Longitudinal fibre-specific white matter damage predicts cognitive decline in multiple sclerosis
Authors: Koubiyr Ismail , Krijnen Eva A , Eijlers Anand J C , Dekker Iris , Hulst Hanneke E , Uitdehaag Bernard M J , Barkhof Frederik , Geurts Jeroen J G , Schoonheim Menno M 
Published: January 2024

Abstract
During the course of multiple sclerosis, many patients experience cognitive deficits which are not simply driven by lesion number or location. By considering the full complexity of white matter structure at macro- and microstructural levels, our understanding of cognitive impairment in multiple sclerosis may increase substantially. Accordingly, this study aimed to investigate specific patterns of white matter degeneration, the evolution over time, the manifestation across different stages of the disease and their role in cognitive impairment using a novel fixel-based approach. Neuropsychological test scores and MRI scans including 30-direction diffusion-weighted images were collected from 327 multiple sclerosis patients (mean age = 48.34 years, 221 female) and 95 healthy controls (mean age = 45.70 years, 55 female). Of those, 233 patients and 61 healthy controls had similar follow-up assessments 5 years after. Patients scoring 1.5 or 2 standard deviations below healthy controls on at least two out of seven cognitive domains (from the Brief Repeatable Battery of Neuropsychological Tests, BRB-N) were classified as mildly cognitively impaired or cognitively impaired, respectively, or otherwise cognitively preserved. Fixel-based analysis of diffusion data was used to calculate fibre-specific measures (fibre density, reflecting microstructural diffuse axonal damage; fibre cross-section, reflecting macrostructural tract atrophy) within atlas-based white matter tracts at each visit. At baseline, all fixel-based measures were significantly worse in multiple sclerosis compared with healthy controls (P &lt; 0.05). For both fibre density and fibre cross-section, a similar pattern was observed, with secondary progressive multiple sclerosis patients having the most severe damage, followed by primary progressive and relapsing–remitting multiple sclerosis. Similarly, damage was least severe in cognitively preserved (n = 177), more severe in mildly cognitively impaired (n = 63) and worst in cognitively impaired (n = 87; P &lt; 0.05). Microstructural damage was most pronounced in the cingulum, while macrostructural alterations were most pronounced in the corticospinal tract, cingulum and superior longitudinal fasciculus. Over time, white matter alterations worsened most severely in progressive multiple sclerosis (P &lt; 0.05), with white matter atrophy progression mainly seen in the corticospinal tract and microstructural axonal damage worsening in cingulum and superior longitudinal fasciculus. Cognitive decline at follow-up could be predicted by baseline fixel-based measures (R2 = 0.45, P &lt; 0.001). Fixel-based approaches are sensitive to white matter degeneration patterns in multiple sclerosis and can have strong predictive value for cognitive impairment. Longitudinal deterioration was most marked in progressive multiple sclerosis, indicating that degeneration in white matter remains important to characterize further in this phenotype.