Case Reports

. 2021 Mar 1;9(1):32.

doi: 10.1186/s40478-021-01122-9.

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI)

Douglas H Smith¹, Jean-Pierre Dollé², Kamar E Ameen-Ali³, Abigail Bretzin⁴, Etty Cortes^{5

6

7}, John F Crary^{6

7}, Kristen Dams-O'Connor^{8

9}, Ramon Diaz-Arrastia¹⁰, Brian L Edlow^{11

12}, Rebecca Folkerth¹³, Lili-Naz Hazrati^{14

15

16}, Sidney R Hinds^{17

18}, Diego Iacono¹⁹, Victoria E Johnson², C Dirk Keene²⁰, Julia Kofler²¹, Gabor G Kovacs^{22

23}, Edward B Lee²⁴, Geoffrey Manley^{25

26}, David Meaney^{27

28}, Thomas Montine²⁹, David O Okonkwo³⁰, Daniel P Perl³¹, John Q Trojanowski³², Douglas J Wiebe⁴, Kristine Yaffe³³, Thomas McCabe³⁴, William Stewart^{35

36}

Affiliations

¹ Center for Brain Injury and Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. smithdou@pennmedicine.upenn.edu.
² Center for Brain Injury and Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK.
⁴ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Pathology, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
⁶ Neuropathology Brain Bank and Research Core, Ronald M. Loeb Center for Alzheimer's Disease, Departments of Pathology and Neuroscience, Icahn School of Medicine, New York, NY, USA.
⁷ Department of Pathology, Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
⁸ Department of Rehabilitation Medicine, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
⁹ Department of Neurology, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
¹⁰ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
¹¹ Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, 175 Cambridge Street - Suite 300, Boston, MA, USA.
¹² Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
¹³ Department of Forensic Medicine, New York University School of Medicine, New York, NY, USA.
¹⁴ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁶ Canadian Concussion Center, Toronto, ON, Canada.
¹⁷ Brain Tissue Repository and Neuropathology Core, Center for Neuroscience and Regenerative Medicine (CNRM), Uniformed Services University (USU), Bethesda, MD, USA.
¹⁸ Chronic Effects of NeuroTrauma Consortium (CENC), Fort Detrick, MD, USA.
¹⁹ The Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), Bethesda, MD, USA.
²⁰ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
²¹ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²² Tanz Centre for Research in Neurodegenerative Disease (CRND) and Department of Laboratory Medicine and Pathobiology, University of Toronto, Krembil Discovery Tower, 60 Leonard Ave, Toronto, ON, Canada.
²³ Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
²⁴ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Neurological Surgery, University of California San Francisco, 505 Parnassus Ave, Rm M779, San Francisco, CA, USA.
²⁶ Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, Bldg. 1, Rm 101, San Francisco, CA, USA.
²⁷ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
²⁹ Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA.
³⁰ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
³¹ DoD/USU Brain Tissue Repository and Neuropathology Core, F. Edward Hébert School of Medicine, Uniformed Services University (USU), Bethesda, MD, USA.
³² Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³³ Department of Neurology, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
³⁴ School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK.
³⁵ Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK. william.stewart@glasgow.ac.uk.
³⁶ Department of Neuropathology, Queen Elizabeth University Hospital, 1345 Govan Rd, Glasgow, G51 4TF, Queen, UK. william.stewart@glasgow.ac.uk.

PMID: 33648593
PMCID: PMC7919306
DOI: 10.1186/s40478-021-01122-9

Case Reports

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI)

Douglas H Smith et al. Acta Neuropathol Commun. 2021.

. 2021 Mar 1;9(1):32.

doi: 10.1186/s40478-021-01122-9.

Authors

Affiliations

¹ Center for Brain Injury and Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. smithdou@pennmedicine.upenn.edu.
² Center for Brain Injury and Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK.
⁴ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Pathology, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
⁶ Neuropathology Brain Bank and Research Core, Ronald M. Loeb Center for Alzheimer's Disease, Departments of Pathology and Neuroscience, Icahn School of Medicine, New York, NY, USA.
⁷ Department of Pathology, Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
⁸ Department of Rehabilitation Medicine, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
⁹ Department of Neurology, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
¹⁰ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
¹¹ Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, 175 Cambridge Street - Suite 300, Boston, MA, USA.
¹² Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
¹³ Department of Forensic Medicine, New York University School of Medicine, New York, NY, USA.
¹⁴ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁶ Canadian Concussion Center, Toronto, ON, Canada.
¹⁷ Brain Tissue Repository and Neuropathology Core, Center for Neuroscience and Regenerative Medicine (CNRM), Uniformed Services University (USU), Bethesda, MD, USA.
¹⁸ Chronic Effects of NeuroTrauma Consortium (CENC), Fort Detrick, MD, USA.
¹⁹ The Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), Bethesda, MD, USA.
²⁰ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
²¹ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²² Tanz Centre for Research in Neurodegenerative Disease (CRND) and Department of Laboratory Medicine and Pathobiology, University of Toronto, Krembil Discovery Tower, 60 Leonard Ave, Toronto, ON, Canada.
²³ Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
²⁴ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Neurological Surgery, University of California San Francisco, 505 Parnassus Ave, Rm M779, San Francisco, CA, USA.
²⁶ Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, Bldg. 1, Rm 101, San Francisco, CA, USA.
²⁷ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
²⁹ Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA.
³⁰ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
³¹ DoD/USU Brain Tissue Repository and Neuropathology Core, F. Edward Hébert School of Medicine, Uniformed Services University (USU), Bethesda, MD, USA.
³² Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³³ Department of Neurology, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
³⁴ School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK.
³⁵ Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK. william.stewart@glasgow.ac.uk.
³⁶ Department of Neuropathology, Queen Elizabeth University Hospital, 1345 Govan Rd, Glasgow, G51 4TF, Queen, UK. william.stewart@glasgow.ac.uk.

PMID: 33648593
PMCID: PMC7919306
DOI: 10.1186/s40478-021-01122-9

Abstract

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

Keywords: Chronic traumatic encephalopathy; Concussion; Dementia; Neurodegenerative disease; Traumatic brain injury.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Schematic of CONNECT-TBI program

**Fig. 2**
Outline of workflow, highlighting case submission, remote digital microscopy and expert consensus group review with all sites examining the same scanned section

**Fig. 3**
Process for research tissue sharing. (1) Researcher contacts Administrative Core in project planning phase to establish whether suitable resources within CONNECT-TBI networked archive are available to support their proposal. (2) Application submitted to Scientific Review Board for approval. (3) Following project approval by Scientific Review Board, CONNECT-TBI provides specific case numbers and institution contact details to researcher thereby initiating transfer

**Fig. 4**
Representative images of pathology of illustrative case. Fenestration of the septum pellucidum (a). Cortical pTau in neurons and glia consistent with neurofibrillary tangles of Alzheimer’s disease neuropathologic change and astrocytic pathology of aging-related tau astrogliopathy (b, e; PHF-1), with abundant neurofibrillary tangles also present in hippocampal sector CA1 (d; PHF-1). In addition, frequent neuritic amyloid plaques and cerebral amyloid (arrowhead) were present (c; 6f3d). Elsewhere, numerous cytoplasmic inclusions immunoreactive for phospho-TDP-43 were identified in the dentate granule cell layer (f; 1D3). Within the substantia nigra numerous classical Lewy bodies were present (G; arrow), with frequent cortical Lewy bodies revealed in staining for alpha-synuclein (h; KM51)

See this image and copyright information in PMC

References

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COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI)

Affiliations

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Research Materials