Greater diffusion restriction in white matter tracts in preclinical AD

Abstract

AbstractBackgroundThe Alzheimer’s Continuum is biologically defined by beta‐amyloid deposition, encompassing individuals with or without other biomarker or clinical changes (Jack et al., 2018). Beta‐amyloid deposition is superimposed upon white matter degeneration in aging, but the degree to which these co‐occurring changes are characterized in vivo in the preclinical stage is less understood. The goal of this study was to use Diffusional Kurtosis Imaging (Jensen & Helpern, 2010) and biophysical modeling (Fieremans et al., 2011) to detect and describe amyloid‐related white matter changes in preclinical AD.Method141 cognitively unimpaired older adults ages 45 to 85 completed 3T brain MRI, amyloid PET (florbetapir, F18), and standard clinical and neuropsychological procedures (Besser et al., 2018). 51 had amyloid PET mSUVr values ≤ 1.21 and were designated as being on the Alzheimer’s Continuum (AB+); all other subjects were AB‐. DKI data were pre‐processed (Ades‐Aron et al., 2018), maps were computed using in‐house scripts (https://github.com/m‐ama/PyDesigner), and tensor‐based registration was performed using DTI‐TK (Zhang et al., 2007) as integrated with TBSS (Smith et al., 2006). Voxelwise and region of interest analyses of skeletonised maps were conducted to determine differences between AB+ and AB‐ groups, covarying for age, on conventional diffusivity (i.e. MD, FA) and biophysical modeling metrics that indicate extra‐axonal myelin/gliotic changes (i.e. D e,⊥) and changes in axonal density (i.e. AWF).ResultVoxelwise analysis indicated significantly greater diffusion restriction (i.e. lower MD, higher FA) in AB+ versus AB‐ subjects, with medium‐to‐large effect sizes (age‐adjusted |d|= 0.6 to 0.8). Region of interest analyses of the corpus callosum corroborated these findings, suggesting that these differences occur in late‐myelinating (genu) but not early‐myelinating (splenium) tracts (Fig. 1.B). This effect was likely driven by changes in the extra‐axonal space (i.e. lower D e,⊥ in AB+).ConclusionThe Alzheimer’s Continuum in preclinical AD is associated with greater diffusion restriction in white matter, preferentially in regions that myelinate later in life. Potential mechanisms include myelin breakdown and repair, oligodentritic activation, and inflammation (i.e. microgliosis, astrocytosis), suggesting non‐amyloid pathological changes upon which to focus disease monitoring or treatment development at the very earliest stages of disease.