title: Functionally relevant white matter degradation in multiple sclerosis: a tract-based spatial meta-analysis.
abstract: OBJECTIVE
  To identify statistical consensus between published studies for distribution and functional relevance of tract white matter (WM) degradation in multiple sclerosis (MS).
  
  
  METHODS
  By systematically searching online databases, tract-based spatial statistics studies were identified that compared fractional anisotropy (FA; a marker for WM integrity) in MS patients to healthy control subjects, correlated FA in MS patients with physical disability, or correlated FA in MS patients with cognitive performance. Voxelwise meta-analysis was performed by using the Signed Differential Mapping method for each comparison. Moderating effects of mean age, mean physical disability score, imager magnet strength, lesion load, and number of diffusion directions were assessed by means of meta-regression.
  
  
  RESULTS
  Meta-analysis was performed on data from 495 patients and 253 control subjects across 12 studies. MS diagnosis was significantly associated with widespread lower tract FA (nine studies; largest cluster, 4379 voxels; z = 7.1; P < .001). Greater physical disability was significantly associated with lower FA in the right posterior cingulum, left callosal splenium, right inferior fronto-occipital fasciculus, and left fornix crus (six studies; 323 voxels; z = 1.7; P = .001). Impaired cognition was significantly associated with lower FA in the callosal genu, thalamus, right posterior cingulum, and fornix crus (seven studies; largest cluster, 980 voxels; z = 2.5; P < .001).
  
  
  CONCLUSIONS
  WM damage is widespread in MS with differential and only minimally overlapping distributions of low FA that relates to physical disability and cognitive impairment. The higher number of clusters of lower FA in relation to cognition and their higher z scores suggest that cerebral WM damage may have a greater relevance to cognitive dysfunction than physical disability in MS, and that low anterior callosal and thalamic FA have specific importance to cognitive status.
authors.affiliation: From the Departments of Radiological Sciences (T.W., D.K., D.P.A., R.A.D.) and Clinical Neurology (C.S.C.), Division of Clinical Neurosciences, University of Nottingham, Queen's Medical Centre, Derby Rd, Nottingham NG7 2UH, England.
authors.forename: Thomas
authors.initials: T
authors.lastname: Welton
authors.forename: Daniel
authors.initials: D
authors.lastname: Kent
authors.forename: Cris S
authors.initials: CS
authors.lastname: Constantinescu
authors.forename: Dorothee P
authors.initials: DP
authors.lastname: Auer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dineen
mesh_terms: D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009103:Multiple Sclerosis / Q000473:pathology*; D066127:White Matter / Q000473:pathology*