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White matter damage is associated with matrix metalloproteinases in vascular dementia
G A Rosenberg1, N Sullivan, M M Esiri
1Department of Neurology, University of New Mexico, Albuquerque 87131, USA. grosenberg@salud.unm.edu
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:
Insights
Matrix metalloproteinases (MMPs) may contribute to white matter damage in vascular dementia (VaD). Microglia and macrophages play a role in progressive VaD, suggesting potential therapeutic targets for this condition.
Area of Science:
- Neurology
- Pathology
- Biochemistry
Background:
- Vascular dementia (VaD), including Binswanger's disease (BD), is linked to vascular issues and white matter injury.
- Binswanger's disease is characterized by hypertension, gait, and intellectual disturbances.
- Matrix metalloproteinases (MMPs) are implicated in cerebral infarction, prompting investigation into their role in VaD.
Purpose of the Study:
- To investigate the potential involvement of matrix metalloproteinases (MMPs) in the pathogenesis of vascular dementia (VaD).
- To examine the expression and localization of specific MMPs and microglial/macrophage markers in brain tissues from VaD patients.
Main Methods:
- Immunohistochemical staining of brain tissues from 5 VaD patients (BD or multi-infarct dementia [MID]) and 8 controls.
- Antibodies used included those for glial fibrillary acidic protein (GFAP), PG-M1 (microglial/macrophage marker), MMP-2, MMP-3, and MMP-9.
- Comparison of marker expression in VaD tissues versus control tissues from elderly individuals with and without neurological diseases.
Main Results:
- Microglial/macrophage cells (PG-M1+) were observed around infarcts and, in BD patients, near damaged arterioles and in white matter.
- MMP-2 showed normal localization in perivascular areas and reactive astrocytes in stroke patients.
- MMP-3 was found in microglial/macrophage cells around acute infarcts and persisted in macrophages in BD, while disappearing in chronic gliosis.
Conclusions:
- Matrix metalloproteinases (MMPs) appear to contribute to white matter damage in vascular dementia (VaD).
- Microglia/macrophage-mediated damage is suggested as a factor in progressive forms of VaD.
- These findings indicate potential therapeutic targets for progressive VaD.