage (50‐200 mg/day), implemented for three years. The endpoint was survival. Secondary outcomes had been rates of illness progression evaluated by functional measures. An overall total of 767 patients were randomized stratified at baseline as PSP (362 patients) or MSA (398 patients). There have been no adverse events of riluzole, with no considerable safety problems. There was no clear proof of a drug impact on survival within the PSP or MSA strata or in the whole study population. Also, the rate of progression had been comparable in both therapy groups (Table 1).105

The possible therapeutic vantages associated with the NMDA‐receptor antagonist memantine in LBD and PDD have been of great interest because of its effectiveness in AD.106 Nonetheless, outcomes regarding its efficacy have been conflicting. 32 LBD had been included with 40 PDD patients and randomly assigned to memantine (20 mg a day) versus placebo in a double‐blind, placebo‐controlled, multicenter clinical trial. The primary outcome was CGIC, which had been ranked after a clinical meeting with all the patients and their caregivers. Secondary outcomes included the 24‐week results for the MMSE, the NPI, the disability assessment for dementia (DAD), and the UPDRS III motor subscale. A considerable benefit of memantine regarding the CGIC score and rate on attentional test had been seen. A post hoc evaluation revealed that these results derived primarily by improvement within the PDD group.107 Nevertheless, in a further randomized, double‐blind, placebo‐controlled trial enrolling LBD and PDD patients (34 with LBD and 62 with PDD with memantine, and 41 with LBD and 58 with PDD with placebo), LBD patients who obtained memantine (20 mg/day) revealed higher enhancement according to CGIC ratings than people who obtained placebo, whereas no significant difference had been mentioned in patients with PDD. Furthermore, NPI scores demonstrated improvement within the memantine LBD compared to the placebo group, whereas this result was not replicated in memantine PDD patients. In many associated cognitive scores, there had been no considerable differences between the two groups (Table 1).108 Memantine in PDD and LBD patients is well‐tolerated and safe, and the observed occurrence of adverse events (tiredness and falls) is comparable to the placebo group.

3.2.15. New treatment option for atypical parkinsonism: transdermal rotigotine (RTG)

A recent open‐label trial showed that transdermal RTG, a non‐ergot dopamine agonist with high affinity for human dopamine D1, D2, and D3 receptors, is efficacious and well‐tolerated in patients with APS.10 Sixty‐one patients with the diagnosis of APS (MSA, PSP, CBD, PDD, LBD, and frontotemporal dementia with parkinsonism) underwent treatment with transdermal RTG adjusted to the least effective dose (4.9 mg on common) for two years. The primary outcomes were assessed by UPDRS subscale III for the motor evaluation and the NPI rating for behavioral aspects. Results discovered a significant decrease at two‐year follow‐up of UPDRS III (22.6 ± 7.7) and NPI scores (33.1 ± 8.8) as compared with baseline scores (36.1 ± 8.3 and 64.2 ± 9.1, respectively). Only 7 patients suffered from adverse events (specifically sleepiness, vomiting, tachycardia nausea, and drowsiness) and were dropped out. Of note, there were no complications due to dopaminergic‐induced behavioral disorders. In previous studies, enrolling patients with PD, besides the control of motor symptoms, RTG have shown a good control of sleep disturbance as well as a reduced risk for developing impulsive shopping, binge eating, gambling, and hypersexual behavior, usually referred as impulse control disorders (ICDs).109, 110, 111 A possible explanation could reside in the affinity of RTG also to some families of receptors out of dopaminergic domain, namely the adrenergic (α2B‐adrenergic) and serotoninergic (5‐HT1A) receptors family. Of note, both α2B and 5‐HT1A receptors are well recognized for their positive modulation of the emotion and affective behavior.112, 113, 114, 115, 116, 117, 118

3.2.16. Supportive treatments

In APS, the concomitant presence of both motor and cognitive impairments often leads to the need for non‐pharmacologic therapies. Physical, occupational, and speech rehabilitation have been considered as therapeutic tools in these patients in recent clinical trials. A patient with combined features of CBD and PSP has carried out a long‐term rehabilitation program for a total period of 10 years. This program included trunk area and legs with strengthening and stretching extremity of the lower extremities and treadmill walking exercise. This patient took part regularly to the program twice a week, for 1 hour each session, for 10 years and had been reassessed in years 9 and 10. Outcomes demonstrated a decreased rate of falls, preserved stability and endurance, and maintained gait utilizing a walker.119

Another open‐label trial verified the efficacy of a rehabilitation program on postural instability throughout a dynamic antigravity postural system associated with a vibration system on 10 PSP patients. The subjects underwent the training with a three sessions/week routine for 2 months. Patients had been examined at baseline and each week throughout the 2‐month therapy course as well as 30 days following the end of treatment plan. The following parameters were investigated: static baropodometry, dynamic baropodometry, and stabilometry. All the variables investigated showed enhancement at the end of therapy in comparison with the beginning. Dynamic baropodometric characteristics enhancement lasted until the end of the 30 days of follow‐up.120

Another study aimed to the rehabilitation of gait in individuals with PSP, assessed the benefits of mixed rehabilitation program combining postural balance with eye movements exercise training compared to balance training only. Nineteen subjects with mild PSP had been assigned either to a treatment group (balance with eye movements training, n = 10) or to a control group (balance training only, n = 9). Outcomes unveiled considerable improvements in stability and walking function in the double training group, whereas in the control team only some improvement in step size had been detected. The eye movement training has been demonstrated a promising complementary method in association with the postural exercise in the rehabilitation of gait in PSP patients.121 Alternative rehabilitation, such as occupational therapy, can be useful in coping with cognitive dysfunction observed in APS.

It has to be remarked that the continuous support to the caregiver is an essential part of the non‐pharmacological therapies in order to avoid an unbearable burden in everyday life; namely, the family has to be guided to the acceptance of the wheelchair as a tool of safety.12

4. CONCLUSION AND FUTURE DIRECTIONS

Increasing progress in genetic and clinico‐pathological features of APS will make physicians more skilled with the diagnosis. Transdermal rotigotine, autologous mesenchymal stem cells, tideglusib, intravenous immunoglobulin, and coenzyme Q10 along with donepezil, rivastigmine, memantine, and the DBS have shown some benefits in alleviating symptoms in APS. Disease‐modifying treatments would be the primary challenge in future due to the substantial level of disability for the patients and the impressive burden for the caregivers. A deeper and much more detailed investigation of the pathological aspects underlying these disorders is required. New clinical trial with trophic agents and stem cells, among others, should be planned. On the other hand, the discovery of biological markers aiming to an early diagnosis and to the design of pharmacological trials and assessment of outcomes should be enhanced.12

Moretti DV. Available and future treatments for atypical parkinsonism. A systematic review. CNS Neurosci Ther. 2019;25:159–174. 10.1111/cns.13068