Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment

Abstract

Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-β pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.

Keywords: Alzheimer’s disease; PET imaging; beta-amyloid; magnetic resonance imaging; perfusion imaging.

Figure 1

Associations between cerebral blood flow and amyloid-β load. CBF values were centred and standardized. Associations were tested simultaneously in healthy controls (NL, green), early and late MCI (EMCI, blue, and LMCI, red, respectively), and Alzheimer’s disease dementia (AD, black). The fitted lines are from linear regression models, co-varied for age, sex and CBF in a reference region (precentral cortex). The data in the top of each panel are the regression coefficients B (standard error) and P-values for amyloid-β standardized uptake value ratio (SUVR) in the linear regression models fitted for all subjects simultaneously (thick solid line). The dashed lines represent models fitted within diagnostic groups. Data in the bottom of each panel are for likelihood ratio tests, comparing linear regression models with and without the interaction between diagnostic groups and amyloid-β standardized uptake value ratio, to assess differences between diagnostic groups (a significant P-value suggests that the relationship between regional CBF and amyloid-β standardized uptake value ratio differs by diagnosis).

Figure 2

Effects of amyloid-β standardized uptake value ratio (SUVR) and diagnostic group on CBF. CBF values were adjusted for age, sex, and CBF in a reference region (precentral cortex), centered and standardized. Amyloid-β-negative healthy controls (NL) (dichotomized by amyloid-β standardized uptake value ratio ≥1.11) were compared with amyloid-β-positive controls, early and late MCI (EMCI and LMCI), and Alzheimer’s disease dementia (AD), and with amyloid-β-negative early MCI and late MCI. Values above each column are P-values from linear regression models, for the combination of amyloid-β and diagnosis as predictor of CBF, co-varied for age, sex and reference CBF (precentral cortex). Shown P-values are not corrected for multiple comparisons.