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. 2016 Jan;131(1):75-86.
doi: 10.1007/s00401-015-1515-z. Epub 2015 Dec 14.

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy

Ann C McKee  1   2   3   4   5 , Nigel J Cairns  6 , Dennis W Dickson  7 , Rebecca D Folkerth  8 , C Dirk Keene  9 , Irene Litvan  10 , Daniel P Perl  11 , Thor D Stein  12   13   14   15 , Jean-Paul Vonsattel  16 , William Stewart  17 , Yorghos Tripodis  13   18 , John F Crary  19 , Kevin F Bieniek  7 , Kristen Dams-O'Connor  20 , Victor E Alvarez  21   12   13   14 , Wayne A Gordon  20 ; TBI/CTE group
Collaborators, Affiliations

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy

Ann C McKee et al. Acta Neuropathol. 2016 Jan.

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies.

Keywords: Brain trauma; Chronic traumatic encephalopathy; Neurodegenerative disorders; Tauopathy; Traumatic brain injury.

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Figures

Fig. 1
Fig. 1
Low magnification inspection of p-tau-stained slides often revealed the irregular spatial pattern of CTE pathology. AT8-stained slides of cerebral cortex in 3 cases of CTE showing irregular patches of p-tau pathology most dense at the depths of the sulci
Fig. 2
Fig. 2
The microscopic features of the pathognomonic lesion of CTE. The pathognomonic feature of CTE is a perivascular accumulation of p-tau aggregates in neurons, astrocytes and cell processes in an irregular spatial pattern in the cerebral cortex and found preferentially at the depths of the sulci. a A large perivascular p-tau lesion is found at the sulcal depths in a subject with CTE. b–f Multiple perivascular foci are often found in the cortex in CTE. g The p-tau aggregates in CTE include strikingly rounded structures in the neuropil that often are most dense in the areas surrounding the vessel. h The rounded p-tau immunoreactive cell processes are more densely distributed than those found in argyrophilic grain disease. All sections immunostained for AT8, bars indicate 100 µm, except in g and h where the small bars indicate 10 µm
Fig. 3
Fig. 3
Hippocampal pathology in CTE. Examples of hippocampal pathology in 2 cases of CTE of moderate severity. In example 1 (a–f), there is a mild hippocampal atrophy, b mild neuronal loss in CA1, c sparse NFTs in CA1, Bielschowsky silver stain, d sparse NFTs in CA1, AT8 immunostain, e moderate numbers of diffusely immunopositive AT8 stained neurons in CA4, and f occasional AT8 immunopositive NFTs in the dentate gyrus. In example 2 (g–l), there is g more severe hippocampal atrophy, h clear neuronal loss in CA1, i moderate density of NFTs in CA1, Bielschowsky silver stain, j moderate density of NFTs in CA1, AT8 immunostain, k high numbers of AT8-stained neurons and NFTs in CA4, and l moderate numbers of AT8 immunopositive NFTs in the dentate gyrus. Bars indicate 100 µm
Fig. 4
Fig. 4
pTDP-43 pathology in CTE. a pTDP-43 neuronal inclusions in the amygdala. b p-TDP-43 inclusions and dot-like neurites in CA1. c p-TDP-43 dot-like neurites in entorhinal cortex. d pTDP-43 inclusions and dot-like neurites in the dentate granule cell layer. All sections immunostained for p-TDP-43, bars indicate 100 µm
Fig. 5
Fig. 5
Age-related p-tau astrogliopathy that may be present. a and b. Subpial p-tau immunopositive astrocytes may be found at the glial limitans in the sulcal depths but are non-specific and non-diagnostic for CTE (asterisks). c However, p-tau immunopositive subpial astrocytes accompanied by perivascular foci of p-tau positive neurons and astrocytes (arrowhead) at the depths of the sulci are diagnostic for CTE. d and e p-Tau immunopositive astrocytes surrounding small venules in the deep white matter of the temporal lobe are not diagnostic for CTE and are often found in association with aging [22]. f p-Tau positive astrocytes may also be found in the crests of the white matter of the frontal and temporal lobes with aging and other conditions that are not diagnostic for CTE [22]. All sections immunostained for AT8, bars indicate 100 µm
Fig. 6
Fig. 6
Minimum recommended brain regions for evaluation for CTE. The following sections from the NIA-AA blocking scheme are recommended for p-tau immunostaining in evaluation for CTE (blue rectangles). In the cortical sections (blocks 1–5, 12, 13), the depths of the cortical sulci should be included in the section. 1 Middle frontal gyrus, 2 superior and middle temporal gyri, 3 inferior parietal lobule, 4 hippocampus, 5 amygdala and entorhinal cortex, 6 basal ganglia at level of anterior commissure with basal nucleus of Meynert, 7 thalamus, 8 midbrain with substantia nigra, 9 pons with locus coeruleus, 10 medulla oblongata, 11 cerebellar cortex and dentate nucleus; additional sections if high suspicion of CTE (red rectangles): 12 superior frontal gyrus, 13 temporal pole, 14 hypothalamus and mammillary body
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