Journal of Parkinson's Disease

Alpha-synuclein has been implicated in neurodegenerative diseases such as Parkinsons disease and Dementia with Lewy bodies, with A53T and A30P mutations shown to be disease-causing. It has been reported that transgenic mice with tyrosine hydroxylase promotor-driven expression of A53T / A30P mutant alpha-synuclein in dopamine neurons provide a useful preclinical model of these conditions by virtue of developing dopaminergic neuronal cell death and related behavioral deficits. Here, we report a lack of replication of this finding. Despite detecting robust overexpression of A53T / A30P mutant alpha-synuclein in dopamine neurons, we observed neither cell death or related behavioral deficits in these mice. Our results demonstrate that preclinical models of synucleinopathy need careful validation in the field.

Functionality is considered the third health indicator, complementing the traditional mortality and morbidity metrics. However, functionality is rarely assessed systematically in Parkinsons disease (PD) clinical practice and research, where symptom-based scales predominate. Identifying declines across various dimensions of functionality in PD is essential for patient education, disease management, and guiding new intervention strategies. The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a comprehensive assessment tool developed by the World Health Organization (WHO) based on the International Classification of Functioning, Disability and Health (ICF) to standardize the measurement of functionality and disability impacts across diverse health conditions and cultural contexts. This study aimed to characterize functionality across PD severity stages using the WHODAS 2.0, independent of age, sex, socioeconomic status (SEC), and education. A total of 352 patients were divided into four clinically severity PD stage groups according to the Hoehn & Yahr (H&Y) scale. The age, sex, SEC and education levels were controlled to guarantee paired groups. All participants were evaluated remotely using the Telephone - Montreal Cognitive Assessment (T-MoCA), Beck Depression Inventory (BDI), Movement Disorder Society - Unified Parkinsons Disease Rating Scale, Part I (MDS-UPDRS I) and Part II (MDS-UPDRS II) and WHODAS 2.0. The most affected functionality dimensions were Mobility, Activities of Daily Life related to the Household, and Participation. The nonparametric Kruskal-Wallis test revealed a significant effect of the group for all functionality dimensions. Notably, Mobility, Activities of Daily Life related to the Household, and Self-Care showed a gradual decline starting from stage 1 of H&Y. In contrast, Cognition, Getting Along and Participation exhibited progressive impairment only from stage 2 of H&Y. This study is the first to describe functionality in PD using WHODAS 2.0 across severity stages controlling for key demographic factors. Findings highlight that WHODAS captures functional limitations not identified by symptom-focused scales such as MDS-UPDRS. Incorporating WHODAS into routine assessment may improve patient-centered care by informing interventions targeting functional limitations from early disease stages. HighlightsWHODAS 2.0 captures functionality domains not assessed by MDS-UPDRS. Functional decline in mobility, self-care, and household tasks starts at early PD stages. Participation, cognition, and interpersonal relationships decline from stage 2 onwards. Functionality decline is independent of age, sex, education, and socioeconomic status. WHODAS provides a biopsychosocial assessment essential for person-centered PD care.

BackgroundParkinsons disease (PD) therapeutic strategies have evolved since the introduction of levodopa in the 1960s, but there is limited data on their impact on disease progression markers. ObjectiveDelineate the current landscape of PD progression at tertiary subspecialty care and research centers. MethodUsing Accelerating Medicine Partnership-PD (AMP-PD) data harmonized from seven biomarker discovery studies (2010-2020), we extracted: overall [Schwab and England (S&E), PD Questionnaire (PDQ-39)]; motor [Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS)-II and -III and Hoehn & Yahr (HY)]; and non-motor [MDS-UPDRS-I, University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Epworth Sleepiness Scale (ESS)] scores. Age at diagnosis was set as 0 years, and data were tracked for 15 subsequent years. ResultsSubjects (3,001 PD cases: 2,838 white, 1,843 males) mean age at diagnosis was 60.2{+/-}10.3 years and disease duration was 9.9{+/-}6.0 years at the baseline evaluation. Participants largely reported independence (S&E, 5y: 86.6{+/-}12.3; 10y: 78.9{+/-}19.3; 15y: 78.5{+/-}17.0) and good quality of life (PDQ-39, 5y: 15.5{+/-}12.3; 10y: 22.1{+/-}15.8; 15y: 24.3{+/-}14.4). Motor scores displayed a linear progression, whereas non-motor scores plateaued [~]10-15 years. Younger onset age correlated with slower overall (S&E), motor (MDS-UPDRS-III), and non-motor (UPSIT/MoCA) progression, and females had better overall motor (MDS-UPDRS-II-III) and non-motor (UPSIT) scores than males. ConclusionsTwenty-first century PD patients remain largely independent in the first decade of disease. Female and young age of diagnosis were associated with better clinical outcomes. There are data gaps for non-whites and metrics that gauge non-motor progression for >10 years after diagnosis.

IMPORTANCEWearable-based measures of walking (as proxy for physical activity) may quantify disease progression and modification thereof in early-stage Parkinsons disease (PD). OBJECTIVESEstablishing the validity of digital measures of walking and non-walking in PD. DESIGNRetrospective longitudinal analyses of data from cohorts within 3 larger studies, consisting of wearable sensor, demographic, and clinical data collected during 2017-2023, with 1-2 year follow up. SETTINGThree independent multicenter cohort studies. PARTICIPANTSPeople with PD, and age/sex matched non-PD cohort. EXPOSURESNone. MAIN OUTCOMES AND MEASURESDigital measures test-retest reliability, analyzed using intraclass correlation coefficients across consecutive monthly-aggregated data. Digital measures sensitivity: ability to detect within-participant changes, analyzed over 24 months using linear mixed-effect models, and analyzed as effect-size changes-from-baseline comparing 1- and 2-year longitudinal Cohens-d (mean and 95% CIs) vs conventional clinical endpoints. Analyses replicated in two independent PD cohorts (internal validation and external evaluation). Compared within-participant changes between PD and non-PD cohorts using linear mixed-effect model slopes. RESULTSWe analyzed 57 digital measures (51 individual, 6 composite) in a development cohort (N=171), selecting 32 (26 individual, 6 composite) for further study based on their sensitivity and test-retest reliability. During internal validation (N=101), 20 measures could detect statistically significant within-participant changes and 7 showed larger 2-year effect-size changes than conventional clinical measures; non-walking bout (NWB) duration (12.4% yearly change; 2-year Cohens-d 0.623 [95% CI: 0.461,0.811]) and 95th percentile of NWB duration (17.1% yearly change; 2-year Cohens-d, 0.623 [95% CI: 0.461,0.811]) performed best. Measures could detect significant and persisting changes from baseline at 10 months. During external evaluation (N=67), 15 measures could detect statistically significant within-participant changes and 12 showed larger 1-year effect-size changes than conventional clinical measures; 12 measures showed significantly greater change in people with PD than in matched non-PD individuals (N=171). CONCLUSION AND RELEVANCEInternal validation and external evaluation of 32 digital measures that quantified walking and non-walking behaviors in patients with early-stage PD showed that they could have greater sensitivity to detect longitudinal changes than conventional measures, and that these changes were disease-specific (e.g., separate from aging), making them candidates for disease-specific progression markers. Key PointsO_ST_ABSQuestionC_ST_ABSCan wearable sensor-based digital measures of physical activity and mobility serve as markers of disease progression in early-stage Parkinsons disease (PD)? FindingsIn two independent longitudinal cohorts of people with PD, digital measures detected statistically-significant changes in walking and non-walking behaviors after 1 and 2 years of follow-up; additionally, a comparison between people with and without PD (from a third cohort) showed that these changes were disease-specific. Compared with MDS-UPDRS-based conventional metrics, measures of non-walking behavior showed greater effect size (such as mean non-walking bout duration, with an annual increase of 12.4% and a 2-year Cohens-d of 0.623). MeaningWearable sensor-based digital measures can detect and quantify disease-specific changes in walking and non-walking behaviors over time in people with early-stage PD.

Braak and others have proposed that Lewy body pathology LBP in Parkinson disease PD may arise not only in the brain but alternatively from an initial site in the gastrointestinal GI tract with subsequent passage to the central nervous system CNS through the vagus nerve or other routes. We tested this hypothesis by using both immunohistochemistry IHC and RT QuIC a form of alpha synuclein seed amplification assay SAA to detect alpha synuclein LBP in samples from selected brain regions and 10 GI tract sites taken from autopsies of 50 PD subjects and 128 elderly subjects without parkinsonism or dementia including 34 with IHC identified CNS incidental Lewy body disease ILBD and 94 with no Lewy body IHC pathology detected NLB. A positive SAA or IHC result was restricted to the GI tract in only 2 subjects while LBP by either SAA or IHC was restricted to the brain in 11 subjects. To fairly compare GI only with brain only synucleinopathy however we would have to do SAA on brain samples from all ILBD and NLB cases in at least 4 critical brain regions olfactory bulb medulla pons and amygdala. Further SAA of brain regions is estimated based on the proportional results to date to potentially identify 21 additional brain only LBP subjects total of 32 if it were done on all of the NLB subjects. From this brain only LBP is estimated to be 16 times more common than GI only LBP. To assess the clinical impact of SAA positive GI sites we found that the number of positive sites per subject is significantly correlated with UPDRS motor score and SCOPA AUT GI related scores including those for salivation straining constipation and bowel movement.

Background and Objectives: PD is the second most common neurodegenerative disorder and the fastest growing. Genetic factors account for [~]15% of cases. Despite some consistency in symptoms across idiopathic and genetic PD cases, tracking progression and treatment response remains an important challenge especially in the development of new therapies. There have been many traditional approaches to tracking including DaTscan imaging, cardiac 123I-MIBG scintigraphy, MRI, CSF analysis, and following clinical symptom progression. Methods: Our previous work showed that peripheral blood mononuclear cells (PBMCs) expressing dopamine transporter (DAT) and tyrosine hydroxylase (TH) in PD patients may correlate with disease progression and with the response to treatment with levodopa. We describe a single case longitudinal follow up of a 40-45-year-old woman with PD who carried a heterozygous TH mutation. We assessed her clinical features over 18 months with DaT scans and immunophenotyping of her PBMCs. Her data were compared with idiopathic PD (n=130 subjects, both sexes) and healthy controls (n=80, age/sex matched). Results: The results revealed a rise in DAT+ immune cells which occurred coincident to documented worsening of her UPDRS-III motor scores. Unlike idiopathic PD patients, following levodopa therapy, the TH+ immune cell levels remained elevated, despite UPDRS-III score improvement. Discussion: The longitudinal immunophenotyping in this PD patient with a TH mutation suggested that DAT+ and TH+ PBMCs could be candidate biomarkers for PD progression and possibly treatment effectiveness. This study provides proof of concept to explore this approach to investigate immunophenotyping in PD progression.

BackgroundThe definite diagnosis of Parkinsons disease (PD) is usually made by the detection of -synuclein aggregates in the brain post mortem with the rare exception of some genetic forms. Traces of -synuclein aggregates in extracerebral tissue biopsies may serve as an appropriate biomarker to confirm a clinical diagnosis in vivo. ObjectivesWe set out to determine whether the detection of -synuclein aggregates in submandibular gland biopsies is an effective means for diagnosing PD patients. MethodsWe examined submandibular gland biopsies from 25 patients with PD under investigation and 25 age-matched controls to detect -synuclein aggregates using real-time quaking induced conversion (RT-QuIC) as a seed amplification-assay and immunohistochemical -synuclein aggregate detection and paraffin-embedded tissue blot (PET-blot) as confirmatory methods. ResultsOur RT-QuIC assay detected -synuclein aggregates in submandibular gland biopsies with a sensitivity of 81,1%, which increased to 90% after a clinical follow-up, and a specificity of 100%. The PET-blot with mAb5C12 confirmed 50% of the RT-QuIC positives and offered a sensitivity of 45,8% (50% after clinical follow-up) and a specificity of 100%. Immunohistochemical detection using the same antibody confirmed 28% of the RT-QuIC positives, but found two of the controls to be positive and therefore provided a sensitivity of 26,1% (28,6% after clinical follow-up) and a specificity of 92%. ConclusionsThe RT-QuIC Assay demonstrated comparable sensitivity to the clinical diagnosis (when neuropathologic examination represents the gold standard) and exhibited a similar level of specificity as the PET-blot.

The number of people living with Parkinsons disease (PD) is expected to rise in the coming years. This study analyzed health care utilization patterns of Medicare beneficiaries with a PD diagnosis (ICD-10 code G20) who were enrolled in 2019. Utilization analysis included PD-related specialists and primary care physicians, therapy services, and mental health services. We found 685,116 (1.2%) Medicare beneficiaries had PD (56.3% male, 77.9% over age 70, 85.3% White, and 16.0% rural residents). Few Medicare beneficiaries with PD sought care from a movement disorder specialist (MDS) (9.1%); another 50.9% visited a general neurologist. Results reveal low utilization rates for therapy and even lower rates for mental health services. Overall healthcare utilization varied significantly by demographic group with women, people of color, and rural residents being less likely to access specialist care. Our findings emphasize the need for further research on population-specific barriers to accessing PD-related health care.

Dance-based interventions have consistently been shown to improve limb motor function in Parkinsons disease (PD), yet their potential impact on other motor domains, particularly those supporting laryngeal-orofacial control needed for speech production, remains largely unexplored. Beyond motor speech functions, dance may also influence higher-order language processes, including semantic organization. To test these hypotheses, we conducted a 12-week randomized trial comparing an Amazonian Dance intervention to a matched-physical intensity control condition (Nordic Walking), incorporating automated speech and language analysis to provide objective, fine-grained quantification of communication outcomes. Participants in the dance arm showed significant improvements in prosody (Main Tone), voice quality (Harmonic to Noise Ratio), and semantic organization (Granularity), whereas the walking group showed declines in these metrics. The dance-related gains in prosody and semantics remained significant even after adjusting for demographic, cognitive, and clinical covariates. These findings suggest that dance may enhance both speech-motor and higher-order language functions in PD, potentially through mechanisms such as auditory-motor coupling, improved internal timing, and the engagement of overlapping neural substrates between dance and speech and/or language.

BackgroundLoss of smell commonly predates the diagnosis of Parkinsons disease (PD). However, smell loss has multiple causes, and the relationship between idiopathic anosmia (IA) and PD remains incompletely understood. ObjectivesTo assess the presence of prodromal features of PD in individuals with IA and to examine the relationship between anosmia duration and prodromal features. MethodsWithin the PREDICT-PD study, patients with IA investigated at specialist smell clinics were compared with healthy controls at low risk of PD (HC) and patients with PD. In-person assessments included MDS-UPDRS I-III, functional motor tasks, cognitive tasks, autonomic symptoms, orthostatic hypotension, pain, sleep and mood. We compared these features and PD risk according to the PREDICT-PD algorithm between the groups and examined the relationship between the duration of anosmia and severity of prodromal features using linear regression models. ResultsWe recruited 42 IA, 28 HC and 22 PD participants, matched for age and gender. Overall motor scores were not different between IA and HC. IA had worse cognition, sleep, pain, depressive and some symptoms of dysautonomia than HC, with trends towards worse anxiety scores and higher PD risk scores. Shorter duration of anosmia was negatively correlated with MDS-UPDRS II scores but no other prodromal feature. ConclusionsSome individuals with IA exhibit non-motor features suggestive of prodromal PD. This supports the known association of olfactory dysfunction with subsequent PD but suggests that, even after excluding secondary causes of anosmia, other conditions may underlie anosmia or smell loss may be temporally remote from PD.

BackgroundData-driven approaches identified Mild Motor Predominant (MMP), Intermediate (IM), and Diffuse Malignant (DM) as Parkinsons Disease (PD) subtypes with different motor and non-motor impairment at diagnosis. It remains unclear whether these subtypes remain stable over time or whether they represent distinct biological substrates. The alpha-synuclein seed amplification assay in CSF (CSF-Syn-SAA) might provide further insights. Objectiveto evaluate the association between baseline CSF-Syn-SAA parameters and 10-year clinical evolution of PD subtypes. Methods323 sporadic PD patients from PPMI dataset were classified as MMP, IM, or DM at baseline and 10-year follow-up based on motor, cognitive, sleep and dysautonomia features. CSF-Syn-SAA parameters were collected at baseline using a 150-hrs protocol. CSF A{beta}1-42, tTau and pTau181, CSF and serum NfL were also considered at baseline. ResultsReaction times (T50, TTT) and area under the curve (AUC) respectively were shorter and larger in DM compared to IM/MMP. The difference in baseline amplification parameters was more evident when comparing subtypes based on 10-year clinical features (T50, 2=0.036; TTT, 2=0.031; AUC, 2=0.033; all p values < 0.05) than when comparing subtypes based on baseline clinical features (T50, 2=0.012; TTT, 2=0.012; AUC, 2=0.013; all p<0.05). Shorter T50 and TTT at baseline were associated with greater risk of DM versus MMP at 10-year follow-up (T50, OR=3.3, 95%CI: 1.3-8.1, p=0.010; TTT, OR=4.6, 95%CI: 1.8-11.6, p=0.001). A{beta}, Tau and NfL were similar between groups. ConclusionsBaseline CSF-Syn-SAA parameters predicted long-term PD progression. Faster reactions were associated with a more severe 10-year PD phenotype considering motor and non-motor features. Plain Language SummaryO_ST_ABSBackgroundC_ST_ABSThe diagnosis of Parkisons Disease is drastically changing by the development of Alpha-Synuclein Seed Amplification Assay. The assay enables, for the first time, the detection of pathological forms of alpha-synuclein in cerebrospinal fluid in living patients. Alpha-Synuclein Seed Amplification is very accurate in discerning individuals with Parkinsons Disease versus healthy subjects, but it remains unknown whether it can also inform about prognosis. ObjectiveWe assessed the ability of the assay to predict the 10-year clinical progression of Parkinsons Disease. MethodsPublic data from an international cohort were used. At time of diagnosis, we classified 323 individuals with Parkinsons Disease into three clinical subtypes: Mild Motor Predominant, Intermediate, and Diffuse Malignant. These subtypes were characterized by a progressively increasing burden of motor and non-motor symptoms. Subjects with available follow-up data were re-classified using the same subtypes after 10 years of disease. Time-dependent signal changes of Alpha-Synuclein Seed Amplification Assay in Cerebrospinal Fluid were measured at baseline and used to predict the 10-year phenotype. ResultsFirstly, we found that subtypes were not stable categories. Around a half of participants changed subtype over time, mostly shifting towards a more aggressive one. Notably, our results showed that faster reactions on Alpha-Synuclein Seed Amplification Assay at baseline were associated with a 10-year phenotype more aggressive in terms of motor symptoms, dysautonomia, sleep and cognitive impairment, i.e the Diffuse Malignant subtype. ConclusionCharacteristics of the assay underlying the final positivity or negativity outcomes performed at a milder and early stage of PD may identify a subgroup of subjects that are more likely to undergo a more rapid clinical deterioration. Further studies, however, are needed to confirm and expand this result.

BackgroundPatients in late-stage Parkinsons disease (PDLS) are caregiver dependent, have low quality of life, and higher health care costs. ObjectiveTo estimate the prevalence of PDLS patients in the current United States (US) health care system. MethodsWe downloaded the 2010-2022 data from the TriNetX Diamond claims network that consists of 92 USA health care sites. PD was identified using standard diagnosis codes, and PDLS was identified by the usage of wheelchair dependence, personal care assistance and/or presence of diagnoses of dementia. Age of PDLS identification, and survival information are obtained and stratified by demographic and the disability subgroups. ResultsWe identified 1,031,377 PD patients in the TriNetX database. Of these, 18.8% fit our definition of PDLS (n=194,297), and 10.2% met two or more late-stage criteria. Among all PDLS, the mean age of PDLS identification was 78.1 ({+/-}7.7), and 49% were already reported as deceased. PDLS patients were predominantly male (58.5%), with similar distribution across PDLS subgroups. The majority did not have race (71%) or ethnicity (69%) information, but for the available information, >90% (n=53,162) were white, 8.2% (n=5,121) Hispanic/Latino, 7.8% (n=4,557) black, and <0.01% (n=408) Asian. Of the PDLS cohort, 71.6% identified with dementia, 12.9% had personal care assistance, and 4.8% were wheelchair bound. ConclusionsLate-stage patients are a significant part of PD landscape in the current US healthcare system, and largely missed by traditional motor-based disability staging. It is imperative to include this population as a clinical, social, and research priority.

BackgroundParoxysmal dyskinesias (PxDs) are characterised by bouts of involuntary dystonic and choreiform movements. The patho-mechanisms underlying these debilitating disorders remain poorly understood, and drug treatments are often limited. We recently generated a Drosophila model of a PxD-linked mutation causing BK potassium channel gain- of-function (BK GOF), and showed that BK GOF perturbs movement in Drosophila by disrupting neurodevelopment. However, whether locomotor capacity in BK GOF flies can be pharmacologically restored following neurodevelopmental insults has remained unclear. ObjectiveTo identify pharmacological suppressors of motor defects caused by BK GOF. MethodsUsing adult BK GOF flies, we performed an unbiased, in vivo, locomotion-based screen of 370 FDA-approved drugs. To test the impact of positive hits from this screen on motor circuit activity, we used optical imaging to record the intrinsic rhythmic activity of Drosophila larval motor circuits driving peristalsis and turning behaviors. ResultsWe found that inhibitors of acetylcholinesterase - a protein that degrades acetylcholine in cholinergic synapses - partially rescued movement defects caused by BK GOF. Inhibition of acetylcholinesterase also partially restored intrinsic activity of motor circuits controlling forward movement and turning in BK GOF larvae. ConclusionsOur findings indicate that elevating cholinergic tone can reverse motor circuit dysfunction in an animal model of PxD caused by BK GOF. Furthermore, our study provides proof-of-principle that Drosophila can be utilised for screens to uncover putative drug treatments for involuntary movement disorders.

ImportanceHigher physical activity levels have been suggested as a potential modifiable risk factor for lowering the risk of incident Parkinsons disease (PD). This study uses objective measures of physical activity to investigate the role of reverse causation in the observed association. ObjectiveTo investigate the association between accelerometer-derived daily step count and incident PD, and to assess the impact of reverse causation on this association. DesignThis prospective cohort study involved a follow-up period with a median duration of 7.9 years, with participants who wore wrist-worn accelerometers for up to 7 days. SettingThe study was conducted within the UK Biobank, a large, population-based cohort. ParticipantsThe analysis included 94,696 participants aged 43-78 years (56% female) from the UK Biobank who provided valid accelerometer data and did not have prevalent PD. ExposureDaily step counts were derived using machine learning models to determine the median daily step count over the monitoring period. Main Outcomes and MeasuresThe primary outcome was incident PD, identified through hospital admission and death records. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between daily step count and incident PD, with adjustments for various covariates and evaluation of reverse causation by splitting follow-up periods. ResultsDuring a median follow-up of 7.9 years (IQR: 7.4-8.4), 407 incident PD cases were identified. An inverse linear association was observed between daily step count and incident PD. Participants in the highest quintile of daily steps (>12,369 steps) had an HR of 0.41 (95% CI 0.31-0.54) compared to the lowest quintile (<6,276 steps; HR 1.00; 95% CI 0.84-1.19). A per 1,000 step increase was associated with an HR of 0.92 (95% CI 0.89-0.94). However, after excluding the first six years of follow-up, the association was not significant (HR 0.96, 95% CI 0.92-1.01). Conclusions and RelevanceThe observed association between higher daily step count and lower incident PD is likely influenced by reverse causation, suggesting changes in physical activity levels occur years before PD diagnosis. While step counts may serve as a predictor for PD, they may not represent a modifiable risk factor. Further research with extended follow-up periods is warranted to better understand this relationship and account for reverse causation. Key PointsO_ST_ABSQuestionC_ST_ABSIs there an association between accelerometer-derived daily step count and the risk of incident Parkinsons disease, considering the potential impact of reverse causation? FindingsIn this prospective cohort study of 94,696 UK Biobank participants, an inverse association was found between daily step count and incident Parkinsons disease over a median follow-up of 7.9 years. However, this association was attenuated when excluding the first six years of follow-up. MeaningWhile daily step counts may be associated with incident Parkinsons disease, these observations are likely influenced by reverse causation, indicating changes in daily behaviours years before diagnosis.

BackgroundThere is a relative dearth of research on patients with Parkinsons disease (PD) from under-represented ethnic groups in the United Kingdom. ObjectivesThe East London Parkinson Disease project seeks to understand the clinical manifestations and determinants of PD in a diverse population. MethodsPatients with PD were recruited from the Royal London Hospital. Healthy controls came from community engagement events and partners of patients. Data on clinical features assessed by motor and non-motor scales were collected between January 2019 and February 2024, and compared between groups. Parametric, non-parametric tests, and unmatched logistic models, adjusted for age, gender and duration of disease were used. ResultsWe assessed 218 patients with PD and 90 controls. Among them, 50% of patients and 64% controls identified as South Asian or Black. Males comprised 63% of patients and 70% of controls. After adjusting for age, gender, disease duration and treatment burden, South Asian and Black patients had significantly worse motor scores compared to White patients (mean [SD], 42.2 [18.8], and 47 [16.6] vs 35.2 [16.4], p<0.001 and p<0.001). Cognitive impairment was more prevalent in South Asian (73%) and Black patients (75%) than in White patients (45%, p=0.002). ConclusionsOur results suggest that patients with PD from South Asian and Black ethnic groups may have more severe motor and certain non-motor features, including cognitive impairment, compared to White patients.

There is considerable concern about the long-term consequences of COVID-19 infection, generally referred to as post-acute sequelae, including declines in cognitive and motor abilities. The degree to which COVID-19 contributes additional burden to normal aging trajectories remains unclear. Additionally, the impact of COVID-19 on subjects under study for age-related neurological diseases is a potential confounder that needs definition. This study investigated whether having had a COVID-19 illness was associated with a differential decline in cognitive or motor function in older adults, utilizing data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and Brain and Body Donation Program (BBDP), a longitudinal clinicopathological study based in metropolitan Phoenix, Arizona. Subjects were included if they 1) had completed a questionnaire about their experience with COVID-19 illness 2) were classified as cognitively normal at pre-pandemic diagnostic cognitive consensus conferences and 3) had one or more subsequent diagnostic conferences between July 1, 2020 and August 30, 2025. All subjects had serial standardized research-dedicated clinical evaluations including the Montreal Cognitive Assessment (MoCA) and the Unified Parkinsons Disease Rating Scale (UPDRS). Specific objectives were to compare, between those who reported having had or not having had COVID-19, rates of conversion to cognitive impairment or dementia as well as pre-pandemic and final MoCA and UPDRS motor scores. A total of 100 subjects self-reported having had COVID-19 while 71 denied having had it. Their related acute illness severity was generally mild, with only 10% having had hospital treatment and none having required ventilator support. Post-acute symptoms were also mild; only 1 subject reported having "long Covid". Both cognitive and motor performance, as measured by MoCA and UPDRS part 3 scores, declined slightly (not statistically significant) over the study period. Conversion of cognitive diagnosis from normal to impaired or dementia occurred in 26% of those having had COVID-19 and in 32% of those not having had COVID-19; the difference was not significant. All subjects diagnosed with PD at the start of the study were also diagnosed with PD at the end of the study; no subjects converted from not having to having probable PD. Logistic regression analysis indicated that subjects report of having had COVID-19 was not significantly associated with conversion to cognitive impairment or dementia while greater age, male sex, possession of one or more apolipoprotein E-{varepsilon}4 alleles, and a diagnosis of probable PD all conferred a significantly greater likelihood of conversion. The results suggest that having a mild COVID-19 illness is not associated with greater declines on cognitive or motor screening tests than would be expected from age-related changes alone. Limitations of this analysis include small sample sizes, potential misclassification of COVID-19 status, and reliance on relatively crude clinical metrics that may miss significant functional changes. Additionally, we were unable to separately assess for varying COVID-19 severity dependent on whether or not the subject had been vaccinated, the number and type of vaccinations, and the particular SARS-CoV-2 variants that were circulating at the time of illness.

Parkinsons disease (PD), a progressive neurodegenerative disorder, manifests with motor and non-motor symptoms. Despite similar incidence, clinical care for Hispanic patients with PD is poor compared to white non-Hispanic individuals. As a result, their participation in PD research also does not reflect expected values. These disparities suggest an underutilization of quality healthcare, socio-economic disadvantage, stigma, and cultural differences. Using a community health worker pilot program, we trained 298 Promotores de Salud to reach, educate, and engage the Hispanic community in healthcare. Outcomes demonstrated improved knowledge of PD among Promotores, as well as increased access and utilization of educational resources.

The aetiology of Parkinsons disease (PD) has been linked to the aggregation and spread of misfolded alpha-synuclein via the gut-brain axis. We previously reported the effects of a biological response modifier, beta-glucan, produced by the AFO-202 strain of Aureobasidium Pullulans, which improves clinical symptoms and controls gut Enterobacteriaceae associated with curli and amyloid-alpha-synuclein production. In this study, we report the effects of beta-glucan on PD. Eight patients with PD were recruited, five of whom completed the study. Each participant was administered 3 g of AFO-202 B-glucan orally daily for 90 days in addition to their regular prescription drugs. Pre- and post-study comparison revealed that the mean UPDRS decreased from 43.25 {+/-} 13.75 at baseline to 40 {+/-} 13.65 post intervention. Improvements in cognition, walking and balance, postural stability, and constipation scales were observed. The mean constipation severity score decreased from 3 {+/-} 1.73 to 1.75 {+/-} 0.43 post intervention. The serum creatinine kinase levels decreased and the blood glucose and lipid levels normalised. The MRI Parkinsons index (MRPI) improved in one patient. This safe AFO-202 B-glucan produced beneficial disease-modifying improvements in the UPDRS and MRI that were clinically significant in the short timeframe of 90 days. Further validation in larger, longer-term clinical trials will help confirm the use of beta-glucan as a potential adjuvant treatment for PD which may pave way for future evaluations of these beta-glucans in other synculeinopathies as well Lewy-body related pathogenesis.

Cognitive impairments appear at or before motor signs in about one third of patients with Parkinsons disease (PD) and have a cumulative prevalence of roughly 80% overall. These deficits exact an unrelenting toll on patients quality and activities of daily life due in part to a lack of available treatments to ameliorate them. This study used three well-validated novel object recognition-based paradigms to explore the suitability of rats with knockout of the PTEN-induced putative kinase1 gene (Pink1) for investigating factors that induce cognitive decline in PD and for testing new ways to mitigate them. Longitudinal testing of rats from three to nine months of age revealed significant impairments in male Pink1-/- rats compared to wild type controls in Novel Object Recognition, Novel Object Location and Object-in-Place tasks. Task-specific differences in the progression of object discrimination/memory deficits across age were also seen. Finally, testing using an elevated plus maze, a tapered balance beam and a grip strength gauge showed that in all cases recognition memory deficits preceded potentially confounding impacts of gene knockout on affect or motor function. Taken together, these findings suggest that knockout of the Pink1 gene negatively impacts the brain circuits and/or neurochemical systems that support performance in object recognition tasks. Further investigations using Pink1-/-rats and object recognition memory tasks should provide new insights into the neural underpinnings of the visual recognition memory and visuospatial information processing deficits that are often seen in PD patients and accelerate the pace of discovery of better ways to treat them.

Skin biopsies of patients with parkinsonism, mild cognitive impairment or dementia might offer a simple and relatively non-invasive means to determine whether -synuclein aggregates might be the underlying pathology. Accurate biomarkers are critically needed for Lewy body disease (LBD) clinical trials but currently there are none that have undergone full regulatory scrutiny. We sought to simulate the rigor of a diagnostic study done with regulatory oversight in this study of the accuracy of skin biopsies processed by -synuclein seeding amplification assays (SAA) in predicting the clinical diagnoses of Parkinson disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB). Our study design utilized parallel blinded performances of assays in two independent, experienced SAA assay laboratories. For control subjects without clinical LBD, we used a clinically heterogeneous set, simulating a cross-section of elderly, in comparison with previous studies that have mainly used cases and controls that have been prescreened to accentuate group differences. Subjects clinically diagnosed with PD, PDD and DLB as well as those without a suspected LBD were recruited from three sites, including the Mayo Clinic Arizona, Barrow Neurological Institute and Banner Sun Health Research Institute (BSHRI), all located in metropolitan Phoenix, Arizona. The LBD group was designated as Group 1 while the non-LBD groups were divided between a Group 2 and a Group 3, based on the absence (Group 2) or presence (Group 3) of potential clinical risk factors for LBD, including mild cognitive impairment, dementia, REM sleep behavior disorder and hyposmia. Skin punch biopsies were collected from the posterior cervical area and three biopsies were analyzed by SAA between the two labs. Sensitivity across assays ranged between 50.0% and 60.0% while specificity ranged between 69.6% and 100%. Comparisons of Group 1, with the highest clinical diagnostic confidence for the presence of an LBD, versus Group 2, with no clinical indicators of relevant abnormalities, produced the greatest specificities, between 77.3% and 100%, while sensitivities were less variable, ranging between 50% and 60% on group comparisons. Specificities were lower when Group 3 subjects, with potential LBD risk factors, were included in the calculations. Pairwise agreement between biopsy assays ranged from excellent, with a kappa of 0.816, to moderate, between 0.47 and 0.67. Agreement may have been affected by differing protocols, as substrate and testing strategies were different between the two laboratories. Also, it might be possible that variability in -synuclein seed concentrations within different skin biopsies might have contributed to differences in the outcome of the testing by the two labs. The greater agreement for Biopsy 3 was perhaps to be expected given that a single biopsy was analyzed by both labs and the homogenates were prepared by a single lab (Lab 2) and then shared between labs; homogenates for Biopsies 1 and 2 were separately prepared and separately assayed in Labs 1 and 2. A separate analysis of subjects diagnosed with PDD or DLB indicated that skin SAA may have a greater sensitivity for clinically advanced LBD. Nine of these eleven subjects had at least one positive assay, for a sensitivity of 81.82%, substantially better than the 57.1% sensitivity for probable PD subjects without dementia. This suggests that skin SAA may have greater utility as a diagnostic and progression biomarker of Lewy body dementias, as compared with PD subjects without dementia.