Robert S. Wilson, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): The overall goal of the proposed study is to identify the neurobiologic mechanisms underlying the association of psychological distress with dementia in aged humans. Recent research has shown that measures of psychological distress are related to risk of dementia and rate of cognitive decline but not with common age-related neuropathology associated with cognitive impairment (e.g., tau positive tangles, cerebral infarction). Based on a long history of mainly animal research, we hypothesize that psychological distress leads to neurodegenerative, stress hormone receptor, and neurotrophic changes in limbic structures that mediate the stress response and memory function, making the brain more vulnerable to common age-related pathology and increasing the likelihood that such pathology will be clinically expressed as dementia. The proposed study will take advantage of clinical and post-mortem data, and brain tissue, from older persons participating in the Religious Orders Study, all of whom agreed to annual detailed clinical evaluation and brain donation at the time of death. On post-mortem examination, we propose to quantify in three limbic regions neurons and dendrites, mineralocorticoid and glucocorticoid receptors, and the expression of brain-derived neurotrophic factor and its receptor and to examine their association with measures of psychological distress, dementia and cognitive function measured proximate to death. We then propose to examine the association of these post-mortem limbic indices with post-mortem indices of common age-related pathology (i.e., amyloid deposition, tangle formulation, cerebral infarction, Lewy bodies) and test the hypotheses that the post-mortem indices of limbic structure (i) mediate the association of psychological distress with incidence of dementia and level of cognition measured proximate to death and (ii) increase the likelihood that common age-related pathology is expressed clinically as dementia or cognitive impairment proximate to death. [unreadable] [unreadable] [unreadable]

Summary Over 90% of Alzheimer's disease (AD) patients suffer from behavioral and psychological symptoms of dementia (BPSD) including agitation, aggression, depression, apathy and psychosis. BPSD can present at almost any stage of AD, and in some patients, these symptoms can even appear before dementia develops. The severity of BPSD increases significantly with disease progression, and affects the quality of life of both patients and their caregivers. In many patients, BPSD is the main reason for institutionalization. However, the mechanisms underlying BPSD are not known, and there is no specific treatment strategy available. Although BPSD presents differently in each patient, the presence of certain symptoms in a patient make the co-occurrence of other symptoms more likely. In an ongoing collaboration with Rush Alzheimer's Disease Center, we have developed a method for clustering the symptoms of BPSD into four domains (affective, hyperactivity/disinhibition, psychosis and apathy). Based on these domains, we then conducted an RNA-seq and found different gene expression profiles in AD patients with and without BPSD. This evidence supports the notion that distinct molecular pathways may be involved in the appearance of BPSD. In this proposal, we hypothesize that individual BPSD domains in patients with AD are due to definable perturbations in molecular pathways and that these pathways can be analogized in AD mouse models, allowing for a causal investigation of the relationship between specific pathway alterations and domain behaviors. We will test this hypothesis through both human study and animal work. For the human study, 1) we will expand on our behavioral analyses by increasing subjects for pre-mortem clinical assessments and defining BPSD trends over time in AD patients. 2) Within each behavioral domain, we will employ RNA-seq to investigate gene expression patterns in different brain sub-regions that are unique to each BPSD domain and the gene expression pattern will be compared across normal, MCI and AD subjects. 3) Finally, we will identify which pathways are most clearly associated with each of the BPSD domains using bioinformatics and biochemical analyses. For the animal model work, 1) we will characterize how mouse behaviors analogous to human BPSD symptoms evolve during AD-like neuropathgenesis progression 2) We will identify the most promising molecular candidates for intervention from our RNA-seq findings using these AD/BPSD models. 3) Finally, we will determine whether altering these pathways leads to changes in BPSD-like behavior using virally mediated genetic manipulations (AAV9/CRISPR-Cas9). Overall, this project will establish a translational pipeline by associating BPSD symptom domains with molecular alterations in human AD patients, and by demonstrating that manipulations of these pathways can cause BPSD-like behaviors in transgenic mouse models of AD. These data-driven approaches will lead to a better understanding of the molecular mechanisms that underlie BPSD in AD and potentially identify novel targets for future therapeutic interventions.