Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects.

Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5'-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

Using a smartwatch and smartphone to assess early Parkinson's disease in the WATCH-PD study.

Digital health technologies can provide continuous monitoring and objective, real-world measures of Parkinson's disease (PD), but have primarily been evaluated in small, single-site studies. In this 12-month, multicenter observational study, we evaluated whether a smartwatch and smartphone application could measure features of early PD. 82 individuals with early, untreated PD and 50 age-matched controls wore research-grade sensors, a smartwatch, and a smartphone while performing standardized assessments in the clinic. At home, participants wore the smartwatch for seven days after each clinic visit and completed motor, speech and cognitive tasks on the smartphone every other week. Features derived from the devices, particularly arm swing, the proportion of time with tremor, and finger tapping, differed significantly between individuals with early PD and age-matched controls and had variable correlation with traditional assessments. Longitudinal assessments will inform the value of these digital measures for use in future clinical trials.

Identifying and characterising sources of variability in digital outcome measures in Parkinson's disease.

Smartphones and wearables are widely recognised as the foundation for novel Digital Health Technologies (DHTs) for the clinical assessment of Parkinson's disease. Yet, only limited progress has been made towards their regulatory acceptability as effective drug development tools. A key barrier in achieving this goal relates to the influence of a wide range of sources of variability (SoVs) introduced by measurement processes incorporating DHTs, on their ability to detect relevant changes to PD. This paper introduces a conceptual framework to assist clinical research teams investigating a specific Concept of Interest within a particular Context of Use, to identify, characterise, and when possible, mitigate the influence of SoVs. We illustrate how this conceptual framework can be applied in practice through specific examples, including two data-driven case studies.

Video-based Parkinson's disease assessments in a nationwide cohort of Fox Insight participants.

INTRODUCTION: Parkinson'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. METHODS: Individuals 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. RESULTS: A 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. CONCLUSION: Among the Fox Insight cohort, self-reported diagnosis is accurate and interest in virtual research studies is high.

Current and projected future economic burden of Parkinson's disease in the U.S.

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.

Optimal frequency for measuring health care resource utilization in Parkinson's disease using participant recall: the FS-TOO resource utilization substudy.

OBJECTIVE: The aim of this substudy was to determine the agreement between 2 approaches for measuring health care resource utilization (eg, number of hospital visits, number of primary care physician visits) in trial participants with Parkinson's disease (PD). METHODS: A substudy of the 1-year multicenter futility trial of GPI-1,485 and coenzyme Q(10) (FS-TOO) was performed to assess health care resource utilization agreement by measuring participant utilization recall after 12 months versus measuring participant utilization recall at regular 3-month intervals. Trial participants were selected from patients in the National Institutes of Health-sponsored FS-TOO multicenter study. Persons aged >or=30 years with confirmed PD diagnosis within the previous 5 years were eligible for inclusion in the substudy. Participants were also required to have at least 2 of 3 cardinal manifestations of PD (tremor, rigidity, and bradykinesia). Participants were excluded from the study if they had presence of atypical Parkinson's syndromes due to drugs, metabolic identified neurogenetic disorders, encephalitis, or other degenerative diseases. Agreement was determined using Lin's concordance and Cohen's kappa statistics. RESULTS: Between March and July of 2004, a total of 424 potential subjects were identified and evaluated for trial eligibility. Of these, 213 subjects (139 men, 74 women; mean [SD] age, 61.5 [10.3] years) met entry criteria and were included in the study. Trial participants were randomized equally to 1 of 3 groups. The 3 groups had similar baseline characteristics in terms of demographic data (age, race, sex, employment status, and annual income), total Unified Parkinson Disease Rating Scale (UPDRS) score, and UPDRS subscores. In this substudy, 141 participants had a true baseline visit, indicating a clinical baseline date, and 182 participants completed the Baseline Resource Utilization Form within 3 months of the true baseline visit. The comparison of concordance between the summed information over 3-month recalls and the 12-month recall from baseline was derived from these 182 participants. The level of agreement between the 2 approaches was high, ranging from 64.4% to 95.1%. Where disagreement was identified, the more frequent measurement approach (every 3 months) led to higher estimates, ranging from 20.4% to 77.4%. CONCLUSION: The results of this trial indicate internal consistency with the self-reported measures of health care resource utilization, suggesting that these simple measures might provide reliable information about units of health care resource utilization in the context of clinical trials for PD.

Comparison of Huntington's Disease in Europe and North America.

BACKGROUND: In a rare disorder such as Huntington's disease (HD), a global network of clinical trial sites with access to patients speeds up recruitment into clinical trials. The objective was to test the hypothesis that demographics, HTT genotype, clinical spectrum, and progression are similar in HD participants of two large observational HD studies, the European Huntington's Disease Network's European REGISTRY study and the North American COHORT study. METHODS: REGISTRY cross-sectional data were available from a total of 7,384 participants (1,125 [15.2%] premanifest and 6,259 [84.8%] manifest HD). COHORT cross-sectional data from 1,499 participants at 44 study sites were available (175 pre-HD [11.7%], 1,324 manifest HD [88.3%]). Participants were assessed clinically using the Unified Huntington's Disease Rating Scale (UHDRS). Longitudinal data were available for total motor score and cognitive performance in more than 50% of REGISTRY participants and more than 70% of COHORT participants. RESULTS: Demographics, HTT genotypes, phenotype, and progression were similar in the two studies. Patients in Europe were prescribed antidyskinetics more frequently, and antidepressants less frequently, than in North America. In either study, participants on antidyskinetic medication had higher UHDRS total motor scores, worse function assessment scores, and worse cognitive scores than those taking antidepressants or no medication. In contrast, motor, function assessment, and cognitive scores were broadly similar in participants taking antidepressants or no medication. The differences in cognitive performances between languages were small. CONCLUSIONS: Our data suggest that HD patients, and the way they are assessed, are similar across two continents with different cultures and languages.