Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease

Abstract

Objective: The Alzheimer's continuum is biologically defined by beta-amyloid deposition, which at the earliest stages is superimposed upon white matter degeneration in aging. However, the extent to which these co-occurring changes is characterized is relatively underexplored. The goal of this study was to use diffusional kurtosis imaging (DKI) and biophysical modeling to detect and describe amyloid-related white matter changes in preclinical Alzheimer disease. Methods: Cognitively unimpaired participants ages 45 to 85 years completed brain magnetic resonance imaging, amyloid positron emission tomography (florbetapir), neuropsychological testing, and other clinical measures at baseline in a cohort study. We tested whether beta-amyloid-negative (ABÀ) and -positive (AB+) participants differed on DKIbased conventional (ie, fractional anisotropy [FA], mean diffusivity [MD], mean kurtosis) and modeling (ie, axonal water fraction [AWF], extra-axonal radial diffusivity [D e,⊥ ]) metrics, and whether these metrics were associated with other biomarkers. Results: We found significantly greater diffusion restriction (higher FA/AWF, lower MD/D e,⊥ ) in white matter in AB+ than ABÀ (partial η 2 =0.08-0.19), more notably in the extra-axonal space within primarily late myelinating tracts. Diffusion metrics predicted amyloid status incrementally over age (area under the curve = 0.84) with modest yet selective associations, where AWF (a marker of axonal density) correlated with speed/executive functions and neurodegeneration, whereas D e,⊥ (a marker of gliosis/myelin repair) correlated with amyloid deposition and white matter hyperintensity volume. Interpretation: These results support prior evidence of a nonmonotonic change in diffusion behavior, where an early increase in diffusion restriction is hypothesized to reflect inflammation and myelin repair prior to an ensuing decrease in diffusion restriction, indicating glial and neuronal degeneration.

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

“…A diffusion MRI study of young onset AD showed loss of U fibers (superficial white matter) and dispersion of these fibers in AD (Veale et al, 2021). Moreover, MRI shows greater diffusion restriction in white matter in AD patients (Hanyu et al, 1997) and in preclinical AD where patients are cognitively normal but have positive amyloid positron emission tomography (florbetapir) (Benitez et al, 2022). Other MRI studies show Diffusion Tensor Imaging (DTI) abnormalities in preclinical AD (normal cognition, but abnormal CSF AD markers) (Hoy et al, 2017).…”

Association of cortical and subcortical microstructure with disease severity: impact on cognitive decline, and language impairments in frontotemporal lobar degeneration

“…Subcortical white matter tract abnormalities in FTLD are relatively understudied compared with primary neurodegenerative diseases like Alzheimer's disease. Although the precise neurological correlations remain elusive, several studies have suggested a key association of white matter abnormalities in neurodegeneration [11,41,42]. These studies have demonstrated that subcortical MD and FA are measures of anisotropy of free water diffusion in white matter tracts, with the axon and myelin being destroyed, adding to the anisotropy [41,42].…”

“…Although the precise neurological correlations remain elusive, several studies have suggested a key association of white matter abnormalities in neurodegeneration [11,41,42]. These studies have demonstrated that subcortical MD and FA are measures of anisotropy of free water diffusion in white matter tracts, with the axon and myelin being destroyed, adding to the anisotropy [41,42]. The patients with bvFTD showed a widespread pattern of MD and FA abnormalities affecting most of the white matter bilaterally.…”

White matter dementia then… and now

“…The etiology of AD is not well understood, and a broad perspective is needed to complement the amyloid hypothesis. In the white matter, the myelin hypothesis discussed above relies substantially on vascular disease as an early event in AD pathogenesis, and it is noteworthy that AD brains commonly harbor co-existent vascular pathology that often manifests in life as WMH (51)(52)(53)(54)(55)(56). Alternatively, however, WMH in AD patients may reflect Wallerian degeneration subsequent to cortical pathology, or the impact of amyloid angiopathy on perivascular white matter (51,56).…”

“…An increase in MRI vascular lesion volume has been noted years before the onset of AD, or even of MCI ( 52 ), and these lesions have been shown to lead to overlying cortical atrophy in patterns typical of AD ( 53 ). With respect to white matter microstructure, DTI studies have demonstrated a decline in white matter integrity before the appearance of AD dementia ( 54 ), and diffusion kurtosis imaging (DKI) has also found greater diffusion restriction in preclinical AD ( 55 ). Another factor is age-related myelin loss, known as white matter retrogenesis, which is thought to produce a vulnerable substrate for acquired insults ( 56 ).…”