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NIH grant 1R01NS147038-01A1: Biological Mechanisms Underlying Progressive Decline Following Geriatric Traumatic Brain Injury
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Andrew Robert Mayer. Award: $690732.
Start: 2026-09-11T00:00:00.
Abstract: Geriatric “mild” traumatic brain injury (gTBI) is a significant and growing public health concern due to the high number of individuals affected each year. A growing body of evidence suggests that a substantial minority (40-50%) of this population experiences progressive post-traumatic decline (i.e., dementia), resulting in poor clinical outcomes for affected individuals. Because progressive decline post-gTBI frequently overlaps with or accelerates Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD), understanding these mechanisms is essential for reducing AD/ADRD burden in older adults. In spite of this dual public health threat, the biological mechanisms underlying poor cognitive and clinical outcomes following gTBI remain relatively unknown, with the majority of the literature focusing on tissue loss (i.e., atrophy). In contrast, post-traumatic pathology of the cerebrovasculature remains grossly understudied following gTBI, despite evidence that it contributes to other secondary injury cascades highly relevant to AD/ADRD. Quantification of the biological mechanisms that contribute to poor outcomes following gTBI represents the necessary first step for future precision-medicine interventions in this high-risk population, and represents an area of interest identified by the ADRD summits. The current study therefore prospectively collects blood-based (within 48 hours of injury, 3-10 days and ~4 months post-injury) and advanced imaging (3-10 days, ~4 months) biomarkers of microstructure changes (Aim 1) and cerebrovascular dysfunction (cerebrovascular reactivity, perfusion, arterial transit time; Aim 2) in 103 gTBI and 64 age, sex and socio-economic status matched geriatric controls (GC). Disruptions to the coupling between the cerebrovascular and bulk CSF flow is further examined as an Exploratory Aim. A comprehensive Common Data Elements battery is collected at 3-10 days, ~4 months and ~1 year post-injury to examine for long-term and progressive changes indicative of AD/ADRD. Rigorously defined (i.e., 10th percentile cutoff) multi-domain clinical outcomes are quantified via reliable change or standardized scores. Extensive preliminary data establishes the feasibility of the proposal in terms of data collection, reasonable patient burden and high retention rates (>80%). Preliminary data also provides evidence of progressive microstructural changes and cerebrovascular dysfunction in the first 4 months post-gTBI that are greater in those individuals who exhibit clinical decline over the same time interval, similar to finding previously observed in other AD/ADRD samples. The current study therefore addresses two critical gaps in the literature regarding a lack of imaging and blood-based biomarker data on post-traumatic cerebrovascular functioning in gTBI, and how microstructural injuries and cerebrovascular impairment contribute to poor clinical outcomes/progressive clinical decline in ways that are mechanistically aligned with AD/ADRD-related neurodegeneration. Our focus on identifying patients with poor outcomes within the first few months of gTBI is consistent with our long-term objective to develop therapies that treat gTBI early in the disease course, when treatments are more likely to be efficacious for combatting AD/ADRD relevant pathological processes and preventing post-traumatic decline.document fetched 2026-09-20 02:42