CEREBROVASCULAR RESISTANCE AND CEREBRAL AMYLOIDOSIS: EFFECTS ON COGNITIVE DECLINE, CORTICAL ATROPHY AND PROGRESSION TO DEMENTIA

Abstract

Vascular risk factors have been increasingly implicated in Alzheimer's disease (AD). Blood pressure and decreased cerebral blood flow (CBF) are of particular interest given their links to AD biomarkers and clinical progression. We therefore hypothesized that elevated ratio of blood pressure to CBF, indicative of cerebrovascular resistance, would predict amyloid retention, cognitive decline, cortical thinning, and progression to dementia over a 2-year period, independent of neuronal metabolism. Older adults with (n = 33) and without (n = 199) AD underwent arterial spin labeling magnetic resonance imaging to measure regional CBF in brain regions susceptible to aging and AD. An estimated cerebrovascular resistance index (CVRi) was then calculated as the ratio of mean arterial pressure to regional CBF. Positron emission tomography with florbetapir-fluorine-18 (18F) and fludeoxyglucose was used to quantify amyloid retention and neuronal metabolism, respectively. Non-demented participants were classified as Aβ– or Aβ+ based on florbetapir-indexed amyloid load. Cognitive performance was evaluated via annual assessments of global cognition, memory, and executive function. Linear mixed models and regression were used to assess CVRi prediction of cognitive performance, amyloid, and atrophy over 2 years. CVRi prediction of progression to dementia was evaluated using logistic regression. CVRi was significantly elevated in non-demented Aβ+ versus Aβ– participants, with further elevation observed in AD patients. CVRi group differences were also of greater statistical effect size and encompassed a greater number of brain regions, than those for CBF alone, including frontal, parietal, temporal, and hippocampal areas. Cognitive decline over 2-year follow-up was accelerated by elevated baseline CVRi, particularly for amyloid-positive individuals. Higher CVRi was also associated with elevated inferior temporal amyloid retention and cortical thinning 2 years later. Finally, increased CVRi predicted greater progression to dementia, beyond that attributable to amyloid-positivity. Findings suggest that increased cerebrovascular resistance may represent a previously unrecognized contributor to Alzheimer's disease that is independent of neuronal hypometabolism, predates changes in brain perfusion, exacerbates and works synergistically with amyloidosis to produce cognitive decline, and drives amyloid-independent brain atrophy during the earliest stage of disease.