Disease Rating Scale Motor Score Research Articles

Effectiveness of Balance Exercise and Brisk Walking on Alleviating Nonmotor and Motor Symptoms in People With Mild-to-Moderate Parkinson Disease: A Randomized Clinical Trial With 6-Month Follow-up

ObjectiveTo investigate the effects of balance exercise and brisk walking on nonmotor and motor symptoms, balance and gait functions, walking capacity, and balance confidence in Parkinson disease (PD) at posttraining and 6-month follow-up. DesignTwo-arm, assessor-blinded randomized controlled trial SettingUniversity research laboratory and the community ParticipantsNinety-nine eligible individuals with mild-to-moderate PD InterventionsParticipants were randomized to balance and brisk walking group (B&B, n=49) or active control group (n=50). B&B received ten 90-minute sessions of balance exercises and brisk walking supervised by physical therapists for 6 months (week 1-6: weekly, week 7-26: monthly), whereas control practiced whole-body flexibility and upper limb strength exercise at same dosage (180 min/wk). Both groups performed unsupervised home exercises 2-3 times/wk during intervention and continued at follow-up. Main Outcome MeasuresPrimary outcomes were Movement Disorder Society Unified Parkinson Disease Rating Scale nonmotor (MDS-UPDRS-I) and motor (MDS-UPRDS-III) scores. Secondary outcomes were mini-Balance Evaluation Systems Test (mini-BEST) score, comfortable gait speed (CGS), 6-minute walk test (6MWT), dual-task timed-Up-and-Go (DTUG) time, and Activities-Specific Balance Confidence Scale score. ResultsEighty-three individuals completed the 6-month intervention with no severe adverse effects. The mean between-group (95% CI) difference for the MDS-UPDRS nonmotor score was 1.50 (0.19-2.81) at 6 months and 1.09 (−0.66 to 2.85) at 12 months. The mean between-group (95% CI) difference for the MDS-UPDRS motor score was 3.75 (0.69-6.80) at 6 months and 4.57 (1.05-8.01) at 12 months. At 6 and 12 months, there were significant between-group improvements of the B&B group in mini-BEST score, CGS, 6MWT, and DTUG time. ConclusionsThis combined balance and brisk walking exercise program alleviates nonmotor and motor symptoms and improves walking capacity, balance, and gait functions posttraining, with positive carryover effects for all except nonmotor outcomes, at 6-month follow-up in mild-to-moderate PD.

Prediction of Treatment Response and Effect on Clinical Manifestations for Normal Pressure Hydrocephalus of Sleep Related Breathing Disorders

Objectives: Sleep disorders and normal pressure hydrocephalus (NPH) are increasingly important issues observed in neurological disorders. However, the correlation between these diseases has not been sufficiently studied. Thus, we discuss the correlation between sleep disorders and the clinical features of NPH. Methods: Overall, 40 patients with idiopathic NPH were included in the study. To evaluate the sleep disorders and psychiatric problems, surveys were administered, including the 36-Item Short Form Survey, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), Berlin Questionnaire, STOP-Bang Questionnaire, Hospital Anxiety and Depression Scale (HADS), Morningness-Eveningness Questionnaire, and the REM Sleep Behavior Disorder Screening Questionnaire. To evaluate the severity of dementia and ataxia, all of the patients completed the Korean mini-mental state examination; Korea frontal assessment battery score, amd unified Parkinson’s disease rating scale-motor scores before and after cerebrospinal fluid (CSF) drainage. The Pearson’s chi-square test, independent Student’s t-test, Mann–Whitney U test, and linear regression analysis were used to analyze the relationship between sleep disorders and symptom improvement after CSF drainage. Results: Of the 40 patients, 21 patients had poor sleep quality (PSQI>5), 8 patients had insomnia (ISI≥8), 11 patients had daytime sleepiness (ESS≥11), 9 (STOP-Bang≥3) to 13 (Berlin≥2 categories) patients had sleep apnea, 13 patients were anxious (HAS≥8), and 27 patients were depressed (HDS≥8). A linear regression analysis showed that sleep apnea was significantly correlated with cognitive function, and insomnia was correlated with cognitive, motor, and frontal lobe functions. Additionally, patients with severe sleep apnea demonstrated a greater recovery of cognitive function after CSF drainage. Conclusions: Obstructive sleep apnea (OSA) is closely related to the clinical symptoms and treatment effectiveness of NPH. The diagnosis and proper treatment of OSA is expected to improve the prognosis of patients with NPH.

Efficacy of Wearable low-intensity pulsed Ultrasound treatment in the Movement disorder in Parkinson’s disease (the SWUMP trial): protocol for a single-site, double-blind, randomized controlled trial

BackgroundParkinson’s disease (PD) is a progressive, neurodegenerative illness marked by the loss of dopaminergic neurons, causing motor symptoms. Oral levodopa replacement therapy remains the gold standard in the treatment of PD. It is, nevertheless, a symptomatic treatment. There is currently no effective treatment for PD. Therefore, new therapies for PD are highly desirable. Low-intensity pulsed ultrasound (LIPUS) has been shown to improve behavioral functions in PD animal models. It is a new type of neuromodulation approach that combines noninvasiveness with high spatial precision. The purpose of this study is to establish a new clinical protocol for LIPUS in the treatment of movement disorders in patients with PD.MethodsThis protocol is a single-site, prospective, double-blind, randomized controlled trial (RCT). Forty-eight participants with clinically confirmed PD will be randomly allocated to one of two groups: LIPUS group or sham group. All of the participants continue to use pharmacological therapy as a fundamental treatment. The primary outcome is the difference between groups from baseline to 4 months in the change in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (part III). The secondary outcomes include the rating scales such as the Mini-Mental State Examination (MMSE), and other three rating scales, and medical examinations including high-density electroencephalography (hdEEG) and functional magnetic resonance imaging (fMRI). The primary safety outcome will be assessed at 4 months, and adverse events will be recorded.DiscussionThis study represents the clinical investigation into the efficacy of therapeutic LIPUS in the treatment of PD for the first time. If LIPUS is determined to be effective, it could offer a practical and innovative means of expanding the accessibility of ultrasound therapy by using a wearable LIPUS device within a home setting.Trial registrationChinese Clinical Trial Registry ChiCTR2100052093. Registered on 17 October 2021.

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson's disease.

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31min) and time to maximal response was two times shorter (27 vs. 61min) for 4mg SC vs. 50mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.

Safety and efficacy of faecal microbiota transplantation in patients with mild to moderate Parkinson's disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial

Dysregulation of the gut microbiome has been implicated in Parkinson's disease (PD). This study aimed to evaluate the clinical effects and safety of a single faecal microbiota transplantation (FMT) in patients with early-stage PD. The GUT-PARFECT trial, a single-centre randomised, double-blind, placebo-controlled trial was conducted at Ghent University Hospital between December 01, 2020 and December 12, 2022. Participants (aged 50-65 years, Hoehn and Yahr stage 2) were randomly assigned to receive nasojejunal FMT with either healthy donor stool or their own stool. Computer-generated randomisation was done in a 1:1 ratio through permutated-block scheduling. Treatment allocation was concealed for participants and investigators. The primary outcome measure at 12 months was the change in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score obtained during off-medication evaluations. Intention-to-treat analysis was performed using a mixed model for repeated measures analysis. This completed trial is registered on ClinicalTrials.gov (NCT03808389). Between December 2020 and December 2021, FMT procedures were conducted on 46 patients with PD: 22 in the healthy donor group and 24 in the placebo group. Clinical evaluations were performed at baseline, 3, 6, and 12 months post-FMT. Full data analysis was possible for 21 participants in the healthy donor group and 22 in the placebo group. After 12 months, the MDS-UPDRS motor score significantly improved by a mean of 5.8 points (95% CI-11.4 to-0.2) in the healthy donor group and by 2.7 points (-8.3 to 2.9) in the placebo group (p=0.0235). Adverse events were limited to temporary abdominal discomfort. Our findings suggested a single FMT induced mild, but long-lasting beneficial effects on motor symptoms in patients with early-stage PD. These findings highlight the potential of modulating the gut microbiome as a therapeutic approach and warrant a further exploration of FMT in larger cohorts of patients with PD in various disease stages. Flemish PD patient organizations (VPL and Parkili), Research Foundation Flanders (FWO), Biocodex Microbiota Foundation.

Evaluation of Substantia Nigra morphology in Parkinson's Disease.

In the elderly population, Parkinson's Disease (PD) is the second most common neurodegenerative disorder and is associated with morphological changes in the basal ganglia, especially the substantia nigra (SN). This study aimed to evaluate the volume and signal intensity (SI) of SN using Magnetic Resonance Imaging (MRI) to detect structural changes and investigate the relationship between the onset side and disease severity of PD. Clinical features and imaging data of 58 patients with PD were retrospectively analyzed from their medical records. Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences of 3 Tesla (T) MRIs were used for the measurements. The right and left SN volumes and SI measurements were calculated in duplicate by 2 blinded and qualified neuroradiologists. The side of disease onset, disease duration, levodopa equivalent daily dose, Movement Disorder Society-sponsored Unified Parkinson Disease Rating Scale (MDS-UPDRS III) motor score, and modified Hoehn and Yahr (H&Y) scale scores were recorded and compared with SN volume and SI measurements. No statistically significant difference was found between the disease onset side and contralateral SN volume or SI measurements (P > .05). Despite high inter- and intra-rater reliability rates, there was no significant difference in the volume and SI of the contralateral SN according to H&Y stages (P > .05). Furthermore, SN volume and SI measurements were not significantly correlated with disease duration and MDS-UPDRS III motor score (P > .05). SN volume and SI values measured using axial FLAIR 3T MRI are not correlated with the side of onset or disease severity in PD. New imaging methods are required to detect preclinical or early-stage PD.

Alpha-synuclein in peripheral body fluid as a biomarker for Parkinson's disease.

Whether alpha-synuclein in peripheral body fluids can be used for the diagnosis of Parkinson's disease (PD) remains in controversy. This study evaluates diagnostic potential of alpha-synuclein for PD in various peripheral body fluids using a meta-analysis approach. Studies published before October 2022 were searched in Web of Science and PubMed databases. The results were computed using the STATA 12.0 statistical software. In plasma, PD patients exhibited elevated alpha-synuclein levels relative to healthy controls (HCs) [standard mean difference (SMD) = 0.78, 95% confidence interval (CI) = 0.42 to 1.15] with a sensitivity of 0.79 (95% CI: 0.64-0.89) and a specificity of 0.95 (95% CI: 0.90-0.98). Higher plasma alpha-synuclein levels were correlated with longer disease durations, higher Unified Parkinson's Disease Rating Scale motor scores, and higher Hoehn and Yahr stages in PD patients. Plasma neural-derived exosomal alpha-synuclein levels (SMD = 1.82, 95% CI = 0.30 to 3.35), ratio of plasma neural-derived exosomal alpha-synuclein to total alpha-synuclein (SMD = 1.26, 95% CI = 0.19 to 2.33), and erythrocytic alpha-synuclein levels were also increased in PD patients (SMD = 6.57, 95% CI = 3.55 to 9.58). In serum, there was no significant difference in alpha-synuclein levels between PD patients and HCs (SMD = 0.54, 95% CI = -0.27 to 1.34). In saliva, reduced alpha-synuclein levels were observed in PD patients (SMD = -0.85, 95% CI = -1.67 to -0.04). Alpha-synuclein levels in plasma, plasma neural-derived exosome, erythrocyte, and saliva may serve as potential biomarkers for the diagnosis of PD.

Longitudinal free‐water changes in dementia with Lewy bodies

AbstractBackgroundDiffusion‐weighted MRI (dMRI) examines tissue microstructure integrity and white matter pathways in vivo. Prior dementia with Lewy bodies (DLB) studies focused on white matter or voxel‐based techniques. Less is known about longitudinal white and grey matter microstructural changes in DLB. We aimed to characterize longitudinal diffusion microstructural changes in individuals with DLB.MethoddMRI scans were collected on individuals with DLB from the Mayo Clinic Longitudinal Imaging Biomarkers of DLB Program. Demographics, clinical evaluations and MRI were collected at baseline, and 12‐ or 24‐months. Free water (FW) and FW‐corrected fractional anisotropy (FAT) were analyzed in grey and white matter using 122 bilateral template regions and tracts of interest from the Mayo Clinic Adult Lifespan Template. Primary outcomes were differences in FW and FAT between baseline and 12‐ or 24‐months.ResultWe identified 23 individuals with DLB or mild cognitive impairment with Lewy bodies (MCI‐LB) from baseline to 12‐months [mean age 69.3 years (SD 9.5); 95.8% male], and 16 individuals from baseline to 24‐months [mean age 67.5 years (SD 9.3); 100% male]. Participants at both time‐points showed worsening in Montreal Cognitive Assessment and Movement Disorders Society Unified Parkinson’s Disease Rating Scale motor scores (p<0.05). We found significant differences in FW, but not FAT, from baseline to 12‐months. Significant increases in FW at both time‐points compared to baseline were observed in the insula, putamen, parahippocampal, and rolandic operculum regions (pfdr<0.05). We found additional more widespread microstructural changes from baseline to 24‐months, with increased FW in the amygdala, entorhinal, mid and posterior cingulum, inferior frontal, hippocampal, pallidum, precuneus and retrosplenial regions (pfdr<0.05). We found decreased FAT from baseline to 24‐months in the cerebellar and superior occipital regions (pfdr<0.01).ConclusionLonger follow‐up at 24‐months identified broader networks of free water changes in individuals with DLB. Results support dMRI as a promising, non‐invasive tool to track disease progression in DLB. More investigation is needed to evaluate the relationship of microstructural changes with clinical progression in DLB.

Utility of Baseline Pathological, Neuroimaging and Clinical Markers for Progression Prognosis and Subtype Classification in Early Parkinson’s Disease: Implications for Cognitive Impairment

AbstractBackgroundCognitive dysfunction is a well‐recognised PD symptom, but it is highly heterogenous and under‐assessed clinically. Interestingly, PD motor subtypes are associated with different risk of cognitive decline. However, subtype classification is currently reliant on subjective clinician assessment and may consequently be misdiagnosed. Therefore, objective biomarkers of PD progression are critically needed, but must be validated prior to clinical deployment. We assessed the utility of various clinical, neuroimaging and pathological measures as predictors of cognitive outcomes up to 5‐years follow‐up in early PD.MethodData was extracted from the Parkinson’s Progression Markers Initiative. Cognitive assessments were compiled into an overall cognition score via principal component analysis. Distinct subgroups were identified via Fuzzy C‐Means clustering on Year‐5 Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores. Models predicting cluster membership were created via logistic regression and a stratified cross‐validation machine learning pipeline, comparing two predictor inputs: 1) baseline motor assessments; and 2) incorporating additional measures, including prodromal assessments (sleep, olfactory and autonomic function), neuroimaging (proxy SN volume, striatal DaT binding) and biofluid markers (CSF alpha‐syn, p‐tau, a‐beta, and serum IGF‐1) at baseline. Finally, cluster membership was used for retroactive assessment of baseline and follow‐up cognitive data.ResultsTwo clusters were identified, with cluster two (n = 117) demonstrating higher rigidity, lower DaT binding, worsened motor outcomes and increased mood dysfunction at follow‐up compared to tremor‐dominant cluster one (n = 183). Additionally, rigid‐dominant membership was predicted by male sex, higher p‐tau, along with lower a‐beta, predicting 40% of variance (n = 111). This was significantly higher (P<0.001) than baseline motor scores alone, only accounting for 18% of variance. This was supported by machine learning, whereby incorporating additional assessments corresponded to a classification accuracy of 62%, compared to 26% when omitted. Finally, higher probability of belonging to the rigid‐dominant cluster yielded significant negative correlations cognition at baseline and follow‐up.ConclusionIncreased likelihood of rigid‐dominance corresponded to more profound cognitive decline, which may in part result from neuropathological marker concentrations as highlighted by predictive models. Therefore, further tracking of this cohort, specifically conversion into MCI or dementia, could provide insight into pathological contribution to differences in cognitive decline between PD subtypes.

4 An Update: Greater Apathy Associated with Selective Serotonin Reuptake Inhibitor Use in Parkinson’s Disease

Objective:Apathy is a primary lack of motivation that is frequently reported in Parkinson’s disease (PD) and often misdiagnosed as depression. In PD, apathy worsens over time with motor symptom progression. Evidence over the past 15 years has documented that use of selective serotonin reuptake inhibitors (SSRIs) is associated with increased apathy in patients with depression, including individuals with PD. In PD, this appears to be related to downregulation of dopaminergic systems by serotonin. Despite increasing evidence, SSRIs continue to be heavily prescribed in individuals with PD— potentially worsening apathy and decreasing quality of life for these individuals. This study is an update, re-examining the relationship between apathy and the use of SSRIs and other antidepressants in a large cohort of individuals with PD.Participants and Methods:Participants included a convenience sample of 387 nondemented individuals with idiopathic PD who were in their mid-60's (mean age=64.9+8.72 years), well-educated (mean=14.95+2.78 years), predominantly male (72.4%), non-Hispanic white (94.5%), and in mid-stage of disease severity (on medication Unified Parkinson Disease Rating Scale motor score=25.3+10.1). All scored above clinical cutoff for dementia on a cognitive screener (Dementia Rating Scale-2 (DRS) > 125). Medications, cognitive, mood, and clinical data were extracted from chart review. Depression and apathy were measured using the Beck Depression Inventory-II (BDI-Il) and the Apathy Scale (AS). Antidepressant medications were grouped into SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs) and other. Analyses included bootstrapped Pearson’s correlations, Pearson’s chi-square, and linear regressionsResults:Among 387 individuals with PD, 41.3% (N=160) were taking antidepressant medications. Of these 160, 61.3% were on SSRIs, 24.4% on SNRIs, and the remainder on other antidepressants. Approximately 36.9% of the 387 PD patients exceeded recommended clinical cutoffs for apathy (AS >14) and 23.5% for depression (BDI-II >14) (Starkstein et al., 1992; Beck et al., 1996). Individuals taking SSRIs (N=98, x2=5.14, p=0.023) or SNRIs (N=39; x2=5.43, p=0.020) were more likely to be clinically apathetic than those taking other depression medications (N=23; x2=1.28, p=0.26). Results of a multiple regression with age, education, disease duration, motor severity, DRS-2, BDI-II, and all psychotropic medications (anti-depressants, anti-anxiety, anti-psychotics) as independent variables explained 42.8% of the variance in total apathy scores (F[17,285]=12.550, p<0.001). SSRIs were the only medication to significantly predict greater AS scores (ß=0.110, p=0.020) in this model. Less education (ß=-0.119, p=0.017) worse cognition (ß=-0.128, p=0.009), and greater depressive symptoms (ß=0.561, p<0.001) were also significant predictors of apathy.Conclusions:These findings suggest that use of SSRIs, but not other antidepressants, is associated with greater apathy in PD. Given the interactive relationship between serotonin and dopamine, the current findings highlight the importance of considering apathy as a potential adverse effect when determining which anti-depressants to prescribe to individuals with PD. Similarly, switching a SSRI for an alternative anti-depressant in individuals with PD who are apathetic may be a potential treatment for apathy that needs further study. Longitudinal studies are also needed to elucidate the relationship of apathy and anti-depressant use over time, specifically to determine potential causality of this observed association. Funding: T32-NS082168

Comparing the effects of GBA variants and onset age on clinical features and progression in Parkinson's disease.

Glucosylceramidase (GBA) variants and onset age significantly affect clinical phenotype and progression in Parkinson's disease (PD). The current study compared clinical characteristics at baseline and cognitive and motor progression over time among patients having GBA-related PD (GBA-PD), early-onset idiopathic PD (early-iPD), and late-onset idiopathic PD (late-iPD). We recruited 88 GBA-PD, 167 early-iPD, and 488 late-iPD patients in this study. A subset of 50 GBA-PD, 81 early-iPD, and 223 late-iPD patients was followed up at least once, with a 3.0-year mean follow-up time. Linear mixed-effects models helped evaluate the rate of change in the Unified Parkinson's Disease Rating Scale motor and Montreal Cognitive Assessment scores. At baseline, the GBA-PD group showed more severe motor deficits and non-motor symptoms (NMSs) than the early-iPD group and more NMSs than the late-iPD group. Moreover, the GBA-PD group had more significant cognitive and motor progression, particularly bradykinesia and axial impairment, than the early-iPD and late-iPD groups at follow-up. However, the early-onset GBA-PD (early-GBA-PD) group was similar to the late-onset GBA-PD (late-GBA-PD) group in baseline clinical features and cognitive and motor progression. GBA-PD patients exhibited faster cognitive and motor deterioration than early-iPD and late-iPD patients. Thus, subtype classification based on genetic characteristics rather than age at onset could enhance the prediction of PD disease progression.

Longitudinal Imaging of Regional Brain Volumes, SV2A, and Glucose Metabolism In Huntington's Disease.

Development of disease-modifying treatments for Huntington's disease (HD) could be aided by the use of imaging biomarkers of disease progression. Positron emission tomography (PET) with 11 C-UCB-J, a radioligand for the brain-wide presynaptic marker synaptic vesicle protein 2A (SV2A), detects more widespread brain changes in early HD than volumetric magnetic resonance imaging (MRI) and 18 F-fludeoxyglucose (18 F-FDG) PET, but longitudinal 11 C-UCB-J PET data have not been reported. The aim of this study was to compare the sensitivity of 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI for detection of longitudinal changes in early HD. Seventeen HD mutation carriers (six premanifest and 11 early manifest) and 13 healthy controls underwent 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI at baseline (BL) and after 21.4 ± 2.7 months (Y2). Within-group and between-group longitudinal clinical and imaging changes were assessed. The HD group showed significant 2-year worsening of Unified Huntington's Disease Rating Scale motor scores. There was significant longitudinal volume loss within the HD group in caudate (-4.5% ± 3.8%), putamen (-3.6% ± 3.5%), pallidum (-3.0% ± 2.7%), and frontal cortex (-2.0% ± 2.1%) (all P < 0.001). Within the HD group there was longitudinal loss of putaminal SV2A binding (6.4% ± 8.8%, P = 0.01) and putaminal glucose metabolism (-2.8% ± 4.4%, P = 0.008), but these changes were not significant after correction for multiple comparisons. Premanifest subjects at BL only had significantly lower SV2A binding than controls in basal ganglia structures, but at Y2 additionally had significant SV2A loss in frontal and parietal cortex, indicating spread of SV2A loss from subcortical to cortical regions. Volumetric MRI may be more sensitive than 11 C-UCB-J PET and 18 F-FDG PET for detection of 2-year brain changes in early HD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson’s disease in a patient with GBA and LRRK2 covariants after acute hypoxic insult: a case report

BackgroundThe glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with the risk of sporadic Parkinson’s disease (PD). As an environmental factor, hypoxic insults may impair dopamine neurons in the substantia nigra and exacerbate PD symptoms. However, covariants of GBA and LRRK2 combined with hypoxic insults in clinical cases of Parkinsonism have not yet been reported.Case presentationA 69-year-old male patient with PD and his relatives were clinically characterized and sequenced using the whole-exome technique. A novel covariant, c.1448 T > C (p. L483P, rs421016) on GBA and c.691 T > C (p. S231P, rs201332859) on LRRK2 were identified in this patient who first developed bradykinesia and rigidity in the neck at one month after an acute hypoxic insult during mountaineering. The patient presented with a mask-like face, festinating gait, asymmetric bradykinesia, and moderate rigidity. These symptoms were treated with levodopa and pramipexole, resulting in a 65% improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. These parkinsonian symptoms persisted and developed with hallucinations, constipation, and rapid eye movement sleep behavior disorder. After 4 years, the patient exhibited a wearing-off phenomenon and died from pulmonary infection 8 years after disease onset. His parents, wife, and siblings were not diagnosed with PD, and his son carried p. L483P without Parkinsonism-like symptoms.ConclusionsThis is a case report of PD after hypoxic insult in a patient carrying a covariant of GBA and LRRK2. This study may help us understand the interaction between genetic and environmental factors in clinical PD.

Development of anxiety in early Parkinson's disease: A clinical and biomarker study.

Anxiety affects approximately 40% of Parkinson's disease (PD) patients. However, little is known about its predictors and development over time. To identify the clinical factors and biomarkers associated with development of anxiety in patients with newly diagnosed PD, and to test which risk factors predict increases in anxiety over time. Data from the Parkinson's Progression Markers Initiative (PPMI) were utilized. The primary outcome was the State-Trait Anxiety Inventory (STAI). Covariates were demographics, motor and non-motor symptoms, cognitive functions, dopamine transporter imaging data, and cerebrospinal fluid (CSF) biomarkers. We examined the association of risk factors at baseline and over 4 years with changes in anxiety scores over time. A total of 252 patients met the inclusion criteria (mean age: 61.36 years, SD 9.53). At year 4, 42 patients had developed anxiety. Baseline predictors of increase in anxiety scores were greater autonomic dysfunction, dysexecutive function, CSF t-tau levels, excessive daytime sleepiness, and lower olfactory function scores but not motor scores. Over 4 years, change in anxiety scores correlated with deterioration in overall cognitive function, excessive daytime sleepiness, as well as depression and disability, and to a lesser degree worsening of Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor scores and caudate dopaminergic uptake changes. These findings suggest that development of anxiety in PD is not primarily based on a dopaminergic deficit in the basal ganglia but related to non-dopaminergic or extrastriatal pathology. Early dysexecutive function predicts development of anxiety but increase in anxiety levels correlates most strongly with more global cognitive decline.

Longitudinal free-water changes in dementia with Lewy bodies (P8-11.007)

<h3>Objective:</h3> To characterize longitudinal diffusion microstructural changes in individuals with dementia with Lewy bodies (DLB). <h3>Background:</h3> Diffusion-weighted MRI (dMRI) examines tissue microstructure integrity and white matter pathways in vivo. Prior DLB studies focused on white matter or voxel-based techniques. Less is known about longitudinal white and grey matter microstructural changes in DLB. <h3>Design/Methods:</h3> dMRI scans were collected on individuals with DLB from the Mayo Clinic Longitudinal Imaging Biomarkers of DLB Program. Demographics, clinical evaluations and MRI were collected at baseline, and 12 or 24 months. Free-water (FW) and FW-corrected fractional anisotropy (FA_T) were analyzed in grey and white matter using 122 bilateral template regions and tracts of interest in Montreal Neurological Institute space. Primary outcomes were differences in FW and FA_T between baseline and 12 or 24 months. <h3>Results:</h3> We identified 23 individuals with DLB from baseline to 12 months [mean age 69.3 years (SD 9.5); 95.8% male], and 16 individuals from baseline to 24 months [mean age 67.5 years (SD 9.3); 100% male]. Participants at both time-points showed worsening in Montreal Cognitive Assessment and Movement Disorders Society Unified Parkinson’s Disease Rating Scale motor scores (<i>p</i>&lt;0.05). We found significant differences in FW, but not FA_T, from baseline to 12 months. Significant increases in FW at both time-points compared to baseline were observed in the insula, putamen, parahippocampal, and rolandic operculum regions (p&lt;0.05). We found more widespread microstructural changes from baseline to 24 months, with increased FW in the amygdala, entorhinal, mid and posterior cingulum, inferior frontal, hippocampal, pallidum, precuneus and retrosplenial regions (p&lt;0.05). We found decreased FA_T from baseline to 24 months in the cerebellar and superior occipital regions (<i>p</i>&lt;0.01). <h3>Conclusions:</h3> Longer follow-up at 24 months identified broader networks of free-water changes in individuals with DLB. More investigation is needed to evaluate the relationship of microstructural changes with clinical progression in DLB. <b>Disclosure:</b> Dr. Chiu has received research support from NIH/NIA. Mr. Chen has nothing to disclose. Dr. Wang has nothing to disclose. The institution of Dr. Armstrong has received research support from National Institute of Aging. The institution of Dr. Armstrong has received research support from Florida Department of Health. The institution of Dr. Armstrong has received research support from Lewy Body Dementia Association. Dr. Armstrong has received research support from Parkinson Foundation. Dr. Armstrong has received personal compensation in the range of $5,000-$9,999 for serving as a DSMB member with Alzheimer’s Clinical Trials Consortium. Dr. Armstrong has received personal compensation in the range of $5,000-$9,999 for serving as a DSMB member with Alzheimer’s Disease Cooperative Study. Dr. Armstrong has a non-compensated relationship as a Member, Scientific Advisory Council with Lewy Body Dementia Association that is relevant to AAN interests or activities. Dr. Boeve has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Rainwater Charitable Foundation. The institution of Dr. Boeve has received research support from Alector. The institution of Dr. Boeve has received research support from GE Healthcare. The institution of Dr. Boeve has received research support from Transposon. The institution of Dr. Boeve has received research support from Cognition Therapeutics. Dr. Boeve has received publishing royalties from a publication relating to health care. The institution of Dr. Kantarci has received research support from Eli Lilly. The institution of Dr. Kantarci has received research support from NIH. The institution of Dr. Kantarci has received research support from ADDF. David Vaillancourt has received personal compensation for serving as an employee of Automated Imaging Diagnostics. David Vaillancourt has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley. The institution of David Vaillancourt has received research support from NIH. David Vaillancourt has received intellectual property interests from a discovery or technology relating to health care.

Deep Brain Stimulation of the Subthalamic Nucleus in a Patient With X-Linked Dystonia-Parkinsonism. (P11-11.001)

<h3>Objective:</h3> N/A <h3>Background:</h3> X-linked dystonia-parkinsonism (XDP) is one of the genetic causes of generalized dystonia. Both dystonia and parkinsonism components of the disease are frequently resistant to pharmacologic treatment. Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) is an effective treatment modality, especially for dystonic manifestations of XDP. The subthalamic nucleus (STN) is a known DBS target in Parkinson disease but it is less frequently used for treatment of dystonia. In our case report we describe a patient with XDP who underwent bilateral STN DBS with notable improvement in parkinsonism and dystonia. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> Our patient is a right-handed Filipino man from the island of Panay. He developed bilateral parkinsonism, blepharospasm, oromandibular and cervical dystonia at the age of 51. Diagnosis of XDP was confirmed with genetic testing. Marked improvement of Unified Parkinson Disease Rating Scale (UPDRS) motor score in response to levodopa administration was demonstrated (65 off and 36 on). His pre-DBS Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) was 27.5. Bilateral GPi were initially selected as a target for DBS lead placement based on previously published data. Surgical target was subsequently changed to bilateral STN due to distortion in GPi anatomy likely secondary to long-standing disease. Medtronic Percept PC neurostimulator with Sensight DBS leads were used. There was no surgical complications. Patient had an immediate improvement in tremor, bradykinesia and rigidity after his first programming visit; antidystonic effects of stimulation became evident over the next few weeks. There was substantial improvement in limb and oromandibular dystonia and mild effect on cervical dystonia and blepharospasm. His speech clarity became better as well. His motor UPDRS and BFMDRS decreased to 21 and 19, respectively. Gait, posture, ability to perform activities of daily living significantly improved. <h3>Conclusions:</h3> The subthalamic nucleus may be considered an alternative deep brain stimulation target in patients with X-linked dystonia-parkinsonism. <b>Disclosure:</b> Dr. Redko has nothing to disclose. Brian Kopell has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Brian Kopell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbott Neuromodulation. Brian Kopell has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Enspire DBS. Dr. Tse has nothing to disclose.

CircEPS15, as a sponge of MIR24-3p ameliorates neuronal damage in Parkinson disease through boosting PINK1-PRKN-mediated mitophagy

ABSTRACT Despite growing evidence that has declared the importance of circRNAs in neurodegenerative diseases, the clinical significance of circRNAs in dopaminergic (DA) neuronal degeneration in the pathogenesis of Parkinson disease (PD) remains unclear. Here, we performed rRNA-depleted RNA sequencing and detected more than 10,000 circRNAs in the plasma samples of PD patients. In consideration of ROC and the correlation between Hohen-Yahr stage (H-Y stage) and Unified Parkinson Disease Rating Scale-motor score (UPDRS) of 40 PD patients, circEPS15 was selected for further research. Low expression of circEPS15 was found in PD patients and there was a negative positive correlation between the circEPS15 level and severity of PD motor symptoms, while overexpression of circEPS15 protected DA neurons against neurotoxin-induced PD-like neurodegeneration in vitro and in vivo. Mechanistically, circEPS15 acted as a MIR24-3p sponge to promote the stable expression of target gene PINK1, thus enhancing PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and maintain mitochondrial homeostasis. Thus, circEPS15 rescued DA neuronal degeneration through the MIR24-3p-PINK1 axis-mediated improvement of mitochondrial function. This study reveals that circEPS15 exerts a critical role in participating in PD pathogenesis, and may give us an insight into the novel avenue to develop potential biomarkers and therapeutic targets for PD. Abbreviations: AAV: adeno-associated virus; DA: dopaminergic; FISH: fluorescence in situ hybridizations; HPLC: high-performance liquid chromatography; H-Y stage: Hohen-Yahr stage; LDH: lactate dehydrogenase; MMP: mitochondrial membrane potential; MPTP/p: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid; NC: negative control; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PBS: phosphate-buffered saline; ROS: reactive oxygen species; SNpc: substantia nigra pars compacta; TEM: transmission electron microscopy; UPDRS: Unified Parkinson’s Disease Rating Scale-motor score

Identifying clinical features and blood biomarkers associated with mild cognitive impairment in Parkinson's Disease using machine learning.

A broad list of variables associated with mild cognitive impairment (MCI) in Parkinson's Disease (PD) has been investigated separately. However, there is no study including all of them to assess variable importance yet. Shapley variable importance cloud (ShapleyVIC) can robustly assesses variable importance while accounting for correlation between variables. 1) To prioritise the important variables associated with PD-MCI; 2) To explore new blood biomarkers related to PD-MCI. ShapleyVIC-assisted variable selection was used to identify a subset of variables from 41 variables potentially associated with PD-MCI in a cross-sectional study. Backward selection was used to further identify the variables that associated with PD-MCI. Relative risk was used to quantify the association of final predictors and PD-MCI in the final multivariable log-binomial regression model. Among 41 variables analysed, 22 variables were identified as significantly important variables associated with PD-MCI and 8 variables were subsequently selected in the final model, indicating shorter education year, history of hypertension, higher MDS-UPDRS motor score, higher levels of TG, APOA1, and SNCA rs6826785 non-carrier were associated with increased risk of PD-MCI (p<0.05). Our study highlighted the strong association between TG, APOA1, SNCA rs6826785 and PD-MCI by machine learning approach. Screening and management of high TG and ApoA1 levels might help prevent the cognitive impairment in early PD patients. SNCA rs6826785 could be a novel therapeutic target for PD-MCI. ShapleyVIC-assisted variable selection is a novel and robust alternative to traditional approaches for future clinical study to prioritize the variables of interests.

Unveiling the Impact of Outpatient Physiotherapy on Specific Motor Symptoms in Parkinson's Disease: A Prospective Cohort Study.

Understanding how outpatient physiotherapy impacts on specific motor symptoms in Parkinson's disease (PD) is important for multidisciplinary care, but these points have not been clarified. We investigated the impact of outpatient physiotherapy on individual motor symptoms in PD patients. Fifty-five PD patients participated in the prospective cohort study, which examined the changes in motor symptoms after 90 min of outpatient physiotherapy program (1×/week for 10 weeks) and at 3 months follow-up. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score and tremor, rigidity, bradykinesia, and axial scores were assessed and compared pre-intervention, post-intervention, and at follow-up. Significant level was set at 0.05. Their MDS-UPDRS motor score and axial score significantly decreased post-intervention and at the follow-up. In the analysis differentiating effects based on the severity of motor symptoms according to the MDS-UPDRS motor score, only the moderate-severe group showed significant decreases in their MDS-UPDRS motor score, bradykinesia, and axial scores post-intervention, as well as in their MDS-UPDRS motor score, rigidity, bradykinesia, and axial scores at the follow-up. These findings suggest the outpatient physiotherapy might provide benefits, particularly in managing axial symptoms and bradykinesia, for community dwelling PD patients with moderate-severe motor symptoms within a multidisciplinary care framework.

Diffusion along perivascular spaces as marker for impairment of glymphatic system in Parkinson’s disease

The brain glymphatic system is involved in the clearance of misfolding α-synuclein, the impaired glymphatic system may contribute to the progression of Parkinson’s disease (PD). We aimed to analyze the diffusion tensor image along the perivascular space (DTI-ALPS) and perivascular space (PVS) burden to reveal the relationship between the glymphatic system and PD. A cross-sectional study using a 7 T MRI of 76 PD patients and 48 controls was performed to evaluate the brain’s glymphatic system. The DTI-ALPS and PVS burden in basal ganglia were calculated. Correlation analyses were conducted between DTI-ALPS, PVS burden and clinical features. We detected lower DTI-ALPS in the PD subgroup relative to controls, and the differences were more pronounced in patients with Hoehn & Yahr stage greater than two. The decreased DTI-ALPS was only evident in the left hemisphere in patients in the early stage but involved both hemispheres in more advanced PD patients. Decreased DTI-ALPS were also correlated with longer disease duration, higher Unified Parkinson’s Disease Rating Scale motor score (UPDRS III) and UPDRS total scores, as well as higher levodopa equivalent daily dose. Moreover, the decreased DTI-ALPS correlated with increased PVS burden, and both indexes correlated with PD disease severity. This study demonstrated decreased DTI-ALPS in PD, which might initiate from the left hemisphere and progressively involve right hemisphere with the disease progression. Decreased DTI-ALPS index correlated with increased PVS burden, indicating that both metrics could provide supporting evidence of an impaired glymphatic system. MRI evaluation of the PVS burden and diffusion along PVS are potential imaging biomarkers for PD for disease progression.