Alzheimer's disease (SDAT) is the fourth most common cause of death in the U.S. affecting over 2 million people. It represents 60% of all cases of senile dementia, but no specific diagnostic test for it, short of brain biopsy, is available to avoid misdiagnosis of treatable dementias. Of SDAT patients 92% have been found at autopsy to have cerebrovascular amyloidosis (Congophilic angiopathy). These fibrillar vascular deposits are presumed to have a deleterious effect by making incompetent the blood-brain barrier. It is suggested that they may, therfore, be causal in the pathogenesis of the neurofibrillary tangles and neuritic plaques characteristic of SDAT. The proposed research is directed at determining the chemical nature of the cerebrovascular amyloid fibrils in this condition by isolation, solubilization, fractionation and analytical methods, e.g. amino acid sequence analysis, previously utilized by the applicant to define the protein composition of the fibrils in acquired systemic """"""""primary"""""""" amyloidoses. Utilization of these methods should define the fibril protein chemically, but may not elucidate its origin. Monoclonal antibodies raised to the fibril protein will be employed in double immunodiffusion, radioimmunoassay and immunohistochemical techniques to determine the fibril proteinis/ origin and to quantitate the level of the protein precursor in tissue and body fluids for potential diagnostic purposes. These antibodies will also be employed for immunoabsorbant chromatography to isolate the fibril precursor protein (presumed to be of serum origin) and to characterize it chemically. These studies will determine the mechanism of fibril formation, e.g. if a lysosomal defect in the endothelial processing of the fibril protein precursor causes the amyloid deposits. Evidence of either a cerebrovascular enzymic defect in processing of the fibril precursor or the existence of a protein synthetic abnormality may lead to therapeutic approaches to arrest the course of SDAT. The recent finding of cerebrovascular amyloidosis, in addition to plaques and tangles, in 100% of Down's syndrome adults may indicate that they may be a predictable model for SDAT. Therefore, the above studies will also be performed on tissues and body fluids from such Down's cases. The uniqueness of this investigation is that it focuses on the amyloid angiopathy of SDAT in order to determine the nature of the amyloid fibril protein and its pathogenesis, but more importantly it has the potential to define a specific diagnostic serum test for SDAT and to lead directly to an understanding of its etiology and pathogenesis.
| Miller, Michael I; Priebe, Carey E; Qiu, Anqi et al. (2009) Collaborative computational anatomy: an MRI morphometry study of the human brain via diffeomorphic metric mapping. Hum Brain Mapp 30:2132-41 |
