Topographical pattern of blood‐brain barrier impairment in preclinical and clinical Alzheimer’s disease

Abstract

AbstractBackgroundWhile blood‐brain barrier (BBB) damage in some brain regions has been suggested in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), the topographical pattern of BBB impairment associated with AD process in whole brain level is still poorly understood. Using high‐resolution 3‐dimensional (3D) dynamic contrast‐enhanced (DCE) scans of BBB permeability (Ktrans) for the whole brain, we aimed to reveal topographical pattern of BBB impairment related to Alzheimer’s disease (AD) including preclinical as well as clinically impaired state.MethodNinety‐one participants were included in the study [45 cognitively normal (CN) older adults, 24 individuals with mild cognitive impairment (MCI), and 22 patients with AD dementia]. Comprehensive clinical and neuropsychological assessments were administered to all participants. High‐resolution DCE‐ as well as T1‐weighted‐MRI scans were obtained in addition to amyloid‐PET scans. Amyloid‐beta (Ab) positivity was obtained using previously established cut‐offs. Preprocessing of Ktrans maps incorporated FreeSurfer‐based (v6.0) segmentation to ensure exclusion of the voxels within cerebrospinal fluid (CSF) spaces. Voxel‐wise analyses were conducted using SPM12 implemented in MATLAB 2018b.ResultSubtle BBB impairment, as measured by Ktrans map images based on high‐resolution 3D DCE‐MRI, was observed at multiple brain regions even in preclinical AD (i.e., Ab‐positive CN) as well as AD with cognitive impairment (i.e., Ab‐positive MCI and AD). The brain regions with impaired Ktrans closely corresponded to the AD‐signature regions (Figure). Compared to Ab‐negative CN, Ab‐positive CN showed increased breakdown of BBB in the precuneus, posterior‐cingulate cortex, and medial temporal lobe. Moreover, compared to Ab‐negative CN, Ab‐positive MCI and AD patients showed increased breakdown of BBB in more diffuse regions including bilateral frontal, parietal and inferior temporal areas. In contrast, when using low‐resolution BBB images for the same participants, BBB damage was not detected in preclinical AD and observed at only limited brain regions in AD with cognitive impairment.ConclusionWe demonstrated topographical pattern of BBB impairment associated with preclinical AD as well as AD with cognitive impairment through technically advanced high‐resolution DCE‐MRI. The findings suggest that subtle BBB changes detectable from high‐resolution DCE‐MRI has potential as a biomarkers for detection and monitoring of BBB impairment in whole AD continuum.