Thomas G. Beach, MD PhD - US grants

Alzheimer's disease (AD) is the major cause of dementia in the elderly. The central pathogenetic step in AD involves metabolism of the beta- amyloid precursor protein (APP), resulting in brain deposition of a cleavage product, the Abeta peptide. There are genetic forms of AD but in the majority of cases, termed sporadic AD, the cause of Abeta deposition is not known. It is hypothesized that Abeta deposition in these cases results from the loss of cortical cholinergic afferents, which is known to occur early in the course of AD and also in normal aging. Cell culture work suggests that cholinergic neurotransmission shifts APP metabolism into a non-amyloidogenic pathway and therefore protects against Abeta accumulation. Supporting this concept, it has been found that immunotoxin-induced cortical cholinergic denervation results in cerebral Abeta deposition in rabbits. The proposed studies would exploit this animal model, which uses a monoclonal antibody against the p75 neurotrophin receptor, coupled to saporin, a toxin, to specifically lesion the neurons of the nucleus basalis of Meynert, which are the source of the cortical cholinergic innervation. Specific Aim #1 would determine the time course and tissue distribution of Abeta appearance and deposition. Specific Aim #2 would determine to what extent Abeta deposition is specifically dependent on cholinergic mechanisms. Control, non- cholinergic denervating lesions will be assessed for induction of Abeta deposition. These will include immunotoxin-induced cortical noradrenergic denervation and ibotenic acid-induced thalamocortical denervation. Cholinergic therapy, using both physostigmine, a acetylcholinesterase inhibitor, and xanomeline, a muscarinic agonist, will be given to attempt to reverse or prevent Abeta deposition. Specific Aim #3 will determine whether the cortical vasculature is innervated by cholinergic fibers and whether that innervating is lost in the animal model or in AD. This could lead to impaired cerebral vasoregulation and increased susceptibility to ischemia, further compromising cortical function in AD.

The Neuropathology Core is an essential part of the ADCC. The clinical syndromes generated by Alzheimer's disease (AD) and other neurodegenerative disorders associated with aging are not, of themselves, pathognomonic diagnostic phenomena. Neuropathological examination of the post-mortem brain is therefore the only means by which a definite diagnosis can be attained. A second major role of the Neuropathology Core is to provide neuropathologically characterized brain tissue to basic scientists, both within the ADCC and outside it, enabling them to discover the underlying molecular mechanisms of disease and design appropriate therapeutic interventions. A detailed understanding of the genetic and molecular processes of disease pathogenesis, obtained by comparative study of diseased and non-diseased brain tissue, remains the major approach to finding such interventions. A third important goal of the Neuropathology Core is to help develop a collaborative synergy that will enhance the research productivity of the entire Center. Our Specific Aims are as follows: 1) To provide precise neuropathologic diagnoses of patients who have been clinically studied. 2)To provide basic scientists with neuropathologically characterized brain tissue suitable for the elucidation of the molecular mechanisms of AD and related disorders. 3) To share neuropathological skills, expertise and knowledge with all ADCC investigators, facilitating a collaborative synergy that will enhance the research productivity of all. 4) To optimize usage of collected neuropathologic data within the ADCC and the scientific community at large. 5) To assist researchers in the study of the earliest stages of Alzheimer's disease, with the goal of identifying therapeutic strategies that will prevent the disease or slow its progress.

DESCRIPTION (provided by applicant): Parkinson's disease (PD) and related Lewy body disorders (LBD), including incidental Lewy body disease (ILDB), Alzheimer's disease with Lewy bodies (ADLB) and dementia with Lewy bodies (DLB) may affect up to 40% of the elderly population. Current FDA-approved therapies for PD are still based on neurochemical deficits discovered more than 40 years ago. Experimental model-systems and molecular genetics research since that time, while contributing exponentially to the knowledge base, have not converted this work into new approved agents. Renewed and intensified human tissue-based research may help break this stalemate. Essential to such studies, however, is the availability of high quality diseased and normal control tissue with maximal preservation of molecular entities and detailed clinical characterization. The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute is uniquely suited to fill this critical need, as demonstrated by its 20 years of operation and a median 2.8 hour postmortem interval (PMI) for the entire collection of 1,200 brains. Other unique features include a focus on normal aging, comprehensive standardized antemortem cognitive, motor and non-motor assessments and the accompanying donation of bodily organs. The BBDP has the proven capability of serving as a national resource. In the most recent 5 year period it has supported 91 different researchers located in 20 different states, collectively holding 126 NIH grants. There is no other brain bank in the US or world with these unique capabilities. This proposal would enable the BBDP to become a powerful resource for researchers focused on PD and related disorders. The Specific Aims are directed at supporting a major expansion of service to researchers investigating PD and other LBDs. To accomplish this, resource availability will be publicized, additional staff will be hired and a web portal will be developed so that external researchers may search for and request tissue as well as linked clinical data. Steering and Resources Committees with external investigator representation will manage the resource and evaluate requests, allowing the BBDP to supply between 50 and 100 LBD-focused research projects over the five year funding period.

PROJECT SUMMARY/ABSTRACT ? NEUROPATHOLOGY CORE The Neuropathology Core is an essential part of the Alzheimer's Disease Core Center (ADRC). During life, the signs and symptoms of Alzheimer's disease (AD) are not sufficiently different from several other conditions, resulting in misdiagnosis, even at the most advanced centers, in 25% or more of subjects, when newly developed imaging and biofluids biomarkers are not used. Even with such biomarkers, the presence of concurrent and clinically significant major pathologies is rarely detected. Examination of the brain after death by an experienced Neuropathologist allows the Center's research results to be appropriately interpreted. This is particularly important for our Center's overarching theme, to provide the resources needed to establish the accuracy of emerging blood-based biomarkers (BBBs) in the diagnosis of AD and related dementias (ADRD) and use them to detect, track, and study preclinical AD, including in persons from diverse backgrounds, and to find an effective AD prevention therapy by 2025. A second major role of the Neuropathology Core is to provide an extensive resource of rapidly autopsied, neuropathologically and molecularly characterized tissue for researchers inside and outside of Arizona, enabling them to discover the underlying molecular mechanisms of disease and design appropriate therapeutic interventions. A detailed understanding of the genomics and related molecular processes of disease pathogenesis, obtained by comparative study of diseased and non-diseased brain tissue is critical to finding such interventions. A third important goal of the Neuropathology Core is to support the Arizona ADRC's overarching theme and address National Alzheimer's Project Act (NAPA) Implementation Milestones. Our Specific Aims: 1) To provide comprehensive neuropathological assessments and extremely precise neuropathologic diagnoses in ADRC Clinical Core and Affiliated Brain and Body Donation Program (BBDP) research participants who donate their brains after they die. 2) To provide an extensively shared resource of rapidly autopsied, high-quality neuropathologically characterized brain tissue and other body tissues for researchers to advance the study of AD/ADRD, support the study of molecular mechanisms, and therapeutic targets, including in those with AD and a wide range of ADRDs as well as cognitively unimpaired persons with and without preclinical AD. 3) To provide an extensively shared resource of ADRC and organizationally supported annual blood samples, neuropathological diagnoses, and data to help researchers inside and outside of Arizona evaluate promising BBBs for AD/ADRD in neuropathologically characterized brain donors by providing neuropathological validation of blood samples acquired in the last 1-2 years of life. The last aim is intended to support the role of BBBs in the diagnosis and preclinical detection, tracking and study of AD, the inclusion of under-represented Hispanic/Latino, Native American and other under-represented minority groups, help find an effective AD prevention therapy by 2025, and help fulfill National Alzheimer's Project Act (NAPA) goals.

Abstract With increasing longevity in our population, dementia is widely recognized as an impending public health crisis. Lewy body dementia (LBD), encompassing dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), is the second most common cause. LBD is characterized by abnormal aggregation and accumulation of a protein, ?-synuclein (aSyn). PDD and DLB are clinically separated only by the relative timing of the onset of parkinsonism and dementia. At present, advances in the treatment of these conditions are critically hampered by the lack of non-invasive, inexpensive biomarkers that can provide accurate diagnostic and prognostic information. This situation may soon be resolved, as in recent years it has become apparent, through our own studies and those of others, that biopsies of peripheral tissue sites can detect diagnostically significant aSyn. Our project will assess aSyn in punch biopsies of the skin. Our preliminary data from new ?seeding assay? methods including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), from autopsy-confirmed LBD subjects, indicate high sensitivity and specificity for predicting the presence of aSyn in the skin of affected subjects. Further work is necessary to confirm these results in living subjects with these conditions, which is the objective of this proposed project. We will biopsy, twice during a four year period, 90 subjects with aSyn disease, 30 each with PD, PDD and DLB, as well as 30 normal control subjects. Two independent laboratories will blindly perform separately-developed seeding assays, rigorously testing the interlaboratory reliability and providing estimates of aSyn density change over time. The seeding assay results will be compared with those obtained by the current gold-standard biopsy method, immunohistochemistry (IHC). All subjects will receive cognitive and movement disorder assessments at two timepoints in this four year project, enabling comparisons of assay measures with cognitive and motor decline rates. Many of the subjects will be enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study with an autopsy rate exceeding 90%. This will allow, in a substantial subset, eventual neuropathological confirmation of the molecular cause of parkinsonism and dementia in each subject.