Association Between Orthostatic Hypotension and Dementia in Patients With Parkinson Disease and Multiple System Atrophy

Abstract

Background and objectives: Orthostatic hypotension (OH) increases dementia risk in patients with Parkinson disease (PD), although the underlying mechanisms and whether a similar association between OH and cognitive impairment exists in other synucleinopathies remain unknown. The aim is to evaluate the association between OH and dementia risk in patients with PD, and cognitive impairment risk in patients with multiple system atrophy (MSA), and to explore relevant clinical and neuropathologic factors to understand underlying pathogenic mechanisms.

Methods: This is a retrospective cohort study. Medical records throughout the entire disease course of consecutive patients with neuropathology-confirmed PD and MSA from the Queen Square Brain Bank were systematically reviewed. Time of onset and severity of OH-related symptoms were documented, and their association with other clinical and neuropathologic variables was evaluated. Dementia risk for patients with PD and cognitive impairment risk for patients with MSA were estimated using multivariable hazard regression.

Results: One hundred thirty-two patients with PD and 137 with MSA were included. Patients with MSA developed OH more frequently, earlier in the disease course and with more severe symptoms. Cumulative dementia prevalence was higher in patients with PD. Multivariable adjusted regression models showed that early OH, but not its symptom severity, increased dementia risk in patients with PD by 14% per year (hazard ratio [HR] = 0.86; 95% CI, 0.80-0.93) and cognitive impairment risk in patients with MSA by 41% per year (HR = 0.59; 95% CI, 0.42-0.83). Early OH was not associated with increased α-synuclein, β-amyloid, tau, Alzheimer, or cerebrovascular pathologies. No significant associations were found between severity of OH symptoms and other clinical or neuropathologic variables.

Discussion: Early OH, but not its symptom severity, increases the risk of cognitive impairment in patients with PD and MSA. OH is not associated with more extensive Lewy, β-amyloid, tau, Alzheimer, or cerebrovascular pathologies. It is likely that OH contributes to cognitive impairment in patients with PD and MSA by hypoxia-induced nonspecific neurodegeneration. Further research should evaluate whether improving brain perfusion by treating OH may modify the risk of dementia in these conditions.

Figure 1. Scatterplot Showing the Association Between Time of Onset of Orthostatic Hypotension and Time to Development of Cognitive Impairment for Cases With MSA (Orange) and Dementia for PD Cases (Blue)

Figure 2. Kaplan-Meier of Cumulative Risk of Dementia in PD and Risk of Cognitive Impairment in MSA by Time of Onset of Orthostatic Hypotension (A) and (C) and Severity of Symptoms of Orthostatic Hypotension (B) and (D)