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

Smith, Douglas H.; Dollé, Jean-Pierre; Ameen‐Ali, Kamar E.; Bretzin, Abigail C.; Cortés, Etty; Crary, John F.; Dams-O’Connor, Kristen; Edlow, Brian L.; Folkerth, Rebecca D.; Hazrati, Lili‐Naz; Hinds, Sidney; Iacono, Diego; Johnson, Victoria E.; Keene, C. Dirk; Kofler, Julia; Kovács, Gábor G.; Lee, Edward B.; Manley, Geoffrey T.; Meaney, David F.; Montine, Thomas J.; Okonkwo, David O.; Perl, Daniel P.; Trojanowski, John Q.; Wiebe, Douglas J.; Yaffe, Kristine; McCabe, Thomas; Stewart, William

doi:10.1186/s40478-021-01122-9

Cited by 14 publications

(13 citation statements)

References 31 publications

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“…Further studies are also required to better determine the relative contribution of neuronal and astrocytic tau to the pathognomonic lesion of CTE-NC, how to conceptualize the subset of cases that almost meet criteria for CTE-NC, and to address age-related and Alzheimer’s disease coexisting neuronal tau pathology in this context. The COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI) initiative 95 has been established to address these issues, among others, and will provide an international multi-institutional effort to fill these knowledge gaps.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of chronic traumatic encephalopathy in the Sydney Brain Bank

McCann

Bahar

Burkhardt

et al. 2022

Brain Communications

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Chronic traumatic encephalopathy neuropathologic change can only be definitively diagnosed post-mortem. It has been associated with repetitive mild neurotrauma sustained in amateur and professional contact, collision, and combat sports, although it has also been documented in people with a single severe traumatic brain injury and in some people with no known history of brain injury. The characteristic neuropathology is an accumulation of perivascular neuronal and astrocytic phosphorylated tau in the depths of the cortical sulci. The tau-immunopositive neurons and astrocytes that are considered pathognomonic for chronic traumatic encephalopathy are morphologically indistinguishable from Alzheimer-related neurofibrillary tangles and aging-related tau astrogliopathy, respectively, although they are found in different spatial distributions throughout the cortex. The Sydney Brain Bank collection consists of neurodegenerative diseases and neurologically normal controls. We screened 636 of these cases for chronic traumatic encephalopathy neuropathologic change. A subset of 109 cases had a known history of traumatic brain injury. Three cortical regions were screened for the presence of neuronal and astrocytic phosphorylated tau according to the current 2021 National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus criteria for chronic traumatic encephalopathy. Five cases (0.79%) showed pathological evidence of chronic traumatic encephalopathy and three of these had a history of traumatic brain injury. Three cases had coexisting Alzheimer’s and/or Lewy body disease pathology meeting criteria for neurodegenerative disease. Another eight cases almost met criteria for chronic traumatic encephalopathy neuropathological change except for an absence of neuronal tau or a strict perivascular arrangement. Aging-related tau astrogliopathy was found in all eight cases as a co-existing neuropathology. Traumatic brain injury was associated with increased odds (OR 1.79, CI 1.18-2.72) of having a higher neurofibrillary tangle stage and phosphorylated TDP-43 (OR 2.48, CI 1.35-4.54). Our study shows a very low rate of chronic traumatic encephalopathy neuropathological change in brains with or without neurodegenerative disease from the Sydney Brain Bank. Our evidence suggests that isolated traumatic brain injury in the general population is unlikely to cause chronic traumatic encephalopathy neuropathologic change but may be associated with increased brain aging.

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Section: Discussionmentioning

confidence: 99%

Prevalence of chronic traumatic encephalopathy in the Sydney Brain Bank

McCann

Bahar

Burkhardt

et al. 2022

Brain Communications

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“…There is a long history of epidemiological evidence that TBI represents one of the strongest environmental risk factors for several progressive neurodegenerative disorders of cognitive impairment and dementia that are characterized by the pathological accumulation of hyperphosphorylated tau (p-Tau). In particular, TBI has been linked to Alzheimer’s disease (AD) and a unique clinicopathological entity termed chronic traumatic encephalopathy (CTE) [ 8 , 17 , 29 , 46 , 66 , 67 ]. Yet, the exact mechanism(s) driving pathological tau accumulation and spread, cognitive impairment, and dementia after TBI are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: characterization of a novel model and systematic review of the literature

Kahriman

Bouley

Smith

et al. 2021

acta neuropathol commun

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Traumatic brain injury (TBI) constitutes one of the strongest environmental risk factors for several progressive neurodegenerative disorders of cognitive impairment and dementia that are characterized by the pathological accumulation of hyperphosphorylated tau (p-Tau). It has been questioned whether mouse closed-head TBI models can replicate human TBI-associated tauopathy. We conducted longitudinal histopathological characterization of a mouse closed head TBI model, with a focus on pathological features reported in human TBI-associated tauopathy. Male C57BL/6 J mice were subjected to once daily TBI for 5 consecutive days using a weight drop paradigm. Histological analyses (AT8, TDP-43, pTDP-43, NeuN, GFAP, Iba-1, MBP, SMI-312, Prussian blue, IgG, βAPP, alpha-synuclein) were conducted at 1 week, 4 weeks, and 24 weeks after rTBI and compared to sham operated controls. We conducted a systematic review of the literature for mouse models of closed-head injury focusing on studies referencing tau protein assessment. At 1-week post rTBI, p-Tau accumulation was restricted to the corpus callosum and perivascular spaces adjacent to the superior longitudinal fissure. Progressive p-Tau accumulation was observed in the superficial layers of the cerebral cortex, as well as in mammillary bodies and cortical perivascular, subpial, and periventricular locations at 4 to 24 weeks after rTBI. Associated cortical histopathologies included microvascular injury, neuroaxonal rarefaction, astroglial and microglial activation, and cytoplasmatic localization of TDP-43 and pTDP-43. In our systematic review, less than 1% of mouse studies (25/3756) reported p-Tau using immunostaining, of which only 3 (0.08%) reported perivascular p-Tau, which is considered a defining feature of chronic traumatic encephalopathy. Commonly reported associated pathologies included neuronal loss (23%), axonal loss (43%), microglial activation and astrogliosis (50%, each), and beta amyloid deposition (29%). Our novel model, supported by systematic review of the literature, indicates progressive tau pathology after closed head murine TBI, highlighting the suitability of mouse models to replicate pertinent human histopathology.

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“…Slides were then collated into three sets, each of 21 or 22 slides, for distribution and scoring. Nine neuropathologists with experience in the neuropathological assessment of neurodegenerative disease and co-investigators on the Collaborative Neuropathology Network Characterising Outcomes of TBI (CONNECT-TBI) programme [ 44 ] participated in assessing these digital slide sets for pathology (RF, LNH, DI, CDK, JK, GGK, AN, DPP, DSP). Participating neuropathologists were blinded not only to case related information (such as demographics, original integrated diagnosis) for each slide, but also to the antibody used and the primary aims of study.…”

Section: Methodsmentioning

confidence: 99%

Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change

Ameen‐Ali

Bretzin

Lee

et al. 2022

acta neuropathol commun

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Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer’s disease neuropathologic change (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC.

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

Cited by 14 publications

References 31 publications

Prevalence of chronic traumatic encephalopathy in the Sydney Brain Bank

Prevalence of chronic traumatic encephalopathy in the Sydney Brain Bank

Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: characterization of a novel model and systematic review of the literature

Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change

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