NIH – Neuropathological Assessment of TBI-related Neurodegeneration and Neurocognitive Decline – Center Without Walls (NATBI CWOW) (U54 Clinical Trial Not Allowed)

March 12, 2019 by School of Medicine Webmaster

Both traumatic brain injury (TBI) and exposure to repeated head impacts can result in a chronic TBI-related (cTBI) syndrome that manifest as a heterogeneous combination of symptoms across multiple domains, including but not limited to, the cognitive, behavioral, oculomotor, vestibular, disrupted sleep, psychosocial, and affective domains. Data from the CDC and National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) have shown that cTBI may negatively affect a person’s quality of life and increase risk of seizures, accidental drug poisoning, infections, pneumonia, and decrease life expectancy.  Further, there has been a resurgence of both research and public interest in the neuropathological consequence of cTBI, particularly as it relates to risk of Alzheimer’s Disease and Alzheimer’s Disease related dementia (ADRD), and Chronic Traumatic Encephalopathy (CTE). In 2012, the National Institute for Neurological Disorders and Stroke (NINDS) convened the Neuropathology of Chronic Traumatic Encephalopathy Workshop that outlined research strategies and resources needed to fill knowledge gaps for advancing understanding of CTE including neuropathology.  Following this workshop, the NIH launched a major effort to define the pathologic characteristics of CTE, supporting a set of CTE Neuropathological Diagnosis Consensus Conferences to develop consensus guidelines for the pathological diagnosis of CTE.  The investigators enumerated multiple unaddressed issues including the role of comorbid neurogenerative disease including AD and ADRD, characterization of other proteinopathies involved in CTE (e.g. TDP-43, beta amyloid, vascular dysfunction, and alpha-synuclein positive lewy bodies), a need for neuropathological differential diagnoses, understanding of the effect of brain injury exposure to neurodegeneration, and clinical correlates to disease burden.

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).  Recommendations for MED emphasized the need for improved and early antemortem diagnosis, as well as the need for more basic research to understand risk factors that may lead to the initiation of multiple neuropathological processes and pathologies.

Specific Research Objectives and Requirements:

Research proposed in response to this FOA should seek to comprehensively characterize the neuropathological features of cTBI associated with neurodegeneration and neurocognitive decline, describe associations between neuropathological burden (presence and severity of any single or multiple pathologies) and antemortem clinicopathologic symptoms, and outline the prevalence of cTBI-related parkinsonism, cTBI-related Alzheimer’s, and CTE in the participating brain banks.  A comprehensive characterization should include identification of 1) microscopic changes, including proteinopathies (tau, beta-amyloid, alpha-synuclein, TDP-43), inflammation, gliosis, and neuronal loss, as well as 2) macroscopic changes, including vascular pathology, hemorrhage, and cortical and white matter atrophy. When present, abnormal protein deposition should lead to identification of the specific pathological protein isoforms.

To assess the relationship between postmortem cTBI neuropathological burden and antemortem clinicopathology, applicants will need to propose methods to assess the antemortem symptomatology and clinical presentation including degree of cognitive impairment, memory dysfunction, psychiatric symptoms and neuromotor deficits.  Each CWOW application should propose hypotheses aimed at the relationships among TBI exposure (including repetitive head impacts, single and multiple traumatic brain injuries (TBIs) across TBI severity), length of survival after injury, co-morbidities (e.g. post-traumatic epilepsy), neuropathological burden, and risk for neuropathological dementia diagnoses.  Finally, to outline the prevalence of cTBI-related parkinsonism, cTBI-related Alzheimer’s, and CTE applicants should have access to two or more existing brain banks with extensive collections of AD or ADRD diagnosed tissue.  Each brain bank should specialize in collecting tissue related to a different AD/ADRD so that neuropathological comparisons can be made across a range of disorders.  The aggregate tissue inventory across these brain banks must include an extensive collection of AD or ADRD diagnosed tissue, CTE diagnosed tissue, and tissue from person’s with a history of TBI.

To achieve this goal, it is expected that a multi-site, multidisciplinary team with expertise in 1) the long-term clinical and pathophysiological consequence of TBI and head impact exposure, 2) clinical assessment of dementia, including CTE and 3) neuropathological diagnosis of neurodegenerative disease, including CTE, will be needed.

All centers will be expected to develop a publicly available digital library of pathology slides and associated diagnoses.  This digital library should be hosted by the Federal Interagency Traumatic Brain Injury Research (FITBIR) informatics platform and should include high resolution digital images of all slides evaluated by the CWOW research projects. The CWOW will also be expected to make tissue collected and used by this CWOW available for broad data sharing either through a CWOW brain bank resource or via the NIH Neurobiobank.

Non-responsive studies include:

  • Studies that primarily use of prospective designs for tissue acquisition.
  • Studies limited to only one TBI severity.
  • Preclinical research studies using animal models.
Special Consideration

Required components:

Each application must have an Administrative Core, Data Coordinating Core, Brain Banking Core, and at least three Research Projects. The Research Projects must interact and synergize with other projects and cores within the NATBI CWOW.  Synergy must be evident among research projects and core, such that successful completion of the aims could not be accomplished without the Center structure.

Administrative Core: The Program Director(s)/Principal Investigators (PD/PIs) should serve as the lead(s) of this Core. The Administrative Core should coordinate the integration and management of activities within the CWOW including management of reporting, establishing milestones, organizing communications among sites, and resolving disputes.

Data Coordinating Core: The Data Coordinating Core (DCC) must provide a data management plan capable of coordinating and curating data collected across all NATBI CWOW research projects. The DCC will be responsible for data submission and the creation of the digital pathology library into the FITBIR informatics platform.  The end goal of the data management plan should be to develop a resource of clinical and neuropathological data for the broader scientific community.

Brain Banking Core: The Brain Banking Core (BCC) must provide resources to house and process the post-mortem brain tissue sufficient to support the needs of the projects.  To provide consistency among centers the BCC will be responsible for histological processing of all post-mortem tissue needed for the projects. If previously collected pre-mortem brain tissue will be used, clear details on how the specimens were processed and stored must be provided.  For any newly collected samples, applicants are encouraged to follow protocols established the NINDS Neuropathological CTE Consensus Conference for biospecimen collection, blocking, staining and storage.

Research Projects: Any combination of at least three research projects can be used to address the list of research areas of interest.

As the research strategy is prepared, it is important to note that NINDS seeks applications wherein 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-11-023 and NOT-OD-15-103). The NINDS also expects that applications will conform to the principles outlined in Landis et al., 2012 and show consideration for biological variables described in NOT-OD-15-102. PCS-EMA CWOW applications deemed not responsive to the FOA will be withdrawn without review.

Milestones: All projects should be supported by a timeline and yearly milestones for completion. Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative criteria for success.  Achievement of milestones will be evaluated by NINDS, and funding of non-competing award years will depend on milestone accomplishment.  Note that these awards will be managed as cooperative agreements; therefore, projects that do not comply with terms, conditions, and established milestones of the award and of this program may be terminated early.

Deadline:  April 15, 2019 (letters of intent due 30 days prior to deadline)


Filed Under: Funding Opportunities