Orthostatic hypotension and dementia incidence: links and implications

Abstract

Orthostatic hypotension (OH) is a common condition, particularly in patients with α-synucleinopathies such as Parkinson’s disease, and has a significant impact on activities of daily living and quality of life. Recent data suggest an association with cognitive impairment. Herein, we review the evidence that OH increases the odds of incident mild cognitive impairment and dementia. Potential mechanisms underlying the putative relationship are discussed, including cerebral hypoperfusion, supine hypertension, white matter hyperintensities, and neurodegeneration. Finally, we highlight the challenges with respect to treatment and the negative impact on the quality of life and long-term prognosis presented by the coexistence of OH and dementia. Large population-based studies have reported that OH is associated with about a 20% increased risk of dementia in the general population, while smaller cohort studies suggest an even greater effect in patients with α-synucleinopathies (3- to 7-fold higher than controls). Ultimately, OH exposure is difficult to quantify, predominantly limited to pressure regulation during a one-time orthostatic challenge, and the causative association with dementia may turn out to be bidirectional, especially in α-synucleinopathies. Early diagnosis and treatment of OH may improve long-term prognosis.

Keywords:

• α-synucleinopathies
• cognitive impairment
• dementia
• orthostatic hypotension
• review

Abbreviations

ARIC, Atherosclerosis Risk in Communities; BP, blood pressure; CBF, cerebral blood flow; DBP, diastolic blood pressure; DLB, dementia with Lewy Bodies; DOH, delayed onset orthostatic hypotension; GÅS-SNAC, Good Aging in Skåne study within the Swedish National Study on Aging and Care; IOH, initial orthostatic hypotension; MCI, mild cognitive impairment; MMSE, mini-mental state exam; OH, orthostatic hypotension; OH-30, delayed recovery orthostatic hypotension; PD, Parkinsons disease; SBP, systolic blood pressure; SH, supine hypertension; TILDA, the Irish Longitudinal Study on Aging; WMH, white matter hyperintensities.

Author contributions

ADR drafted the original article. All authors made substantial contributions to the conception of data; took part in critically revising the article; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

Alberto J Espay has received grant support from the NIH, Great Lakes Neurotechnologies and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for AbbVie, Adamas, Acadia, Acorda, Neuroderm, Impax, Sunovion, Lundbeck, Osmotica Pharmaceutical, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from USWorldMeds, Lundbeck, Acadia, Sunovion, the American Academy of Neurology, and the Movement Disorders Society. Aristide Merola has received grant support from Lundbeck, AbbVie, and Abbott; personal fees from Abbott, AbbVie, Theravance, and Medtronic; speaker honoraria from AbbVie, Lundbeck, Abbott, CSL Behring, and Theravance; and is supported by NIH (KL2 TR001426). Richard Camicioli has received grant support from the Canadian Institutes for Health Research CIHR (Canadian Consortium on Neurodegeneration in Aging), the Michael J Fox Foundation, and grant funding via subcontracts to the University of Calgary from Brain Canada/Parkinson Canada as a co-Investigator (Canadian Open Parkinson Network and Functional Assessment of Vascular Reactivity); he is on a gait advisory board for the Michael J Fox Foundation; and he is on editorial boards for Parkinsonism and Related Disorders, Frontiers in Neuroscience of Aging and Dementia and Geriatric Cognitive Disorders. Anthony E Lang has received support through employment at University Health Network, University of Toronto; grants from Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, National Parkinson Foundation, Parkinson Society Canada, and W. Garfield Weston Foundation; consultancies for AbbVie, Acorda, Biogen, Intracellular, Lundbeck, Sun Pharma, Kallyope, Retrophin, Paladin, Seelos, Theravance, Roche, and Corticobasal Degeneration Solutions; advisory board memberships with Jazz Pharma, PhotoPharmics, and Sunovion; honoraria from Sun Pharma, AbbVie and Sunovion; royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press; personal fees from AbbVie, Accorda, Bristol-Myers Squibb, Biogen, Merck, Sun Pharma/SPARC, Corticoasal Solutions, Paladin, Medichem, Medtronic, Theravance, Jazz Pharma, Retrophin, Seelos, Syneos, Roche, Ono pharma, Intracellular, Jansen, Kallyope, Lundbeck, Lilly. Mario Masellis is supported by the Department of Medicine (Sunnybrook Health Sciences Centre and the University of Toronto), the Sunnybrook Foundation, the Hurvitz Brain Sciences Research Program and the Sunnybrook Research Institute; receives support as co-lead of the Ontario Neurodegenerative Disease Research Initiative funded by the Ontario Brain Institute; he has served as an advisor to Ionis Pharmaceuticals, Alector, Arkuda Therapeutics, and UCB; is an Associate Editor/Board Member for Current Pharmacogenomics and Personalized Medicine; received an investigator-initiated research grant from Teva; royalties from Henry Stewart Talks; personal fees from Arkuda Therapeutics, Ionis Pharmaceuticals, Alector, and Henry Stewart Talks; contract research support from Roche, Novartis, Eli Lilly and Axovant; reports grants from Parkinson Canada, Ontario Brain Institute/Ministry of Research Innovation and Science of Ontario, Ontario Ministry of Research, Innovation and Science, Canadian Institutes of Health Research, Alzheimer’s Drug Discovery Foundation (ADDF), Brain Canada, Weston Brain Institute, Roche, Washington University, Axovant, and Novartis. The authors report no other conflicts of interest in this work.