What Huntington's Disease Patients Say About Their Illness: An Online Direct-to-Participant Pilot Study.

Background: Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement. Objective: We assessed feasibility of online data collection from adults with diagnosed Huntington's disease (HD) who directly reported their problems and impact in their own words. Methods: Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington's disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms. Results: All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common. Conclusions: Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations.

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.

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.

Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain.

Huntington's disease (HD) results from expansion of a polyglutamine tract (polyQ) in mutant huntingtin (mHTT) protein, but mechanisms underlying polyQ expansion-mediated toxic gain-of-mHTT function remain elusive. Here, deletion and antibody-based experiments revealed that a proline-rich domain (PRD) adjacent to the polyQ tract is necessary for mutant huntingtin (mHTT) to inhibit fast axonal transport and promote axonal pathology in cultured mammalian neurons. Further, polypeptides corresponding to subregions of the PRD sufficed to elicit the toxic effect on fast axonal transport, which was mediated by JNK kinases and involved PRD binding to one or more SH3-domain containing proteins. Collectively, these data suggested a mechanism whereby polyQ tract expansion in mHTT promotes aberrant PRD exposure and interactions of this domain with SH3 domain-containing proteins including some involved in activation of JNK kinases. In support, biochemical and immunohistochemical experiments linked aberrant PRD exposure to increased JNK activation in striatal tissues of the zQ175 mouse model and from post-mortem HD patients. Collectively, these findings support a critical role of PRD on mHTT toxicity, suggesting a novel framework for the potential development of therapies aimed to halt or reduce axonal pathology in HD.

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.