In vivo myelin imaging and tissue microstructure in white matter hyperintensities and perilesional white matter

Abstract

White matter hyperintensities negatively impact white matter structure and relate to cognitive decline in aging. Diffusion tensor imaging detects changes to white matter microstructure, both within the white matter hyperintensity and extending into surrounding (perilesional) normal appearing white matter. However, diffusion tensor imaging markers are not specific to tissue components, complicating interpretation of previous microstructural findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction) and interstitial fluid (geometric mean T2). Here we combined diffusion tensor imaging and myelin water imaging to examine tissue characteristics in white matter hyperintensities and perilesional white matter in 80 individuals (47 older adults and 33 individuals with chronic stroke). To measure perilesional normal appearing white matter, white matter hyperintensity masks were dilated in 2 mm segments up to 10 mm in distance from the white matter hyperintensity. Fractional anisotropy, mean diffusivity, myelin water fraction, and geometric mean T2 were extracted from white matter hyperintensities and perilesional white matter. We observed a spatial gradient of higher mean diffusivity and geometric mean T2, and lower fractional anisotropy, in the white matter hyperintensity and perilesional white matter. In the chronic stroke group, myelin water fraction was reduced in the white matter hyperintensity but did not show a spatial gradient in perilesional white matter. Across the entire sample, white matter metrics within the white matter hyperintensity related to whole-brain white matter hyperintensity volume; with increasing white matter hyperintensity volume there was increased mean diffusivity and geometric mean T2, and decreased myelin water fraction in the white matter hyperintensity. Normal appearing white matter adjacent to white matter hyperintensities exhibits characteristics of a transitional stage between healthy white matter and white matter hyperintensities. This effect was observed in markers sensitive to interstitial fluid, but not in myelin water fraction, the specific marker of myelin concentration. Within the white matter hyperintensity, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests white matter hyperintensities have penumbra-like characteristics in perilesional white matter that specifically reflect increased interstitial fluid, with no changes to myelin concentration. In contrast, within the white matter hyperintensity there are varying levels of demyelination, which vary based on the severity of cerebrovascular disease. Diffusion tensor imaging and myelin imaging may be useful clinical markers to predict white matter hyperintensity formation, and to stage neuronal damage within white matter hyperintensities.

Amyloid-PET of the white matter: relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease

“…The association in the NAWM may potentially reflect mild vascular damage and an early, pre-lesional role for FW in affecting cognitive function. 18, 26 Apart from the significant FW-cognition relationship, we observed that FW (but not FW-adjusted FA) mediated the association between PET and executive function in WMH. In contrast, lower FW-adjusted FA only showed a weak relationship with lower MoCA score within WMH and with lower MMSE score within NAWM (the sensitivity of MoCA to WMH may be related to its wider application as a screening tool for vascular cognitive impairment by covering domains of executive function) 55 .…”

“…First, while demyelinating fibers are an early feature in AD, 5 their direct effects on diffusion may be less pronounced in a sample enriched for SVD. 18, 40 Indeed, our group has previously shown that WM disease may primarily reflect chronic vasogenic edema (blood-brain barrier [BBB] leakage) or perivascular stasis (compromised circulation of interstitial fluid) induced by venous collagenosis and chronic hypoperfusion; 22, 23, 42 which may be a trigger of downstream neuroinflammation, damage to myelin membranes with potential formation of intramyelinic fluid-filled vacuoles, and axonal (Wallerian) degeneration due to cortical neuronal injury in cases with concomitant AD pathology. 40, 41, 43 Second, previous autopsy studies reported no PiB staining/binding to WM tracts, 3, 10 suggesting that demyelination alone does not account for the reduced PET signal.…”

“…Both groups were matched for vascular risk factors including hypertension, pulse pressure, body mass index, sex, and smoking status. 30 All participants underwent 18 F-AV45 PET, 3T MRI including 3D T1, FLAIR, and dMRI, and a neuropsychological assessment. MRI-PET and MRI-neuropsychology acquisitions were acquired in close proximity (54±80 and 27±78 days ± standard deviation, respectively).…”

“…To investigate the effects of age or sex on 18 F-AV45 SUVR in the WM, we employed linear mixed effect models with an interaction term between age or sex and WM region (NAWM and WMH) and subject as a random factor.…”

“…1. Introduction 18 F-Florbetapir ( 18 F-AV45) is one of the most commonly used positron emission tomography (PET) ligands to detect and quantify amyloid-β (Aβ) burden in the cortex of patients with Alzheimer's disease (AD). Specifically, Aβ-ligands are thought to target the cross beta-sheet structure of the insoluble Aβ fibrils.…”