White Matter Damage Is Associated With Matrix Metalloproteinases in Vascular Dementia

Abstract

Background and Purpose —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.