COLLABORATIVE NEUROPATHOLOGY NETWORK CHARACTERIZING OUTCOMES of TBI

Established in 2019, CONNECT-TBI is the foundational work of TRANSFORM-TBI launched in 2024. Central to our ongoing research, the CONNECT-TBI archives provide a valuable resource to the international TBI research community.

CONNECT-TBI is a unique, international, multi-center, multi-investigator project. Our goal is to support researchers investigating the pathology of traumatic brain injury (TBI) and its outcomes, including TBI related neurodegeneration (TReND).

As a 'Center Without Wall', CONNECT-TBI brings together a network of expert neuropathologists, clinicians and academics across 13 leading institutions to:

  1. coordinate existing research tissue archives and standardize procedures for new tissue donations
  2. streamline access to these resources and make them available for global research

Established in 2019, CONNECT-TBI is funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA). In 2023, Transdisciplinary Research Accelerating Neuropathology Studies and Facilitating Open Research Methods in TBI (TRANSFORM-TBI) received U-01 funding to build on the work of CONNECT-TBI, accelerating our understanding of acute TBI and the association between TBI and neurodegenerative disease, including Alzheimer’s disease and Alzheimer’s disease related disorders (AD/ADRD).

An overview of the process: The participating brain banks commit their cases to the archive, ship brain tissue to the CONNECT-TBI brain bank where the tissue is stained and scanned. While the contributing brain bank records the clinical data elements associated with each case, the consensus experts review each case to define more conclusively the neuropathological characteristics of a clinical diagnosis. Additionally, the archived brain tissue is available to the broader TBI research community for relevant TReND projects.

BACKGROUND

In the past several decades, there has been increasing awareness of the neuropathological effects of traumatic brain injury (TBI) and their relation to increased risk of a range of neurodegenerative diseases, including Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD).

Intense media attention has focused on the association of repetitive mild TBI within contact sports and increased risk of the specific neurodegenerative pathology of chronic traumatic encephalopathy (CTE). Unfortunately, there has been comparatively little attention paid to the complex of neurodegenerative pathologies that arise after exposure to TBI across the full spectrum of injury mechanisms and severities; this is a complex of pathologies we consider under the more encompassing term TBI-related neurodegeneration (TReND). Furthermore, only a few studies have examined TReND and its relation to the pathologies of aging and wider neurodegeneration, in particular the pathologies of AD/ADRD.

Perhaps the greatest barrier to progress in this field has been the limited amount of suitable human brain tissue. To overcome this, CONNECT-TBI aims to:

  • Establish a comprehensive tissue resource in the research of TBI comprised of both existing material and prospective case material from patients across a wide range of injury sub-types and severities. This will include former athletes across multiple global sports, long-term survivors of mild, moderate, or severe TBI, former military personnel exposed to blast and non-blast TBI, and multiple international, prospective studies in TBI.
  • Characterize the extent, distribution, and range of neuropathologies that occur following exposure to all types and severities of TBI and consider the influence of injury type and survival interval on chronic TBI (cTBI) pathology.
  • Describe the association between extent, distribution, and phenotype of cTBI neuropathology within context with clinical presentations.
  • Contrast cTBI neuropathology with that of aging and wider neurodegenerative disease, including AD/ADRD and investigate the prevalence of cTBI pathology in patients with neurodegenerative disease.
  • Develop a networked archive of biospecimens linked to comprehensive data representing a central point of access to unique tissue resources to support the broader TBI research community.

ADMINISTRATIVE CORE

The CONNECT-TBI program represents a multidisciplinary collaboration uniting 26 internationally regarded experts in TBI and neurodegeneration across 12 leading institutions to deliver a single point of access to an unparalleled research tissue resource. To achieve this, we have developed an administrative strategy to coordinate and manage this strong collaborative team to ensure successful and timely delivery of the overall goals and all scientific, brain banking, budgetary, reporting and governance activities within CONNECT-TBI. Led by Program PIs Drs. Douglas Smith and Willie Stewart as co-directors, the Administrative Core will provide internal and external project oversight and review mechanisms against CONNECT-TBI milestones. The Administrative Core will also work to establish and coordinate tissue archiving and access procedures for external, research led enquiries, including procedures for broad and enduring institutional review and material transfer. To this end, the goals of the CONNECT-TBI Administrative Core are to:

  • Establish multidisciplinary project oversight and review via an Internal Governance Committee and External Advisory Board, with a calendar for meetings and to monitor progress against milestones.
  • Establish network governance procedures, including those to facilitate broad and enduring institutional review and material transfer agreement procedures for the CONNECT-TBI archive.
  • Create the CONNECT-TBI website to: facilitate communication on program achievements; act as the access point for enquiries and tissue applications from external researchers; and as a central and accessible repository for all CONNECT-TBI program generated protocols.

Coordinate management of data transfer from CONNECT-TBI to Federal Interagency TBI Research (FITBIR) Informatics system to enable access of acquired data to the broader TBI research community.

BRAIN BANK CORE

The CONNECT-TBI Brain Bank Core will serve as the coordinating and archiving center for these activities and act as the central histologic processing site to facilitate the multi-institutional neuropathologic study of postmortem central nervous system tissues from patients exposed to TBI, including Expert Consensus Group activities. To achieve this, the activities of the Brain Bank Core will integrate with those of the Administrative and Data Management Cores and the Research Projects within CONNECT-TBI to deliver the overarching aims of the project. To this end, the specific aims of the CONNECT-TBI Brain Bank Core are to:

  • Conduct a census of existing tissue holdings and clinical datasets in collaborating centers to populate a centralized database, generating the CONNECT-TBI research tissue archive.
  • Establish a multi-center, autopsy brain donation network with case accrual from former athletes across multiple global sports, long-term survivors of single mild, moderate or severe TBI, former military personnel exposed to blast and non-blast TBI, and multiple ongoing international prospective studies in TBI.
  • Establish a central TBI histology repository by collecting, staining and whole slide digital scanning sections from well characterized TBI cases.
  • Establish and refine best practice protocols for evaluation of cTBI neuropathologies, including CTE, to facilitate studies by CONNECT-TBI investigators and disseminate these to wider research and diagnostic communities.

Provide post-mortem TBI CNS samples to support Research Projects within CONNECT-TBI and external investigators approved by the Administrative Core.

DATA CORE

The activities of the CONNECT-TBI Data Coordinating Core are designed to capitalize on these opportunities, in response to the pressing need to accelerate our understanding of “TBI-Related Neurodegeneration” (TReND), and in so doing, create a centrally located and shared repository of digital neuropathological data and clinical data to support global studies in TBI, including the research projects proposed under CONNECT-TBI. This will be achieved through harmonization and collation of existing neuropathological and clinical data holdings in TBI across our network of nine leading research centers, and sharing and analyses of these data by CONNECT-TBI investigators and also for investigators in the wider research community. This will be achieved by integrating the activities and site-bridging infrastructure of the Data Coordinating Core with those of the Administrative Core and the Brain Bank Core and the research projects within CONNECT-TBI to deliver the overarching aims of the project. To this end, the specific aims of the CONNECT-TBI Data Coordinating Core are:

  • Develop Common Data Elements (CDEs) and Unique Data Elements (UDEs) for digital neuropathological data and clinical data that will be collected in all CONNECT-TBI center projects.
  • Establish a multi-center, digital neuropathological data and clinical data reporting network with case accrual from each center project.
  • Make the collected neuropathological data and clinical data available by sharing with center site investigators approved by the Administrative Core and by submitting into FITBIR.
  • Establish a central TBI data repository by collecting digital neuropathological data and clinical data from TBI cases and normal controls at each center and posting a library of their holdings.

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