Neuropathology in chronic traumatic encephalopathy: a systematic review of comparative post-mortem histology literature

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma and is characterised by the perivascular accumulation of hyperphosphorylated tau (p-tau) in the depths of cortical sulci. CTE can only be diagnosed postmortem and the cellular mechanisms of disease causation remain to be elucidated. Understanding the full scope of the pathological changes currently identified in CTE is necessary to identify areas requiring further research. This systematic review summarises the current literature on CTE pathology from postmortem human tissue histology studies published until 31 December 2021. Publications were included if they quantitively or qualitatively compared postmortem human tissue pathology in CTE to neuropathologically normal cases or other neurodegenerative diseases such as Alzheimer's disease (AD). Pathological entities investigated included p-tau, beta-amyloid, TDP-43, Lewy bodies, astrogliosis, microgliosis, axonopathy, vascular dysfunction, and cell stress. Of these pathologies, p-tau was the most frequently investigated, with limited reports on other pathological features such as vascular dysfunction, astrogliosis, and microgliosis. Consistent increases in p-tau, TDP-43, microgliosis, axonopathy, and cell stress were reported in CTE cases compared to neuropathologically normal cases. However, there was no clear consensus on how these pathologies compared to AD. The CTE cases used for these studies were predominantly from the VA-BU-CLF brain bank, with American football and boxing as the most frequent sources of repetitive head injury exposure. Overall, this systematic review highlights gaps in the literature and proposes three priorities for future research including: 1. The need for studies of CTE cases with more diverse head injury exposure profiles to understand the consistency of pathology changes between different populations. 2. The need for more studies that compare CTE with normal ageing and AD to further clarify the pathological signature of CTE for diagnostic purposes and to understand the disease process. 3. Further research on non-aggregate pathologies in CTE, such as vascular dysfunction and neuroinflammation. These are some of the least investigated features of CTE pathology despite being implicated in the acute phase response following traumatic head injury.

Keywords: Chronic traumatic encephalopathy; Dementia pugilistica; Neuropathology; Systematic review.

Fig. 1

PRISMA flow diagram for selection of records included in this review. The search terms “chronic traumatic encephalopathy”, “dementia pugilistica”, “repetitive mild traumatic brain injury”, and “chronic traumatic encephalopathy neuropathology” were used to query the Pubmed, Scopus, and Embase databases for all relevant articles published until 31 December 2021, resulting in 5236 records. Duplicate records (3258) were removed using an excel query. The remaining 1978 records were screened to determine only those that examined human postmortem tissue. From these 104 records, all case studies (only one CTE case described) and descriptive studies (no comparison to normal aging or other disease groups) were excluded, resulting in 42 articles that met the eligibility criteria for this review

Fig. 2

Characteristics of the systematic review results. a Histogram of the number of comparative CTE neuropathology studies published by year. b Bar graph illustrating the number of publications using CTE postmortem tissue from each brain bank. c Bar graph of the number of publications investigating different brain regions. d Stacked bar graph of the number of publications from the VA-BU-CLF brain bank or other brain banks that study cases from each head injury exposure category

Fig. 3

Summary of pathology findings in CTE postmortem tissue neuropathology studies. Stacked bar charts illustrating the number of human postmortem tissue publications that describe an increase, no change or decrease in CTE cases compared to neuropathologically normal cases (a) and Alzheimer’s disease cases (b) for each pathology category. Only studies where the amount of the pathology was compared between groups have been included in these graphs. Studies that describe differences in distribution were not included. Note that studies in each pathology category investigated different brain regions