Cerebral amyloid angiopathy (CAA) is a microvascular cerebral cortical abnormality associated with brain aging and Alzheimer's disease (AD), and with non-traumatic intracerebral hemorrhage in elderly and demented patients. Though recognized as one of the microscopic hallmarks of AD for many years, its complications and pathogenesis are poorly understood, especially as it pertains to hemorrhagic stroke and ischemic lesions of the central nervous system (CNS). For example, it has not been ascertained whether CAA is causally or temporally related to other forms of cerebrovascular disease (e.g. atherosclerosis, arteriosclerosis). In this clinicopathologic study utilizing autopsy material in a prospective fashion, we propose to: 1) quantitatively assess topography and severity of CAA in patients with clinical AD, with vascular dementia, with stroke but no dementia, and in controls, using sensitive immunohistochemical and silver stains, 2) look for biochemical parameters in the cerebrospinal fluid (CSF) that might reflect the severity of neocortical CAA, 3) examine the relationship between CAA and atherosclerosis and cerebral arteriosclerosis, and the relationship of each entity or group of entities to ischemic stroke, 4) study mediators of reversibility of in vitro deposition of Alzheimer A4 peptide in CAA- affected microvessels using an extraordinarily sensitive radiolabel binding assay, and 5) examine (using double and single label immunohistochemistry and NADPH-diaphorase histochemistry) possible cellular mechanisms of CAA-related microangiopathy. These studies will provide vital information relevant to understanding the role of CAA in AD and stroke, but more importantly will provide insights into the poorly understood interface between dementias secondary to brain parenchymal disease and those secondary to cerebral cortical ischemia. GRANT-P01AG124359001 The imaging core will coordinate research activities involving MRI and PET data acquired at the participating clinical sites of this proposal. The imaging core defines standardized acquisition protocols for structural and functional images. MRI will be segmented into six volumetric compartments: gray matter, white matter, cerebrospinal fluid, lacunes, infarcts, and white matter signal hyperintensities. Qualitative ratings of images will also be performed. Segmented images will be transformed into standardized stereotaxic coordinate space so that a common language for describing the location of lesions can be maintained across laboratories. In particular, the imaging core will localize MRI lacunes, infarcts, and white matter signal hyperintensities with respect to the standardized stereotaxic coordinate frame. The volume of each lesion can also be determined from the segmentation data. All of the resultant data will be stored in an image repository accessible to all participating centers for hypothesis testing and integration with the central coordinating core. In conjunction with the central core, the imaging core will develop methods for correlating in vivo anatomic and functional imaging data with each patient's postmortem neuropathologic outcome. Thus, the imaging core will provide an overall cohesion of the collection of imaging data, provide image analysis and create a data repository for program wide access to shared information at the different clinical sites. This cohesion will enable the investigators to increase sample sizes, and hence, establish stronger statistical inferences between clinical, neuropathological and imaging measurements in patients with vascular dementia.
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