In Their Own Words: Fears Expressed by People with Parkinson's Disease in an Online Symptom Database.

Parkinson's disease (PD) carries substantial psychosocial burden. Using a database of responses by people with PD reporting up to five "most bothersome problems," we identified 225 fear-based verbatims, which were organized using the framework method into 26 categories. Commonly-reported fears included uncertainty of progression (n = 60, 26.7%), fear of future cognitive impairment (n = 24, 10.7%) and fear of becoming a burden on others (n = 23, 10.2%). Fears in PD are wide-ranging and can constitute the most bothersome aspect of the condition. These data can be used to design interventions to lessen the psychosocial burden of PD.

OFF episode quality of life impact scale (OFFELIA): A new measure of quality of life for off episodes in Parkinson's disease.

INTRODUCTION: OFF Episodes occur in people with Parkinson's disease when their medication wears off, and motor and/or non-motor symptoms emerge. Existing measures used to assess OFF Episodes focus on the time spent in OFF Episodes through diaries or by identifying symptoms, but they are limited in their ability to capture the severity and functional impact of OFF episodes. The aim of this study was to develop and validate a new instrument, called "OFFELIA," that measures the impact of OFF episodes on the quality of life of individuals with Parkinson's disease. METHODS: Participants completed a cross-sectional questionnaire, "Impact and Communication on OFF Periods," while enrolled in the online clinical study Fox Insights. The data collected was used to develop OFFELIA. Psychometric testing was performed on 18 candidate items using classical, exploratory factor analysis, and item response theory methods. RESULTS: 569 individuals with Parkinson's disease completed the questionnaire. All items were retained for the final measure, with 17 items aggregated into two multi-item scales (functioning and psychological well-being) and one item reported separately as it did not function well with the other items (employment). Known group comparisons based on average duration, frequency and unpredictability of OFF episodes indicated that OFFELIA subscales were more sensitive than existing generic and condition-specific measures. CONCLUSION: Initial evidence supports the validity of OFFELIA, a new instrument that assesses the impact of OFF periods on daily life. This instrument can be used in assessing clinical therapeutic strategies targeting OFF episodes in Parkinson's disease.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series.

BACKGROUND: Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). METHODS: Following the MDSGene protocol, we systematically investigated genotype-phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. RESULTS: Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. CONCLUSIONS: The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association between Subjective Cognitive Complaints and Incident Functional Impairment in Parkinson's Disease.

BACKGROUND: Early identification of subjective cognitive complaints (SCC) in Parkinson's disease (PD) may improve patient care if it predicts cognition-related functional impairment (CFI). OBJECTIVES: The aim was to determine the cross-sectional and longitudinal association between SCC and CFI in PD. METHODS: Data were obtained from Fox Insight, an online longitudinal study that collects PD patient-reported outcomes. Participants completed a PD Patient Report of Problems that asked participants for their five most bothersome disease problems. SCCs were placed into eight categories through human-in-the-loop curation and classification. CFI had a Penn Parkinson's Daily Activities Questionnaire (PDAQ-15) score ≤49. Cox proportional hazards models and Kaplan-Meier survival analyses determined if baseline SCC was associated with incident CFI. RESULTS: The PD-PROP cohort (N = 21,160) was 55.8% male, mean age was 65.9 years, and PD duration was 4.8 years. At baseline, 31.9% (N = 6750) of participants reported one or more SCCs among their five most bothersome problems, including memory (13.2%), language/word finding (12.5%), and concentration/attention (9.6%). CFI occurred in 34.7% (N = 7332) of participants. At baseline, SCC was associated with CFI (P-value <0.001). SCC at baseline was associated with incident CFI (hazard ratio [HR] = 1.58 [95% confidence interval: 1.45, 1.72], P-value <0.001), as did cognitive impairment not otherwise specified (HR = 2.31), executive abilities (HR = 1.97), memory (HR = 1.85), and cognitive slowing (HR = 1.77) (P-values <0.001). Kaplan-Meier curves showed that by year 3 an estimated 45% of participants with any SCC at baseline developed new-onset CFI. CONCLUSIONS: Self-reported bothersome cognitive complaints are associated with new-onset CFI in PD. Remote electronic assessment can facilitate widespread use of patient self-report at population scale. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The epidemiology of Parkinson's disease.

The epidemiology of Parkinson's disease shows marked variations in time, geography, ethnicity, age, and sex. Internationally, prevalence has increased over and above demographic changes. There are several potential reasons for this increase, including the decline in other competing causes of death. Whether incidence is increasing, especially in women or in many low-income and middle-income countries where there is a shortage of high-quality data, is less certain. Parkinson's disease is more common in older people and men, and a variety of environmental factors have been suggested to explain why, including exposure to neurotoxic agents. Within countries, there appear to be ethnic differences in disease risk, although these differences might reflect differential access to health care. The cause of Parkinson's disease is multifactorial, and involves genetic and environmental factors. Both risk factors (eg, pesticides) and protective factors (eg, physical activity and tendency to smoke) have been postulated to have a role in Parkinson's disease, although elucidating causality is complicated by the long prodromal period. Following the establishment of public health strategies to prevent cardiovascular diseases and some cancers, chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining a deserved higher priority. Multipronged prevention strategies are required that tackle population-based primary prevention, high-risk targeted secondary prevention, and Parkinson's disease-modifying therapies for tertiary prevention. Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson's disease at a global level.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

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 (Aß)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 Aß42/40 . 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.

Internal tremor in people with Parkinson's Disease: Demographic characteristics and comorbid symptoms.

Introduction: Internal tremor (IT) occurs in > 30 % of people with Parkinson's Disease (PwPD), but remains largely uninvestigated. Our objective was to describe demographic characteristics and associated symptoms in PwPD who reported IT. Methods: This was a matched case-control survey study. Data were from PwPD in the Fox Insight study who answered the Patient Report of Problems (PD-PROP) assessment, a series of open-ended questions that asks people to report in their own words their most bothersome PD-related problems. Cases were those who reported IT ≥ 1 times compared with PwPD controls who did not report IT and were matched 1:3 by age and disease duration. Results: 243 PwPD reported IT as a bothersome problem. Mean (SD) age of cases was 64.9 (9.4) years and disease duration was 3.8 (4.0) years. The proportion of women was greater among cases compared to controls (74 % vs 47 %, p < 0.0001). External tremor as a PD-PROP symptom was reported by 98 % cases and 48 % controls (p < 0.0001). Several non-motor symptoms were more common among cases than controls, including anxiety (35 % vs 20 %), fatigue (41 % vs 31 %), and pain (57 % vs 37 %). The odds of IT was significantly higher in women when adjusting for anxiety and motor experiences of daily living score (OR 3.07, 95 %CI 2.14-4.41, p < 0.0001). Conclusion: PwPD with IT report a range of associated symptoms, including external tremor, anxiety, and pain. Sex differences in the experience of IT may exist. Studies of IT are needed to understand its etiology and inform clinical care.

Non-steroidal anti-inflammatory drug use and markers of Parkinson's disease progression: A retrospective cohort study.

BACKGROUND: Previous studies demonstrated reduced incidence of Parkinson's disease (PD) with regular non-steroidal anti-inflammatory drug (NSAID) exposure, particularly ibuprofen. No studies have investigated the impact of NSAID exposure on markers of disease progression for established PD. METHODS: This is a retrospective observational study using two cohorts. The Deprenyl and Tocopheral Anti-Oxidative Therapy of Parkinsonism (DATATOP) study enrolled 800 drug naïve people with PD with a median follow-up duration of 6.5 years. The DATATOP primary outcome measures were mortality at last study visit. The Parkinson's Progression Markers Initiative (PPMI) cohort was limited to drug naïve PD participants (423 at time of analysis). The PPMI primary outcome measure was annual rate of change in ipsilateral putamen 123I-ioflupane binding ratio at four years study duration. Regular NSAID exposure was defined as any scheduled NSAID use (as needed use was excluded). Analysis was performed separately for recent exposure and cumulative exposure time (CET). RESULTS: Total CET median and interquartile range (years) for ibuprofen, non-aspirin NSAID, and aspirin were respectively 0.9 (0.3-2.9), 1.1 (0.3-2.6), and 1.5 (0.4-2.8) for DATATOP and 0.4 (0.01-2.2), 1.4 (0.3-4.4), and 5.5 (2.6-7.1) for PPMI. Exposure was usually discontinuous. Exposure to ibuprofen was low in both cohorts. There was no significant association between NSAID recent exposure or CET and primary outcome measures in either cohort. CONCLUSIONS: NSAID exposure in established PD does not appear to provide protective effect although exposure may not have occurred continuously enough in these two cohorts to provide benefit. Statistical power for ibuprofen exposure analyses was limited.

Patients' Preferences for Adjunctive Parkinson's Disease Treatments: A Discrete-Choice Experiment.

Background: Several adjunctive medications are available to reduce OFF time between levodopa/carbidopa (LD/CD) doses for people with Parkinson's disease (PD). Objective: To explore how individuals with PD balance benefits and burdens when considering adjunctive medications. Methods: US adults (30-83 years) with self-reported PD, currently treated with LD/CD, who experienced OFF episodes were recruited through the Fox Insight study to complete a discrete-choice experiment survey. Respondents selected among experimentally designed profiles for hypothetical adjunctive PD treatments that varied in efficacy (additional ON time), potential adverse effects (troublesome dyskinesia, risk of diarrhea, risk of change in bodily fluid color), and dosing frequency or the option "No additional medicine". Data were analyzed with random-parameters logit models. Results: Respondents (N=480) would require ≥60 additional minutes of daily ON time to accept either a 40% risk of change in bodily fluid color or 10 additional minutes with troublesome dyskinesia daily. Respondents would require 40 additional minutes of daily ON time to accept a 10% risk of diarrhea and 22 additional minutes of daily ON time to switch from 1 additional pill each day to 1 pill with each LD/CD dose. On average, respondents preferred adjunctive PD medication over no additional medication. Results predicted that 59.1% of respondents would select a hypothetical treatment profile similar to opicapone, followed by no additional medication (27.5%) and a hypothetical treatment profile similar to entacapone (13.4%). Limitations: The data collected were based on responses to hypothetical choice profiles in the survey questions. The attributes and levels selected for this study were intended to reflect the characteristics of opicapone and entacapone; attributes associated with other adjunctive therapies were not evaluated. Conclusion: Patients with PD expressed interest in adjunctive treatment to increase ON time and would accept reduced ON time to avoid adverse effects.

Brain hypometabolism in non-demented microtubule-associated protein tau H1 carriers with Parkinson's disease.

BACKGROUND AND PURPOSE: The microtubule-associated protein tau (MAPT) H1 homozygosity (H1/H1 haplotype) is a genetic risk factor for neurodegenerative diseases, such as Parkinson's disease (PD). MAPT H1 homozygosity has been associated with conversion to PD; however, results are conflicting since some studies did not find a strong influence. Cortical hypometabolism is associated with cognitive impairment in PD. In this study, we aimed to evaluate the metabolic pattern in nondemented PD patients MAPT H1/H1 carriers in comparison with MAPT H1/H2 haplotype. In addition, we evaluated domain-specific cognitive differences according to MAPT haplotype. METHODS: We compared a group of 26 H1/H1 and 20 H1/H2 carriers with late-onset PD. Participants underwent a comprehensive neuropsychological cognitive evaluation and a [18F]-Fluorodeoxyglucose PET-MR scan. RESULTS: MAPT H1/H1 carriers showed worse performance in the digit span forward test of attention compared to MAPT H1/H2 carriers. In the [18F]-Fluorodeoxyglucose PET comparisons, MAPT H1/H1 displayed hypometabolism in the frontal cortex, parahippocampal, and cingulate gyrus, as well as in the caudate and globus pallidus. CONCLUSION: PD patients MAPT H1/H1 carriers without dementia exhibit relative hypometabolism in several cortical areas as well as in the basal ganglia, and worse performance in attention than MAPT H1/H2 carriers. Longitudinal studies should assess if lower scores in attention and dysfunction in these areas are predictors of dementia in MAPT H1/H1 homozygotes.

Predictors of Cognitive Change in Parkinson Disease: A 2-year Follow-up Study.

BACKGROUND: Mild cognitive impairment is common in Parkinson disease (PD-MCI). However, instability in this clinical diagnosis and variability in rates of progression to dementia raises questions regarding its utility for longitudinal tracking and prediction of cognitive change in PD. We examined baseline neuropsychological test and cognitive diagnosis predictors of cognitive change in PD. METHODS: Persons with PD, without dementia PD (N=138) underwent comprehensive neuropsychological assessment at baseline and were followed up to 2 years. Level II Movement Disorder Society criteria for PD-MCI and PD dementia (PDD) were applied annually. Composite global and domain cognitive z -scores were calculated based on a 10-test neuropsychological battery. RESULTS: Baseline diagnosis of PD-MCI was not associated with a change in global cognitive z -scores. Lower baseline attention and higher executive domain z -scores were associated with greater global cognitive z -score worsening regardless of cognitive diagnosis. Worse baseline domain z -scores in the attention and language domains were associated with progression to MCI or PDD, whereas higher baseline scores in all cognitive domains except executive function were associated with clinical and psychometric reversion to "normal" cognition. CONCLUSIONS: Lower scores on cognitive tests of attention were predictive of worse global cognition over 2 years of follow-up in PD, and lower baseline attention and language scores were associated with progression to MCI or PDD. However, PD-MCI diagnosis per se was not predictive of cognitive decline over 2 years. The association between higher executive domain z -scores and greater global cognitive worsening is probably a spurious result.

A blood-based marker of mitochondrial DNA damage in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.

Disease Progression and Sphingolipids and Neurofilament Light Chain in Early Idiopathic Parkinson's Disease.

Parkinson's disease(PD) lacks a biomarker for disease progression. To analyze how cerebrospinal fluid (CSF), glucosylceramide (GlcCer), sphingomyelin (SM), or serum neurofilament light chain (NfL) associate with progression of PD in a retrospective cohort, we used linear mixed-model regressions between baseline biomarkers and change in dopamine transporter brain-imaging (DaTscan©), Montreal cognitive assesment (MoCA), or global composite outcome (GCO) score. In 191 PD patients, biomarkers were not associated with DaTscan or MoCA change over 2.1 years. Higher baseline GlcCer/SM ratio and serum-NfL nonsignificantly associated with increase in GCO score. Results do not support a role for CSF-sphingolipid/serum-NfL to predict cognitive and DaTscan progression in early-PD. Potential prediction of global clinical change warrants further study.

Genotype-phenotype relations for episodic ataxia genes: MDSGene systematic review.

BACKGROUND: Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms. METHODS: We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/). RESULTS: Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'. CONCLUSION: Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.

Rare neurovascular genetic and imaging markers across neurodegenerative diseases.

INTRODUCTION: Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status. METHODS: The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1). RESULTS: NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood. DISCUSSION: Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

What Patients Say: Large-Scale Analyses of Replies to the Parkinson's Disease Patient Report of Problems (PD-PROP).

BACKGROUND: Free-text, verbatim replies in the words of people with Parkinson's disease (PD) have the potential to provide unvarnished information about their feelings and experiences. Challenges of processing such data on a large scale are a barrier to analyzing verbatim data collection in large cohorts. OBJECTIVE: To develop a method for curating responses from the Parkinson's Disease Patient Report of Problems (PD-PROP), open-ended questions that asks people with PD to report their most bothersome problems and associated functional consequences. METHODS: Human curation, natural language processing, and machine learning were used to develop an algorithm to convert verbatim responses to classified symptoms. Nine curators including clinicians, people with PD, and a non-clinician PD expert classified a sample of responses as reporting each symptom or not. Responses to the PD-PROP were collected within the Fox Insight cohort study. RESULTS: Approximately 3,500 PD-PROP responses were curated by a human team. Subsequently, approximately 1,500 responses were used in the validation phase; median age of respondents was 67 years, 55% were men and median years since PD diagnosis was 3 years. 168,260 verbatim responses were classified by machine. Accuracy of machine classification was 95% on a held-out test set. 65 symptoms were grouped into 14 domains. The most frequently reported symptoms at first report were tremor (by 46% of respondents), gait and balance problems (>39%), and pain/discomfort (33%). CONCLUSION: A human-in-the-loop method of curation provides both accuracy and efficiency, permitting a clinically useful analysis of large datasets of verbatim reports about the problems that bother PD patients.

White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases.

BACKGROUND: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. METHODS: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. RESULTS: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. CONCLUSIONS: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.