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Introduction: Daytime sleepiness, reported in about 50 % of patients with Parkinson's disease (PD), is associated with high morbidity, poor quality of life and increased risk for accidents. While an association between dysautonomia and daytime sleepiness in early, de-novo PD has been reported, our understanding of the role of medications, cognitive status and co-morbidites on this relationship is inadequate., Methods: Data were analyzed from the prospective Cincinnati Cohort Biomarkers Program. The primary outcome of interest was excessive daytime sleepiness (EDS), as measured by the Epworth Sleepiness Scale (ESS; ESS score > 10). The primary exposure variable was orthostatic hypotension (OH). Linear and logistic regression analyses followed by moderated graphical network analyses were conducted to explore the complex association between OH and ESS. Edge weight from graphical network analysis indicates the strength of the association., Results: Data on 453 subjects with PD were analyzed. Median disease duration was 5.8 years and nearly 90 % were H&Y stage <3. OH was not associated with EDS. OH was associated with depression (edge weight, 0.22) in cognitively impaired patients but not in cognitively normal patients. In addition, depression was associated with ESS (edge weight, 0.37; moderation weight, 0.22) in cognitively impaired patients to a greater extent than in cognitively normal patients (edge weight, 0.22)., Conclusions: OH is not directly associated with daytime sleepiness in early, treated PD. However, OH seems to be associated with ESS via depression in cognitively impaired patients. This complex relationship deserves additional study., Competing Interests: Declaration of competing interest All authors reports no relevant financial disclosures or conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Smartphone applications (apps) are instruments that assist with objective measurements during the clinical assessment of patients with movement disorders. We aim to test the hypothesis that Parkinson's disease (PD) patients will exhibit an increase in tapping variability and a decrease in tapping speed over a one-year period, compared to healthy controls (HC)., Methods: Data was prospectively collected from participants enrolled in our Cincinnati Cohort Biomarker Program, in 2021-2023. Participants diagnosed with PD and age-matched HC were examined over a one-year-interval with a tapping test performed with customized smartphone app. Tapping speed (taps/s), inter-tap intervals and variability (movement regularity), and sequence effect were measured., Results: We included 295 PD patients and 62 HC. At baseline, PD subjects showed higher inter-tap variability than HC (coefficient-of-variation-CV, 37 ms [22-64] vs 26 ms [8-51]) (p = 0.007). Conversely, there was no difference in inter-tap intervals (411 ms [199-593] in PD versus 478 ms [243-618] in HC) and tapping speed (3.42[2.70-4.76] taps/s in PD versus 3.21 taps/s [2.57-4.54] in HC) (p > 0.05). Only PD subjects (n = 135), at the one-year follow-up, showed a decreased tapping speed vs baseline (3.44 taps/s [2.86-4.81] versus 3.39 taps/s [2.58,4.30]) (p = 0.036), without significant changes in inter-tap variability (CV, 32 ms [18,55] baseline versus 34 ms [22,59] follow-up) (p = 0.142). No changes were found in HC at the one-year follow up (all p values>0.05)., Conclusions: Inter-tap variability (dysrhythmia) but no inter-tap intervals or tapping speed are reliably distinctive feature of an app-based bradykinesia assessment in PD., Competing Interests: Declaration of competing interest Dr. Luca Marsili has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support, and personal compensation as a consultant/scientific advisory board member for Acadia. Dr. Marsili has received a grant (collaborative research agreement) from the International Parkinson's and Movement Disorders Society for the MDS-UTRS Validation Program (Role: PI), Non-Profit. Dr. Alberto J. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from USWorldMeds, Acadia, and Sunovion. Dr. Espay is cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies. Drs. Abanto, Mahajan, Duque, Chinchihualpa Paredes, Deraz, and Bologna report no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024. Published by Elsevier B.V.)

Background: Bradykinesia is a cardinal feature in parkinsonisms. No study has assessed the differential features of bradykinesia in patients with pathology-proven synucleinopathies and tauopathies., Objective: We examined whether bradykinesia features (speed, amplitude, rhythm, and sequence effect) may differ between pathology-proven synucleinopathies and tauopathies., Methods: Forty-two cases who underwent autopsy were included and divided into synucleinopathies (Parkinson's disease and dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy). Two raters blinded to the diagnosis retrospectively scored the Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and Modified Bradykinesia Rating Scale on standardized videotaped neurological examinations. Bradykinesia scores were compared using the Mann-Whitney test and logistic regression models to adjust for disease duration., Results: Demographic and clinical parameters were similar between synucleinopathies and tauopathies. There were no differences between speed, amplitude, rhythm, and sequence effect in synucleinopathies and tauopathies in unadjusted comparisons and adjusted models (all P > 0.05)., Conclusions: Clinical bradykinesia features do not distinguish the underlying neuropathology in neurodegenerative parkinsonisms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Clinical trials of putative disease-modifying therapies in neurodegeneration have obeyed the century-old principle of convergence, or lumping, whereby any feature of a clinicopathologic disease entity is considered relevant to most of those affected. While this convergent approach has resulted in important successes in trials of symptomatic therapies, largely aimed at correcting common neurotransmitter deficiencies (e.g., cholinergic deficiency in Alzheimer's disease or dopaminergic deficiency in Parkinson's disease), it has been consistently futile in trials of neuroprotective or disease-modifying interventions. As individuals affected by the same neurodegenerative disorder do not share the same biological drivers, splitting such disease into small molecular/biological subtypes, to match people to therapies most likely to benefit them, is vital in the pursuit of disease modification. We here discuss three paths toward the splitting needed for future successes in precision medicine: (1) encourage the development of aging cohorts agnostic to phenotype in order to enact a biology-to-phenotype direction of biomarker development and validate divergence biomarkers (present in some, absent in most); (2) demand bioassay-based recruitment of subjects into disease-modifying trials of putative neuroprotective interventions in order to match the right therapies to the right recipients; and (3) evaluate promising epidemiologic leads of presumed pathogenetic potential using Mendelian randomization studies before designing the corresponding clinical trials. The reconfiguration of disease-modifying efforts for patients with neurodegenerative disorders will require a paradigm shift from lumping to splitting and from proteinopathy to proteinopenia., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Otological symptoms contribute to the disability of established Parkinson's disease (PD). We sought to evaluate whether prodromal onset may affect PD progression., Methods: A retrospective cohort design was used to compare time to advanced disease, defined as a Hoehn & Yahr stage ≥3 in consecutive PD patients with history of auditory and/or vestibular symptoms appearing before versus after PD onset. Time from PD onset to H&Y ≥ 3 was determined using Cox proportional hazards, with adjusted results summarized as hazards ratio (HR)., Results: After adjusting for age at PD onset, there was a lower risk of progression to advanced disease in patients with prodromal otological symptoms compared to those with otological symptoms after PD onset (HR = 0.34; 95%CI: 0.15-0.75, p = 0.008). This association remained significant after adjusting for age at PD onset and MDS-UPDRS III (HR = 0.25; 95% CI: 0.10-0.63, p = 0.003) and propensity score-adjusted analysis (HR = 0.46; 95% CI: 0.24-0.91, p = 0.025)., Conclusion: Prodromal otological symptoms might be associated with a reduced risk of motor progression in PD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms., Objectives: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA)., Methods: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire., Results: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy., Conclusions: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Urinary dysfunction and constipation, manifestations of pelvic floor dysfunction are common sources of disability and impaired quality of life in women with Parkinson's disease (PD)., Objective: We sought to evaluate the pelvic floor health amongst women with PD and their reporting of bladder and bowel symptoms., Methods: We surveyed women with PD and age-matched controls about pelvic floor health using validated questionnaires. All participants completed the Pelvic Floor Disability Index (PFDI-20), the Pelvic Floor Impact Questionnaire (PFIQ-7) and the Patient-Reported Outcomes Measurement Information System (PROMIS) short form version 2.0 Cognitive Function 8a. Additionally, PD patients underwent the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scale and the Montreal Cognition Assessment (MoCA)., Results: Women with PD (n = 59; age, 70.4±8.6 years, PROMIS cognitive score, 52.0±7.8) self-reported urinary symptoms to a greater extent than controls (n = 59; age, 70.2±8.7 years, PROMIS cognitive score, 51.0±10) (68% vs 43%, p < 0.01). The difference was mirrored by higher (worse) scores on both PFDI-20 (35.4 vs 15.6; p = 0.01) and PFIQ-7 (4.8 vs 0; p < 0.01) for PD women compared to controls. Only 63% of all participants with self-reported pelvic floor symptoms had previously reported these symptoms to a health care provider. There was no difference in utilization of specialty care between the two groups (30% vs 46%, p = 0.2)., Conclusion: Pelvic floor dysfunction, more common amongst women with PD, is underreported and undertreated. Our study identifies a key gap in care of women with PD.