The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including 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," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.

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

FIGURE 1.

Diagnostic lesions of chronic traumatic encephalopathy (CTE) in 4 cases. (A–D) Pathognomonic CTE lesions in 4 cases immunolabeled by the anti-phosphorylated tau antibody AT8. (A) 25-Year-old former collegiate football player (CTE stage II, case #23). The CTE focus appears neuronal and composed of perivascular NFTs and dotlike neurites surrounding a small cerebral blood vessel. Glial tau pathology is not immediately evident. (B) A 27-year-old former professional football player (CTE stage II, case #15). The CTE focus is neuronal and composed of perivascular NFTs and dotlike neurites surrounding a small cerebral blood vessel. (C) A 40-year-old former professional football player (CTE stage III, case #14). The CTE focus is neuronal and astrocytic, and composed of p-tau-immunoreactive NFTs, dotlike and threadlike neurites and cellular processes, surrounding a small cerebral blood vessel. (D) A 69-year-old former professional football player (CTE stage IV, Case #9). The CTE focus is composed of tau-immunoreactive NFT (black arrowhead), astrocytes (red arrowhead), dot and threadlike neurites and cell processes surrounding a small cerebral blood vessel. Scale bars: 100 µm.

FIGURE 2.

ARTAG and CTE p-tau pathology immunolabeled by the anti-phosphorylated tau antibody AT8. (A) Subpial ARTAG with superficial astrocytic p-tau pathology, not diagnostic of CTE. (B) CTE focus at depth of the sulcus. (C) Subpial ARTAG. (D) CTE focus at sulcal depth in addition to subpial ARTAG. (Sulcal depths indicated by asterisks; scale bars: 100 µm).

FIGURE 3.

Working protocol for the diagnosis of chronic traumatic encephalopathy (CTE).