Researchers from the Brain Injury Research Center of Mount Sinai have been awarded $8.3 million from the National Institutes of Health (NIH) to investigate the clinical and biological features that distinguish chronic, static effects of traumatic brain injury from those associated with progressive, post-traumatic neurodegeneration.
According to the Centers for Disease Control and Prevention, 2.5 million people in the United States sustain a traumatic brain injury (TBI) each year, not including those injuries treated in outpatient/urgent care or military settings, or those experienced by people who do not seek care. For decades, TBI has been regarded as one of the strongest environmental risk factors for dementia, and for Alzheimer's disease in particular. TBI may also confer risk for other Alzheimer's-related dementias. Therefore, the long-term effects of TBIs are of increasing public health importance as the U.S. population ages.
"While understanding the long-term implications of TBI is of critical importance, very little is actually known about the clinical and pathological signatures of post-TBI neurodegeneration or its overlap with Alzheimer's disease and related dementias," said Kristen Dams-O'Connor, PhD, Director of the Brain Injury Research Center of Mount Sinai. "Most epidemiological studies define TBI using medical claims data that are available only for a brief portion of the lifespan, or studies use unvalidated self-report measures that lack detail about injury characteristics. Alzheimer's disease and related dementias are often defined by algorithms that code acute and/or chronic-static effects of TBI as dementia or infer TBI/dementia relationships based solely on the temporal order of diagnoses. These studies combine into one category the chronic stable TBI impairments with subsequent post-traumatic neurodegeneration, ignoring other relevant risk factors and erroneously assuming that post-traumatic neurodegeneration fits neatly into Alzheimer's disease and other existing dementia categories."
To address these gaps in knowledge and advance scientific knowledge of TBI-related neurodegeneration, through this new grant, researchers from the Brain Injury Research Center of Mount Sinai will leverage existing NIH-funded research infrastructure to define the risk factors and clinical and biological signatures of post-traumatic neurodegeneration, while creating rich data resources to share with the scientific community.
The Late Effects of TBI (LETBI) study was first funded by the NIH in 2014, and additional funding in 2019 supports longitudinal follow-up of individuals with TBI who enrolled in this prospective brain donor program. Participants complete cognitive assessments, mood questionnaires, motor evaluations, neuroimaging, and blood draws every 2-3 years, and they make known their wishes for brain donation upon death. Since 2019, the LETBI study has studied individuals with TBI at Mount Sinai, Massachusetts General Hospital, and the University of Washington. This new $5 million NIH grant will allow the LETBI project to expand to include four additional sites: Spaulding Rehabilitation Network, based in Massachusetts; Indiana University; the Kessler Foundation; and New York University. All of these sites, like Mount Sinai and the University of Washington, are designated by the National Institute of Disability Independent Living and Rehabilitation Research (NIDILRR) as TBI Model Systems of Care. With this new NIH funding, the team will enroll into the LETBI study more than 200 individuals who have been followed prospectively from the time of injury through TBI Model Systems research protocols for at least five years post-injury. By leveraging the research infrastructure of the NIDILRR-funded TBI Model Systems, this cohort will have excellent characterization of TBI acute care and post-acute functional trajectories prior to entering the LETBI study.
Specific aims of this research project include:
- Identifying head trauma exposure thresholds associated with post-traumatic neurodegeneration risk. Many people sustain a TBI and recovery completely, with no long-term consequences; others experience progressive decline over time. It is not known what patterns or types of TBI exposure may initiate or accelerate a neurodegenerative process.
- Examining post-traumatic neurodegeneration in a life course framework to elucidate early life environmental factors associated with risk and resilience. TBI is just one of many things a person may experience that can increase risk for dementia. Early-life stressors, trauma, and pre-injury health conditions can all influence risk for post-TBI decline but have not yet been investigated in a life course epidemiology framework.
- Identifying fluid and imaging biomarkers to define the underlying pathology(ies) of post-traumatic neurodegeneration. Clinical measures developed using advanced psychometric methods are capable of detecting even subtle changes in cognition and neurobehavioral function. By collecting longitudinal MRI scans and blood draws concurrently with these clinical measures, quantifying biological markers that change in parallel to these clinical metrics can shed light on pathological processes that may be driving clinical decline.
- Seeking post-mortem validation of the in vivo biomarkers of post-traumatic neurodegeneration in the LETBI autopsy cohort. The gold standard for diagnosing neurodegenerative disease is brain autopsy. In this prospective brain donor program, any candidate biological markers identified during life can be validated in postmortem brain tissue.
"The implications of TBI for Alzheimer's disease and related dementias are of great public concern, and more research is needed," said Dr. Dams-O'Connor. "Our strong, interdisciplinary team is ideally positioned to take on this challenge. We will leverage resources that have taken years to develop and combine those resources with optimized clinical tools, precision molecular biomarkers, novel imaging methods, neuropathological innovations, and sophisticated statistical methods to improve our knowledge about late effects of TBI and post-traumatic neurodegeneration, thereby advancing the research agenda of the National Alzeimer's Disease Project Act and sharing rich data resources in service of accelerated post-TBI dementia diagnostics and therapeutics."
