Quantitative MRI of cerebral white matter hyperintensities: A new approach towards understanding the underlying pathology

Interest in white matter hyperintensities (WMH), a radiological biomarker of small vessel disease, is continuously increasing. This is, in most part, due to our better understanding of their association with various clinical disorders, such as stroke and Alzheimer's disease, and the overlapping pathology of WMH with these afflictions. Although post-mortem histological studies have reported various underlying pathophysiological substrates, in vivo research has not been specific enough to fully corroborate these findings. Furthermore, post-mortem studies are not able to capture which pathological processes are the driving force of the WMH severity. The current study attempts to fill this gap by non-invasively investigating the influence of WMH on brain tissue using quantitative MRI (qMRI) measurements of the water content (H2O), the longitudinal (T-1) and effective transverse relaxation times (T-2*), as well as the semi-quantitative magnetization transfer ratio (MTR), and bound proton fraction (f(bound)). In total, seventy subjects (age range 50-80 years) were selected from a population-based aging cohort study, 1000 BRAINS. Normal appearing grey (NAGM) and white matter (NAWM), as well as deep (DWMH) and periventricular (PWMH) white matter hyperintensities, were segmented and characterized in terms of their quantitative properties. The subjects were then further divided into four grades according to the Fazekas rating scale of severity. Groupwise analyses of the qMRI values in each tissue class were performed. All five qMRI parameters showed significant differences between WMH and NAWM (p < 0.001). Importantly, the parameters differed between DWMH and PWMH, the latter having higher H2O, T-1, T-2* and lower MTR and f(bound) values (p < 0.001). Following grading according to the Fazekas scale, DWMH showed an increase in the water content, T-1 and a decrease in bound proton fraction corresponding to severity, exhibiting significant changes in grade 3 (p < 0.001), while NAWM revealed significantly higher H2O values in grade 3 compared to grade 0 (p < 0.001). PWMH demonstrated an increase in T-2* values (significant in grade 3, P < 0.001). These results are in agreement with previous histopathological studies and support the interpretation that both edema and myelin loss due to a possible breakdown of the blood-brain barrier and inflammation are the major pathological substrates turning white matter into DWMH. Edema being an earlier contributing factor to the pathology, as expressed in the elevated water content values in NAWM with increasing severity. In the case of PWMH, an altered fluid dynamic and cerebrospinal fluid leakage exacerbate the changes. It was also found that the pathology, as monitored by qMRI, evolves faster in DWMH than in the PWMH following the severity.