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BackgroundThe penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well understood.ObjectiveTo determine the relationship between occupational pesticide exposure and PD in people with LRRK2 and GBA risk variants.MethodsParticipants of the Parkinson's Progression Markers Initiative (PPMI) with a LRRK2-G2019 S or GBA risk variant provided information about occupational pesticide exposure. We compared exposure in carriers with and without PD. Among carriers with PD, we used Cox proportional hazard models to compare time-to impairment in balance, cognition, and activities of daily living (ADLs) between participants with and without prior occupational pesticide exposure.Results378 participants with a risk variant provided exposure information; 176 with LRRK2-G2019 S (54 with and 122 without PD) and 202 with GBA variants (47 with and 155 without PD). Twenty-six participants reported pesticide exposure. People with a GBA variant and occupational pesticide exposure had much higher odds of PD (aOR: 5.4, 95% CI 1.7-18.5, p

BackgroundLittle is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD).ObjectivesWe used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD.MethodsPD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment.ResultsDemographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003-0.005) and higher LEDD over time (P range

BackgroundSince the onset of the coronavirus disease 2019 pandemic, the caregiving routine for care partners of people with Parkinson's disease (PwPD) changed substantially.ObjectivesTo understand the nature and severity of burden in care partners of PwPD during the ongoing pandemic. We also sought to describe care partners' perceived change in burden and factors associated with increased burden.MethodsCross-sectional online questionnaire-based study among care partners of PwPD, registered in the Fox Insight study. The questionnaire consisted of the Modified Caregiver Strain Index, whether an aspect of strain had changed over the course of the pandemic and additional pandemic-specific infection and lifestyle-related items.ResultsTwo hundred seventy-three non-paid primary care partners responded to the questionnaire, 73% female with a median age at enrollment of 64 years, 56% reporting a household income greater than 75,000 USD per year, and 61% retired. An increase in burden compared to before the pandemic was prevalent, ranging from 33% to 63% for individual items. Emotional strain increased most frequently (63%). Decreases in burden were uncommon; work adjustments (7%) and time demands (6%) decreased most frequently. PD-related factors and care partner roles in personal care of the PwPD were the factors that were associated with strain in multivariable analysis, whereas social and pandemic-related factors were not.ConclusionIn this affluent and mostly retired cohort, increases in emotional strain during the pandemic were prevalent. Despite this, caregiving roles in personal care and severity of symptoms in the PwPD were more strongly associated with strain than social and pandemic-related factors.

BackgroundTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with antipsychotic use. Data from RE-KINECT, a real-world study of antipsychotic-treated outpatients, were analyzed to assess the effects of possible TD on patient health and social functioning.MethodsAnalyses were conducted in Cohort 1 (patients with no abnormal involuntary movements) and Cohort 2 (patients with possible TD per clinician judgment). Assessments included: EuroQoL's EQ-5D-5L utility (health); Sheehan Disability Scale (SDS) total score (social functioning); patient- and clinician-rated severity of possible TD ("none", "some", "a lot"); and patient-rated impact of possible TD ("none", "some", "a lot"). Regression models were used to analyze the following: associations between higher (worse) severity/impact scores and lower (worse) EQ-5D-5L utility (indicated by negative regression coefficients); and associations between higher (worse) severity/impact scores and higher (worse) SDS total score (indicated by positive regression coefficients).ResultsIn Cohort 2 patients who were aware of their abnormal movements, patient-rated TD impact was highly and significantly associated with EQ-5D-5L utility (regression coefficient: - 0.023, P

The etiologies of Parkinson's disease (PD) remain unclear. Some, such as certain genetic mutations and head trauma, are widely known or easily identified. However, these causes or risk factors do not account for the majority of cases. Other, less visible factors must be at play. Among these is a widely used industrial solvent and common environmental contaminant little recognized for its likely role in PD: trichloroethylene (TCE). TCE is a simple, six-atom molecule that can decaffeinate coffee, degrease metal parts, and dry clean clothes. The colorless chemical was first linked to parkinsonism in 1969. Since then, four case studies involving eight individuals have linked occupational exposure to TCE to PD. In addition, a small epidemiological study found that occupational or hobby exposure to the solvent was associated with a 500% increased risk of developing PD. In multiple animal studies, the chemical reproduces the pathological features of PD.Exposure is not confined to those who work with the chemical. TCE pollutes outdoor air, taints groundwater, and contaminates indoor air. The molecule, like radon, evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected. Despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited. Here, through a literature review and seven illustrative cases, we postulate that this ubiquitous chemical is contributing to the global rise of PD and that TCE is one of its invisible and highly preventable causes. Further research is now necessary to examine this hypothesis.

Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos. Exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics or antiemetics is associated with a spectrum of movement disorders including TD. The differential diagnosis of TD is based on history of DRBA exposure, recent discontinuation or dose reduction of a DRBA, and movement phenomenology. Common diagnostic challenges are the abnormal behaviors and dyskinesias associated with advanced age or chronic mental illness, and other movement disorders associated with DRBA therapy, such as akathisia, parkinsonian tremor, and tremor related to use of mood stabilizing agents (eg, lithium, divalproex). Duration of exposure may help rule out acute drug-induced syndromes such as acute dystonia or acute/subacute akathisia. Another important consideration is the potential for TD to present together with other drug-induced movement disorders (eg, parkinsonism, parkinsonian tremor, and postural tremor from mood stabilizers) in the same patient, which can complicate both diagnosis and management. After documentation of the phenomenology, severity, and distribution of TD movements, treatment options should be reviewed with the patient and caregivers.

BackgroundTo date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline.MethodsThis is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity.DiscussionSPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health.Trial registrationClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

BackgroundThe Unified Dyskinesia Rating Scale (UDysRS) evaluates dyskinesia in patients with Parkinson's disease (PD). A minimal clinically important change (MCIC)-the smallest change in a treatment outcome that a patient considers important-remains undefined for the UDysRS.ObjectiveTo utilize pivotal amantadine delayed-release/extended-release (DR/ER) trial data to derive MCICs for the UDysRS total score in patients with PD experiencing dyskinesia.MethodsPivotal trials included PD patients with ≥1 h daily ON time with troublesome dyskinesia and baseline scores ≥2 on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, item 4.2. Patients randomized to amantadine DR/ER or placebo completed two consecutive 24-h diaries before each clinic visit and were evaluated during ON time with dyskinesia using the UDysRS, MDS-UPDRS, and Clinician Global Impression of Change (CGI-C). The UDysRS changes from baseline to week 12 were anchored to corresponding changes in MDS-UPDRS item 4.2 scores. A minimal clinically important improvement in the CGI-C and diary-reported ON time with troublesome dyskinesia (≥0.5 h) were supportive anchors. Receiver operating characteristic curves determined the UDysRS change values optimizing sensitivity and specificity to at least minimal improvement on each anchor.ResultsThe analyses included 196 patients. Week 12 UDysRS total score reduction of ≥8 points corresponded to at least minimal MDS-UPDRS item 4.2 improvement. UDysRS reduction of ≥9 points corresponded to decreased ON time with troublesome dyskinesia of ≥0.5 h per patient diaries, and UDysRS reduction of ≥10 points corresponded to at least minimal improvement on the CGI-C.ConclusionAnchored to the MDS-UPDRS Part IV, item 4.2, an 8-point reduction in the UDysRS total score can be considered an MCIC for PD patients with dyskinesia.

BackgroundParkinson's disease (PD) is a chronic, disabling neurodegenerative disorder.ObjectiveTo predict a future diagnosis of PD using questionnaires and simple non-invasive clinical tests.MethodsParticipants in the prospective Kuakini Honolulu-Asia Aging Study (HAAS) were evaluated biannually between 1995-2017 by PD experts using standard diagnostic criteria. Autopsies were sought on all deaths. We input simple clinical and risk factor variables into an ensemble-tree based machine learning algorithm and derived models to predict the probability of developing PD. We also investigated relationships of predictive models and neuropathologic features such as nigral neuron density.ResultsThe study sample included 292 subjects, 25 of whom developed PD within 3 years and 41 by 5 years. 116 (46%) of 251 subjects not diagnosed with PD underwent autopsy. Light Gradient Boosting Machine modeling of 12 predictors correctly classified a high proportion of individuals who developed PD within 3 years (area under the curve (AUC) 0.82, 95%CI 0.76-0.89) or 5 years (AUC 0.77, 95%CI 0.71-0.84). A large proportion of controls who were misclassified as PD had Lewy pathology at autopsy, including 79%of those who died within 3 years. PD probability estimates correlated inversely with nigral neuron density and were strongest in autopsies conducted within 3 years of index date (r = -0.57, p

BackgroundInvestigation of sex-related motor and non-motor differences and biological markers in Parkinson's disease (PD) may improve precision medicine approach.ObjectiveTo examine sex-related longitudinal changes in motor and non-motor features and biologic biomarkers in early PD.MethodsWe compared 5-year longitudinal changes in de novo, untreated PD men and women (at baseline N = 423; 65.5%male) of the Parkinson's Progression Markers Initiative (PPMI), assessing motor and non-motor manifestations of disease; and biologic measures in cerebrospinal fluid (CSF) and dopamine transporter deficit on DaTscanTM uptake.ResultsMen experienced greater longitudinal decline in self-reported motor (p

BackgroundTraditional in-person Parkinson's disease (PD) research studies are often slow to recruit and place unnecessary burden on participants. The ongoing COVID-19 pandemic has added new impetus to the development of new research models.ObjectiveTo compare recruitment processes and outcomes of three remote decentralized observational PD studies with video visits.MethodsWe examined the number of participants recruited, speed of recruitment, geographic distribution of participants, and strategies used to enhance recruitment in FIVE, a cross-sectional study of Fox Insight participants with and without PD (n = 203); VALOR-PD, a longitudinal study of 23andMe, Inc. research participants carrying the LRRK2 G2019S variant with and without PD (n = 277); and AT-HOME PD, a longitudinal study of former phase III clinical trial participants with PD (n = 226).ResultsAcross the three studies, 706 participants from 45 U.S. states and Canada enrolled at a mean per study rate of 4.9 participants per week over an average of 51 weeks. The cohorts were demographically homogenous with regard to race (over 95%white) and level of education (over 90%with more than a high school education). The number of participants living in primary care Health Professional Shortage Areas in each study ranged from 30.3-42.9%. Participants reported interest in future observational (98.5-99.6%) and interventional (76.1-87.6%) research studies with remote video visits.ConclusionRecruitment of large, geographically dispersed remote cohorts from a single location is feasible. Interest in participation in future remote decentralized PD studies is high. More work is needed to identify best practices for recruitment, particularly of diverse participants.

Maintaining consistent levodopa benefits while simultaneously controlling dyskinesia can be difficult. Recently, an amantadine delayed release/extended release (DR/ER) formulation (Gocovri®) indicated for dyskinesia received additional FDA approval as an adjunct to levodopa for the treatment of OFF episodes. We evaluated OFF time reductions with amantadine-DR/ER in a pooled analysis of two phase III amantadine-DR/ER trials (NCT02136914, NCT02274766) followed by a 2-year open-label extension trial (NCT02202551). OFF outcomes were analyzed for the mITT population, as well as stratified by baseline OFF time of ≥2.5 h/day or

BackgroundCerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).ObjectiveThe aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.MethodsAbsolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies.ResultsBaseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P

IntroductionGocovri (amantadine) extended release capsules are approved for treatment of dyskinesia and as a levodopa adjunct for OFF episodes in patients with Parkinson's disease (PD). We report treatment-related effects on non-motor symptoms (NMS) assessed as secondary outcomes in two trials using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I.MethodsEASE LID and EASE LID 3 enrolled levodopa-treated patients with PD and ≥ 1 h/day ON time with troublesome dyskinesia. Patients were randomized to Gocovri (274 mg) or placebo taken daily at bedtime. Treatment differences from baseline to week 12 in MDS-UPDRS Part I were evaluated for the pooled population (N = 196) from both trials. Correlation analyses of NMS (MDS-UPDRS Part I) with dyskinesia using Unified Dyskinesia Rating Scale (UDysRS) scores were performed.ResultsFor changes in the MDS-UPDRS Part I items, the treatment difference favored Gocovri in daytime sleepiness (P = 0.006) and depression (P = 0.049) scores, but favored placebo in cognitive impairment (P = 0.038), and  hallucinations and psychosis (P

BackgroundCare partners support people with Parkinson's disease through a long journey ranging from independence to dependence for many daily tasks. Longitudinal studies are important to understand the evolution of this process and predictors of future needs of care partners.MethodsA scoping review was conducted, searching PubMed for longitudinal studies examining care partner burden, needs or coping in Parkinson's disease published through May 2020.ResultsEight observational studies and 19 interventional studies met the eligibility criteria. Longitudinal observation ranged from 7 weeks to 10 years, involving between six and 8515 care partners. All studies addressed care partner burden, while two and three studies respectively addressed needs and coping. Only one study related burden to specific stages or duration of disease. Results from identified studies show that care partners in Parkinson's disease are at risk for increasing burden over time. Multiple predictors of future burden have been identified related to the person with Parkinson's disease, the care partner, or an intervention. No studies examined the evolution of needs and coping in caregiving in Parkinson's disease.ConclusionThe scarcity of longer term, observational research on the temporal evolution of burden and particularly needs and coping in caregiving for someone with PD is a main identified gap. Even within these observational studies, the impact of caregiving is not often reported. Longitudinal studies on these topics are needed to help understand their change over time and relation to each other, which can inform support planning for care partners.

The Trial of Parkinson's And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414 ) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants' homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.

IntroductionParkinson's disease (PD) research is hampered by slow, inefficient recruitment and burdensome in-person assessments that may be challenging to conduct in a world affected by COVID-19. Fox Insight is an ongoing prospective clinical research study that enables individuals to participate in clinical research from their own homes by completing online questionnaires. To date, over 45,000 participants with and without PD have enrolled. We sought to validate self-reported PD diagnosis in the Fox Insight cohort, assess the validity of other self-reported health information, and evaluate the willingness of participants to participate in video-based research studies.MethodsIndividuals with and without self-reported PD enrolled in Fox Insight were invited to participate in this virtual research study. Participants completed online questionnaires and two virtual visits, during which we conducted standard cognitive and motor assessments. A movement disorder expert determined the most likely diagnosis, which was compared to self-reported diagnosis.ResultsA total of 203 participants from 40 U.S. states, 159 with remote clinician-determined PD and 44 without, completed the study (59% male, mean (SD) age 65.7 (9.8)). Level of agreement between self-reported PD diagnosis in Fox Insight and clinician-determined diagnosis was very good ((kappa = 0.85, 95% CI 0.76-0.94). Overall, 97.9% of participants were satisfied with the study, 98.5% were willing to participate in a future observational study with virtual visits, and 76.1% were willing to participate in an interventional trial with virtual visits.ConclusionAmong the Fox Insight cohort, self-reported diagnosis is accurate and interest in virtual research studies is high.

BackgroundThe objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker.MethodsWe quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers.ResultsIn the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P

BackgroundThe penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown.ObjectivesThe objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD.MethodsSymptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups.ResultsA total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91).ConclusionsRegular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.

ObjectiveWe analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.MethodsAmyloid-β 1 to 42 (Aβ42 ), total tau (t-tau) and phosphorylated tau (p-tau) at the threonine 181 position were measured using the high-precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear-mixed effects models.ResultsWe found patients with PD had lower CSF t-tau (median = 157.7 pg/mL; range = 80.9-467.0); p-tau (median = 13.4 pg/mL; range = 8.0-40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8-3,707.0) than HCs at baseline (CSF t-tau median = 173.5 pg/mL; range = 82.0-580.8; p-tau median = 15.4 pg/mL; range = 8.1-73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1-3,297.0; p

Parkinson's disease (PD) is one of the world's fastest growing neurological disorders. Much is unknown about PD-associated economic burdens in the United States (U.S.) and other high-income nations. This study provides a comprehensive analysis of the economic burdens of PD in the U.S. (2017) and projections for the next two decades. Multiple data sources were used to estimate the costs of PD, including public and private administrative claims data, Medicare Current Beneficiary Survey, Medical Expenditure Panel Survey, and a primary survey (n = 4,548) designed for this study. We estimated a U.S. prevalence of approximately one million individuals with diagnosed Parkinson's disease in 2017 and a total economic burden of $51.9 billion. The total burden of PD includes direct medical costs of $25.4 billion and $26.5 billion in indirect and non-medical costs, including an indirect cost of $14.2 billion (PWP and caregiver burden combined), non-medical costs of $7.5 billion, and $4.8 billion due to disability income received by PWPs. The Medicare program bears the largest share of excess medical costs, as most PD patients are over age 65. Projected PD prevalence will be more than 1.6 million with projected total economic burden surpassing $79 billion by 2037. The economic burden of PD was previously underestimated. Our findings underscore the substantial burden of PD to society, payers, patients, and caregivers. Interventions to reduce PD incidence, delay disease progression, and alleviate symptom burden may reduce the future economic burden of PD.

Autonomic nervous system involvement precedes the motor features of Parkinson's disease (PD). Our goal was to develop a proof-of-concept model for identifying subjects at high risk of developing PD by analysis of cardiac electrical activity. We used standard 10-s electrocardiogram (ECG) recordings of 60 subjects from the Honolulu Asia Aging Study including 10 with prevalent PD, 25 with prodromal PD, and 25 controls who never developed PD. Various methods were implemented to extract features from ECGs including simple heart rate variability (HRV) metrics, commonly used signal processing methods, and a Probabilistic Symbolic Pattern Recognition (PSPR) method. Extracted features were analyzed via stepwise logistic regression to distinguish between prodromal cases and controls. Stepwise logistic regression selected four features from PSPR as predictors of PD. The final regression model built on the entire dataset provided an area under receiver operating characteristics curve (AUC) with 95% confidence interval of 0.90 [0.80, 0.99]. The five-fold cross-validation process produced an average AUC of 0.835 [0.831, 0.839]. We conclude that cardiac electrical activity provides important information about the likelihood of future PD not captured by classical HRV metrics. Machine learning applied to ECGs may help identify subjects at high risk of having prodromal PD.

ObjectiveTo determine whether initial presurgical evaluation of deep brain stimulation (DBS) candidacy with video telemedicine (VTEL) can reliably predict surgical candidacy (patients who will eventually undergo DBS surgery) and decrease resource utilization when compared to an in-person evaluation.MethodsIn this retrospective, cohort analysis, all out-of-state referrals to the San Francisco Veterans Affairs from 2008 to 2013 for DBS therapy were reviewed and their surgical outcomes were assessed until 2017. Patients were designated as good, borderline, or poor surgical candidates after initial evaluation, and their rates of undergoing DBS were recorded. An assessment of patient travel costs was performed.ResultsThere were 60 out-of-state DBS referrals identified out of the 148 initial presurgical DBS evaluations completed for surgical treatment of dystonia, essential tremor, or Parkinson disease; 24 patients underwent in-person consultation and 36 patients underwent evaluation via VTEL. There was no difference between the rates of undergoing surgical treatment with DBS based on surgical candidacy for patients in the in-person and VTEL cohorts. Patients who underwent initial presurgical screening via VTEL saved time and money.ConclusionsVTEL can be used to facilitate presurgical screening for DBS and saves costs.

Purpose/backgroundRE-KINECT (NCT03062033) was designed to assess the presence and impact of possible tardive dyskinesia (TD) in antipsychotic-treated outpatients.Methods/proceduresThe study included adults with 3 or more months of lifetime antipsychotic exposure and 1 or more psychiatric disorder. Based on clinician observation and assessment, patients were assigned to cohort 1 (without involuntary movements or with non-TD involuntary movements) or cohort 2 (with involuntary movements confirmed by clinician as possible TD). Baseline assessments included the following: patient characteristics; location/severity of involuntary movements; and impact of possible TD on health-related quality of life, including the EuroQoL 5-Dimensions 5-Level questionnaire.Findings/resultsOf 739 eligible patients, 204 (27.6%) had clinician-confirmed possible TD (cohort 2). Compared with cohort 1, patients in cohort 2 were significantly older (P < 0.0001), more likely to have schizophrenia or schizoaffective disorder (P < 0.0001) and longer lifetime exposure to antipsychotics (P < 0.0001), and less likely to be working or studying, based on clinician perception (P = 0.0010). Clinician- and patient-rated severity of possible TD movements was significantly correlated in each of 4 body regions (head/face, neck/trunk, upper extremities, lower extremities), for maximum severity in any region, and for total number of affected regions (P < 0.001 for all correlations). For the patient-rated EuroQoL 5-Dimensions 5-Level, the health state visual analog scale score was significantly lower (worse) in cohort 2 versus cohort 1 (66.8 vs 69.7; P = 0.0002), as was the utility index score (0.71 vs 0.76; P < 0.0175).Implications/conclusionsResults from this real-world population indicate that TD occurs frequently and can significantly reduce quality of life in patients with a psychiatric disorder.

BackgroundThere are limited data on the phenotypic and dopamine transporter (DAT) imaging characterization of the Parkinson's disease (PD) patients with leucine rich kinase 2 (LRRK2) and glucosylceramidase beta (GBA) mutations.ObjectiveThe objective of this study was to examine baseline clinical and DAT imaging characteristics in GBA and LRRK2 mutation carriers with early PD compared with sporadic PD.MethodsThe Parkinson's Progression Markers Initiative is an ongoing observational longitudinal study that enrolled participants with sporadic PD, LRRK2 and GBA PD carriers from 33 sites worldwide. All participants are assessed annually with a battery of motor and nonmotor scales, 123-I Ioflupane DAT imaging, and biologic variables.ResultsWe assessed 158 LRRK2 (89% G2019S), 80 GBA (89 %N370S), and 361 sporadic PD participants with the mean (standard deviation) disease duration of 2.9 (1.9), 3.1 (2.0), and 2.6 (0.6) years, respectively. When compared with sporadic PD, the GBA PD patients had no difference in any motor, cognitive, or autonomic features. The LRRK2 PD patients had less motor disability and lower rapid eye movement behavior disorder questionnaire scores, but no meaningful difference in cognitive or autonomic features. Both genetic cohorts had a higher score on the impulse control disorders scale when compared with sporadic PD, but no difference in other psychiatric features. Both genetic PD cohorts had less loss of dopamine transporter on DAT imaging when compared with sporadic PD.ConclusionsWe confirm previous reports of milder phenotype associated with LRRK2-PD. A previously reported more aggressive phenotype in GBA-PD is not evident early in the disease in N370s carriers. This observation identifies a window for potential disease-modifying interventions. Longitudinal data will be essential to define the slope of progression for both genetic cohorts.Trial registrationClinicalTrials.gov (NCT01141023). © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

BackgroundCurrent cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized.ObjectivesTo determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization.MethodsWe identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration.ResultsCD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68).ConclusionsCD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society.

Parkinson disease is a complex, age-related, neurodegenerative disease associated with dopamine deficiency and both motor and nonmotor deficits. Many environmental and genetic factors influence Parkinson disease risk, with different factors predominating in different patients. These factors converge on specific pathways, including mitochondrial dysfunction, oxidative stress, protein aggregation, impaired autophagy, and neuroinflammation. Ultimately, treatment of Parkinson disease may focus on targeted therapies for pathophysiologically defined subtypes of Parkinson disease patients.

BackgroundGocovri® (amantadine) extended release capsules are approved for the treatment of dyskinesia in patients with Parkinson's disease (PD) receiving levodopa-based therapy.ObjectiveTo evaluate the long-term safety, tolerability, and efficacy of Gocovri in patients with PD experiencing levodopa-induced dyskinesia.MethodsIn this 2-year open-label trial, patients completing double-blind Gocovri clinical trials or excluded from prior trials because of deep-brain stimulation (DBS) received Gocovri 274 mg once daily at bedtime. The primary objective was to evaluate long-term safety and tolerability. In addition, dyskinesia and OFF time were assessed using Part IV (Motor Complications) scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).ResultsAmong 223 enrolled patients (mean PD duration, 11.7 years; mean levodopa use, 9.3 years), 75.8% completed 1 year of treatment and 57.8% completed the trial, with a median treatment duration of 1.9 years. Common adverse events were fall (32.7%), hallucination (24.2%), peripheral edema (16.1%), constipation (13.5%), and urinary tract infection (10.3%); 31 patients (13.9%) discontinued because of adverse events considered related to study drug. At baseline, MDS-UPDRS Part IV scores were lower for patients continuing Gocovri (mean, 6.5 points) than for previous placebo (9.4) or DBS groups (10.5) but were similar for all groups by week 8 (6.3, 6.2, 6.4, respectively), and remained low for the duration of the trial (at week 100: 6.9, 7.3, 7.0, respectively).ConclusionsIn patients with PD, Gocovri showed long-term safety and tolerability consistent with double-blind trial findings, and durable reduction in motor complications (dyskinesia and OFF time).

BackgroundClinical research in Parkinson's disease (PD) faces practical and ethical challenges due to two interrelated problems: participant under-recruitment and lack of diversity. Fox Insight (FI) is a web-based longitudinal study collecting patient-reported outcomes and genetic data worldwide to inform therapeutic studies. FI's online platform provides an opportunity to evaluate online strategies for recruiting large, diverse research cohorts.ObjectiveThis project aimed to determine 1) whether FI's digital marketing was associated with increased enrollment overall and from under-represented patient groups, compared to traditional recruitment methods; 2) the clinical and demographic characteristics of samples recruited online, and 3) the cost of this online recruitment.MethodFI recruitment during a 6-week baseline period without digital promotion was compared to recruitment during several periods of digital outreach. Separate online recruiting intervals included general online study promotion and unique Facebook and Google ad campaigns targeting under-represented subgroups: early PD, late/advanced PD, and residents of underrepresented/rural geographic areas.ResultsEarly PD, late PD, and geotargeting campaigns enrolled more individuals in their respective cohorts compared to baseline. All online campaigns also yielded greater total FI enrollment, attracting more participants who were non-White, Hispanic, older, female, and had lower educational attainment and income, and more medical comorbidities. Cost per new participant ranged from $21 (Facebook) to $108 (Google).ConclusionDigital marketing may allow researchers to increase, accelerate, and diversify recruitment for PD clinical studies, by tailoring digital ads to target PD cohort characteristics.

BackgroundThe effect of the COVID-19 pandemic on people with Parkinson's disease (PD) is poorly understood.ObjectiveTo rapidly identify areas of need and improve care in people with PD during the COVID-19 pandemic, we deployed a survey to assess COVID-19 symptoms and the pandemic's effect among those with and without COVID-19.MethodsPeople with and without PD participating in the online study Fox Insight (FI) were invited to complete a survey between April 23 and May 23, 2020. Among people reporting COVID-19 diagnoses, we compared symptoms and outcomes in people with and without PD. Among people not reporting COVID-19, we assessed access to healthcare and services and PD symptoms.Results7,209/9,762 active FI users responded (approximately 74% response rate), 5,429 people with PD and 1,452 without PD. COVID-19 diagnoses were reported by 51 people with and 26 without PD. Complications were more frequent in people with longer PD duration. People with PD and COVID-19 experienced new or worsening motor (63%) and nonmotor (75%) symptoms. People with PD not diagnosed with COVID-19 reported disrupted medical care (64%), exercise (21%), and social activities (57%), and worsened motor (43%) and non-motor (52%) symptoms. Disruptions were more common for those living alone, with lower income and non-White race.ConclusionsThe COVID-19 pandemic is associated with wide-ranging effects on people with PD, and certain groups may be at particular risk. FI provides a rapid, patient-centered means to assess these effects and identify needs that can be used to improve the health of people with PD.

BackgroundThe Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.MethodsThis cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FindingsBetween Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

Ongoing biomarker development programs have been designed to identify serologic or imaging signatures of clinico-pathologic entities, assuming distinct biological boundaries between them. Identified putative biomarkers have exhibited large variability and inconsistency between cohorts, and remain inadequate for selecting suitable recipients for potential disease-modifying interventions. We launched the Cincinnati Cohort Biomarker Program (CCBP) as a population-based, phenotype-agnostic longitudinal study. While patients affected by a wide range of neurodegenerative disorders will be deeply phenotyped using clinical, imaging, and mobile health technologies, analyses will not be anchored on phenotypic clusters but on bioassays of to-be-repurposed medications as well as on genomics, transcriptomics, proteomics, metabolomics, epigenomics, microbiomics, and pharmacogenomics analyses blinded to phenotypic data. Unique features of this cohort study include (1) a reverse biology-to-phenotype direction of biomarker development in which clinical, imaging, and mobile health technologies are subordinate to biological signals of interest; (2) hypothesis free, causally- and data driven-based analyses; (3) inclusive recruitment of patients with neurodegenerative disorders beyond clinical criteria-meeting patients with Parkinson's and Alzheimer's diseases, and (4) a large number of longitudinally followed participants. The parallel development of serum bioassays will be aimed at linking biologically suitable subjects to already available drugs with repurposing potential in future proof-of-concept adaptive clinical trials. Although many challenges are anticipated, including the unclear pathogenic relevance of identifiable biological signals and the possibility that some signals of importance may not yet be measurable with current technologies, this cohort study abandons the anchoring role of clinico-pathologic criteria in favor of biomarker-driven disease subtyping to facilitate future biosubtype-specific disease-modifying therapeutic efforts.

BackgroundOnline tools for data collection could be of value in patient-oriented research. The Fox Insight (FI) study collects data online from individuals with self-reported Parkinson's disease (PD). Comparing the FI cohort to other cohorts assessed through more traditional (in-person) observational research studies would inform the representativeness and utility of FI data.ObjectiveTo compare self-reported demographic characteristics, symptoms, medical history, and PD medication use of the FI PD cohort to other recent observational research study cohorts assessed with in-person visits.MethodsThe FI PD cohort (n = 12,654) was compared to 3 other cohorts, selected based on data accessibility and breadth of assessments: Parkinson's Progression Markers Initiative (PPMI; PD n = 422), Parkinson's Disease Biomarker Program (PDBP; n = 700), and PD participants in the LRRK2 consortium without LRRK2 mutations (n = 508). Demographics, motor and non-motor assessments, and medications were compared across cohorts. Where available, identical items on surveys and assessments were compared; otherwise, expert opinion was used to determine comparable definitions for a given variable.ResultsThe proportion of females was significantly higher in FI (45.56%) compared to PPMI (34.36%) and PDBP (35.71%). The FI cohort had greater educational attainment as compared to all other cohorts. Overall, prevalence of difficulties with motor experiences of daily living and non-motor symptoms in the FI cohort was similar to other cohorts, with only a few significant differences that were generally small in magnitude. Missing data were rare for the FI cohort, except on a few variables.DiscussionPatterns of responses to patient-reported assessments obtained online on the PD cohort of the FI study were similar to PD cohorts assessed in-person.

The National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry is one of the oldest, national population-based twin registries in the USA. It comprises 15,924 White male twin pairs born in the years 1917-1927 (N = 31.848), both of whom served in the armed forces, chiefly during World War II. This article updates activities in this registry since the most recent report in Twin Research and Human Genetics (Page, 2006). Records-based data include information from enlistment charts and Veterans Administration data linkages. There have been three major epidemiologic questionnaires and an education and earnings survey. Separate data collection efforts with the NAS-NRC registry include the National Heart, Lung, and Blood Institute (NHLBI) subsample, the Duke Twins Study of Memory in Aging and a clinically based study of Parkinson's disease. Progress has been made on consolidating the various data holdings of the NAS-NRC Twin Registry. Data that had been available through the National Academy of Sciences are now freely available through National Archive of Computerized Data on Aging (NACDA).

ObjectiveWhile excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up.MethodsIdentification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years.ResultsAlthough EDS was more common in the presence vs absence of LP (p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP (p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies.ConclusionsThe association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.

BackgroundAggregation of α-synuclein is central to the pathophysiology of PD. Biomarkers related to α-synuclein may be informative for PD diagnosis/progression.ObjectivesTo analyze α-synuclein in CSF in drug-naïve PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative.MethodsOver up to 36-month follow-up, CSF total α-synuclein and its association with MDS-UPDRS motor scores, cognitive assessments, and dopamine transporter imaging were assessed.ResultsThe inception cohort included PD (n = 376; age [mean {standard deviation} years]: 61.7 [9.62]), healthy controls (n = 173; age, 60.9 [11.3]), hyposmics (n = 16; age, 68.3 [6.15]), and idiopathic rapid eye movement sleep behavior disorder (n = 32; age, 69.3 [4.83]). Baseline CSF α-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal α-synuclein decreased significantly in PD at 24 and 36 months, did not change in prodromal PD over 12 months, and trended toward an increase in healthy controls. The decrease in PD was not shown when CSF samples with high hemoglobin concentration were removed from the analysis. CSF α-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan.ConclusionsCSF α-synuclein decreases early in the disease, preceding motor PD. CSF α-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF α-synuclein may be an indirect index of changes in the balance between α-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to α-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed. © 2019 International Parkinson and Movement Disorder Society.

ObjectiveTo determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC).BackgroundCerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery effort in PD with still limited data on safety and feasibility of serial LPs in PD participants.Design/methodsParkinson's Progression Marker Initiative (PPMI) is a longitudinal observation study designed to identify PD progression biomarkers. All PPMI participants undergo LP at baseline, 6, 12 months and yearly thereafter. CSF collection is performed by a trained investigator using predominantly atraumatic needles. Adverse events (AEs) are monitored by phone one week after LP completion. We analyzed safety data from baseline LPs.ResultsPPMI enrolled 683 participants (423 PD/196 HC/64 SWEDDs) from 23 study sites. CSF was collected at baseline in 97.5% of participants, of whom 5.4% underwent collection under fluoroscopy. 23% participants reported any related AEs, 68% of all AE were mild while 5.6% were severe. The most common AEs were headaches (13%) and low back pain (6.5%) and both occurred more commonly in HC and SWEDDs compared to PD participants. Factors associated with higher incidence of AEs across the cohorts included female gender, younger age and use of traumatic needles with larger diameter. AEs largely did not impact compliance with the future LPs.ConclusionsLPs are safe and feasible in PD research participants. Specific LP techniques (needle type and gauge) may reduce the overall incidence of AEs.

Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10-4; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts.

BackgroundOrganochlorine pesticides are associated with an increased risk of Parkinson's disease. A preliminary analysis from the Honolulu-Asia Aging Study suggested that heptachlor epoxide, a metabolite from an organochlorine pesticide extensively used in Hawaii, may be especially important. This was a cross sectional analysis to evaluate the association of heptachlor epoxide and other organochlorine compounds with Lewy pathology in an expanded survey of brain organochlorine residues from the longitudinal Honolulu-Asia Aging Study.MethodsOrganochlorines were measured in frozen occipital or temporal lobes in 705 brains using gas chromatography with mass spectrometry. Lewy pathology was identified using hematoxylin and eosin- and α-synuclein immunochemistry-stained sections from multiple brain regions.ResultsThe prevalence of Lewy pathology was nearly doubled in the presence versus the absence of heptachlor epoxide (30.1% versus 16.3%, P < 0.001). Although associations with other compounds were weaker, hexachlorobenzene (P = 0.003) and α-chlordane (P = 0.007) were also related to Lewy pathology. Most of the latter associations, however, were a result of confounding from heptachlor epoxide. Neither compound was significantly related to Lewy pathology after adjustment for heptachlor epoxide. In contrast, the association of heptachlor epoxide with Lewy pathology remained significant after adjustments for hexachlorobenzene (P = 0.013) or α-chlordane (P = 0.005). Findings were unchanged after removal of cases of PD and adjustment for age and other characteristics.ConclusionsOrganochlorine pesticides are associated with the presence of Lewy pathology in the brain, even after exclusion of PD cases. Although most of the association is through heptachlor epoxide, the role of other organochlorine compounds is in need of clarification. © 2018 International Parkinson and Movement Disorder Society.

Background: We recently reported an increased risk of Parkinson's disease (PD) in service members who resided at Marine Base Camp Lejeune, North Carolina, when water supplies were contaminated with trichloroethylene and other volatile organic compounds (VOCs). Prior studies suggest that environmental exposures may affect PD phenotype or progression, but this has not been reported for VOCs. Objective: The objective of this study was to test whether PD progression is faster in individuals exposed to VOCs in water at Camp Lejeune. Methods: A cohort of 172,128 marines residing at Camp Lejeune between 1975 and 1985 was previously assembled. We identified individuals with PD in Veterans Health Administration and Medicare databases between 2000 and 2021. Using estimates derived by the US Agency for Toxic Substances and Disease Registry, we classified individuals as exposed or unexposed to VOCs in residential water. We used Kaplan–Meier and Cox regression models to test differences between exposed and unexposed groups in the time from PD diagnosis until psychosis, fracture, fall, or death. Results: Among 270 persons with PD, 177 (65.6%) were exposed to VOCs in residential water. Median cumulative exposure was 4970 μg/L‐months, >50‐fold the permissible level. Time until psychosis, fracture, and fall were all shorter in the exposed group, with adjusted hazard ratios (HRs) exceeding 2: psychosis HR, 2.19 (95% confidence interval [CI]: 0.99–4.83); fracture HR, 2.44 (95% CI: 0.91–6.55); and fall HR, 2.64 (95% CI: 0.97–7.21). A significant dose response was observed for time to fall (P trend, 0.032). No differences were observed for time until death. Conclusions: PD progression may be faster in persons exposed to trichloroethylene and other VOCs in water decades earlier. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

ObjectiveThe Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials.MethodsA total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org.ResultsApproximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P

OBJECTIVE:The objective of this study was to assess longitudinal change in clinical and dopamine transporter imaging outcomes in early, untreated PD. METHODS:We describe 5-year longitudinal change of the MDS-UPDRS and other clinical measures using results from the Parkinson's Progression Markers Initiative, a longitudinal cohort study of early Parkinson's disease (PD) participants untreated at baseline. We also provide data on the longitudinal change in dopamine transporter 123-I Ioflupane striatal binding and correlation between the 2 measures. RESULTS:A total of 423 PD participants were recruited, and 358 remain in the study at year 5. Baseline MDS-UPDRS total score was 32.4 (standard deviation 13.1), and the average annual change (assessed medications OFF for the treated participants) was 7.45 (11.6), 3.11 (11.7), 4(11.9), 4.7 (11.1), and 1.74(11.9) for years 1, 2, 3, 4, and 5, respectively (P

BackgroundADS-5102 (amantadine) extended release capsules (GOCOVRI™) are a treatment for dyskinesia in patients with Parkinson's disease (PD). ADS-5102 reduced dyskinesia and OFF time in phase 3 controlled trials of up to six months. Amantadine immediate release (IR) is used for dyskinesia, but suboptimal durability and tolerability limit its clinical utility.MethodsIn an ongoing, open-label, phase 3 study in the US and Western Europe (NCT02202551), patients with PD received 274 mg of ADS-5102 (equivalent to 340 mg amantadine HCl) once daily at bedtime for up to two years. Study outcomes included safety and assessment of motor complications, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV. This manuscript focuses on those patients switched to ADS-5102 from amantadine IR. Results in two groups of patients who previously completed a randomized controlled trial (EASE LID or EASE LID 3) are also presented according to use of ADS-5102 or placebo in that study before enrollment in the open-label study.ResultsChange in MDS-UPDRS Part IV at week 8 was -0.3 in the previous ADS-5102 subgroup (n = 61), -3.4 in the previous placebo subgroup (n = 79), and -3.4 in the previous amantadine IR subgroup (n = 32). Effects were maintained to week 64. In the previous amantadine IR subgroup (mean treatment duration, 2.5 years), mean amantadine IR dose was 221 mg. Safety data were consistent with previous randomized controlled trials of ADS-5102.ConclusionThese open-label data suggest ADS-5102 provides incremental reduction from baseline in MDS-UDPRS Part IV score in patients switched directly from amantadine IR, without exacerbating adverse events.