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Introduction: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases., Methods: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ) 42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD)., Results: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ 42/40 ., Discussion: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The global burden of Parkinson's disease (PD) has more than doubled over the past three decades, and this trend is expected to continue. Despite generally poorer access to health care services in rural areas, little previous work has examined health system use in persons with PD by rurality. We examined trends in the prevalence of PD and health service use among persons with PD by rurality in Ontario, Canada., Methods: We conducted a repeated, cross-sectional analysis of persons with prevalent PD aged 40+ years on April 1st of each year from 2000 to 2018 using health administrative databases and calculated the age-sex standardized prevalence of PD. Prevalence of PD was also stratified by rurality and sex. Negative binomial models were used to calculate rate ratios with 95% confidence intervals comparing rates of health service use in rural compared to urban residents in 2018., Results: The age-sex standardized prevalence of PD in Ontario increased by 0.34% per year (p<0.0001) and was 459 per 100,000 in 2018 (n = 33,479), with a lower prevalence in rural compared to urban residents (401 vs. 467 per 100,000). Rates of hospitalizations and family physician visits declined over time in both men and women with PD in rural and urban areas, while rates of emergency department, neurologist, and other specialist visits increased. Adjusted rates of hospitalizations were similar between rural and urban residents (RR = 1.04, 95% CI [0.96, 1.12]), while rates of emergency department visits were higher among rural residents (RR = 1.35, 95% CI [1.27, 1.42]). Rural residents had lower rates of family physician (adjusted RR = 0.82, (95% CI [0.79, 0.84]) and neurologist visits (RR = 0.74, 95% CI [0.72, 0.77])., Interpretation: Lower rates of outpatient health service use among persons residing in rural regions, contrasting with higher rates of emergency department visits suggest inequities in access. Efforts to improve access to primary and specialist care for persons with PD in rural regions are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Maclagan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years., Methods: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale., Results: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline., Conclusion: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology., (© 2023 European Academy of Neurology.)

Introduction: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap., Methods: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes., Results: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation., Discussion: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design., (© 2022 the Alzheimer's Association.)

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?, Methods/design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery., Results: We found three components in the ZBI. The first was "overall burden" and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = -0.566, basic ADLs r = -0.43), (2) moderately related to cognition (MoCA r = -0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners., Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions., (© 2022 John Wiley & Sons Ltd.)

Importance: Persons with dementia and Parkinson disease (PD) are vulnerable to disruptions in health care and services., Objective: To examine changes in health service use among community-dwelling persons with dementia, persons with PD, and older adults without neurodegenerative disease during the first wave of the COVID-19 pandemic., Design Setting and Participants: Repeated cross-sectional analysis using population-based administrative data among community-dwelling persons with dementia, persons with PD, and adults 65 years and older at the start of each week from March 1 through the week of September 20, 2020 (pandemic period), and March 3 through the week of September 22, 2019 (historical period), in Ontario, Canada., Exposures: COVID-19 pandemic as of March 1, 2020., Main Outcomes and Measures: Main outcomes were weekly rates of emergency department visits, hospitalizations, nursing home admissions, home care, virtual and in-person physician visits, and all-cause mortality. Poisson regression models were used to calculate weekly rate ratios (RRs) with 95% CIs comparing pandemic weeks with historical levels., Results: Among those living in the community as of March 1, 2020, persons with dementia (n = 131 466; mean [SD] age, 80.1 [10.1] years) were older than persons with PD (n = 30 606; 73.7 [10.2] years) and older adults (n = 2 363 742; 74.0 [7.1] years). While all services experienced declines, the largest drops occurred in nursing home admissions (RR for dementia: 0.10; 95% CI, 0.07-0.15; RR for PD: 0.03; 95% CI, 0.00-0.21; RR for older adults: 0.11; 95% CI, 0.06-0.18) and emergency department visits (RR for dementia: 0.45; 95% CI, 0.41-0.48; RR for PD: 0.40; 95% CI, 0.34-0.48; RR for older adults: 0.45; 95% CI, 0.44-0.47). After the first wave, most services returned to historical levels except physician visits, which remained elevated (RR for dementia: 1.07; 95% CI, 1.05-1.09; RR for PD: 1.10, 95% CI, 1.06-1.13) and shifted toward virtual visits. Older adults continued to experience lower hospitalizations. All-cause mortality was elevated across cohorts., Conclusions and Relevance: In this population-based repeated cross-sectional study in Ontario, Canada, those with dementia, those with PD, and older adults sought hospital care far less than usual, were not admitted to nursing homes, and experienced excess mortality during the first wave of the pandemic. Most services returned to historical levels, but virtual physician visits remained a feature of care. While issues of equity and quality of care are still emerging among persons with neurodegenerative diseases, policies to support virtual care are necessary., Competing Interests: Conflict of Interest Disclosures: Dr Bronskill reported receiving grants from the Ontario Neurodegenerative Disease Research Initiative through the Ontario Brain Institute and Drs Bronskill and Vedel reported receiving a grant from the Canadian Institutes of Health Research (CIHR VR5-172692) during the conduct of the study. Dr Jones and Mr Harris reported postdoctoral and doctoral fellowships, respectively, from the Alzheimer Society of Canada during the conduct of the study. Dr Swartz reported receiving personal fees (administrative stipend) from the Ontario Brain Institute/Ontario Neurodegenerative Disease Research Initiative during the conduct of the study. No other disclosures were reported., (Copyright 2022 Bronskill SE et al. JAMA Health Forum.)

Background: Preclinical and epidemiological data suggest that phosphoglycerate kinase 1 activators could have neuroprotective properties and prevent PD., Objectives: The objective of this study was to compare the association between increased use of phosphoglycerate kinase 1 activators and increased use of tamsulosin with PD incidence., Methods: Our retrospective cohort study included men older than age 66 years newly exposed to phosphoglycerate kinase 1 activators or tamsulosin and compared their PD incidence, using health care administrative data of Ontario, Canada., Results: Among 265,745 men, each additional year of cumulative use of phosphoglycerate kinase 1 activators or tamsulosin was associated with 6% and 8% reduction, respectively, in the hazard of PD incidence. These hazards were not significantly different (P = 0.2094). A secondary analysis with the observation window starting after 6 months and 1 and 2 years showed similar results., Conclusions: Increasing exposure to phosphoglycerate kinase 1 activators and tamsulosin were both associated with small reductions in PD incidence. These results support further investigation of phosphoglycerate kinase 1 activators and tamsulosin for possible PD disease-modifying properties. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objectives: To compare long-term survival of Parkinson's disease (PD) patients with deep brain stimulation (DBS) to matched controls, and examine whether DBS was associated with differences in injurious falls, long-term care, and home care., Methods: Using administrative health data (Ontario, Canada), we examined DBS outcomes within a cohort of individuals diagnosed with PD between 1997 and 2012. Patients receiving DBS were matched with non-DBS controls by age, sex, PD diagnosis date, time with PD, and a propensity score. Survival between groups was compared using the log-rank test and marginal Cox proportional hazards regression. Cumulative incidence function curves and marginal subdistribution hazard models were used to assess effects of DBS on falls, long-term care admission, and home care use, with death as a competing risk., Results: There were 260 DBS recipients matched with 551 controls. Patients undergoing DBS did not experience a significant survival advantage compared to controls (log-rank test p = 0.50; HR: 0.89, 95% CI: 0.65-1.22). Among patients <65 years of age, DBS recipients had a significantly reduced risk of death (HR: 0.49, 95% CI: 0.28-0.84). Patients receiving DBS were more likely than controls to receive care for falls (HR: 1.56, 95% CI: 1.19-2.05) and home care (HR: 1.59, 95% CI: 1.32-1.90), while long-term care admission was similar between groups., Conclusions: Receiving DBS may increase survival for younger PD patients who undergo DBS. Future studies should examine whether survival benefits may be attributed to effects on PD or the absence of comorbidities that influence mortality.

Background: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease., Methods: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort., Results: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2)., Conclusion: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Objective: To examine whether sociodemographic characteristics and health care utilization are associated with receiving deep brain stimulation (DBS) surgery for Parkinson's disease (PD) in Ontario, Canada., Methods: Using health administrative data, we identified a cohort of individuals aged 40 years or older diagnosed with incident PD between 1995 and 2009. A case-control study was used to examine whether select factors were associated with DBS for PD. Patients were classified as cases if they underwent DBS surgery at any point 1-year after cohort entry until December 31, 2016. Conditional logistic regression modeling was used to estimate the adjusted odds of DBS surgery for sociodemographic and health care utilization indicators., Results: A total of 46,237 individuals with PD were identified, with 543 (1.2%) receiving DBS surgery. Individuals residing in northern Ontario were more likely than southern patients to receive DBS surgery [adjusted odds ratio (AOR) = 2.23, 95% confidence interval (CI) = 1.15-4.34]; however, regional variations were not observed after accounting for medication use among older adults (AOR = 1.04, 95% CI = 0.26-4.21). Patients living in neighborhoods with the highest concentration of visible minorities were less likely to receive DBS surgery compared to patients living in predominantly white neighborhoods (AOR = 0.27, 95% CI = 0.16-0.46). Regular neurologist care and use of multiple PD medications were positively associated with DBS surgery., Conclusions: Variations in use of DBS may reflect differences in access to care, specialist referral pathways, health-seeking behavior, or need for DBS. Future studies are needed to understand drivers of potential disparities in DBS use.

Purpose: The aim of the study was to assess the feasibility of an approach combining computational methods and pharmacoepidemiology to identify potentially disease-modifying drugs in Parkinson's disease (PD)., Methods: We used a two-step approach; (a) computational method using artificial intelligence to rank 620 drugs in the Ontario Drug Benefit formulary based on their predicted ability to inhibit alpha-synucleinaggregation, a pathogenic hallmark of PD; and (b) case-control study using administrative databases in Ontario, Canada. Persons aged 70-110 years with incident PD from April 2002-March 2013. Controls were randomly selected from persons with no previous diagnosis of PD., Results: A total of 15 of the top 50 drugs were deemed feasible for pharmacoepidemiologic analysis, of which seven were significantly associated with incident PD after adjustment, with five of these seven associated with a decreased odds of PD. Methylxanthine drugs pentoxifylline (OR, 0.72; 95% CI, 0.59-0.89) and theophylline (OR, 0.77; 95% CI, 0.66-0.91), and the corticosteroid dexamethasone (OR, 0.72; 95% CI, 0.61-0.85) were associated with decreased odds of PD., Conclusions: Our findings demonstrate the feasibility of this approach to focus the search for disease-modifying drugs. Corticosteroids and methylxanthines should be further investigated as potential disease-modifyingdrugs in PD., (© 2020 John Wiley & Sons Ltd.)

Objectives: The main purpose of this study was to investigate 4 methods of eliciting subjective cognitive complaints (SCCs) in Parkinson's disease (PD) patients without dementia and determine the relationship between their SCC and cognitive performance., Design: This study was a retrospective analysis of a prospective cohort study., Setting: Six North American movement disorder clinics., Measurements: SCCs were elicited through a modified Neurobehavioral Inventory administered to patients and close contacts, a general complaint question, and Movement Disorders Society Unified Parkinson's Disease Rating Scale item question 1.1 administered to patients. Clinical evaluation, formal neuropsychological testing and Disability Assessment for Dementia were conducted in Ontario state. Agreement between SCCs eliciting methods was calculated. Associations between SCC, cognitive testing, and mild cognitive impairment (MCI) were assessed., Results: Of 139 participating nondemented PD patients, 42% had PD-MCI at baseline. Agreement between SCC eliciting methods was low. Neither patient-reported nor close contact-reported SCCs were associated with impaired baseline cognitive testing or PD-MCI nor were they associated with cognitive decline over time. In PD patients with normal baseline cognition, 26% of patients with 1-year follow-up and 20% of patients with 2-year follow-up met MCI criteria., Conclusions: Agreement between SCC eliciting methods is poor and no SCC method was associated with cognitive testing or decline over time. With no clear superior method for eliciting SCCs, clinicians should consider performing regular screening.

Background: Antipsychotic drugs are commonly used to treat psychosis in patients with Parkinson disease; however, individuals with parkinsonism are at risk for serious adverse effects with antipsychotic use. The choice of antipsychotic is critical., Objective: To examine the frequency and pattern of antipsychotic prescribing to patients with Parkinson disease and parkinsonism over time., Methods: Individuals with parkinsonism aged 66 or older in Ontario were studied in a retrospective cohort study from 2005-2013 and followed for prevalent and/or incident antipsychotic drug dispensing., Results: In 2005, 15% of 22,837 individuals with prevalent parkinsonism were dispensed an antipsychotic drug. By 2013, the proportion was 11% of 34,262 individuals. Primary care physicians represented the vast majority of prescribers. Of individuals receiving antipsychotics in 2013, 20% were dispensed a typical antipsychotic drug. Among individuals with incident parkinsonism, living in a nursing home, older age, male sex, a greater number of comorbidities, and a prior diagnosis of dementia were significantly associated with an increased rate of receiving an antipsychotic during follow-up. Among those who received an antipsychotic, factors associated with typical antipsychotic exposure were absence of a prior diagnosis of dementia, higher Charlson comorbidity index, more concurrent medications, more recent year of first parkinsonism diagnosis and not having seen a neurologist, psychiatrist, or geriatrician., Conclusion: A substantial proportion of individuals with parkinsonism are exposed to antipsychotic drugs, including typical antipsychotics. Given the risks of these drugs to individuals with parkinsonism, education of prescribers, particularly primary care physicians, is needed., (Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Domperidone is commonly used to treat nausea and gastrointestinal disorders. Recent data suggests that it may increase the risk of sudden cardiac death, particularly in older people. Little is known about how it is used in contemporary practice. This study sought to characterize the population of older adults newly dispensed domperidone, describe dosages of domperidone used, and determine the frequency of co-prescribing domperidone with medications that may increase the arrhythmogenic potential of domperidone., Methods: This is a retrospective cohort study using administrative health database information from Ontario, Canada. Prescription medication records were obtained from the Ontario Drug Benefit Claims Database. Diagnostic codes were obtained from the Ontario Health Insurance Plan Database, the Canadian Institute for Health Information Discharge Abstract Database, and the same-day surgery database. Patients who received a new prescription for domperidone between April 1, 2003 and March 31, 2010 were included., Results: A total of 122,233 patients met inclusion criteria; 85 % were between 66 and 84 years old and 63 % were female. The mean estimated daily domperidone dose was 35 mg, and the estimated daily dose was <40 mg for 62 % of users. Strong or moderately strong cytochrome P-450 (CYP) 3A4 inhibitors were co-prescribed for 4.3 and 10.7 % of users, while medications with a known risk or possible risk for torsades de pointes (TdP) were co-prescribed to 18.3 and 18.8 % of users., Conclusions: Older domperidone users were commonly co-prescribed drugs with the potential to increase the risk for TdP. These combinations should be avoided, as iatrogenic QT prolongation is a modifiable risk factor for TdP.

Introduction: Pergolide is an ergot derived dopamine agonist that is widely used for the treatment of Parkinson's disease. Studies have found an association between pergolide and valvular heart abnormalities although there is still much to be learned about the clinical significance of the valvular changes, who is at risk, and whether there is duration of exposure effect., Objective: To assess the long term risk of hospital admissions for valvular heart disease (VHD) or congestive heart failure (CHF, a clinically overt outcome of VHD) in new users of pergolide compared to new users of levodopa. The secondary objective was to assess whether there are any characteristics that can predict who is at higher risk of developing this outcome., Design: Retrospective, population-based cohort study., Setting: Ontario, Canada., Subjects: Ontario residents aged 66 and older, newly started on treatment with either pergolide or levodopa., Outcomes: Admission to hospital with the most responsible diagnosis of congestive heart failure or valvular heart disease., Results: The risk for admission for valvular heart disease or congestive heart failure were higher in those with 1-4 years exposure to pergolide compared with no exposure to pergolide (VHD: hazard ratio 2.4, p = 0.04; CHF: hazard ratio 1.6, p = 0.02). No such pattern was found with exposure to levodopa., Conclusion: Our study demonstrates that treatment with pergolide is associated with a higher risk of hospital admission for valvular heart disease or congestive heart failure and that this risk is greater in those with 1-4 years exposure than in those with less exposure. We did not find an increased risk beyond four years.

Objective: To compare the incidence of admissions to hospital for stroke among older adults with dementia receiving atypical or typical antipsychotics., Design: Population based retrospective cohort study., Setting: Ontario, Canada. Patients 32,710 older adults (< or = 65 years) with dementia (17,845 dispensed an atypical antipsychotic and 14,865 dispensed a typical antipsychotic)., Main Outcome Measures: Admission to hospital with the most responsible diagnosis (single most important condition responsible for the patient's admission) of ischaemic stroke. Observation of patients until they were either admitted to hospital with ischaemic stroke, stopped taking antipsychotics, died, or the study ended., Results: After adjustment for potential confounders, participants receiving atypical antipsychotics showed no significant increase in risk of ischaemic stroke compared with those receiving typical antipsychotics (adjusted hazard ratio 1.01, 95% confidence interval 0.81 to 1.26). This finding was consistent in a series of subgroup analyses, including ones of individual atypical antipsychotic drugs (risperidone, olanzapine, and quetiapine) and selected subpopulations of the main cohorts., Conclusion: Older adults with dementia who take atypical antipsychotics have a similar risk of ischaemic stroke to those taking typical antipsychotics.