White matter damage is associated with matrix metalloproteinases in vascular dementia.
OBJECTIVE
Vascular disease causes multi-infarct dementia (MID) or Binswanger's disease (BD), the latter of which is a progressive form of vascular dementia (VaD) associated pathologically with fibrinoid and hyaline changes in brain arterioles with injury to the white matter. Clinically, BD patients have long-standing hypertension with disturbances of gait and intellect. Because matrix metalloproteinases (MMPs) are important in cerebral infarction, we hypothesized that disturbances in the MMPs may be involved in VAD:


METHODS
Brain tissues from 5 patients with VaD of the BD or multi-infarct type (MID) were immunostained with antibodies to glial fibrillary acidic protein (GFAP), a microglial/macrophage cell marker (PG-M1), gelatinase A (MMP-2), stromelysin-1 (MMP-3), and gelatinase B (MMP-9). Control tissues were from 8 elderly patients: 4 with strokes without dementia and 4 without neurological diseases.


RESULTS
PG-M1+ cells appeared around infarcts in patients with strokes without dementia and in patients with VAD: In 2 of the 3 BD patients, PG-M1 cells were prominent near damaged arterioles and scattered diffusely in white matter. MMP-2 was seen normally in perivascular macrophages and in astrocytic processes near blood vessels and was present in patients with strokes in reactive astrocytes. MMP-9 was rarely seen. MMP-3 was seen in PG-M1+ microglial/macrophage cells around the acute infarctions. In BD, MMP-3 persisted in tissue macrophages and disappeared in long-standing white matter gliosis.


CONCLUSIONS
These observations suggest that MMPs may participate in the damage to the white matter associated with VAD: Microglia/macrophage-induced damage, which is amenable to treatment, may be a factor in the progressive forms of VAD:
Rosenberg
G A
GA
Department of Neurology, University of New Mexico, Albuquerque 87131, USA. grosenberg@salud.unm.edu
Sullivan
N
N
Esiri
M M
MM
D000368:Aged; D000943:Antigens, Differentiation / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015140:Dementia, Vascular / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000201:enzymology* / Q000473:pathology*
D000943:Antigens, Differentiation; D005904:Glial Fibrillary Acidic Protein; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9