Abhimanyu Mahajan

Background and ObjectivesEvidence for the effect of physical activity on disease progression in Parkinson disease (PD) remains limited. We aimed to examine whether physical activity is associated w...

Background: Reliable clinical phenotyping is crucial for diagnosis, treatment, and research in hyperkinetic movement disorders, yet its interrater reliability remains uncertain. Objectives: To quantify interrater agreement in clinical phenotyping of hyperkinetic movement disorders among experts in a large, phenotypically diverse cohort. Methods: Within the NEMO project, 161 patients with hyperkinetic movement disorders underwent standardized video assessments. Each patient was independently classified by three international movement disorders experts in a structured, stepwise procedure. Experts first assessed videos alone, then received clinical history and examination, and finally diagnostic test results. At each step, they assigned primary and secondary phenotypes and rated their diagnostic confidence. Interrater agreement was assessed using Fleiss’ and Cohen's kappa. Results: Across all phenotypes, interrater agreement on the primary phenotype increased with added information ( κ = 0.457 to κ = 0.607). Agreement with the NEMO reference classification similarly improved ( κ = 0.478 to κ = 0.656). Among patients with a single dominant phenotype, agreement reached κ = 0.78. In 93% of cases, at least two out of three experts reached consensus. Agreement was substantially lower in patients with mixed or complex presentations, such as myoclonus‐dystonia and functional movement disorders. Diagnostic certainty rose throughout, though secondary phenotype agreement remained poor. Experts rarely revised initial impressions, suggesting robust pattern recognition but also potential confirmation bias. Conclusions: Movement disorders specialists can reliably identify hyperkinetic phenotypes, even without in‐person assessment. While complex, mixed and functional presentations remain diagnostically challenging, our findings reinforce the value of expert phenotyping in clinical care, training, and research, and provide a benchmark for future studies and computational approaches.

Background: Scales for Outcomes in Parkinson's Disease Autonomic Dysfunction Scale (SCOPA‐AUT) is a widely used, self‐reported scale to evaluate autonomic dysfunction in PD. Recent literature on interoception has raised questions about validity. Several knowledge gaps remain minimal detectable change (MDC), best subscale structure, validation against objective autonomic measures, and performance in prodromal populations. Objective: To critically expand knowledge of SCOPA‐AUT's measurement properties with novel analyses to increase confidence as an outcome measure. Methods: Data from the Parkinson's Progression Markers Initiative (PPMI) were analyzed. Exploratory and confirmatory factor analyses determined subscale structure. Test–retest reliability helped derive the MDC. Criterion and construct validity were assessed using objective measures (e.g., orthostatic hypotension (OH)) with area‐under‐the‐curves and correlations. Mixed models identified the best predictors of self‐reported autonomic dysfunction. Results: Data on 4450 individuals, including healthy controls ( n = 343), prodromal ( n = 2539) and established PD ( n = 1503) participants, were analyzed. The total scale had strong reliability ( ω = 0.86; ICC = 0.78), with an MDC≥6. The published six‐subscale structure showed adequate fit, but splitting the gastrointestinal domain into upper (oral) and lower (intestinal) factors significantly improved model fit. Criterion validity against objective OH was poor (AUC = 0.59). SCOPA‐AUT correlated most strongly with non‐motor experiences of daily living ( r _s = 0.62, large effect), which was also its strongest longitudinal predictor, followed by motor experiences of daily living. Conclusions: SCOPA‐AUT is a reliable, valid scale in prodromal and established PD. The published subscale, while adequate, may benefit from modification. SCOPA‐AUT correlates robustly with non‐motor, followed by motor experiences of daily living, supporting its continued use.

Background: Cardiovascular autonomic dysfunction and cognition associate with each other throughout the disease course in Lewy body disease, and this relationship is poorly understood. Methods: We performed a cross-sectional imaging analysis to investigate the locus coeruleus – basal forebrain tract. Deterministic tractography based on quantitative anisotropy was performed. Using Bayesian semiparametric proportional-odds modeling, we evaluated the association between neurogenic orthostatic hypotension and tract characteristics with adjustment for age at imaging, sex, and education. Results: In the demographic-adjusted model, neurogenic orthostatic hypotension was associated with lower bilateral fourth-quarter volume (OR = 0.19; Pr[OR < 1] = 0.987), left fourth- quarter volume (OR = 0.13; Pr[OR < 1] = 0.997), left total surface area (OR = 0.19; Pr[OR < 1] = 0.990), and left total volume (OR = 0.22; Pr[OR < 1] = 0.982). These associations were directionally consistent and of similar magnitude after additional adjustment for cognitive severity, high blood pressure, disease duration, and combined high blood pressure and disease duration. Participants with impaired cognition showed lower bilateral fourth-quartervolume (OR = 0.33; Pr[OR < 1] = 0.964) Conclusion: Neurogenic orthostatic hypotension is associated with lower locus coeruleus-basal forebrain tract volume. The inverse correlation between volume and cognitive impairment suggest a mechanistic relationship.

Background: Anxiety, fatigue, and excessive daytime sleepiness (EDS) frequently co‐occur in Parkinson's disease (PD) and can influence the clinical determination of apathy. Objective: To distinguish patient‐reported apathy from other non‐motor symptoms. Methods: Individuals with PD meeting UK Brain Bank criteria underwent paired OFF‐ and ON‐ dopaminergic medication assessments, including the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), Hamilton Anxiety and Depression Rating Scales (HAM‐A, HAM‐D), Symbol Digit Modalities Test, Stroop, and Scales for Outcomes in Parkinson's Disease‐Autonomic Dysfunction assessment. Medication‐related changes in anxiety, depression, and cognition were defined using established minimally clinically important differences. Apathy, fatigue, and sleepiness were determined based on MDS‐UPDRS Part I scores ≥1. Associations were examined using chi‐squared tests, multivariable ordinal logistic regression, and symptom‐network analyses. Results: Among 199 participants (36–85 years, 61% male), 90% (53/59) of those with apathy also reported both fatigue and sleepiness. Exploratory network analysis grouped apathy with anxiety and depression, whereas fatigue clustered with somatic symptoms (eg, pain, constipation) and daytime sleepiness remained peripheral. Apathy was independently associated with medication‐related change in anxiety after adjustment for fatigue and sleepiness ( P < 0.001), while fatigue was associated with autonomic dysfunction ( P < 0.05). Conclusion: Despite overlapping presentation, apathy in PD closely tracks affective change linked to dopaminergic state, whereas fatigue and sleepiness reflect broader somatic burden. These distinctions may support more specific recognition and phenotyping of apathy.

Cognitive fluctuations are reported in 90% of individuals with dementia with Lewy bodies (DLB) and along with dysautonomia, are a key source of disability. Through this effort, we sought to investigate the relationship between autonomic burden and cognitive fluctuations, neuropsychiatric burden and quality of life in moderate-advanced DLB. This multicenter, prospective, observational, longitudinal cohort study, Predicting ACcurately End-of-Life in Dementia With Lewy Bodies and Promoting Quality End-of-Life Experiences (PACE-DLB), was conducted in the United States to study individuals with moderate-advanced DLB. The primary exposure for the current analysis was time-varying total autonomic burden, as measured by the autonomic symptom checklist (ASC) at baseline and follow-up visits. The primary outcomes were cognitive fluctuations measured by Clinician Assessment of Fluctuations (CAF) scores and neuropsychiatric burden as measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) scores. Secondary outcomes included quality of life (QoL) captured through the Quality of Life-Alzheimer's Disease scale. Mixed-effects regression analyses were conducted to assess the effect of autonomic burden on each primary outcome, with age, sex, education, Charlson Comorbidity Index, anticholinergic burden, levodopa equivalent daily dosage, and EPWORTH sleepiness scale scores adjusted as potential confounders. We additionally conducted modified graphical network model analyses. A total of 189 patients with 745 longitudinal observations were included in the analysis. Mean age of the cohort was 74.92 years (SD 7.77 years) with 22% female participants. At baseline, ASC was directly associated with CAF (RC = 0.16; 95% CI 0.01-0.31; p = 0.032) and NPI-Q (RC = 3.27; 95% CI 2.37-4.18; p < 0.001). In longitudinal analysis, ASC remained directly associated with CAF (RC = 0.18; 95% CI 0.11-0.24; p < 0.001) and NPI-Q (RC = 2.10; 95% CI 1.49-2.71; p < 0.001). ASC scores were inversely associated with QoL of the caregiver (RC = -0.04; 95% CI -0.06 to -0.02) in longitudinal adjusted analysis. Graphical network modeling incorporating possible relationships across characteristics showed that autonomic burden was directly and stably associated with cognitive fluctuations (weight = 0.15) and neuropsychiatric burden (weight = 0.47). Autonomic burden correlates with severity of cognitive fluctuations and neuropsychiatric burden in moderate-advanced DLB. It also correlates with the QoL of the caregiver over time. These results encourage investigation into novel potential therapeutic avenues in moderate-advanced DLB.