Pathological basis of diffusely abnormal white matter: insights from magnetic resonance imaging and histology.
BACKGROUND
The pathological basis of diffusely abnormal white matter (DAWM) in multiple sclerosis (MS) has not been elucidated in detail, but may be an important element in disability and clinical progression.


METHODS
Fifty-three subjects with MS were examined with T₁, multi-echo T₂ and magnetization transfer (MT). Twenty-three samples of formalin-fixed MS brain tissue were examined with multi-echo T₂ and subsequently stained for myelin phospholipids using luxol fast blue, for axons using Bielschowsky, immunohistochemically for the myelin proteins myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3' phosphohydrolase (CNP) and for astrocytes using glial fibrillary acidic protein (GFAP). Regions of interest in DAWM were compared with normal appearing white matter.


RESULTS
Fourteen of 53 subjects with MS in the in vivo study showed the presence of DAWM. Subjects with DAWM were found to have a significantly lower Expanded Disability Status Scale (EDSS) and shorter disease duration (DD) when compared with subjects without DAWM (EDSS: 1.5 versus 3.0, p = 0.031; DD: 5.4 versus 10.3 years, p = 0.045). DAWM in vivo had reduced myelin water and MT ratio, and increased T₂ and water content. Histological analysis suggests DAWM, which shows a reduction of the myelin water fraction, is characterized by selective reduction of myelin phospholipids, but with a relative preservation of myelin proteins and axons.


CONCLUSIONS
These findings suggest that the primary abnormality in DAWM is a reduction or perturbation of myelin phospholipids that correlates with a reduction of the myelin water fraction.
Laule
Cornelia
C
Pathology & Laboratory Medicine, University of British Columbia, Vancouver, Canada. claule@physics.ubc.ca
Vavasour
Irene M
IM
Leung
Esther
E
Li
David K B
DK
Kozlowski
Piotr
P
Traboulsee
Anthony L
AL
Oger
Joel
J
Mackay
Alex L
AL
Moore
G R Wayne
GR
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000737:chemistry / Q000473:pathology; D001369:Axons / Q000737:chemistry / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001923:Brain Chemistry; D004185:Disability Evaluation; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000378:metabolism / Q000473:pathology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000378:metabolism / Q000473:pathology*; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins / Q000032:analysis; D010743:Phospholipids / Q000032:analysis; D010727:Phosphoric Diester Hydrolases / Q000032:analysis; D011237:Predictive Value of Tests; D013194:Staining and Labeling; D014157:Transcription Factors / Q000032:analysis; D014867:Water / Q000032:analysis; D055815:Young Adult
D005904:Glial Fibrillary Acidic Protein; C499048:MBP protein, human; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D014157:Transcription Factors; D014867:Water; D010727:Phosphoric Diester Hydrolases; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571337:CNP protein, human