1201 - Brain Injury and Neurodegenerative Disease: Studying Athletes and Military Veterans

Session Description: Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS-NIBIB neuropathologic criteria CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at post-mortem examination with CTE, in work conducted by multiple groups across the US, as well as the UK, Canada, Ireland, Brazil, South Korea, New Zealand, and Australia. Keeping abreast of these international scientific advances, and their clinical implications, has been difficult. We now know more about the relationship between CTE and genetics, age of first exposure to head impacts, comorbid neuropathologic disease, and in vivo imaging, plasma, and CSF biomarkers. As a result of these studies, the role of inflammation, white matter rarefaction, imaging correlates, clinical correlates, exposure risk factors, and controversies in diagnosis are better understood.

This session will utilize case reports from military veterans and former professional athletes to illustrate these key advances in the understanding of CTE in an engaging and interactive format. Attendees will leave the talk with knowledge about what is known regarding CTE pathogenesis (Daneshvar), with special focus on military cohorts (Cifu), and professional football players (Zafonte), which will improve clinical practice and understanding surrounding this important topic.

Why is this session needed? : Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS-NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds have been diagnosed at post-mortem examination with CTE. CTE has been reported in military veterans, as well as amateur and professional athletes, including a bull-rider, boxers, wrestlers, and American and Australian rules football, rugby union, rugby league, soccer, and ice hockey players, in work conducted by multiple groups across the US, as well as the UK, Canada, Ireland, Brazil, South Korea, New Zealand, and Australia. Keeping abreast of these international scientific advances is difficult. Our understanding of the clinical correlates of CTE has similarly rapidly advanced, with new work examining the validity of existing clinical diagnostic criteria and proposing new clinical diagnostic criteria. Recently, there has been improved understanding of the relationship between CTE and genetics, age of first exposure to head impacts, comorbid neuropathologic disease, and in vivo imaging, plasma, and CSF biomarkers. As a result of these studies, the role of inflammation, white matter rarefaction, imaging correlates, clinical correlates, exposure risk factors, and controversies in diagnosis are better understood.

The proposed session will utilize case reports from former professional athletes to illustrate these key advances in the understanding of CTE in an engaging and interactive format. Attendees will leave the talk with knowledge about what is known regarding CTE pathogenesis (Daneshvar; over 40 publications on the long term effects of neurotrauma), with special focus on military cohorts (Cifu; Director of of the Chronic Effects of Neurotrauma Consortium, the largest study of late effects of TBI in military veterans), and professional football players (Zafonte; Director of the Football Players Health Study, the largest study of professional football players), which will improve clinical practice and understanding surrounding this important topic.

Daneshvar will focus on work pertaining to CTE pathogenesis. First, he will focus on the relationship between CTE and ARTAG. Specifically, in 2014, the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Biomedical Imaging and Bioengineering (NIBIB) organized a consensus meeting to establish the neuropathological criteria for the diagnosis of CTE. By the time the consensus panel met in November 2015, aging-related tau astrogliopathy (ARTAG) was recognized as an age-related p-tau pathology characterized by multiple patterns of astrocytic p-tau, including subpial thorn shaped astrocytes (TSA) that are commonly found in CTE. In 2016, the consensus panel met again to review and refine the preliminary pathological criteria for CTE provided by the first NINDS-NIBIB consensus conference using a second blinded sample of CTE cases representing all severities of disease: mild to severe. They also clarified the relationship between ARTAG and CTE, and confirmed that subpial TSA and purely astrocytic perivascular p-tau pathology represented ARTAG and did not meet the minimum criteria for CTE. This interim period created some confusion about the diagnosis of CTE, and is relevant to evaluating the evidence behind what causes CTE. Next, he will discuss the data from international academic neuropathology centers interested in CTE, and what that reveals about CTE causation. Over the past decade, Investigators analyzed community populations, international routine neuropathology series and brain banks, and a convenience sample of consecutive autopsies of military personnel, for the presence of CTE. Finally, he will explore recent neuropathological studies on CTE focused on the nature of the p-tau pathology, the role of 3R and 4R tau isoforms, and the presence of astrocytes in the CTE lesion. By synthesizing the data across these sources, the audience will have a more complete understanding of how CTE pathology informs potential pathophysiologic mechanisms.

Cifu will focus on the how this pathology manifests phenotypically in military veterans. Of particular interest is the relationship between neurodegenerative sequalae of military service in a population at high risk for post-traumatic stress disorder. Disambiguating between the clinical manifestation of neurodegenerative disease and comorbid processes is particularly challenging. In part, recent work examining traumatic encephalopathy syndrome (TES) sheds light into this relationship. In 2014, research diagnostic criteria for TES were proposed, which were later found to have good sensitivity (0.97) but low specificity (0.21). Requiring the presence of cognitive symptoms decreased sensitivity somewhat (0.90) with substantial improvements in specificity (0.48). In 2019, the First NINDS Consensus Workshop to Define the Diagnostic Criteria for TES, a multidisciplinary panel reached consensus for four primary criteria for the diagnosis of TES, which include: (1) substantial exposure to RHI; (2) core clinical features of cognitive impairment (episodic memory and/or executive functioning) or neurobehavioral dysregulation (explosiveness, impulsivity, rage, violent outbursts, and emotional lability), or both, and a progressive course (3) clinical features not fully accounted for by other disorders. For those meeting the first three criteria for TES, (4) a level of functional dependence and dementia is graded according to descriptions of the following levels: independent, subtle/mild functional limitation, mild dementia, moderate dementia, or severe dementia. As such, cognitive impairment may help disambiguate neurodegenerative processes from other processes associated with military service. He will further explore how the accuracy of the diagnosis of TES may be improved based on new and upcoming studies examining fluid and neuroimaging biomarkers of CTE pathology.

Zafonte will discuss recent work examining factors associated with the phenotype of TES in professional football players. In particular, recent work has identified potentially comorbid disease processes (e.g., hypertension, sleep apnea, diabetes, pain, testosterone dysfunction, depression, anxiety, ADHD) that may be more prevalent in those exposed to repetitive head impacts. Several of these processes may exacerbate cognitive decline in those with neurodegenerative processes. Many of these processes independently have cognitive sequalae, Most importantly, these comorbid processes are modifiable. These studies, therefore, provide a window into how clinicians could fundamentally alter the trajectory of those with cognitive decline following extensive exposure to repetitive head impacts.

Was this session previously presented at the Annual Assembly?: Although CTE has previously been discussed at annual assemblies, to our knowledge, no prior presentations have focused on both the military and civilian exposures to neurotrauma, and how these may manifest differently.