Andrew D Robertson,1,2 Sean J Udow,3 Alberto J Espay,4 Aristide Merola,4 Richard Camicioli,5 Anthony E Lang,6–8 Mario Masellis2,6,91Schlegel-UW Research Institute for Aging, University of Waterloo, Waterloo, ON, Canada; 2Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 3Division of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; 4Department of Neurology, James and Joan Gardner Family Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, USA; 5Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada; 6Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada; 7Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; 8Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; 9Cognitive and Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, ON, CanadaAbstract: 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
