Pathways Relating Amnestic MCI to a Mild Traumatic Brain Injury History (PATH)

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PROJECT ABSTRACT: The objective of this NIA K23 proposal is to support my continued scientific growth towards becoming an independent translational, interventional neuropsychologist. Alzheimer’s clinical syndrome (ACS) involves amnestic mild cognitive impairment (aMCI), a stage preceding dementia, and has multiple risk factors. Traumatic brain injury (TBI) is one significant risk factor that remains poorly understood. An earlier onset of ACS has been linked to a TBI history, and my group published one of the first theoretical mechanistic models that posited biological changes involved in Alzheimer’s disease and related dementias (ADRD) may be increased from TBI. While moderate and severe TBI have a well-established link to ACS, it is unclear if mild TBI (mTBI), the most common TBI type, has a similar relationship. More information is needed to determine if biological changes in ACS, and possibly ADRD, might relate to mTBI. Such information can be generated from biomarker probing. The recent advent of high definition transcranial direct current stimulation (HD-tDCS) and blood-derived biomarker tools provide sophisticated new methods to probe biomarkers, specifically neural circuit integrity and neuronal injury/inflammation. To accomplish my career development and research goals, we have created a comprehensive training plan to develop new skills to probe biomarkers of neural circuit integrity and neuronal injury/inflammation to inform if biological changes in ACS relate to a history of mTBI. Through the K23, I will gain new knowledge about biological changes in ADRD and TBI, different fluid-based biomarker approaches, multiple noninvasive brain stimulation methods, translational research, leadership/ governance, and scientific networking. Training will include mentorship, didactic coursework, hands-on experiences, and the scientific study. The mentoring team is an interdisciplinary group of leaders with expertise in ADRD, TBI, noninvasive brain stimulation, biomarkers, neurobehavioral research design, and academic career development. The scientific study’s overarching hypothesis is that the risk for aMCI associated with mTBI will manifest as reduced HD-tDCS-measured neural circuit integrity and elevated blood biomarkers of neuronal injury/inflammation. The proposal will leverage the UT Southwestern Alzheimer Disease Center to enroll adults with aMCI. Aim 1 will determine if neural circuit integrity involved in verbal episodic memory in aMCI is reduced based on a history of mTBI by using a within-subjects design to apply three HD-tDCS conditions. Aim 2 will determine if key blood-derived markers of neuronal injury/inflammation in aMCI are elevated based on having an mTBI history. The K23 proposal will provide essential data and first-authored publications to prepare my first NIA R01, enable me to independently design clinical/translational research that incorporates biomarkers, and position me to achieve my overall career goal of informing the biological mechanisms linking onset of ACS, and potentially ADRD, to a history of TBI. Once these goals have been achieved, I will utilize the new insights to explore potential therapeutic interventions later in my career.