'Under pressure': is there a link between orthostatic hypotension and cognitive impairment in α-synucleinopathies?
Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterised by abnormal neuroglial α-synuclein accumulation. These α-synucleinopathies have in common parkinsonism and non-motor features including orthostatic hypotension (OH) and cognitive impairment. However, the nature of the relationship between OH and cognitive impairment is unclear. We therefore systematically reviewed the literature for evidence of an association between OH and cognitive impairment in α-synucleinopathies and discuss possible mechanisms and implications of this relationship. Abstracts from 313 original research articles were surveyed, and a total of 132 articles were considered for this review. Articles were stratified as: 'direct-evidence studies' based on the direct assessment for a relationship between OH and cognitive impairment in α-synucleinopathies, and 'indirect-evidence studies' based on an association being referred to as a secondary outcome. Ten 'direct-evidence papers' were identified, seven of which reported a positive association between OH and cognitive impairment, while seven of 12 'indirect-evidence papers' similarly did as well. The papers that reported no association between OH and cognitive impairment used less sensitive measures of cognition. A relationship between OH and cognitive impairment in patients with α-synucleinopathies exists, but the underlying mechanisms remain unclear. Three hypotheses are proposed: (1) OH and cognitive impairment occur concurrently due to diffuse brain and peripheral deposition of α-synuclein, (2) OH-mediated cerebral hypoperfusion impairs cognition and (3) the two act synergistically to accelerate cognitive decline. Longitudinal neuroimaging studies and clinical trials may help clarify the nature of this relationship.
Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|L.C. Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
Sean J
SJ
Udow
Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
Andrew D
AD
Robertson
Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
Bradley J
BJ
MacIntosh
Department of Neurology, Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA.
Alberto J
0000-0002-3389-136X
AJ
Espay
Cognition and Brain Sciences Unit, Medical Research Council, Cambridge, UK.|Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
James B
0000-0001-7216-8679
JB
Rowe
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.|Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
Anthony E
AE
Lang
Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|L.C. Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Mario
M
Masellis
D059345:Cerebral Small Vessel Diseases / Q000150:complications / Q000175:diagnosis; D060825:Cognitive Dysfunction / Q000175:diagnosis*; D006801:Humans; D007024:Hypotension, Orthostatic / Q000175:diagnosis*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000175:diagnosis; D020961:Lewy Body Disease / Q000175:diagnosis*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008609:Mental Status Schedule; D019578:Multiple System Atrophy / Q000175:diagnosis*; D009457:Neuroglia / Q000378:metabolism; D010300:Parkinson Disease / Q000175:diagnosis*; D000072078:Positron Emission Tomography Computed Tomography; D012307:Risk Factors; D013223:Statistics as Topic; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein
AUTONOMIC; COGNITION; LEWY BODY; MULTISYSTEM ATROPHY; PARKINSON'S DISEASE