Diffusely Abnormal White Matter, T₂ Burden of Disease, and Brain Volume in Relapsing‐Remitting Multiple Sclerosis

Abstract

BACKGROUND AND PURPOSE Multiple sclerosis (MS) diffusely abnormal white matter (DAWM) is a mildly hyperintense magnetic resonance imaging abnormality distinct from typical lesions. Our goal was to investigate the prevalence and natural history of DAWM in a large cohort (n = 348) of relapsing–remitting MS (RRMS) patients. METHODS The presence of DAWM and relationship to changes in T2 burden of disease (BOD), brain volume (brain fractional ratio, BFR), and disability (Expanded Disability Status Scale, EDSS) were investigated at baseline and year 7–8 (long‐term follow‐up, LTF). RESULTS DAWM was present in 25.3% (88 of 348) of patients at baseline. At LTF, DAWM was unchanged in 69.3% (61 of 88), decreased in 28.4% (25 of 88), and increased in 2.3% (2 of 88) of patients. Baseline BOD and change in BOD did not significantly differ between patients with and without DAWM. DAWM was associated with greater reduction in BFR at LTF (P = .038). DAWM and DAWM change did not predict EDSS or EDSS progression. CONCLUSIONS DAWM is present in a quarter of RRMS patients, and rarely increases or develops de novo. DAWM predicts brain atrophy but does not predict physical disability. Because of its posterior periventricular location, further investigation is warranted to evaluate its relationship to other measures of disability, including visual spatial processing and cognitive function.

T2 Relaxometry Evidence of Microstructural Changes in Diffusely Abnormal White Matter in Relapsing–Remitting Multiple Sclerosis and Clinically Isolated Syndrome: Impact on Visuomotor Performance

“…Similar results were found among CIS patients (mean = 2.45, SD = 1.68 and mean = 3.09, SD = 2.34, respectively; P = 0.1). This is in agreement with the notion that DAWM is a phenomenon present in the early stages of the disease 1,7 . It was predominantly detected in posterior periventricular WM, in proximity to focal WM lesions, although it was also found in areas with no visible WM lesions.…”

Diffusely abnormal white matter converts to T2 lesion volume in the absence of acute inflammation

“…Our analysis supports the concept that a slowly progressive increase in T2 lesion volume may be driven by the conversion of DAWM to chronic FWML, and that this phenomenon is not exclusive to SPMS, but is also present in RRMS. We have previously shown that DAWM-to-FWML transformation is more pronounced in SPMS patients that have confirmed disability progression for 12 and 24 weeks 11 . We now extend the findings of this transformation to RRMS, where disability progression independent of relapses is increasingly appreciated to also occur 23 .…”

“…However, the image processing pipeline generates robust and consistent results, and it has been previously validated in test-retest settings and used in multi-scanner datasets 11 . Our RRMS cohort is a distinct group, different than the SPMS group, and included patients in very different stages of the disease.…”

“…Our group has recently shown that SPMS participants exhibit DAWM transformation into FWML over time 10 and that this transformation is significantly associated with clinical progression, making it a potential MRI marker of progressive biology in MS 10 . The few studies that have assessed changes of DAWM and FWML over time in RRMS populations have found that it rarely increases in this stage of MS 11 .…”

Aquaporin-4 Expression during Toxic and Autoimmune Demyelination

“…In models of disease involving blood–brain barrier disruption, including brain tumor [ 22 ], brain abscess [ 46 ], subarachnoid hemorrhage [ 47 ], and status epilepticus [ 48 ], Aqp4 null mice develop more severe brain edema than wild-type mice, suggesting that the mode of edema formation (vasogenic versus cytotoxic edema) is important to define the role of AQP4. Edema formation, to a variable extent, has been demonstrated in MS [ 49 , 50 , 51 , 52 ] as well as the EAE [ 53 , 54 ] and cuprizone animal models [ 55 , 56 ]. Comparable to our results, Wolburg-Buchholz and colleagues demonstrated the loss of polarized AQP4 localization in astrocytic end-feet surrounding microvessels during EAE [ 57 ].…”