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RELATIONSHIP BETWEEN AMYLOID-PET BINDING, WHITE MATTER MICROSTRUCTURE AND COGNITION IN A MIXED COHORT OF SMALL VESSEL DISEASE AND ALZHEIMER’S PATHOLOGY
Abstract
Aims
To investigate the neurobiological underpinnings of amyloid-PET binding in the white matter (WM) using free-water diffusion MRI in a multi-centre mixed cohort of small vessel disease (SVD) and Alzheimer’s disease (AD) pathology.
Methods
We included sixty participants with moderate-to-severe white matter hyperintensity burden (WMH; median(IQR): 30.51(22.14)cm3) from dementia/stroke-prevention clinics (48% amyloid-positive). Additionally, we included sixty cognitively normal/early-MCI with mild-to-moderate WMH (median(IQR): 5.82(9.29)cm3) from ADNI (22% amyloid-positive). We applied a bi-tensor diffusion MRI model that differentiates between extracellular (free-water fraction) and tract-specific WM compartments (free-water adjusted fractional anisotropy or FAadjusted) (Fig.1). We tested associations of these diffusion metrics with amyloid-SUVR in both WMH and normal-appearing WM, and with cognition (MMSE, semantic, and executive function). To further investigate how the diffusion metrics and the demographical variables including age, sex, education, WMH volume, and cortical amyloid-SUVR covary with WM amyloid-SUVR, we performed partial-least-square analysis using ten-fold cross-validation with five repeats.
Results
In WMH, amyloid-SUVR was significantly lower compared to normal-appearing WM and associated strongly with higher free-water (β=-0.36±0.13, P=0.005; 95%CIbootstrap[-0.50,-0.23]). Partial-least-square analysis in the moderate-to-severe burden group showed that free-water was most strongly associated with amyloid-SUVR in WMH (Fig.2-left; component-1 explaining 24% variance), while FAadjusted was strongly associated with amyloid-SUVR in normal-appearing WM (Fig.2-right; component-1 explaining 31% variance). Free-water within both WMH and normal-appearing WM significantly predicted cognitive impairment.
Conclusions
In mixed AD and SVD, representative of the more common AD population, amyloid-PET changes in WM lesions may largely reflect extracellular free-water. In contrast, normal-appearing WM changes may reflect tract-specific injury (possibly demyelination).