Alzheimer's Disease Center Pilot 1: NELTNER

Beta-amyloid peptide (Aâ) deposition is a universal feature in Alzheimer’s disease (AD) brains. Neuropathologic, genetic, and clinical data have led to the “amyloid cascade hypothesis”, the predominant hypothesis regarding the pathogenesis of AD. However, the link between diffuse Aâ deposits (or diffuse plaques, DPs) and the cognitively impairing pathologies of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) remains elusive. The full natural history of DPs has yet to be delineated although there are biomarker modalities that assess brain and CSF Aâ . We believe that this is a crucial question with intuitive relevance to clinical diagnostics. Quantitative neuropathology has been shown by the UK Alzheimer’s Disease Center (UK-ADC) workers to be important for research and clinical applications. However, due to technical limitations, quantification of AD neuropathology is usually only performed using semi-quantitative rubrics. At the UK-ADC, extensive counts of these pathologies by painstaking visual inspection of modified Bielschowsky stains have been performed for multiple sections in hundreds of autopsy cases. However such quantification is not standardized and cannot be assessed or compared across institutions and would be difficult to expand to other modalities. We propose to take quantified neuropathology to a new level with the use of the Aperio ScanScope and its companion software. We will use this technology to test a key hypothesis related to the natural history of diffuse plaques. Aim #1: Stain 400 cases with PHF-1 and beta-amyloid antibodies and use the Aperio ScanScope and associated software to quantitate NFTs, NPs, and total beta-amyloid load in specific cortical areas of AD and control subjects. Correlate the results to the values within the existing quantitative database. This will by itself be ground-breaking work for quantitative assessment of AD-type neuropathology and will establish the protocol by which anyone can quantitate AD-type pathology. Aim #2: Examine different DP parameters within a specific subset of ADC patients (namely having high DP counts but low NFT and NP counts) and compare them to those seen in both similar patients with low DP counts as well as patients with definite AD pathology. These parameters would include but not be limited to: total amyloid burden, plaque morphology, size, location, and density. Aim #3: Use the ScanScope image analyses program to test the following hypothesis: more dense compact plaques will be seen in cases of AD, especially with those having severe cerebral artery angiopathy; alternatively the ill-defined fluffy plaques will occur in those without AD type changes. These experiments would be publishable and we feel would also be directly linked to future possible NIH grant proposals.