Diagnosis of Chronic Traumatic Encephalopathy (CTE) in Living Patients

Educational Objectives

The goal of this program is to improve diagnosis of chronic traumatic encephalopathy (CTE). After hearing and assimilating this program, the clinician will be better able to:

1. Cite clinical features associated with CTE.
2. Explain progression in CTE.
3. List core clinical features of traumatic encephalopathy syndrome.

Summary

Requirements for diagnosing chronic traumatic encephalopathy (CTE): include a description of the clinical features and course, the development, validation, and refinement of diagnostic criteria for the clinical syndrome associated with CTE, and development and validation of sensitive and specific fluid and neuroimaging biomarkers of pathology

History of CTE: Martland (1928) described the long-term consequences of getting hit as a professional boxer; Bowman et al (1940) first used the term "chronic traumatic encephalopathy"; they described a 28-yr-old professional boxer experiencing cognitive, behavioral, and mood symptoms who presented with short-term memory problems, depression, irritability, childish behavior, and paranoia, none of which improved over 18 mo; Critchley (1949) used the term CTE to diagnose a group of sailors who were former boxers with similar profiles; Critchley (1957) described the course of CTE and stated that CTE is a progressive condition and is not only irreversible but advances steadily; it involves multiple minor cerebral contusions, possibly with initial pinpoint hemorrhages, which are later replaced by gliosis, cortical atrophy, and internal hydrocephalus

Diagnosing CTE during life (step 1): should be beyond “punch drunk” and beyond descriptions without a neuropathologic diagnosis; the next step is to describe the clinical features associated with neuropathologically confirmed CTE; features associated with CTE were diverse and nonspecific in deceased individuals

Clinical features associated with CTE: based on Dr. McKee’s Brain Bank; changes in emotional and behavior control — include rage, short fuse, irritability, and emotional lability but not social disinhibition; this neurobehavioral dysregulation occurs earlier in life during the 30s to 50s; cognitive impairment — includes poor short-term memory and executive dysfunction; often begins later in life during 50s to 70s; dementia — question is whether cognitive impairment significant enough to impact routine life; it is a clinical syndrome that is eventually seen in most neurodegenerative diseases; neurodegenerative diseases are diagnosed through postmortem neuropathologic examination; each of these diseases also has an associated clinical syndrome of dementia and prodromal states (eg, mild cognitive impairment and mild behavioral impairment)

CTE and dementia: CTE eventually causes dementia, but CTE does not cause Alzheimer disease (AD); CTE may be caused by repetitive head impact (RHI) exposure that causes dementia; however, RHI does not cause AD; CTE dementia can be misdiagnosed as AD dementia; football does not necessarily lead to AD, but RHI exposure from football can eventually lead to cognitive impairment and progressive difficulties that lead to dementia related to CTE; not everyone with a history of RHI exposure from football and who has cognitive impairment and dementia has CTE pathology, and even if they have CTE pathology, there may be other primary or comorbid pathologies contributing to the clinical features

CTE progression and clinical features: the initial stage is asymptomatic or preclinical; as CTE progresses, patients may experience beginnings of emotional and behavioral changes; as CTE destroys more tissues, patients have memory impairment and decline in executive function; as the disease progresses further, patients become dependent on others for routine activities and are considered to have dementia

Diagnosing CTE during life (step 2): to develop diagnostic criteria for the clinical manifestations of CTE pathology; 4 diagnostic criteria have been proposed for the clinical presentation of CTE; traumatic encephalopathy syndrome (TES) is a term developed by the speaker’s group in 2014 to represent the clinical manifestation of underlying CTE; the National Institute of Neurological Disorders and Stroke (NINDS), in 2019, had a consensus workshop to define diagnostic criteria for TES; goals at this consensus were to develop evidence informed, expert consensus diagnostic criteria for TES, to improve upon previously proposed research diagnostic criteria for TES by maintaining adequate sensitivity and increasing specificity, and to develop a criteria structure amenable to future updates without requiring complete reorganization (eg, adding biomarkers); NINDS study published in 2021

Stepwise utilization of NINDS consensus diagnostic criteria: step 1 — substantial exposure to RHI; step 2 — core clinical features that are part of criteria that should have a progressive course; step 3 — establish that it is not fully accounted for by another disorder; if the patient meets all 3 steps, the patient is considered to have TES; step 4 — once the diagnosis is established, determine the level of functional dependence and dementia through specific criteria (eg, independent, subtle or mild functional impairment, mild dementia, moderate dementia, severe dementia); depression, anxiety, apathy, and suicidality are not core clinical features of TES; they are used as supportive features to help with, eg, diagnostic specificity

Determining levels of certainty for CTE pathology from TES: if a patient meets TES criteria and meets pathologic criteria for CTE on postmortem examination, then the patient is said to have TES with definite CTE; living patients who meet cognitive impairment criteria with or without neurobehavioral dysregulation are said to have a suggestive level of certainty for CTE; if patients meet criteria for cognitive impairment, the next step is to determine the level of exposure to contact or collision sport; if patients have no or less than substantial exposure, they are considered to have a suggestive level of certainty of CTE; in case of substantial exposure, determine the presence of supportive features; if the patient meets criteria, they are considered to have a possible level of certainty for CTE; in case of extensive exposure, if the patient meets criteria for supporting features, the patient is said to have probable CTE; in the future, there would be an addition of biomarkers; if the patients are positive for biomarkers, they are considered to have probable CTE with biomarker evidence

Diagnosing CTE during life (step 3): to develop sensitive and specific biomarkers for CTE pathology; the AT(N) approach divides the diagnosis from the underlying disease, the AD, and clinical syndrome; “A” represents aggregated β-amyloid, “T” represents aggregated tau, “(N)” is not required in the earlier part of diagnosing pathophysiology but can be used to determine the extent of neurodegeneration and neuronal injury; AT(N) framework was for AD; however, in CTE, there is a no requirement for β-amyloid aggregation, updated markers of tau can be used along with neurodegeneration, there may also be a white matter component to this framework for CTE

Potential biomarkers for CTE: the DETECT study investigated potential biomarkers for CTE; results are preliminary; from DETECT and other studies, there are potential fluid and neuroimaging biomarkers for CTE that are divided into nonspecific and specific to CTE; positron emission tomography has been able to detect abnormal tau in AD; flortaucipir is the most studied radiotracer for tau; flortaucipir is currently approved by the Food and Drug Administration only for AD; Stern et al (2019) reported that flortaucipir was able to detect some difference between former National Football League players and controls showing amyloid deposition at the superior frontal, medial temporal, and left parietal regions; total years of playing football were strongly associated with the extent of binding; there was no significant association between flortaucipir and clinical measures; flortaucipir may not be specific to CTE p-tau; tau pathology alone may not be associated with the neuropsychiatric symptoms and cognitive impairment that was described in former American football players and boxers with a history of RHI exposure

Achievement of CTE diagnosis during life: although there is no current robust criteria to diagnose CTE during life, researcher are close to developing these criteria; several questions are yet to be answered; question 1 — is the type of clinical features specifically related to p-tau pathology; question 2 — is the cognitive impairment only from tauopathy; question 3 — are neurobehavioral dysregulation and neuropsychiatric features related to white-matter degeneration; question 4 — are some of the clinical features not related to p-tau such as may be related to inflammatory responses, moderate to severe traumatic brain injury, white-matter arteriosclerosis, CTE-related rarefaction, or comorbid diseases; question 5 — are clinical features associated with other things, eg, idiopathic psychiatric disorders, sleep disorder, chronic pain, or racial and associated inequities in social, cultural, and educational determinants of health; question 6 — are all clinical features progressive; question 7 — can negative amyloid positron emission tomography (PET) imaging be a biomarker for CTE; question 8 — can current tau PET radiotracers detect CTE p-tau isoforms; question 9 — can current plasma and cerebrospinal fluid p-tau analytes detect CTE p-tau epitopes

Current studies: several studies related to diagnosing CTE are undergoing; DIAGNOSE CTE research project is funded by NINDS; baseline examinations were completed on February 26, 2020, and planned 3-yr follow-up was changed into a remote 4-yr follow-up because of the pandemic; another ongoing study is HITSS, which involves male and female soccer players and male football players at all levels of play in determining risk factors for later-in-life clinical features

Readings

Alosco ML, Stein TD, Tripodis Y, et al. Association of white matter rarefaction, arteriolosclerosis, and tau with dementia in chronic traumatic encephalopathy. JAMA Neurol. 2019;76(11):1298-1308. doi:10.1001/jamaneurol.2019.2244; Bowman KM, Blau A. Psychotic states following head and brain injury in adults and children. In: Brock S, editor. Injuries of Skull, Brain and Spinal Cord: Neuropsychiatric, Surgical, and Medico-Legal Aspects. Baltimore, MD: Williams & Wilkins Co; 1940. pp. 309–60; Critchley M. Punch-drunk syndromes: the chronic traumatic encephalopathy of boxers. 1949. In: Hommage a Clovis Vincent. Maloine: Paris; Critchley M. Medical aspects of boxing, particularly from a neurological standpoint. Br Med J. 1957;1(5015):357-362. doi:10.1136/bmj.1.5015.357; Fesharaki-Zadeh A. Chronic traumatic encephalopathy: A brief overview. Front Neurol. 2019;10:713. Published 2019 Jul 3. doi:10.3389/fneur.2019.00713; Jie CVML, Treyer V, Schibli R, et al. The first FDA-approved PET tracer for imaging tau pathology in Alzheimer’s disease. Pharmaceuticals (Basel). 2021;14(2):110. Published 2021 Jan 30. doi:10.3390/ph14020110; Katz DI, Bernick C, Dodick DW, et al. National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome. Neurology. 2021;96(18):848-863. doi:10.1212/WNL.0000000000011850; Martland HS. Punch drunk. JAMA. 1928;91(15):1103–1107. doi:10.1001/jama.1928.02700150029009; Reams N, Eckner JT, Almeida AA, et al. A clinical approach to the diagnosis of traumatic encephalopathy syndrome: A review [published correction appears in JAMA Neurol. 2016 Nov 1;73(11):1376]. JAMA Neurol. 2016;73(6):743-749. doi:10.1001/jamaneurol.2015.5015; Stern RA, Adler CH, Chen K, et al. Tau positron-emission tomography in former national football league players. N Engl J Med. 2019;380(18):1716-1725. doi:10.1056/NEJMoa1900757; Stern RA, Daneshvar DH, Baugh CM, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;81(13):1122-1129. doi:10.1212/WNL.0b013e3182a55f7f.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Stern was recorded at the Virtual 6th Annual Chronic Traumatic Encephalopathy Conference, held online on October 27, 2022, and presented by Boston University School of Medicine. For information on future CME activities from this sponsor, please visit https://cme.bu.edu/. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.75 CE contact hours.

Lecture ID:

NE140601

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.