Background: Cerebral hypoperfusion has previously been associated with mild cognitive impairment and dementia in various cross-sectional studies, but whether hypoperfusion precedes neurodegeneration is unknown. We prospectively determined the association of cerebral perfusion with subsequent cognitive decline and development of dementia. Methods: Between 2005 and 2012, we measured cerebral blood flow by 2-dimensional phase-contrast magnetic resonance imaging in participants of the population-based Rotterdam Study without dementia. We determined the association of cerebral perfusion (mL/100mL/min) with risk of dementia (until 2015) using a Cox model, adjusting for age, sex, demographics, cardiovascular risk factors, and apolipoprotein E genotype. We repeated analyses for Alzheimer disease and accounting for stroke. We used linear regression to determine change in cognitive performance during 2 consecutive examination rounds in relation to perfusion. Finally, we investigated whether associations were modified by baseline severity of white matter hyperintensities. Results: Of 4759 participants (median age 61.3 years, 55.2% women) with a median follow-up of 6.9 years, 123 participants developed dementia (97 Alzheimer disease). Lower cerebral perfusion was associated with higher risk of dementia (adjusted hazard ratio, 1.31; 95% confidence interval per standard deviation decrease, 1.07-1.61), similar for Alzheimer disease only, and unaltered by accounting for stroke. Risk of dementia with hypoperfusion was higher with increasing severity of white matter hyperintensities (with severe white matter hyperintensities; hazard ratio, 1.54; 95% confidence interval, 1.11-2.14). At cognitive reexamination after on average 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition (global cognition: β=-0.029, P=0.003), which was similar after excluding those with incident dementia, and again most profound in individuals with higher volume of white matter hyperintensities (P value for interaction=0.019). Conclusions: Cerebral hypoperfusion is associated with accelerated cognitive decline and an increased risk of dementia in the general population.

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Keywords Alzheimer disease, Cerebral blood flow, Cerebral perfusion, Dementia, Epidemiology, Small-vessel disease
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Journal Circulation (Baltimore)
Wolters, F.J, Zonneveld, H.I, Hofman, A, van der Lugt, A, Koudstaal, P.J, Vernooij, M.W, & Ikram, M.A. (2017). Cerebral perfusion and the risk of dementia: A population-based study. Circulation (Baltimore), 136(8), 719–728. doi:10.1161/CIRCULATIONAHA.117.027448