Spatially and temporally progressive hypoperfusion in Alzheimer's disease revealed by normative modeling
Xinglin Zeng1, Yiran Li1, Lin Hua2
1Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Introduction:
Cerebral perfusion is implicated in Alzheimer's disease (AD), but its development in AD and mild cognitive impairment (MCI) is not well characterized.
Methods:
We constructed a normative model using > 12,000 arterial spin labeling MRI scans and applied generalized additive models for location, scale, and shape (GAMLSS). Individual deviation z scores were derived by normative model, and outlier regions (z ≤ 2.3) were quantified as the total negative proportion (TNP) of extreme hypoperfusion. These metrics were then related to other AD biomarkers through linear modeling.
Results:
Compared to cognitively normal controls, AD showed higher TNP and greater longitudinal increases (p = 0.003), indicating progressive hypoperfusion. Progressive MCI exhibited greater perfusion decline than stable MCI (p = 0.01). Perfusion changes correlated with cognition, brain volume, amyloid, and apolipoprotein E status (all p < 0.05).
Discussion:
Normative modeling revealed inter-individual heterogeneity in cerebral perfusion trajectories, underscoring its potential relevance for AD development.
