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March 07, 2023; 100 (10) Research Article

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

Iñigo Ruiz Barrio, Yasuo Miki, Zane T. Jaunmuktane, Thomas Warner, Eduardo De Pablo-Fernandez
First published December 16, 2022, DOI: https://doi.org/10.1212/WNL.0000000000201659
Iñigo Ruiz Barrio
From the Queen Square Brain Bank for Neurological Disorders, (I.R.B., Y.M., Z.T.J., T.W., E.d.P-F.), and Reta Lila Weston Institute of Neurological Studies (T.W., E.d.P-F.), Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology, London, United Kingdom; Movement Disorders Unit, (I.R.B.), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; and Department of Neuropathology (Y.M.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
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Yasuo Miki
From the Queen Square Brain Bank for Neurological Disorders, (I.R.B., Y.M., Z.T.J., T.W., E.d.P-F.), and Reta Lila Weston Institute of Neurological Studies (T.W., E.d.P-F.), Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology, London, United Kingdom; Movement Disorders Unit, (I.R.B.), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; and Department of Neuropathology (Y.M.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
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Zane T. Jaunmuktane
From the Queen Square Brain Bank for Neurological Disorders, (I.R.B., Y.M., Z.T.J., T.W., E.d.P-F.), and Reta Lila Weston Institute of Neurological Studies (T.W., E.d.P-F.), Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology, London, United Kingdom; Movement Disorders Unit, (I.R.B.), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; and Department of Neuropathology (Y.M.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
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Thomas Warner
From the Queen Square Brain Bank for Neurological Disorders, (I.R.B., Y.M., Z.T.J., T.W., E.d.P-F.), and Reta Lila Weston Institute of Neurological Studies (T.W., E.d.P-F.), Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology, London, United Kingdom; Movement Disorders Unit, (I.R.B.), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; and Department of Neuropathology (Y.M.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
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Eduardo De Pablo-Fernandez
From the Queen Square Brain Bank for Neurological Disorders, (I.R.B., Y.M., Z.T.J., T.W., E.d.P-F.), and Reta Lila Weston Institute of Neurological Studies (T.W., E.d.P-F.), Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology, London, United Kingdom; Movement Disorders Unit, (I.R.B.), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; and Department of Neuropathology (Y.M.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
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Association Between Orthostatic Hypotension and Dementia in Patients With Parkinson Disease and Multiple System Atrophy
Iñigo Ruiz Barrio, Yasuo Miki, Zane T. Jaunmuktane, Thomas Warner, Eduardo De Pablo-Fernandez
Neurology Mar 2023, 100 (10) e998-e1008; DOI: 10.1212/WNL.0000000000201659

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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.

Glossary

HR=
hazard ratio;
OH=
orthostatic hypotension;
PD=
Parkinson disease;
MSA=
multiple system atrophy;
SH=
supine hypertension

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Submitted and externally peer reviewed. The handling editor was Associate Editor Peter Hedera, MD, PhD.

  • Editorial, page 451

  • CME Course: NPub.org/cmelist

  • Received May 5, 2022.
  • Accepted in final form October 21, 2022.
  • © 2022 American Academy of Neurology
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