Rachel L. Nosheny, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): More than 50% of human immunodeficiency virus type 1 (HIV-1) infected individuals experience neurological and psychiatric problems that are collectively termed the AIDS Dementia Complex (ADC). The current global AIDS crisis highlights the need for therapeutic strategies to treat ADC. A wealth of experimental data has implicated glycoprotein gpl20, an HIV-derived envelope protein that facilitates viral entry into cells, in the cell death associated with ADC. Clinical observations of ADC patients, in vitro characterization of cell types vulnerable to gp 120 neurotoxicity, and preliminary in vivo data in our laboratory suggest that basal ganglia dysfunction, especially of the nigro-striatal pathway, is integral to the neurological manifestations in ADC. Neurotrophic factors are naturally occurring proteins that are essential for brain development and maintenance of neuronal populations affected in ADC. The proposed experiments will examine the hypothesis that gp 120 causes cell death in the basal ganglia and that neurotrophic factors can protect against gp 120-mediated cell death. This neuroprotection in turn may limit neurological complications associated with HIV infection in the brain. [unreadable] [unreadable] [unreadable]

PROJECT SUMMARY/ABSTRACT Alzheimer's Disease (AD) is a growing public health threat with no disease-modifying treatments. A major obstacle to providing care and developing new therapeutics is the difficulty identifying those at risk for AD or in an early disease state. Therefore, the development of scalable, accessible screening tools is a critical unmet need in the field and is the overall goal of this work. The Caregiver and Study Partner Portal (CASPP) is an innovative new web-based tool that I built and publically launched to remotely collect cognitive and functional data from a large, diverse cohort of study partner (SP)-participant dyads. The CASPP is part of the Brain Health Registry (BHR), a public online registry created by my primary mentor Dr. Weiner, currently with over 43,000 participants, which captures cognitive, health, and lifestyle data using self-report questionnaires and neuropsychological tests (NPTs). The specific scientific goal of this proposal is evaluate the construct and predictive validity of the CASPP in a diverse cohort of 10,000 SP-participant dyads. Five year longitudinal CASPP data from SPs of clinically-normal (CN), Mild Cognitive Impairment (MCI), and AD older adults will be analyzed to measure associations between online SP-report and in-clinic decline in NPT scores, participant- reported cognitive function, and SP telephone interview. Data from participant-SP dyads co-enrolled in BHR and the Alzheimer's Disease Neuroimaging Initiative (ADNI) or BHR and the Imaging Dementia-Evidence of Amyloid Scanning (IDEAS) study will be used to test whether CASPP data can predict brain ?-amyloid levels and clinical diagnosis. Use of remote SP report for AD screening is a novel concept that requires me to acquire a specialized set of new skills. To conduct this proposed project and prepare me for an independent AD clinical research career, I will gain training in (1) Validation of cognitive and ADL function in older adults, including measuring construct and predictive validity, and measuring function across cognitive domains using NPTs, self-and SP-reported measures; (2) Challenges of conducting clinical AD research, especially participant recruitment/engagement, online patient-reported outcomes, and recruitment of underrepresented minorities; (3) Advanced study design and biostatistical analyses, especially using multivariable predictive modeling and linear mixed effects to study large, complex datasets. I have assembled a team of mentors and advisors who are committed to facilitating my training in these areas, and I have designed a detailed training plan that includes tutorials, hands-on experience with conducting clinical AD research, academic coursework, and relevant seminars. I plan to use the data I collect to obtain an R01 which will expand the CASPP in order to elucidate the role of SP-reported data in assessing cognitive and ADL function of older adults, and test the CASPP as an AD screening tool. These findings are likely to lead to improved methods for AD screening, better dementia healthcare, and, ultimately, accelerated development of new AD treatments.