What explains gray matter atrophy in long-standing multiple sclerosis?
OBJECTIVE
To identify the measures of focal and diffuse white matter (WM) abnormalities that are related to whole-brain, deep, and cortical gray matter (GM) atrophy in long-standing multiple sclerosis (MS).


METHODS
The institutional review board approved the study; all subjects gave written informed consent. Magnetic resonance (MR) imaging was performed at 3 T in 208 patients with MS of long-standing duration (disease duration ≥ 10 years) and in 60 healthy control subjects. Normalized GM volume (NGMV), normalized WM volume (NWMV), normalized deep GM volume (NDGMV), cortical thickness, and normalized lesion volume (NLV) were quantified. Tissue integrity of normal-appearing WM (NAWM) and lesions was measured by using diffusion-tensor MR imaging. Multivariate associations between measures of GM atrophy and WM abnormalities were assessed in the patient group by using multiple linear regression.


RESULTS
NGMV, NDGMV, and cortical thickness were reduced in patients with MS (all P < .001). The final model for NGMV consisted of NWMV, NLV, and patient age and sex (adjusted R(2) = 0.58, P < .001). NWMV, NLV, and patient sex were the explanatory variables for NDGMV (adjusted R(2) = 0.75, P < .001). The model for cortical thickness consisted of fractional anisotropy of NAWM, NLV, and patient age and sex (adjusted R(2) = 0.32, P < .001). The relationship between GM atrophy and WM abnormalities was weaker in primary and secondary progressive disease than in relapsing-remitting disease.


CONCLUSIONS
Whole-brain and deep GM atrophy were particularly explained by WM atrophy and lesion volume, while cortical atrophy was associated with NAWM integrity loss. The weaker relationship between GM atrophy and WM abnormalities in patients with progressive disease might indicate a more independent neurodegenerative disease process in these patients.
From the Departments of Radiology and Nuclear Medicine (M.D.S., M.D., F.B., H.V.), Anatomy and Neurosciences (M.D., J.J.G.G.), Physics and Medical Technology (P.J.W.P., H.V.), and Neurology (L.J.B., P.K.T., J.K., B.M.J.U.), Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
Martijn D
MD
Steenwijk
Marita
M
Daams
Petra J W
PJ
Pouwels
Lisanne J
LJ
Balk
Prejaas K
PK
Tewarie
Joep
J
Killestein
Bernard M J
BM
Uitdehaag
Jeroen J G
JJ
Geurts
Frederik
F
Barkhof
Hugo
H
Vrenken
D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology*; D002908:Chronic Disease; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity