In a retrospective longitudinal cohort, Parkinson's patients with baseline neurogenic orthostatic hypotension experienced significantly faster decline in global and multiple domain-specific cognitive scores (MoCA) over time, without accelerated motor or nonmotor symptom progression.

This identifies nOH as a clinically assessable prognostic biomarker that could help stratify PD patients for cognitive-risk, monitoring, and trials and suggests autonomic/cerebral-perfusion pathways as potential but currently underexplored therapeutic targets.

INTRODUCTION: Neurogenic orthostatic hypotension (nOH), a common non-motor feature of Parkinson's disease (PD), is defined as a sustained drop in blood pressure (BP) upon standing due to autonomic dysfunction. Although prior studies support an association between nOH and cognitive impairment, its longitudinal impact on cognitive decline in PD remains insufficiently explored. We aimed to determine to what extent baseline nOH is associated with an accelerated decline in global and exploratory domain-specific cognitive functions. METHODS: A retrospective longitudinal cohort study was conducted using clinical data from patients with PD evaluated at the University of California San Diego movement disorders clinics between 2012 and 2024. Participants were classified as having nOH (nOH+) or without nOH (nOH-) based on initial orthostatic BP measurements (≥20 mmHg systolic BP and/or ≥10 mmHg diastolic BP reduction within 3 minutes of standing, with a blunted heart rate response [ΔHR/ΔSBP] < 0.5 bpm/mmHg). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA), including total scores and domain-specific subscores. Longitudinal changes in cognitive function were modeled using linear mixed-effects models, adjusting for time, nOH status, age, sex, and their interaction. Motor and non-motor symptom progression was evaluated using the MDS-UPDRS Parts I-III. RESULTS: Patients with nOH at the first visit showed faster decline in total MoCA scores (Interaction β = -0.57, SE = 0.15, p < 0.001), reflecting declines in abstraction (Interaction β = -0.15, SE = 0.05, p < 0.01), attention (Interaction β = -0.13, SE = 0.04, p < 0.01), delayed recall (Interaction β = -0.18, SE = 0.06, p < 0.001), executive function (Interaction β = -0.16, SE = 0.05, p < 0.001), language (Interaction β = -0.14, SE = 0.05, p < 0.001), and orientation (Interaction β = -0.17, SE = 0.06, p < 0.001) subscores. No significant time × nOH interaction was observed for MDS-UPDRS Parts I-III (all p > 0.6), indicating comparable rates of motor and nonmotor symptom progression between nOH+ and nOH- groups. DISCUSSION: In this single-center, real-world retrospective cohort, the presence of baseline nOH was associated with a more rapid decline in cognitive function. These findings highlight the potential importance of early autonomic assessment in PD and warrant further investigation in larger, multi-center studies to determine generalizability and to better understand the underlying mechanisms contributing to cognitive deterioration.