Brain imaging of neurovascular dysfunction in Alzheimer's disease

Abstract

Neurovascular dysfunction, including blood-brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer's disease (AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), offer new possibilities to understand how the human brain works in health and disease. This includes methods to detect subtle regional changes in the cerebrovascular system integrity. Here, we focus on the neurovascular imaging techniques to evaluate regional BBB permeability (dynamic contrast-enhanced MRI), regional CBF changes (arterial spin labeling- and functional-MRI), vascular pathology (structural MRI), and cerebral metabolism (PET) in the living human brain, and examine how they can inform about neurovascular dysfunction and vascular pathophysiology in dementia and AD. Altogether, these neuroimaging approaches will continue to elucidate the spatio-temporal progression of vascular and neurodegenerative processes in dementia and AD and how they relate to each other.

Keywords: Alzheimer’s disease; Blood–brain barrier; Cerebral blood flow; Magnetic resonance imaging; Neurovascular dysfunction.

Fig. 1

BBB breakdown in the hippocampus during normal aging and aging associated with AD using high-resolution DCE-MRI. Representative BBB K_trans maps within the left hippocampus in young (23–47 years) and older (55–91 years) individuals with no cognitive impairment (NCI), as well as in older MCI and AD patients (Modified from [115], images courtesy of Axel Montagne)

Fig. 2

Decreases in regional CBF with dementia. a Coronal slices display reduced hippocampal, caudate, and thalamic CBF in AD vs. MCI (right) and AD vs. no cognitive impairment (NCI) (left) groups on voxel-level comparison. b The thalamic CBF decreases by 20 % in AD compared to MCI individuals. c Thalamic CBF is associated with global cognitive impairment on the Dementia Rating Scale (DRS) in AD (red) and MCI (green). d Caudate CBF reduction is associated with increased white matter lesions (WMLs) severity across the NCI-MCI-AD spectrum. All ps < 0.05 after correcting for voxel-level multiple comparisons. NCI, n = 46; MCI, n = 23; AD, n = 12 (Modified from [39, 120]; images courtesy of Daniel Nation)

Fig. 3

White matter disruptions in individuals with MCI. Patients with MCI have lower fractional anisotropy, a measure of white matter (WM) integrity, when compared to cognitively normal older adults (n = 37) using tract-based spatial statistics, p < 0.05, threshold-free cluster enhancement-corrected for multiple comparisons. The regions highlighted in red, including the inferior frontal WM and parahippocampal WM (red arrows), may be early sites of damage in individuals at-risk for AD (L left; R right) (images courtesy of Judy Pa)

Fig. 4

Hippocampal subregion segmentation: variations in image acquisition and segmentation protocols. a The figure shows the left hippocampus of a 36-year-old healthy control acquired with different scanners (3 and 7 T) and sequences [T1-weighted (T1w) and T2w imaging]. Images were segmented by multiple groups (using their own segmentation protocol/atlas) participating in the Hippocampal Subfields Group. Images correspond to the head of the hippocampus. b Segmentation examples indicating which substructures were segmented in each protocol (Modified from [62])