Abstract
Purpose of the Study:
This study compared striatal dopamine metabolism and cerebral glucose metabolism in Parkinson’s disease patients with and without freezing of gait (FOG) using Fluorodeoxyglucose positron emission tomography (FDG-PET) and F-DOPA PET. We also compared the two groups’ cognitive, affective, and autonomic functions.
Methods:
Patients were divided into two groups: those with and without FOG. All patients underwent neuropsychological evaluation. Subsequently, both groups underwent FDG-PET and FDOPA-PET. The FDOPA PET/computed tomography images evaluated dopaminergic expression in the basal ganglia. Cortex-ID-based processing of FDG images was visually analyzed for any abnormal hypermetabolism or hypometabolism in the various regions of the brain.
Results:
A total of 30 patients were recruited, 15 in each group. The mean age of participants was 59.33 ± 9.12 years in the freezing of the gait-negative group and 61.13 ± 9.38 years in the freezing of the gait-positive group. FDOPA PET scan analysis revealed symmetrical loss of basal ganglia uptake in the freezers compared to the nonfreezers, which had more asymmetrically reduced uptake (P = 0.025). In FDG PET, a general trend of greater metabolic reduction in the basal ganglia was observed in freezers. Our study showed bilateral involvement of frontoparietal cortices in both freezers and nonfreezers, with more widespread areas of hypometabolism reported in the freezer group.
Conclusion:
Freezers exhibited a more symmetrical loss of dopaminergic uptake on FDOPA PET, whereas nonfreezers showed greater asymmetry. In addition, FDG PET revealed a trend toward greater basal ganglia hypometabolism in freezers, suggesting a more profound striatal dysfunction in patients with freezing of gait.
Keywords: Fludeoxyglucose positron emission tomography, FDOPA-positron emission tomography, freezing, Parkinson’s disease
Introduction
Freezing of gait (FOG) is defined as “brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk.”[1] It considerably impacts a patient’s quality of life, as it can lead to falls and loss of self-independence.[2] FOG is likely caused by the complex interplay between motor, sensory, cognitive, and affective factors instead of being a pure motor problem.[3] Abnormalities in various cognitive domains are commonly seen in patients with freezing of gait.[4] Executive dysfunction, attention deficits, visuospatial dysfunction, and even involvement of the autonomic nervous system have all been documented in patients with FOG.[5,6]
Neurometabolic studies using fludeoxyglucose positron emission tomography (FDG-PET) have demonstrated changes in the frontal and parietal cortical areas in Parkinson’s disease patients with FOG.[7,8] There is a lot of discrepancy across multiple studies, so a precise anatomical correlate for FOG is still unclear.[9,10]
Our study compared Parkinson’s disease patients with and without freezing of gait by studying the correlation between FOG and brain changes using FDG-PET and F-DOPA PET imaging. We also compared the cognitive, affective and autonomic functions of the two groups.
Methods
Patients were recruited at the Postgraduate Institute of Medical Education and Research, Chandigarh, from July 2021 to December 2022 in this prospective observational study after approval from the Institute’s ethics committee (INT/IEC/2022/SPL-16) and with informed consent from all the participants.
Inclusion criteria
Patients with Parkinson’s disease diagnosed according to the UK Brain Bank criteria[11]
Hoehn and Yahr stage ≤4 in off-state
Stable and optimized antiParkinsonian medication at least 4 weeks before enrolment into the study.
Exclusion criteria
Clinically significant comorbidities including stroke, traumatic brain injury, hydrocephalus, intracranial space-occupying lesion, and other significant orthopedic, or rheumatologic disease
Major depression (DSM-IV)
Atypical Parkinsonism
Not willing for PET-computed tomography (CT)
History of deep-brain stimulation in the past.
Participants were divided into two groups (with and without FOG) based on their score on FOG Questionnaire item 3 (“Do you feel that your feet get glued to the floor while walking, making a turn, or when trying to initiate walking [freezing]?”) ≥1 or by demonstration of freezing of gait on neurological assessment.[12]
Participants in both groups underwent 18F-DOPA and 18F-FDG PET/CT on separate days. For FDG-PET/CT, patients were instructed to undergo 4 h of fasting before the study. A blood sugar value of <150 mg was targeted. FDG was injected intravenously at a dose of 111–185 MBq (3–5 mCi), and the scan was acquired after a waiting period of 45 min using a dedicated PET/CT scanner (Discovery MIDR, GE Healthcare Systems, Chicago, USA). The patient was positioned supine with the head immobilized using restraints to prevent movement during the study. The acquisition included an initial CT acquisition of the head region with a voltage of 120 kV and tube current of 250 mA, helical CT without intravenous contrast. This was followed by a static PET acquisition of a single field of view encompassing the head region with an acquisition time of 6–7 min. The PET image was reconstructed using iterative reconstruction, OSEM, with a matrix size of 256 × 256.
For FDOPA–PET/CT, the patient was instructed to stop taking the tablet levodopa/carbidopa 2 days before the scan. The patient positioning and the injected dose were similar to those for FDG PET/CT, with a duration of the PET emission scan of ten minutes. No fasting was necessary, and a low-dose CT with 40 mA tube current was acquired (for attenuation correction and anatomic localisation only) to reduce the patient’s radiation exposure.
All patients underwent a thorough history and clinical examination, including calculation of levodopa equivalent dose, Hoer and Yahn (H and Y) stage and Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS UPDRS) with levodopa challenge test. Levodopa-responsive FOG was defined as a zero score for FOG in UPDRS 3.11 (which specifically assesses freezing of gait) after the levodopa challenge. Blood pressure was measured in the supine position, followed by 1 min, 3 min, and 5 min after standing to look for orthostatic fall. The tremor-dominant (TD) versus postural instability gait difficulty (PIGD) phenotype was found from the MDS-UPDRS score using the criteria mentioned previously.[13] Nonmotor symptoms (NMSs) were evaluated using the NMSs questionnaire.
The following tests were done for neuropsychological evaluation. The cognitive assessment was done in the ON state in all participants.
Handedness questionnaire
Montreal Cognitive Assessment (MoCA)
Frontal Assessment Battery
Addenbrooke’s Cognitive Examination
Patient Health Questionnaire (PHQ-9) for depression
Generalized Anxiety Disorder (GAD-7) scale for anxiety.
Autonomic functions were analyzed by calculating the autonomic function subscore from MDS-UPDRS.
Analysis of PET data
PET/CT images were evaluated by a qualified nuclear medicine physician in coronal, axial, and transaxial sections and in the reformatted coronal and sagittal sections. The raw PET, CT, and fused PET/CT images were evaluated in the reporting console (GE Advantage Workstation). In addition, the FDG PET/CT images were processed using vendor-provided software for brain imaging (CORTEX-ID, GE Health care). Visual analysis was done to assess for any focal hypo- or hypermetabolism in the various regions of the brain on the PET and fused PET/CT images, and the findings were correlated with the corresponding anatomical findings on the CT images. Dopaminergic expression in the basal ganglia was evaluated on the DOPA PET/CT images. The scans were analyzed visually. The FDOPA uptake in the bilateral caudate nucleus and putamen was compared for any asymmetrical uptake in relation to the side of dominant clinical symptoms. In addition, the severity of dopaminergic loss was categorized into mild, moderate, or severe based on uptake reduction in the caudate and putamen (Mild: reduced tracer uptake in the posterior most part of the putamen; Moderate: reduced tracer uptake in the entire putamen; and Severe: reduced tracer uptake in the caudate and putamen).
Images were analyzed visually on the Cortex-ID suite for any abnormal hypermetabolism or hypometabolism in the various brain regions with respect to a reference region of the brain (pons). The software also provided any abnormal hypo/hypermetabolism of the different brain areas by comparing it to the age-matched normal database, and the increase or decrease was recorded in standard deviations from the normal population. SUV max in these areas was calculated and divided by the background average SUV max to get the SUV max/average ratio for both caudate and putamen. For FDG PET, the background was the pons; for FDOPA PET, the background was the occipital lobe.
Statistical analysis
Data were entered into an Microsoft Excel spreadsheet program, and SPSS v23 (IBM, NY, USA Corp.) was used for data analysis. Mean/standard deviation was used for descriptive statistics, and median/ interquartile range for continuous variables. Frequencies and percentages were used for categorical variables. An independent sample t-test was used for continuously distributed data when comparing two groups. Nonparametric tests such as the Wilcoxon test or Mann–Whitney were used to compare nonnormally distributed data. The Chi-square test or Fisher‘s exact test was used for group comparisons of categorical data. Linear correlation between two continuous variables was explored using Pearson’s correlation (for normally distributed data) and Spearman’s correlation (for non-normally distributed data). P < 0.05 was considered statistically significant.
Results
Thirty-six patients were screened. Thirty patients were included in the final analysis, with 15 in each group, as six refused to undergo PET scanning. Baseline characteristics are mentioned in Table 1. The mean age of participants was 59.33 ± 9.12 in the FOG group and 61.13 ± 9.38 in the FOG + group. In the FOG group, 5 (33.3%) patients had left-sided disease onset, and 10 (66.7%) had right-sided onset. In the FOG + group, 4 (26%) patients had left-sided onset, and 11 (73.3%) had right-sided disease onset. Out of the 30 patients enrolled, 13 (43.3%) had the PIGD phenotype, and 14 (46.7%) had the TD phenotype, with 3 (10%) patients in the indeterminate group. The mean FOG-Q score in the FOG + group was 13.33 ± 3.94. Eighty percent of patients in the FOG + group had levodopa-responsive freezing of gait. Freezing of gait was more common in those with the PIGD phenotype.
Table 1.
Baseline characteristics
| Parameter | FOG + (n=15), mean±SD/frequency (%) | FOG − (n=15), mean±SD/frequency (%) | P |
|---|---|---|---|
| Age (years) | 59.33±9.12 | 61.13±9.38 | 0.598 |
| Male | 13 (86.7) | 13 (86.7) | 1.000 |
| Female | 2 (13.3) | 2 (13.3) | |
| Duration of disease (years) | 3.93±3.78 | 7.10±5.64 | 0.082 |
| Hoer and Yahn score | 2.63±0.39 | 2.06±0.45 | 0.001 |
| Hoer and Yahn 1 (n) | 0 | 1 | |
| Hoer and Yahn 2 (n) | 3 | 12 | |
| Hoer and Yahn 2.5 (n) | 5 | 0 | |
| Hoer and Yahn 3 (n) | 7 | 2 | |
| Right handed | 14 (93.3) | 15 (100) | 1.000 |
| Left handed | 1 (6.7) | 0 | |
| LED | 888.60±257.96 | 506.80±237.50 | 0.001 |
| PIGD | 12 | 1 | 0.0001 |
| Indeterminate | 1 | 2 | |
| TD | 2 | 12 | |
| Diabetes | 3 (20.0) | 2 (13.3) | 1.000 |
| Hypertension | 4 (26.7) | 1 (6.7) | 0.330 |
| UPDRS (off) | 49.80±9.73 | 43.13±15.33 | 0.166 |
| UPDRS (on) | 20.93±9.33 | 22.60±16.04 | 0.731 |
| NMS | 30.53±26.74 | 26.60±19.83 | 0.651 |
FOG: Freezing of gait, LED: Levodopa equivalent dose, PIGD: Postural instability and gait dysfunction, TD: Tremor dominant, UPDRS: Unified Parkinson’s Disease Rating Scale, NMS: Nonmotor symptoms, SD: Standard deviation
Cognitive, affective, and autonomic assessment
The mean MMSE score was 27.4 ± 1.84 in the FOG group and 27.7 ± 1.87 in the FOG + group. The mean MOCA score in the FOG group was 23.47 ± 2.99, and the FOG + group was 23.40 ± 3.13. The mean frontal assessment battery score was 13.87 ± 1.92 in the FOG – group and 13.40 ± 2.66 in the FOG + group (P = 0.587). The mean ACE-3 score was 83.60 ± 9.07 in the FOG group and 81.53 ± 8.19 in the FOG + group. Autonomic subscore derived from the UPDRS showed a mean score of 4.67 (3.35) in freezers versus 3.53 (1.99) in nonfreezers (P = 0.270). The mean PHQ-9 score was 5.33 (4.28) in the FOG – group and 6.67 (6.51) in the FOG + group (P = 0.513). The mean GAD-7 score was 5.13 (5.43) in the FOG group and 4.73 (3.93) (P: =0.819) in the FOG + group [Supplementary Tables 1 and 2].
Supplementary Table 1.
The results of the cognitive assessment
| Test | FOG − | FOG + | P |
|---|---|---|---|
| MMSE | 27.47±1.84 | 27.73±1.87 | 0.697 |
| MOCA | 23.47±2.99 | 23.40±3.13 | 0.953 |
| FAB | 13.87±1.92 | 13.40±2.66 | 0.587 |
| ACE total score | 83.60±9.07 | 81.53±8.19 | 0.518 |
| Attention | 16.73 (1.75) | 16.53 (1.68) | 0.752 |
| Memory | 20.13±3.62 | 19.80±3.59 | 0.802 |
| Fluency | 8.4 (2.23) | 8.07 (2.40) | 0.697 |
| Language | 24.93 (1.10) | 24.87 (1.55) | 0.893 |
| Visuospatial | 13.40 (1.99) | 12.27 (2.01) | 0.133 |
FOG: Freezing of gait, MMSE: Mini–mental status examination, MOCA: Montreal cognitive assessment, ACE: Addenbrooke’s cognitive examination, FAB: Frontal assessment battery
Supplementary Table 2.
The results of the autonomic tests
| Autonomic parameters | FOG groups |
P | |
|---|---|---|---|
| Negative (n=15), mean±SD/frequency (%) | Positive (n=15), mean±SD/frequency (%) | ||
| Pulse rate | 82.87±7.21 | 77.33±14.18 | 0.189 |
| Significant postural fall | 2 (13.3) | 1 (6.7) | 1.000 |
| Autonomic sub score | 3.53±1.99 | 4.67±3.35 | 0.270 |
FOG: Freezing of gait, SD: Standard deviation
FDOPA PET scan
FDOPA PET showed symmetrically reduced uptake in 9 out of 15 patients with freezing of gait (60%) and 3 out of 15 patients without freezing of gait (20%). The P value was significant (0.025), implying symmetrical reduction of dopaminergic uptake in freezers compared to nonfreezers [Table 2].
Table 2.
FDOPA-PET scan findings in the patients studied
| SITE | FOG − | FOG + | P |
|---|---|---|---|
| B/L symmetrical reduction | 3 (20) | 9 (60) | 0.025 |
| Asymmetrical reduction | 12 (80.0) | 6 (40.0) |
FOG: Freezing of gait, FDOPA-PET: Fluorodopa F-18 Positron Emission Tomography
Dopaminergic expression was analyzed separately in the caudate and putamen to assess the severity of reduction, categorizing it as either mild-to-moderate or severe. A greater proportion of patients with freezing of gait (FOG+) exhibited severe dopaminergic loss compared to nonfreezers (FOG−). However, it did not reach statistical significance [Table 3].
Table 3.
FDOPA-PET scan findings in the patients studied showing the degree of dopaminergic dysfunction
| Site | Parameter | Fog group |
P | |
|---|---|---|---|---|
| FOG − | FOG + | |||
| Left caudate | Mild/moderate | 4 | 1 | 0.065 |
| Severe | 6 | 11 | ||
| Right caudate | Mild/moderate | 10 | 5 | 0.068 |
| Severe | 5 | 10 | ||
| Left putamen | Mild/moderate | 5 | 3 | 0.682 |
| Severe | 10 | 12 | ||
| Right putamen | Mild/moderate | 5 | 0 | 0.042 |
| Severe | 10 | 15 | ||
FOG: Freezing of gait, FDOPA-PET: Fluorodopa F-18 Positron Emission Tomography
FDG-PET scan
The two groups had no significant difference regarding hypometabolism in the cortical areas or the basal ganglia. However, the SUV ratio was decreased in the left putamen in freezers compared to nonfreezers [Table 4 and Supplementary Tables 3-5].
Table 4.
Basal ganglia metabolic differences in freezing of gait + and freezing of gait − groups based on FDG - PET analysis
| Parameter | FOG group |
P | |
|---|---|---|---|
| FOG − | FOG + | ||
| SUV max/BG right caudate | 1.95±0.39 | 1.85±0.27 | 0.449 |
| SUV max/BG left caudate | 2.01±0.48 | 1.90±0.30 | 0.437 |
| SUV max/BG right putamen | 2.25±0.40 | 2.11±0.28 | 0.290 |
| SUV max/BG left putamen | 2.26±0.42 | 2.00±0.25 | 0.050 |
FOG: Freezing of gait, BG: Background, SUV: Standardized uptake value
Supplementary Table 3.
FDG-PET analysis in freezing of gait group
| Patient number | FDG-PET finding |
|---|---|
| 1 | Normal |
| 2 | Normal |
| 3 | Normal |
| 4 | Normal |
| 5 | Normal |
| 6 | Hypometabolism in bilateral frontal, parietal, lateral temporal, lateral occipital and precuneus; Asymmetric L>R |
| 7 | Hypometabolism in bilateral frontal, temporal, parietal cortex |
| 8 | Hypometabolism in bilateral frontal, parietal and temporal cortex |
| 9 | Hypometabolism in bilateral parietal, temporal and occipital cortices with hypermetabolism in bilateral basal ganglia |
| 10 | Hypometabolism in bilateral lateral prefrontal, lateral temporal and inferior parietal cortex |
| 11 | Hypometabolism in bilateral parieto-temporo-occipital cortices |
| 12 | Normal |
| 13 | Hypometabolism left putamen and cerebellum |
| 14 | Normal |
| 15 | Normal |
FDG-PET: Fluorodeoxyglucose positron emission tomography
Supplementary Table 5.
FDG-PET comparison of z-scores between various brain regions
| Parameters | FOG groups |
P | |
|---|---|---|---|
| Negative (n=15), mean±SD | Positive (n=15), mean±SD | ||
| Parietal association R | 1.41±0.82 | 1.25±0.79 | 0.600 |
| Parietal association L | 1.44±0.92 | 1.43±0.82 | 0.969 |
| Temporal association R | 1.08±0.76 | 0.92±0.62 | 0.542 |
| Temporal association L | 1.23±0.80 | 0.98±0.63 | 0.352 |
| Frontal association R | 1.01±0.83 | 1.05±0.74 | 0.893 |
| Frontal association L | 1.07±0.75 | 1.15±0.78 | 0.776 |
| Occipital A-R | 0.58±0.82 | 0.34±1.01 | 0.481 |
| Occipital A-L | 0.65±0.90 | 0.51±1.23 | 0.729 |
| Posterior cingulate-R | 0.74±0.66 | 0.74±0.68 | 0.981 |
| Posterior cingulate-L | 0.81±0.61 | 0.84±0.67 | 0.911 |
| Anterior cingulate -R | 0.84±0.71 | 0.68±0.54 | 0.481 |
| A C -L | 0.74±0.73 | 0.62±0.60 | 0.649 |
| Medial frontal -R | 0.62±0.94 | 0.71±0.62 | 0.770 |
| Medial frontal-L | 0.68±0.84 | 0.85±0.62 | 0.539 |
| Medial parietal -R | 1.00±1.04 | 0.96±0.87 | 0.930 |
| Medial parietal -L | 1.13±1.04 | 1.04±0.83 | 0.807 |
| Sensori motor -R | 0.82±0.80 | 0.73±0.76 | 0.756 |
| Sensori motor -L | 0.61±0.91 | 0.67±0.92 | 0.869 |
| Visual -R | 0.13±1.38 | 0.14±1.05 | 0.987 |
| Visual -L | 0.21±1.21 | 0.10±1.14 | 0.799 |
| Caudate -R | 1.42±0.84 | 1.27±0.74 | 0.613 |
| Caudate -L | 1.41±1.15 | 1.29±0.76 | 0.756 |
| Cerebellum -R | 0.13±0.26 | 0.05±0.45 | 0.573 |
| Cerebellum -L | 0.08±0.34 | −0.06±0.33 | 0.217 |
| Vermis- R | 0.04±0.55 | 0.07±0.69 | 0.609 |
| Vermis -L | 0.05±0.65 | 0.03±0.74 | 0.747 |
| Pons -R | 0.02±0.53 | −0.22±0.69 | 0.392 |
| Average association -R | 1.09±0.78 | 1.04±0.67 | 0.849 |
| Average association-L | 1.17±0.75 | 1.13±0.69 | 0.887 |
| Average cerebral | 0.87±0.73 | 0.83±0.61 | 0.855 |
| Global average | 0.72±0.65 | 0.67±0.52 | 0.814 |
FOG: Freezing of gait, FDG-PET: Fluorodeoxyglucose positron emission tomography
Supplementary Table 4.
FDG-PET analysis in freezing of gait + group
| Patient number | FDG-PET findings |
|---|---|
| 16 | Bilateral superior parietal hypometabolism |
| 17 | Normal |
| 18 | Normal |
| 19 | Normal |
| 20 | Bilateral frontal, parietal lateral temporal, lateral occipital cortices and precuneus |
| 21 | Normal study |
| 22 | Normal study |
| 23 | Hypometabolism in bilateral parietotemporal cortices |
| 24 | Normal |
| 25 | Normal |
| 26 | Bilateral frontal and parietal cortex hypometabolism |
| 27 | Normal |
| 28 | Hypometabolism in bilateral frontal, prefrontal, anterior cingulate, inferior parietal, lateral temporal cortex and cerebellum |
| 29 | Hypometabolism in bilateral caudate and putamen left > right |
| 30 | Hypometabolism in bilateral frontal, parietal and lateral temporal cortices |
FDG-PET: Fluorodeoxyglucose positron emission tomography
Figures 1 and 2 demonstrate two examples of FDOPA PET and FDG PET findings in a freezer and a nonfreezer.
Figure 1.
Fludeoxyglucose positron emission tomography (FDG PET) and FDOPA PET in a 36-year-old female with a duration of Parkinson’s disease for 3 years with rigidity and bradykinesia (right > left) and no freezing of gait. (a) (CORTEX ID images) and (b and c) (Fused axial FDG PET/computed tomography [CT] images) reveal no abnormal hyper- or hypometabolism in the brain. (d and e), FDOPA PET/CT (Fused axial PET/CT images), reveal severe presynaptic dopaminergic dysfunction in the bilateral striatum (left > right)
Figure 2.
Fludeoxyglucose positron emission tomography (FDG PET) and FDOPA PET in a 59-year-old male with Parkinson’s disease of 13-year duration and symptoms of tremors, bradykinesia and rigidity (Left > right) and off-period gait freezing. (a) (CORTEX ID) and (b and c) (Fused axial FDG PET/computed tomography [CT] images) reveal mild hypometabolism in the bilateral temporal, parietal and prefrontal cortices. (d and e) (Fused axial FDOPA PET/CT images) reveal severe presynaptic dopaminergic dysfunction in the bilateral striatum (right > left)
Discussion
We found that FOG-positive patients had higher H and Y scores, higher mean UPDRS-III scores and LED requirements than the FOG group. Eighty percent of freezers had levodopa-responsive freezing. Freezing of gait is more common in advanced stages of the disease, with an incidence ranging from 10% in H and Y1 to 40% in H and Y4.[14] Higher LED use is an independent risk factor for the development of FOG.[15] Freezing of gait was more common in the akinetic-rigid phenotype than in the tremor-predominant phenotype in our study, as shown in previous studies.[16,17] A more profound reduction of striatal dopamine levels in the akinetic-rigid phenotype affects the cortico-striatal networks and induces freezing behavior.
FDOPA PET scan analysis showed that freezers had a symmetrical loss of basal ganglia uptake compared to the nonfreezers, who had asymmetrical reduction. Bartels et al. also found similar results.[7] Furthermore, it was noted that freezers had a severe decrease in F-DOPA uptake. This was significant in the right and left caudate and the right putamen. Bartels et al. also found a significant reduction of FDOPA and FDG uptake in the caudate in freezers compared to nonfreezers, indicating increased striatal damage.[7] Our findings suggest that the freezing phenomenon results from a more severe dopaminergic dysfunction, which is reflected clinically also as it is more common in advanced disease and with higher Hoehn and Yahr stage, with a higher requirement of levodopa equivalent dose.
The FDG PET scan analysis revealed hypometabolism in the frontal and parietal regions in both freezers and nonfreezers. Although not statistically significant, a few additional areas of hypometabolism were noted in the FOG + group. Moreover, freezers exhibited a greater metabolic reduction in the basal ganglia, especially the left putamen, indicating impaired neuron function in the pathways that control gait initiation and execution.
Previous studies have also shown heterogeneous results involving multiple cortical and subcortical structures, i.e., frontoparietal regions, temporo-occipital cortex, brainstem, cerebellum, basal ganglia, thalamus, and limbic system. Most studies have pointed to lower perfusion or metabolism in the frontoparietal areas in PD with gait freezing.[10] Bartels et al. demonstrated reduced FDG uptake in the parietal regions bilaterally, with maximal involvement in right anteroinferior and posterior parietal regions.[7] Matsui et al. compared perfusion using three-dimensional stereotactic surface projections analysis of 123I SPECT in 24 PD patients with FOG with 34 PD patients without FOG.[18] The authors found decreased perfusion in bilateral Brodmann area 11 (orbitofrontal cortex). Similarly, Imamura et al. also found reduced cerebral perfusion in bilateral BA 10.11 and right BA 32 with maintenance and preventing further decline in cerebral blood flow in the selegiline group at 1-year follow-up.[19]
We found no significant difference between the two groups regarding cognitive, affective, and autonomic assessments. Freezing of gait has been associated with worse cognitive impairment on neuropsychological testing in Parkinson’s disease, contrary to our results.[20,21] One of the reasons for the lack of difference in the FOG + and FOG groups in terms of cognitive functions might be that the evaluation was done in the on state. Most patients in our study had levodopa-responsive freezing, which could have affected the cognitive examination. Dopamine has a complex effect on cognition.[22] On the one hand, it improves several cognitive processes, but overloading the dopaminergic system may also reduce cognitive performance for other cognitive processes.[23] However, the cognitive impairment may also be an independent process from the cognitive dysfunction. The mechanism of freezing of gait may rest in the basal ganglia and its connections, and in the subcortex rather than being a cortical phenomenon. However, this may need further exploration. Neuroimaging studies have found that the involvement of the parietal lobe rather than the frontal lobe is more specific for FOG.[24] Functional MRI and diffusion tensor imaging have shown altered functional connectivity between the pedunculopontine nucleus, corticopontine-cerebellar pathways and visual temporal areas.[25,26]
Besides the small sample size and lack of randomization, our study has significant limitations. It was a cross-sectional study, and follow-up assessments were not performed. More importantly, most patients in the FOG group had levodopa-responsive freezing, which does not represent the true picture, and the findings cannot be generalized. Another limitation was the visual analysis of FDG PET and FDOPA PET images, rather than standardized objective measures like SPM analysis used in previous studies.
Conclusion
Gait freezing occurred more commonly in PD patients with more severe disease and those with a PIGD phenotype. Freezers exhibited a more symmetrical loss of dopaminergic uptake on FDOPA PET, whereas nonfreezers showed greater asymmetry. In addition, FDG PET revealed a trend toward greater basal ganglia hypometabolism in freezers, suggesting a more profound striatal dysfunction. More widespread frontoparietal cortical hypometabolism was also observed in freezers, although cognitive, affective, and autonomic function scores did not differ significantly between groups. These findings reinforce the role of striatal and cortical dysfunction in the pathophysiology of FOG, have potential clinical relevance by helping to identify patients at higher risk of FOG, and could support more targeted interventions, particularly those aimed at cognitive or executive domains, in earlier stages of care.
One may argue about the utility of these costly imaging techniques in the routine clinical care of Parkinson’s disease. Our study demonstrates specific brain changes in patients with freezing of gait, such as more symmetrical dopamine loss and broader areas of reduced brain activity. These findings may not immediately change treatment but can help better understand which patients are more likely to develop freezing. This information could help select patients for clinical trials or develop more targeted treatment approaches.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
References
- 1.Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of gait: Moving forward on a mysterious clinical phenomenon. Lancet Neurol. 2011;10:734–44. doi: 10.1016/S1474-4422(11)70143-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Weiss D, Schoellmann A, Fox MD, Bohnen NI, Factor SA, Nieuwboer A, et al. Freezing of gait: Understanding the complexity of an enigmatic phenomenon. Brain. 2020;143:14–30. doi: 10.1093/brain/awz314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Lewis SJ, Shine JM. The next step: A common neural mechanism for freezing of gait. Neuroscientist. 2016;22:72–82. doi: 10.1177/1073858414559101. [DOI] [PubMed] [Google Scholar]
- 4.Bluett B, Banks S, Cordes D, Bayram E, Mishra V, Cummings J, et al. Neuroimaging and neuropsychological assessment of freezing of gait in Parkinson’s disease. Alzheimers Dement (N Y) 2018;4:387–94. doi: 10.1016/j.trci.2018.04.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Raffo De Ferrari A, Lagravinese G, Pelosin E, Pardini M, Serrati C, Abbruzzese G, et al. Freezing of gait and affective theory of mind in Parkinson disease. Parkinsonism Relat Disord. 2015;21:509–13. doi: 10.1016/j.parkreldis.2015.02.023. [DOI] [PubMed] [Google Scholar]
- 6.Maidan I, Plotnik M, Mirelman A, Weiss A, Giladi N, Hausdorff JM. Heart rate changes during freezing of gait in patients with Parkinson’s disease. Mov Disord. 2010;25:2346–54. doi: 10.1002/mds.23280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Bartels AL, de Jong BM, Giladi N, Schaafsma JD, Maguire RP, Veenma L, et al. Striatal dopa and glucose metabolism in PD patients with freezing of gait. Mov Disord. 2006;21:1326–32. doi: 10.1002/mds.20952. [DOI] [PubMed] [Google Scholar]
- 8.Tard C, Delval A, Devos D, Lopes R, Lenfant P, Dujardin K, et al. Brain metabolic abnormalities during gait with freezing in Parkinson’s disease. Neuroscience. 2015;307:281–301. doi: 10.1016/j.neuroscience.2015.08.063. [DOI] [PubMed] [Google Scholar]
- 9.Ono SA, Sato T, Muramatsu S. Freezing of gait in Parkinson’s disease is associated with reduced 6-[(18)F] Fluoro-l-m-tyrosine uptake in the locus coeruleus. Parkinsons Dis. 2016;2016:5430920. doi: 10.1155/2016/5430920. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Bharti K, Suppa A, Tommasin S, Zampogna A, Pietracupa S, Berardelli A, et al. Neuroimaging advances in Parkinson’s disease with freezing of gait: A systematic review. Neuroimage Clin. 2019;24:102059. doi: 10.1016/j.nicl.2019.102059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181–4. doi: 10.1136/jnnp.55.3.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Giladi N, Shabtai H, Simon ES, Biran S, Tal J, Korczyn AD. Construction of freezing of gait questionnaire for patients with Parkinsonism. Parkinsonism Relat Disord. 2000;6:165–70. doi: 10.1016/s1353-8020(99)00062-0. [DOI] [PubMed] [Google Scholar]
- 13.Stebbins GT, Goetz CG, Burn DJ, Jankovic J, Khoo TK, Tilley BC. How to identify tremor dominant and postural instability/gait difficulty groups with the movement disorder society unified Parkinson’s disease rating scale: Comparison with the unified Parkinson’s disease rating scale. Mov Disord. 2013;28:668–70. doi: 10.1002/mds.25383. [DOI] [PubMed] [Google Scholar]
- 14.Perez-Lloret S, Negre-Pages L, Damier P, Delval A, Derkinderen P, Destée A, et al. Prevalence, determinants, and effect on quality of life of freezing of gait in Parkinson disease. JAMA Neurol. 2014;71:884–90. doi: 10.1001/jamaneurol.2014.753. [DOI] [PubMed] [Google Scholar]
- 15.Forsaa EB, Larsen JP, Wentzel-Larsen T, Alves G. A 12-year population-based study of freezing of gait in Parkinson’s disease. Parkinsonism Relat Disord. 2015;21:254–8. doi: 10.1016/j.parkreldis.2014.12.020. [DOI] [PubMed] [Google Scholar]
- 16.Hall JM, Shine JM, Walton CC, Gilat M, Kamsma YP, Naismith SL, et al. Early phenotypic differences between Parkinson’s disease patients with and without freezing of gait. Parkinsonism Relat Disord. 2014;20:604–7. doi: 10.1016/j.parkreldis.2014.02.028. [DOI] [PubMed] [Google Scholar]
- 17.Jha M, Jhunjhunwala K, Sankara BB, Saini J, Kumar JK, Yadav R, et al. Neuropsychological and imaging profile of patients with Parkinson’s disease and freezing of gait. Parkinsonism Relat Disord. 2015;21:1184–90. doi: 10.1016/j.parkreldis.2015.08.009. [DOI] [PubMed] [Google Scholar]
- 18.Matsui H, Udaka F, Miyoshi T, Hara N, Tamaura A, Oda M, et al. Three-dimensional stereotactic surface projection study of freezing of gait and brain perfusion image in Parkinson’s disease. Mov Disord. 2005;20:1272–7. doi: 10.1002/mds.20520. [DOI] [PubMed] [Google Scholar]
- 19.Imamura K, Okayasu N, Nagatsu T. Cerebral blood flow and freezing of gait in Parkinson’s disease. Acta Neurol Scand. 2012;126:210–8. doi: 10.1111/j.1600-0404.2012.01652.x. [DOI] [PubMed] [Google Scholar]
- 20.Morris R, Smulders K, Peterson DS, Mancini M, Carlson-Kuhta P, Nutt JG, et al. Cognitive function in people with and without freezing of gait in Parkinson’s disease. NPJ Parkinsons Dis. 2020;6:9. doi: 10.1038/s41531-020-0111-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Amboni M, Cozzolino A, Longo K, Picillo M, Barone P. Freezing of gait and executive functions in patients with Parkinson’s disease. Mov Disord. 2008;23:395–400. doi: 10.1002/mds.21850. [DOI] [PubMed] [Google Scholar]
- 22.Pillon B, Czernecki V, Dubois B. Dopamine and cognitive function. Curr Opin Neurol. 2003;16(Suppl 2):S17–22. doi: 10.1097/00019052-200312002-00004. [DOI] [PubMed] [Google Scholar]
- 23.Brugger F, Abela E, Hägele-Link S, Bohlhalter S, Galovic M, Kägi G. Do executive dysfunction and freezing of gait in Parkinson’s disease share the same neuroanatomical correlates? J Neurol Sci. 2015;356:184–7. doi: 10.1016/j.jns.2015.06.046. [DOI] [PubMed] [Google Scholar]
- 24.Rubino A, Assogna F, Piras F, Di Battista ME, Imperiale F, Chiapponi C, et al. Does a volume reduction of the parietal lobe contribute to freezing of gait in Parkinson’s disease? Parkinsonism Relat Disord. 2014;20:1101–3. doi: 10.1016/j.parkreldis.2014.07.002. [DOI] [PubMed] [Google Scholar]
- 25.Wang M, Jiang S, Yuan Y, Zhang L, Ding J, Wang J, et al. Alterations of functional and structural connectivity of freezing of gait in Parkinson’s disease. J Neurol. 2016;263:1583–92. doi: 10.1007/s00415-016-8174-4. [DOI] [PubMed] [Google Scholar]
- 26.Gallardo MJ, Cabello JP, Corrales MJ, Torres-Donaire J, Bravo JJ, Talavera MP, et al. Freezing of gait in Parkinson’s disease: Functional neuroimaging studies of the frontal lobe. Neurol Res. 2018;40:900–5. doi: 10.1080/01616412.2018.1484985. [DOI] [PubMed] [Google Scholar]