PATHOLOGICAL ALTERATIONS OF THE CEREBRAL MICROVASCULATURE IN ALZHEIMERS-DISEASE AND RELATED DEMENTING DISORDERS

Alterations of the cerebral microvasculature have been reported in agi ng and in neurodegenerative disorders such as Alzheimer's disease. How ever, the exact role of microvascular alterations in the pathogenesis of neurodegeneration remains unknown. In the present report, the cereb ral cortex microvasculature was studied by immunohistochemistry using a monoclonal antibody against vascular heparan sulfate proteoglycan pr otein core in normal. aging controls, Alzheimer's disease, Down syndro me, Guam amyotrophic lateral sclerosis/parkinsonian dementia complex, Pick's disease and dementia pugilistica. In ah dementing illnesses, in creased microvascular pathology was evident compared to normal control s. Decreased microvascular density and numerous atrophic vessels were the primary abnormalities observed in all dementing disorders. These m icrovascular abnormalities demonstrated regional and laminar selectivi ty, and were primarly found in layers III and V of frontal and tempora l cortex. Quantitative analysis employing computer-assisted microscopy demonstrated that the decrease in microvascular density in Alzheimer' s disease was statistically significant compared to age-matched contro ls. In addition, extracellular heparan sulfate proteoglycan deposits w ere observed which colocalized with thioflavine S-positive senile plaq ues in Alzheimer's disease, Down syndrome and selected Guam dementia c ases. In some cases, heparan sulfate proteoglycan was seen in senile p laques that appeared to be diffuse or primitive plaques that stained w eakly with thioflavine. Heparan sulfate proteoglycan-containing neuron s were also observed in Alzheimer's disease, as well as in Down syndro me and Guam cases. Glial staining for heparan sulfate proteoglycan was never observed. Our data support previous observations that microvasc ular pathology is found in aging and in Alzheimer's disease. The chang es in Alzheimer's disease exceed those found in normal aging controls. We also found microvascular pathology in all other dementing disorder s studied. Our studies further demonstrated that the microvascular pat hology displays regional and laminar patterns which parallel patterns of neuronal loss. Finally we also found that heparan sulfate proteogly can is present in senile plaques and neurons not only as previously re ported in Alzheimer's disease, but also in Down syndrome and Guam case s. Heparan sulfate proteoglycan in senile plaques may be derived from either the degenerating microvasculature or from degenerating neurons. Further studies are necessary to determine the role of microvascular disease in the progression of Alzheimer's disease and other dementing disorders.