White matter hyperintensities and normal-appearing white matter integrity in the aging brain

Abstract

White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal-appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 × 10−9 m2s−1 (area under curve, 0.982; 95% CI, 0.975–0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe.

Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease

“…These results demonstrate that WMH have reduced integrity compared with NAWM, and that NAWM deteriorates with increasing WMH and age, confirming that NAWM in the presence of even a few WMH is not 'normal'. 18 Furthermore, a high-WMH burden in younger people indicates advancing damage in NAWM and should sound alarm bells to identify remediable causes.…”

Gliovascular Disruption and Cognitive Deficits in a Mouse Model with Features of Small Vessel Disease

“…Consistent with our previously published data, 21 there was no change in MD detected in our model, which is somewhat unexpected as MD is a marker of white matter damage in SVD in humans. 27 A recent study has also shown that other DTI measures (AD and RD) may be sensitive to the effects of cerebral hypoperfusion, and for future studies, these additional measures would be advisable to study. 28 Notably, in the same animals in which imaging was conducted, we observed myelin and axonal disruption alongside a prominent inflammatory response.…”

Brain volumetric changes and cognitive ageing during the eighth decade of life

“…There is not, for instance, a consensus on the explanation for the relation between WMH presence and growth and reduced cognitive ability; a recent review discusses possibilities ranging from WMHs damaging important neural networks, disrupting neurotransmitters such as those involved in the cholinergic system, or merely acting as an indicator of poorer vascular health, which may impair cognitive ability for other reasons [Prins and Scheltens, 2015]. Further insights into the cytoarchitecture of WMH and the accompanying changes in so‐called normal appearing white matter are provided in Muñoz Maniega et al [2015] and in Wardlaw et al [2015]. It is possible that multiple mechanisms operate and interact: it is unlikely that any one single mechanism is responsible for the loss of complex cognitive abilities.…”