BACKGROUND:Research on Parkinson's disease (PD) heterogeneity may inform clinical prognosis. There is currently no fully validated PD subtype classification system. OBJECTIVES:We aimed at assessing the prognostic relevance of a data-driven PD subtype classification system. METHODS:To identify PD subtypes, we conducted cluster analyses in the Longitudinal and Biomarker Studies in Parkinson's Disease study (LABS-PD) cohort including 461 PD patients enrolled within 2 years of diagnosis and followed for at least 5 years. We determined the association of each PD subtype with the mean changes in the Schwab & England Activities of Daily Living (SE-ADL) and Parkinson's Disease Questionnaire-39 (PDQ-39). We evaluated the association of each PD subtype with the death rate and time to death, after mortality ascertainment using the National Death Index database and review of records at study sites. RESULTS:We identified three subtypes: Tremor Predominant, Motor Complications, and Rapid Progression. Over 2 years, the change of SE-ADL score for the "Motor Complications" subtype (-4.26, 95% CI: -6.60, -1.91) was worse compared to the "Tremor Predominant" subtype (0.43, 95% CI: -1.35, 2.22). The adjusted death rate was lower for the "Tremor Predominant" subtype compared to the "Motor Complications" subtype (HR [time to death]: 0.27, 95% CI: 0.14, 0.52). CONCLUSIONS:PD subtypes generated in LABS-PD cohort have prognostic value, for short-term functional ability and long-term survival. Membership in the "Tremor Predominant" subtype 5 years after PD diagnosis was associated with preserved functional ability and longer survival compared to the "Motor Complications" subtype.

Polygenic risk scores (PRS) in Parkinson's disease (PD) are associated with disease risk. Recently, pathway-specific PRS have been created to take advantage of annotations inking variants to biological pathways or cell types. Here, we investigated 8 biological pathways or regions of open chromatin using pathway-specific PRS: alpha-synuclein pathway, adaptive immunity, innate immunity, lysosomal pathway1, endocytic membrane-trafficking pathway, mitochondrial pathway, microglial open chromatin single nucleotide polymorphisms (SNPs), and monocyte open chromatin SNPs. We analysed 7,402 PD patients across 18 'in-person' PD cohorts, and 6,717 patients from the online Fox Insight study. We did not find any significant associations between the 8 pathway-specific PRSs and 8 clinical outcomes in PD. Though this may be due to a lack of statistical power and limited sample size, it may also suggest that the genetic architecture of sporadic PD risk is different from the genetics of PD progression and clinical outcomes.

Objective To understand what Parkinson’s Disease (PD) patients report in their own words about their mood and anxiety problems using the Parkinson’s Disease Patient Report of Problems (PD-PROP). Methods Patient-reported data from the PD-PROP (reporting most bothersome problems due to PD in their own words), Geriatric Depression Scale, MDS-UPDRS II, and the Euro-Q0L from the Fox Insight research database https://foxinsight.michaeljfox.org/ were examined using cross-sectional comparisons and logistic regression analyses to characterize non-depressive mood symptoms and anxiety. Results We identified 21,487 participants who completed at least one PD-PROP questionnaire. Four categories of non-depressive mood symptoms (Anxiety/Worry, Loneliness/Isolation, Negative Emotions NOS (Not Otherwise Specified), Death/Suicidal Ideation) were identified. Women were much more likely than men to report non-depressive mood symptoms as a bothersome PD-related problem. The frequency of Anxiety/Worry reporting decreased with longer duration of PD while Loneliness/Isolation increased. More severe PD motor impairment, as measured by the MDS-UPDRS II, was associated with increased reporting of Negative Emotions and Loneliness/Isolation. Higher Euro-QoL, indicating better quality of life, was associated with decreased reporting of Loneliness/Isolation. Death/Suicidal Ideation was only reported by a small number of participants (<0.5%). Conclusions Women were more likely than men with PD to identify Anxiety/Worry, Negative Emotions, and Loneliness/Isolation as problems. This finding and the higher prevalence of bothersome loneliness/isolation as PD duration increases can guide monitoring for these issues.

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.

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. (c) 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background:Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. Objectives:To investigate the effects of genetic variants on risk and time to LID. Methods:We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1,612 PD patients with and 3,175 without LID. Results:We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants with reduced time to LID onset (HR=1.42, 95% CI=1.09-1.84, p=0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile=1.27, 95% CI=1.03-1.56, p=0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile=1.38, 95% CI=1.07-1.79, p=0.0128; HRfourth_quartile=1.38, 95% CI=1.06-1.78, p=0.0147). Conclusions:This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care.

Background and Objectives:Cognitive impairment is experienced by up to 80% of people with Parkinson disease (PD). Little is known regarding the subjective experience and frequency of bothersome cognitive problems across the range of disease duration as expressed directly in patients' own words. We describe the types and frequency of bothersome cognitive symptoms reported verbatim by patients with PD. Methods:Through the online Fox Insight study and the Parkinson Disease Patient Report of Problems, we asked patients with PD to self-report by keyboard entry up to five most bothersome problems and how these problems affect their functioning. Human-in-the-loop curation, natural language processing, and machine learning were used to categorize responses into 8 cognitive symptoms: memory, concentration/attention, cognitive slowing, language/word finding, mental alertness/awareness, visuospatial abilities, executive abilities/working memory, and cognitive impairment not otherwise specified. Associations between cognitive symptoms and demographic and disease-related variables were examined in our cross-sectional cohort using multivariate logistic regression. Results:Among 25,192 participants (55% men) of median age 67 years and 3 years since diagnosis (YSD), 8,001 (32%) reported a cognitive symptom at baseline. The 3 most frequently reported symptoms were memory (13%), language/word finding (12%), and concentration/attention (9%). Depression was significantly associated with bothersome cognitive problems in all domains except visuospatial abilities. Predictors of reporting any cognitive symptom in PD were depression (adjusted OR 1.5), increasing MDS-UPDRS Part II score (OR 1.4 per 10-point increment), higher education (OR 1.2 per year), and YSD 1, 2, 6-7, and 8-9 vs 0 YSD. Among individuals with at least one cognitive symptom, posterior cortical-related cognitive symptoms (i.e., visuospatial, memory, and language) were reported by 17% (n = 4325), frontostriatal-related symptoms (i.e., executive abilities, concentration/attention) by 7% (n = 1,827), and both by 14.2% (n = 1,020). Odds of reporting posterior cortical symptoms vs frontostriatal symptoms increased with age and MDS-UPDRS part II score, but not depression. Discussion:Nearly one-third of participants with PD, even early in the disease course, report cognitive symptoms as among their most bothersome problems. Online verbatim reporting analyzed by human-in-the-loop curation, natural language processing, and machine learning is feasible on a large scale and allows a detailed examination of the nature and distribution of cognitive symptoms in PD.

Background: Parkinson's disease (PD) and metabolic syndrome are separate entities that share common underlying pathophysiology. Management strategy for metabolic syndrome is clinically better characterized and finding a positive clinical correlation between the two could lead to a better understanding of Parkinson's disease progression and prognosis. Purpose: To explore the relationship between progression in PD and metabolic syndrome to characterize the underlying pathophysiology, which could then impact the clinical management of PD. Methods: Using modified NCEP (National Cholesterol Education Program) ATP III (Adult Treatment Plan) criteria, patients enrolled in STEADY-PD III (Safety, Tolerability, and Efficacy Assessment of Isradipine) were classified into one of three categories of metabolic syndrome and compared on PD progression over a period of 3 years. Results: Participants with metabolic syndrome showed a trend for more progression in terms of PD, as measured by the total Unified Parkinson's Disease Rating Scale (UPDRS), the motor EDL (Experiences of daily living) scores of the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and the Montreal Cognitive Assessment (MoCA). A significant trend for decline in MoCA was found in the group with metabolic syndrome (-0.78), compared with those without metabolic syndrome (0.14). Greater decline in MoCA signifies worse outcomes. Conclusion: The results demonstrate a trend in more clinical progression in PD in subjects with metabolic syndrome. However, results are limited by the sample size and the limited laboratory measurements available. We hope this study will encourage larger sample studies to explore this relationship further.

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.

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 re-ported 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.

Background: The Parkinson’s Disease Patient Report of Problems (PD-PROP) captures the problems and functional impact that patients report verbatim. Online research participation and advances in language analysis have enabled longitudinal collection and classification of symptoms as trial outcomes. Objective: Analyze verbatim reports longitudinally to examine postural-instability symptoms as 1) precursors of subsequent falling and 2) newly occurring symptoms that could serve as outcome measures in randomized controlled trials. Methods: Problems reported by >25,000 PD patients in their own words were collected online in the Fox Insight observational study and classified into symptoms by natural language processing, clinical curation, and machine learning. Symptoms of gait, balance, falling, and freezing and associated reports of having fallen in the last month were analyzed over three years of longitudinal observation by a Cox regression model in a cohort of 8,287 participants. New onset of gait, balance, falling, and freezing symptoms was analyzed by Kaplan-Meier survival techniques in 4,119 participants who had not previously reported these symptoms. Results: Classified verbatim symptoms of postural instability were significant precursors of subsequent falling among participants who were older, female, and had longer PD duration. New onset of symptoms steadily increased and informed sample size estimates for clinical trials to reduce the onset of these symptoms. Conclusion: The tools to analyze symptoms reported by PD patients in their own words and capacity to enroll large numbers of research participants online support the feasibility and statistical power for conducting randomized clinical trials to detect effects of therapeutic interventions.

Background: Postural instability is an intractable sign of Parkinson’s disease, associated with poor disease prognosis, fall risk, and decreased quality of life. Objective: 1) Characterize verbatim reports of postural instability and associated symptoms (gait disorder, balance, falling, freezing, and posture), 2) compare reports with responses to three pre-specified questions from Part II of the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), and 3) examine postural instability symptoms and MDS-UPDRS responses as predictors of future falls. Methods: Fox Insight research participants reported their problems attributed to PD in their own words using the Parkinson Disease Patient Reports of Problems (PD-PROP). Natural language processing, clinical curation, and data mining techniques were applied to classify text into problem domains and clinically-curated symptoms. Baseline postural instability symptoms were mapped to MDS-UPDRS questions 2.11–2.13. T-tests and chi-square tests were used to compare postural instability reporters and non-reporters, and Cochran-Armitage trend tests were used to evaluate associations between PD-PROP and MDS-UPDRS responses; survival methods were utilized to evaluate the predictive utility of PD-PROP and MDS-UPDRS responses in time-to-fall analyses. Results: Of participants within 10 years of PD diagnosis, 9,692 (56.0%) reported postural instability symptoms referable to gait unsteadiness, balance, falling, freezing, or posture at baseline. Postural instability symptoms were significantly associated with patient-reported measures from the MDS-UPDRS questions. Balance problems reported on PD-PROP and MDS-UPDRS 2.11–2.13 measures were predictive of future falls. Conclusion: Verbatim-reported problems captured by the PD-PROP and categorized by natural language processing and clinical curation and MDS-UPDRS responses predicted falls. The PD-PROP output was more granular than, and as informative as, the categorical responses.

ABSTRACTBackgroundThe Quality of Life in Neurological Disorders (Neuro‐QoL) is a publicly available health‐related quality‐of‐life measurement system.ObjectiveThe aim of this study was to evaluate the utility of Neuro‐QoL item banks as outcome measures for clinical trials in Parkinson's disease.MethodsAn analysis of Neuro‐QoL responsiveness to change and construct validity was performed in a multicenter clinical trial cohort.ResultsAmong 310 participants over 3 years, changes in five of eight Neuro‐QoL domains were significant (P < 0.05) but very modest. The largest effect sizes were seen in the cognition and mobility domains (0.35–0.39). The largest effect size for change over the year in which levodopa was initiated was −0.19 for lower extremity function–mobility. For a similarly designed clinical trial, estimated sample size required to demonstrate a 50% reduction in worsening ranged from 420 to more than 1000 participants per group.ConclusionsMore sensitive tools will be required to serve as an outcome measure in early Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.

The PARS (Parkinson Associated Risk Syndrome) study was designed to test whether screening for hyposmia followed by dopamine transporter imaging can identify risk for conversion to clinical PD, and to evaluate progression markers during the prodromal period.

ABSTRACTBackgroundPrevious studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study.ObjectivesWe examined sex associations to PD phenotypes cross‐sectionally and longitudinally in large‐scale data.MethodsWe tested 40 clinical phenotypes, using longitudinal, clinic‐based patient cohorts, consisting of 5946 patients, with a median follow‐up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex‐associated differences in presentation, and linear mixed‐effects models to test sex‐associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non‐PD participants from an online‐only, self‐assessment PD cohort were cross‐sectionally evaluated to determine whether the sex‐associated differences identified in the primary analyses were consistent and unique to PD.ResultsFemale PD patients had a higher risk of developing dyskinesia early during the follow‐up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic‐based cohorts were mostly consistent with the results of the online‐only cohort.ConclusionsWe observed sex‐associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society