PTND PATH FORWARD study: PTND Pathologies and Trajectories of Functional Outcomes With comparison to other ADRDs

About This Grant

PROJECT SUMMARY The long-term objective of this K99/R00 proposal is to provide Dr. Amelia Hicks with the expertise and skills to become an independent investigator studying the intersection of traumatic brain injury (TBI) and Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD). Her career goals are to advance the clinicopathological understanding of post-traumatic neurodegeneration (PTND), explore how diverse biological and environmental factors influence risk and resilience for PTND, and develop personalized interventions that improve long-term outcomes for TBI survivors. The proposed work is strongly aligned with the National Plan to Address Alzheimer’s disease (NAPA), which has identified research at the intersection of TBI and AD/ADRD as a key priority and highlighted the importance of cross-training in these fields to break down research siloes that impede scientific progress. In the K99 phase, Dr. Hicks will complete targeted training activities to address key gaps required to achieve her career goals. Her training objectives are to: (1) become a leader in TBI and PTND proteomics, (2) improve understanding of high level biostatistical analysis, (3) acquire knowledge of TBI and PTND neuropathology and post-mortem tissue analysis, and (4) develop strong professional skills to support transition to independence. This career development will take place within the exceptional research environment of the Brain Injury Research Center at the Icahn School of Medicine at Mount Sinai. The short-term research objective of this K99/R00 is to identify and validate the pathological and multi-domain clinical signatures of PTND. To achieve this, Dr. Hicks will use blood-based proteomic data from the Atherosclerosis Risk in Community Study (ARIC) to identify PTND-associated proteins (K99; Aim 1). Then, using multi-domain (cognitive, neurobehavioral, motor) clinical data she will identify PTND clinical phenotypes and compare clinical trajectories in PTND and ADRD (K99; Aim 2). For the independent R00 phase she will leverage the Late Effects of TBI Study (LETBI) to examine the ARIC PTND-associated proteins in blood and post-mortem brain tissue. She will also identify combinations of multi-domain clinical outcome and compare to ARIC PTND clinical phenotypes (R00; Aim 3). These findings will provide invaluable preliminary data for future research efforts including a novel and competitive R01 submission. The knowledge gained from this project will produce clinically meaningful outcomes of highest importance to patients and families by 1) characterizing clinical signatures of PTND to facilitate clinical diagnosis and prognosis, and 2) advancing pathological disease definition required to identify novel treatments for PTND. Together, the K99/R00 training and research activities will establish Dr. Hicks as one of the only investigators with cross-disciplinary knowledge of neuropsychology, proteomics, and neuropathology, complemented by advanced biostatistics training and professional skills ready to lead impactful, clinically meaningful PTND research as an independent faculty member.