In recent years, there has been a resurgence of both research and public interest in the long-term consequence of TBI, particularly as it relates to neurodegeneration, dementia and Chronic Traumatic Encephalopathy (CTE). Epidemiological data suggest that a history of traumatic brain injury (TBI) is a significant risk factor for Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD) and that the relative risk may be mediated by injury severity and frequency with increased severity and multiple insults resulting in higher risk. Frequency and severity of injury also contribute to the heterogenous expression of chronic static TBI-induced neurocognitive and neuropsychiatric sequelae. For example, more severe injuries often result in long-term static neurocognitive impairments that contribute to overall disability. However, the lack of selective and sensitive tools to differentiate the chronic static TBI-induced sequelae from progressive neurocognitive dysfunction can confuse the risk of dementia following TBI. Similarly, while TBI likely incurs risk for multiple progressive neurodegenerative paths, neither the diagnostic tools nor biomarkers exist to distinguish the potential risk for any specific neurodegenerative path. To date, the best characterized association may be the relationship between frequency of brain injury with CTE, though diagnostics for CTE in living persons remain underdeveloped which hampers progress in this area. Advancing diagnostics of TBI-related neurodegeneration and associated cognitive impairment, including CTE, through the discovery and validation of novel and existing tools has the potential to improve understanding of TBI’s contribution to risk for specific dementias which could lead to improved clinical care and patient stratification in future clinical trials.
In 2012, the National Institute for Neurological Disorders and Stroke (NINDS) held the Report on the Neuropathology of Chronic Traumatic Encephalopathy Workshop that outlined research strategies and resources needed to fill knowledge gaps for advancing understanding of CTE including identifying CTE in living individuals and neuropathology. Discussion of identifying CTE in living individuals suggest that there may be multiple disease progression trajectories that may reflect distinct pathological processes related both to “dosing” of brain injury (a combination of both frequency and severity of exposure to head impacts and/or explosive blast) and patient-specific vulnerabilities. A primary recommendation from this workshop was the need to develop diagnostics for CTE in living persons. They concluded that the development of diagnostics should include neuroimaging, biofluid biomarker, clinical outcome assessments (COAs), and genetic susceptibility investigations into individuals with possible and probable CTE. While this workshop focused on CTE, the knowledge gap for understanding the association between a history of TBI exposure and risk for dementia is parallel and similarly understudied.
In 2011, the National Alzheimer’s Project Act (NAPA) allocated resources “to prevent and effectively treat Alzheimer’s by 2025.” Since then, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held multiple research summits to assess the needs and opportunities relevant to this goal for Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). In particular, the NINDS has convened expert panels in 2013 and again in 2016 that were tasked with recommending research priorities for advancing the state-of-the-science for all ADRDs, including those due to multiple neuropathological mechanisms (i.e., Multiple Etiology Dementias–MED, and Vascular Contributions to Cognitive Impairment and Dementia (VCID), Including Vascular Cognitive Impairment and Vascular Dementia). Recommendations for MED emphasized the need to describe quantitatively the clinical synergies between different etiologies and identify molecular pathways that accelerate cognitive dysfunction or that protect cognition that are agnostic to specific pathologies, i.e., that might act on mechanisms of cell death or synaptic dysfunction common to more than one neurodegenerative process. Recommendations for VCID emphasized investigations of the contributions of additional risk factors for AD, including diabetes/metabolic syndrome, obesity, lipid metabolism, hypertension, diet, exercise, sleep head injury, and aging, on cerebrovascular function.
Specific Research Objectives
Applications to this FOA will be expected to discover and develop biological and clinical measures of TBI-related progressive neurodegeneration and cognitive decline associated with increased risk for dementia including traumatic encephalopathy syndrome (TES) (clinicopathologic diagnostic counterpart to the neuropathological diagnosis of Chronic Traumatic Encephalopathy (CTE)). Results are expected to inform dementia risk prognoses for patients with history of TBI, using objective clinical and pathophysiologically relevant biological measures. Addressing this goal will require (1) enhanced, validated methods for assessing individual’s lifetime exposure to TBI (across varying levels of frequency, severity, and time since injury), (2) accounting for chronic but non-progressive neurocognitive impairment following TBI, and (3) access to an existing longitudinal cohort with a history of TBI exposure and / or dementia cohort with measures of TBI-exposure history. Applicants to this FOA are expected to assess hypothesis-driven objective biological measures and clinical assessments of progressive neurodegeneration, neurocognitive impairment, and neuropsychiatric dysfunction that, in persons with a history of exposure to TBI, may catalyze pathological pathways associated with AD / ADRD and TES. Biological measures may include but are not limited to neuroimaging (such as CT, MRI and PET imaging), vascular reactivity, assessments of sleep, oculomotor and vestibular function, blood-based biomarkers, proteomics, transcriptomics, metabolomics, biofluid markers from samples of CSF and saliva, and known genetic markers of dementia risk.
To address the heterogeneity of post-TBI clinicopathology and extend the generalizability of results, applications to this FOA are expected to recruit both male and female participants with history of TBI across multiple injury severities. These individuals may include former athletes from a variety of sports but should not be limited to the recruitment of or enrich recruitment primarily with former American-rules Football players. To ensure maximal value of this project, a critical feature of this FOA includes the broad sharing of clinical, neuroimaging, physiological, and biospecimen data through the Federal Interagency TBI Research (FITBIR) database.
Areas of interest include but are not limited to:
- Advanced imaging studies, including high field MRI scans, tau-radioligand and/or other PET studies aimed at defining the regional distribution and other characteristic features of TBI-related neurodegeneration and TES.
- Qualitative and quantitative clinical assessment of the progression of the TBI-related neurodegeneration over a 2 – 3 year period in symptomatic individuals considered to be at high risk for TES.
- Evaluation of the utility of various established neuroimaging and other surrogate markers used for clinical diagnosis of dementia for understanding increased risk of dementia and TES in persons with a history of exposure to TBI.
- Investigation of how TBI-related changes in sleep and metabolism may affect cerebrovascular function associated with cognitive impairment.
- Developing blood-based biological measures for assessing relative risk for neurodegenerative diagnosis in individuals with medical history of varying TBI severity and frequency.
- Investigation of the effect of age at time of injury for developing TBI-related neurodegeneration and TES including individuals with late-life TBI.
- Investigation of genetic and epigenetic mediators of dementia and TES risk in patients with a history of TBI exposure.
- Qualitative and quantitative assessment of TBI-related autonomic dysregulation associated with progressive cognitive decline.
Studies not responsive under this FOA include but are not limited to:
- Studies using non-human animal models.
- Studies of primary or secondary injury acutely following TBI.
- Studies that use male former American-rules football athletes as their primary means of recruitment enrichment.
The study team should include expertise in TBI and expertise necessary to diagnose neurodegenerative disorders and recruit and follow a relevant study cohort. In addition, the multidisciplinary team should be able to collect and analyze high quality data such as MRI and PET, genetics, cognitive tests, CSF and blood biomarkers. The study must include relevant TBI Common Data Elements and comply with the data sharing policies of the FITBIR Informatics System as outlined in NOT-NS-17-029.
Common Data Element Use and Data Sharing
It is expected that applications will incorporate the NINDS Core TBI common data elements (CDEs), other appropriate CDEs in the NINDS TBI CDE set, and the Global Unique Identifier (GUID) server supported by NINDS and NIA. Studies are also expected to use NINDS CDEs for both outcome and non-outcome measures (including, but not limited to demographics, medical and injury history, history of abusive injury, family history, medications, neuroimaging, rehabilitation strategy, and standardized outcome assessments) as described by the NINDS CDE Project. Compiling the broad array of CDEs that may be necessary to accomplish the goals of this FOA may require searching across NINDS CDE Disease areas (e.g., TBI, Parkinson’s Disease, Epilepsy, Headache, and Huntington’s Disease). When appropriate biospecimen collection and processing should follow procedures outlined in the NINDS CDE program (see “Studies Involving Biospecimens” section below).
In order to advance the goal of widespread data sharing, investigators funded under this FOA are required to share all data collected in this FOA via FITBIR. FITBIR staff will work with investigators to assist with data harmonization to the NINDS CDE program and the FITBIR Data Dictionary that is based on the NINDS CDE program. For answers to frequently asked questions and how to contact FITBIR, please see: https://fitbir.nih.gov/content/contact-us.
As the research strategy is prepared, it is important to note that NINDS believes applications will be greatly strengthened if the rigorous design, execution, and interpretation of the proposed studies and supporting data are adequately described. NINDS encourages investigators, whenever possible, to address these elements directly in their applications. Investigators are urged to discuss these issues with Scientific/Research staff prior to submission of applications (see:NOT-NS-11-023andNOT-OD-15-103). The NINDS also expects that applications will conform to the principles outlined inLandis et al., 2012and show consideration for biological variables described inNOT-OD-15-102.
Imaging Based Studies
Applications proposing to include neuroimaging approaches are expected, where appropriate, to align with the NINDS neuroimaging CDEs. To optimize widespread data sharing, whenever possible, imaging sequencesshould align with existing large federally-funded TBI cohort studies (e.g., TRACK-TBI, NCAA/DoD CARE Consortium, Chronic Effects of Neurotrauma Consortium (CENC), Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE)).
Studies Involving Biospecimens
Applications proposing to collect biospecimens must use NINDS Biomarkers Repository BioSpecimen Exchange for Neurological Disorders (BioSEND) protocols and procedures, and all specimens collected and banked with BioSEND must come from individuals who have consented to banking and sharing broadly with academia and industry.
Note that costs for collection are NOT included as a component of the NINDS Biomarkers Repository award. Therefore, most costs for the biospecimen banking are borne by the grantees utilizing this resource (see NOT-NS-15-046) Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NINDS Biomarkers Repository website for more information about samples banked at the repository (https://www.biosend.org). In addition, applicants are advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email:firstname.lastname@example.org).
Deadline: March 15, 2019 (letters of intent); April 15, 2019 (full proposals)
Filed Under: Funding Opportunities