Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer's disease patients

Background and Purpose: The underlying cause of white-matter lesions, which are frequent findings in cerebrovascular disease (CVD) and Alzheimer's disease (AD), remains uncertain. We performed immunohistochemical analysis of serum protein extravasation to investigate the function of the blood-brain barrier in white-matter lesions. Methods: White-matter lesions were estimated by use of Kluver-Barrera staining in patients diagnosed clinicopathologically as having ischemic CVD (n=14) and AD (n=12) and from nonneurological control subjects (n=6). Axonal damages were investigated by use of immunohistochemistry for amyloid protein precursor. Alteration of the blood- brain barrier was examined with fibrinogen and immunoglobulins used as markers. The numbers of HLA-DR-positive microglia and glial fibrillary acidic protein-positive astroglia were examined comparatively. Results: White- matter lesions were graded as normal (grade 0) in 14 of the 32 cases (44%), slight (grade I) in 10 cases (31%), moderate (grade II) in 6 cases (19%), and severe (grade III) in 2 cases (6%). Amyloid precursor protein was accumulated most frequently in grade II white-matter lesions. Immunohistochemistry for serum proteins labeled astroglial cell bodies and their processes, which seemed to have sequestered extravasated proteins. The groups with detectable white-matter lesions had significantly higher grading scores for fibrinogen and immunoglobulins than the control group (P<.05). Although the higher scores for serum protein extravasation were statistically significant in ischemic CVD cases (P<.05), there was no significant increase in AD cases. Activated microglia and astroglia were more numerous in the groups with white-matter lesions in both ischemic CVD and AD cases, although this increase in the number of astroglia was not evident in regions with clasmatodendrosis. Conclusions: Dysfunction of the blood-brain barrier is more prominent in white-matter lesions seen in ischemic CVD than in AD and may have a role in the pathogenesis of cerebrovascular white-matter lesions.