Yuge Xiao

Cognitive dysfunction is a prevalent and impactful feature of Parkinson's disease (PD), with substantial heterogeneity in onset, severity, and progression, and a high lifetime risk of dementia. Despite its clinical importance, effective treatments and fit-for-purpose outcome measures remain limited. This article reports outcomes from a multi-stakeholder roundtable convened by The Michael J. Fox Foundation for Parkinson's Research, outlining priorities to advance patient-focused endpoints and improve clinical trial design to accelerate therapeutic development for cognitive dysfunction. In the context of the current understanding of cognitive impairment across the PD/dementia with Lewy bodies (DLB) spectrum and existing neuropsychological assessment approaches, recommendations are made regarding necessary literature reviews, including qualitative data and related conceptual models, disease models including pathophysiology and neuropsychological profile, and clinical outcome assessment (COA) reviews, including content validity, psychometrics, and fitness-for-purpose. Additionally, novel conceptual models of cognitive impairment across the normal, mild cognitive impairment (MCI) and dementia spectrum are needed and may require further qualitative evidence.

Background: Longitudinal qualitative data on what matters to people with Parkinson’s disease are lacking and needed to guide patient-centered clinical care and development of outcome measures. Objective: To evaluate change over time in symptoms, impacts, and relevance of digital measures to monitor disease progression in early Parkinson’s. Methods: In-depth, online symptom mapping interviews were conducted with 33 people with early Parkinson’s at baseline and 1 year later to evaluate (A) symptoms, (B) impacts, and (C) relevance of digital measures to monitor personally relevant symptoms. Maps and transcripts were coded for frequencies, Likert scale rankings (0 = not present to 4 = most bothersome), and thematic findings. Wilcoxon Signed Rank test was used to evaluate change over time. Results: Other than walking and balance, most motor symptoms did not change significantly from baseline to 1 year later. Multiple significant changes were observed in non-motor areas (cognition, speech, sleep, mood, fatigue, pain; p < 0.05) and functional impacts (mobility, effort to do usual activities, personal comfort; p < 0.05). Thematic analysis revealed ability to cope with and compensate for actual or anticipated symptoms reduced disruptions to well-being and changed how bothersome symptoms were. All digital measures targeted symptoms that were personally important to most participants (> 80%). Conclusion: Non-motor and walking/balance symptoms changed sooner than other motor symptoms during the course of 1 year. Evaluation of coping and compensatory mechanisms may be essential to understanding symptom bothersomeness at a given point in time. Smartphone and smartwatch digital measures were relevant to personally meaningful symptoms of early PD.

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson’s disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.