Neuropathological Criteria Creation (NINDS/NIBIB)

Given the controversy surrounding Chronic Traumatic Encephalopathy (CTE) and its presence (or lack thereof) of distinct neuropathologic manifestations as well as the ever increasing media attention it garners, it is unsurprising that both the National Institutes of Health and the National Football League supported a 2013 investigation to determine what, if any, unique neuropathologic criteria distinguish and define CTE as distinct from other neurodegenerative tauopathies. As mentioned in the McKee et al., 2016 article, NINDS/NIBIB called for a series of consensus panels to better define the neuropathological criteria of CTE. Assembling a team of 7 neuropathologists well versed in neurodegenerative diseases, particularly tauopathies, the consensus panel examined 25 cases of various tauopathies that included presumed diagnoses of CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The panel was blinded to any clinical or demographic information, gross neuropathological features of the brain, and the total number of each type of cases within the set of cases (McKee et al. 2016).

The objective of the study was to utilize previously established preliminary criteria for the neuropathologic diagnosis of CTE in order to determine what components would be most useful as part of a well defined system of criteria. The preliminary criteria is elucidated as follows (McKee et al., 2013):

"1. Perivascular foci of p-tau immunoreactive NFTs and ATs in the neocortex 
2. Irregular distribution of p-tau immunoreactive NFTs and ATs at the depths of cerebral sulci 
3. NFTs in the cerebral cortex located preferentially in the superficial layers (often most pronounced in temporal cortex)
4. Supportive, non-diagnostic features: Clusters of subpial ATs in the cerebral cortex, most pronounced at the sulcal depths"

In addition to these CTE preliminary criteria, neuropathologists were provided with additional well-known and supported criteria for other tauopathies to assist in making their presumptive diagnoses. Utilizing a certainty scale (1, unsure; 2, possible; 3, probable; 4, definite), neuropathologists rated their certainty for each presumptive diagnosis of the individual 25 cases. Cohen's Kappa was used as the statistical measure to analyze agreement among the neuropathologists for all of the cases both CTE and non-CTE as well as agreement between the neuropathologists in regards to those cases solely identified as having CTE. Interestingly, there was greatest agreement between neuropathologists for cases having been identified as CTE with a Cohen's kappa value of 0.78 (at the high end of good agreement). Furthermore, a second interesting result was the increase in the level of certainty after clinical features of the cases were made known to investigators (McKee et al. 2016).

Demonstrating the utility of McKee's previous preliminary criteria and the high level of agreement to which a series of neuropathologists were able to identify CTE, the consensus panel recognized a what they consider to be a pathognomonic lesion of CTE distinguishing it from other neurodegenerative disorders. "The pathognomonic lesion of CTE consists of p-tau aggregates in neurons, astrocytes, and cell processes around small vessels in an irregular pattern at the depths of the cortical sulci (McKee et al. 2016)." The group was able to identify other supportive neuropathological features of CTE, but these features are neither necessary nor sufficient in isolation for the diagnosis of CTE.

As noted by the McKee et al., 2016, the study was limited by its relatively small sample size and use of presumptive CTE cases in later stages of disease. Future research should most certainly investigate the manner which the conclusions of this consensus study can be applied to a larger sample size and cases in which CTE is less readibly identified or at an earlier stage of progression. Given the previous inconsistency of methodological diagnostic criteria for CTE, this study should serve as a crucial cornerstone for developing a standardized methodology for identifying CTE in post-mortem cases. By effectively identifying post-mortem CTE cases with both greater precision and accuracy, researchers will be able to more effectively direct their research in to the specific pathogenic mechanisms underlying CTE development and progression. 

McKee, A.C., Cairns, N.J., Dickson, D.W. et al. Acta Neuropathol (2016) 131: 75. doi:10.1007/s00401-015-1515-z

McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64. doi:10.1093/brain/ aws307