Ebook: Handbook of Traumatic Brain Injury and Neurodegeneration

Traumatic Brain Injury and Neurodegenerative Disease: A Marriage Made in Sport?

The watershed moment in understanding of traumatic brain injury (TBI) occurred with Holbourne’s theory that rotational head movement and shear strains were limiting factors in producing parenchymal brain damage [1]. He based this on physical properties of the brain, including its extreme incompressibility and lack of rigidity. Holbourne’s theory was substantiated and elaborated upon in primate experiments, in which coronal plane rotation of sufficient magnitude and pulse duration rendered subjects vulnerable to diffuse axonal injury [2, 3], while sagittal plane rotation and relatively short pulse duration predisposed to bridging vein rupture and subdural hematoma [4]. Related concepts have been invoked to explain the contrecoup contusion phenomenon [5].

Although subsequent modifications were inevitable, the initial theory coupled with experimental observations provided the biomechanical underpinnings for cardinal traumatic brain lesions—namely, subdural hematoma, contusion, and diffuse axonal injury. These same concepts have since been exploited to improve neuroprotection in motor vehicle accidents, military service, and sport, and are still relevant today. Myriad biochemical cascades in TBI have been elaborated, along with advances in diagnosis and acute management of a multiplicity of lesions. It is perhaps noteworthy that the foundational knowledge was acquired in the absence of computer technology, modern molecular biology, and immunohistochemical analysis of autopsied brain tissue.

A parallel line of inquiry into the enigmatic condition known initially as “punch drunk” [6] and later dementia pugilistica (DP) [7] was somewhat different and has been a source of confusion since its description. Punch drunk was called to attention in 1928 not because of acute injury, but because neurological signs were observed in boxers over the course of their boxing career and afterwards. DP was also a stationary condition in most cases [8], a feature distinct from classical neurodegenerative diseases. This may in part explain why no autopsy information on boxers was reported until 1954 [9], despite considerable interest in the topic in the 1930s and 1940s. It is also interesting, though largely unrecognized, that the index autopsy report in boxers was in fact a case of early-onset Alzheimer’s disease, a condition of genetic etiology having nothing to do with boxing. The largest case series of DP to date emphasized a spectrum of brain lesions [10], some clearly traumatic in line with Holbrourne’s theory (e.g., septal fenestrations), but the focus since has been on the neurofibrillary tangle as a bridge between acquired neurotrauma and neurodegeneration.

The third line of inquiry is genuine neurodegenerative disease. Unlike neurotrauma, no acquired etiologies have been verified scientifically aside from spongiform encephalopathies, there is no stationary condition once initiated, and there is often highly selective cell type vulnerability. In all major neurodegenerative disease phenotypes, an invariably progressive and fatal neurological deterioration is associated with consistent neuropathological lesions and anatomically distinct neurodegeneration. None of these features are found consistently in the DP literature or modern case series using the term “chronic traumatic encephalopathy” (CTE). Indeed, neurodegeneration in the true sense, that is, loss of neurons, is neither a required nor supportive criterion in the current consensus iteration of CTE pathology [11].

A bewildering superstructure has nevertheless been assembled for TBI-neurodegeneration theory, which may highlight enthusiasm for hypothesis confirmation rather than hypothesis testing. The search for biomarkers in line with the preferred theory, including PET scanning for putative tau surrogates [12], serum and cerebrospinal fluid protein analyses [13], and examination of a broad array of neuropsychiatric endpoints [14], all emphasize sensitivity over specificity. Sophisticated experimental mechanisms have been invoked to explain disease progression [15], while progression in vivo has not been demonstrated. Constructs hypothesizing causality between TBI and neurodegeneration have been suggested [16], while evidence of marginal risk or no risk in large scale epidemiological surveys [17–24] essentially preclude causality. Sport-neurodegeneration theory is embedded in medical science, yet a quality evidence base is entirely lacking. The TBI-neurodegeneration hypothesis apart from sport is also broadly accepted, yet relies on a literature replete with methodological weaknesses [25]. Remarkably, it has become customary to view sport as a surrogate for environmental TBI exposure [26], yet modern athlete case series are devoid of empirical manifestations of TBI (e.g., contusions, subdural collections, post-traumatic epilepsy). Clearly, more research, and perhaps more skepticism, is needed.

The interested reader should keep in mind that this handbook does not simply explore the deleterious effects of genuine TBI, which are substantial, but rather the relationship between TBI and neurodegeneration. It was inevitable that some articles would touch upon the hypothetical CTE construct given the controversy and media exposure, although the interest in critical review on the part of multiple authors of diverse background was noteworthy. Casson and Viano, for example, bring to bear decades of experience and expertise in contact sport, and review in copious detail the stark differences between boxing and American football, not only clinically, but radiographically, and pathologically [27]. They appropriately highlight that neurological sequelae from boxing has traditionally been defined by clinical examination, whereas the putative condition described in football is purely pathological, or more precisely immunohistochemical, with no discernible clinical substrate. The totality of their review casts doubt, in a definitive sense, on the common rhetorical claim that “repetitive head impacts” from whatever sport is DP by another name.

Brett et al. [28] critically examine neuropathological and clinical criteria for CTE, and identify a noticeable lack of probabilistic assessments, which are otherwise customary when attempting to characterize ill-defined and hypothetical entities. They also expose the problematic emphasis on sensitivity over specificity. Zuckerman et al. [29] describe a number of limitations in CTE research, including ascertainment bias, recall bias, lack of generalizability of samples of convenience, lack of accounting for substance abuse, lack of adequate controls, and a CTE definition that has no lower limit. Schwab and Hazrati [30] further point out pervasive flaws in the CTE studies, including a decided lack of an evidence base as noted, insufficient samples, pathological inconsistencies, unreliable clinical data, and flawed study design. They raise the legitimate possibility of unintended consequences on broader society from promoting a fatalistic view of an uncharacterized process. The problem of amending public policy prematurely is also raised, and may warrant more attention than that afforded by a medical science community immersed in patient care and research.

Iverson et al. [31] provide a thorough evaluation of clinicopathological correlation in the CTE construct, and suggest that CTE neuropathology might be disambiguated from hypothesized clinical features in order to better understand each component in future research. The collective works from Castellani and Perry [32, 33], Castellani et al. [34], and Tripathy et al. [35] suggest a number of additional unresolved questions, such as the kinetics of progression in DP, the existence of a TBI-neurodegenerative proteinopathy construct in general, the role of tau as a driver of disease, the reliability of postmortem diagnostic interpretation in an emotionally charged environment, and the existence, if any, of CTE in military service members.

Overall, the articles consist of a roughly equal proportion of reviews and primary data papers. The majority discuss human disease, either in review form or as original research, with a few articles exploring TBI in animal models [36–39]. The human studies span a spectrum of endpoints, including PET imaging of putative tau surrogates [40], perfusion neuroimaging [41], potential biomarkers such as MCP-1 [42] and BDNF polymorphism [43], and postmortem proteinopathy as noted above.

The overarching theme of this Handbook is thus the marriage between neurodegenerative disease and neurotrauma by virtue of sport or military service, and the legitimacy of that marriage. Overall, it may be gleaned from these pages that, controversy notwithstanding, there is much to be learned about the biological effects of TBI, the presence and extent of genuine TBI in athletes and military service members, pathogenic mechanisms and substrates for long-term sequelae, the relationship between TBI and diverse neuropsychiatric disorders, and targets for therapy. If there is any broad message to the neuroscience community from the collective contributions, it is that the null hypothesis—that there is no relationship between TBI and neurodegenerative proteinopathy—is still very much in play.

Rudy J. Castellani MD

Professor of Pathology and Neuroscience

West Virginia University and

Rockefeller Neuroscience Institute

DISCLOSURE STATEMENT

The author’s disclosure is available online (https://www.j-alz.com/manuscript-disclosures/19-1269).

REFERENCES

[1] Holbourn AHS (1943) Mechanics of head injuries. Lancet 242, 438-441.

[2] Ommaya AK, Corrao PG, Letcher FS (1973) Head injury in the chimpanzee. Part 1: Biodynamics of traumatic unconsciousness. J Neurosurg 39, 152-166.

[3] Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP (1982) Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 12, 564-574.

[4] Gennarelli TA, Thibault LE (1982) Biomechanics of acute subdural hematoma. J Trauma 22, 680-686.

[5] Dawson SL, Hirsch CS, Lucas FV, Sebek BA (1980) The contrecoup phenomenon. Reappraisal of a classic problem. Hum Pathol 11, 155-166.

[6] Martland HS (1928) Punch drunk. J Am Med Assoc 91, 1103-1107.

[7] Millspaugh JA (1937) Dementia Pugilistica. U S Nav Med Bull 35, 297-303.

[8] Roberts A (1969) Brain damage in boxers: A study of prevalance of traumatic encephalopathy among exprofessional boxers, Pitman Medical Scientific Publishing Co., London.

[9] Brandenburg W, Hallervorden J (1954) Dementia pugilistica mit anatomischem Befund. Virchows Arch 325, S680-709.

[10] Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3, 270-303.

[11] McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, Lee H-S, Wojtowicz SM, Hall G, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43-64.

[12] Stern RA, Adler CH, Chen K, Navitsky M, Luo J, Dodick DW, Alosco ML, Tripodis Y, Goradia DD, Martin B, Mastroeni D, Fritts NG, Jarnagin J, Devous MD, Mintun MA, Pontecorvo MJ, Shenton ME, Reiman EM (2019) Tau positron-emission tomography in former national football league players. N Engl J Med 380, 1716-1725.

[13] Agoston DV, Shutes-David A, Peskind ER (2017) Biofluid biomarkers of traumatic brain injury. Brain Inj 31, 1195-1203.

[14] Montenigro PH, Baugh CM, Daneshvar DH, Mez J, Budson AE, Au R, Katz DI, Cantu RC, Stern RA (2014) Clinical subtypes of chronic traumatic encephalopathy: Literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome.Alzheimers Res Ther6, 68.

[15] Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, Miller TM, Diamond MI (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92, 796-812.

[16] Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, Wojnarowicz MW, Casey N, Lu H, Kokiko-Cochran ON, Saman S, Ericsson M, Onos KD, Veksler R, Senatorov VV, Kondo A, Zhou XZ, Miry O, Vose LR, Gopaul KR, Upreti C, Nowinski CJ, Cantu RC, Alvarez VE, Hildebrandt AM, Franz ES, Konrad J, Hamilton JA, Hua N, Tripodis Y, Anderson AT, Howell GR, Kaufer D, Hall GF, Lu KP, Ransohoff RM, Cleveland RO, Kowall NW, Stein TD, Lamb BT, Huber BR, Moss WC, Friedman A, Stanton PK, McKee AC, Goldstein LE (2018) Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain 141, 422-458.

[17] Fann JR, Ribe AR, Schou Pedersen H, Fenger-GrÃÿn M, Christensen J, Benros ME, Vestergaard M (2018) Long-term risk of dementia among people with traumatic brain injury in Denmark: A population-based observational cohort study, Lancet Pscyhiatry 5, 424-431.

[18] Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, Phillips C, Gau BA, Welsh-Bohmer KA, Burke JR, Guralnik JM, Breitner JCS (2000) Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55, 1158-1166.

[19] Gardner RC, Byers AL, Barnes DE, Li Y, Boscardin J, Yaffe K (2018) Mild TBI and risk of Parkinson disease: A Chronic Effects of Neurotrauma Consortium Study. Neurology 90, e1771-e1779.

[20] Seals RM, Hansen J, Gredal O, Weisskopf MG (2016) Physical trauma and amyotrophic lateral sclerosis: A population-based study using Danish National Registries. Am J Epidemiol 183, 294-301.

[21] Godbolt AK, Cancelliere C, HincapiÂťe CA, Marras C, Boyle E, Kristman VL, Coronado VG, Cassidy JD (2014) Systematic review of the risk of dementia and chronic cognitive impairment after mild traumatic brain injury: Results of the international collaboration on mild traumatic brain injury prognosis. Arch Phys Med Rehabil 95(3 Suppl), 245-256.

[22] Hamidou B, Couratier P, BesancÂÿon C, Nicol M, Preux PM, Marin B (2014) Epidemiological evidence that physical activity is not a risk factor for ALS. Eur J Epidemiol 29, 459-475.

[23] Manley GT, Gardner AJ, Schneider KJ, Guskiewicz KM, Bailes J, Cantu RC, Castellani RJ, Turner M, Jordan BD, Randolph C, Dvořák J, Hayden KA, Tator CH, McCrory P, Iverson GL (2017) A systematic review of potential long-term effects of sport-related concussion. Br J Sports Med 51, 969-977.

[24] Mackay DF, Russell ER, Stewart K, MacLean JA, Pell JP, Stewart W (2019) Neurodegenerative disease mortality among former professional soccer players. N Engl J Med 381, 1801-1808.

[25] Hicks AJ, James AC, Spits G, Ponsford J (2019) Traumatic brain injury as a risk factor for dementia and Alzheimer disease: Critical review of study methodologies. J Neurotrauma 36, 3191-3219.

[26] Alosco ML, Mez J, Tripodis Y, Kiernan PT, Abdolmohammadi B, Murphy L, Kowall NW, Stein TD, Huber BR, Goldstein LE, Cantu RC, Katz DI, Chaisson CE, Martin B, Solomon TM, McClean MD, Daneshvar DH, Nowinski CJ, Stern RA, McKee AC (2018) Age of first exposure to tackle football and chronic traumatic encephalopathy. Ann Neurol 83, 886-901.

[27] Casson IR, Viano DC (2019) Long-term neurological consequences related to boxing and American football: A review of the literature. J Alzheimers Dis 69, 935-952.

[28] Brett BL, Wilmoth K, Cummings P, Solomon GS, McCrea MA, Zuckerman SL (2019) The neuropathological and clinical diagnostic criteria of chronic traumatic encephalopathy: A critical examination in relation to other neurodegenerative diseases. J Alzheimers Dis 68, 591-608.

[29] Zuckerman SL, Brett BL, Jeckell A, Yengo-Kahn AM, Solomon GS (2018) Chronic traumatic encephalopathy and neurodegeneration in contact sports and American football. J Alzheimers Dis 66, 37-55.

[30] Schwab N, Hazrati L-N (2018) Assessing the limitations and biases in the current understanding of chronic traumatic encephalopathy. J Alzheimers Dis 64, 1067-1076.

[31] Iverson GL, Keene CD, Perry G, Castellani RJ (2018) The need to separate chronic traumatic encephalopathy neuropathology from clinical features. J Alzheimers Dis 61, 17-28.

[32] Castellani RJ, Perry G (2017) Dementia pugilistica revisited. J Alzheimers Dis 60, 1209-1221.

[33] Castellani RJ, Perry G (2019) Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges. J Alzheimers Dis 67, 447-467.

[34] Castellani RJ, Smith M, Bailey K, Perry G, deJong JL (2019) Neuropathology in consecutive forensic consultation cases with a history of remote traumatic brain injury. J Alzheimers Dis 72, 683-691.

[35] Tripathy A, Shade A, Erskine B, Bailey K, Grande A, deJong JL, Perry G, Castellani RJ (2019) No evidence of increased chronic traumatic encephalopathy pathology or neurodegenerative proteinopathy in former military service members: A preliminary study. J Alzheimers Dis 67, 1277-1289.

[36] Chen M, Song H, Cui J, Johnson CE, Hubler GK, DePalma RG, Gu Z, Xia W (2018) Proteomic profiling of mouse brains exposed to blast-induced mild traumatic brain injury reveals changes in axonal proteins and phosphorylated tau. J Alzheimers Dis 66, 751-773.

[37] Cross DJ, Meabon JS, Cline MM, Richards TL, Stump AH, Cross CG, Minoshima S, Banks WA, Cook DG (2019) Paclitaxel reduces brain injury from repeated head trauma in mice. J Alzheimers Dis 67, 859-874.

[38] Zysk M, Clausen F, Aguilar X, Sehlin D, Syvanen S, Erlandsson A (2019) Long-term effects of traumatic brain injury in a mouse model of Alzheimer’s disease. J Alzheimers Dis 72, 161-180.

[39] Ju S, Xu C, Wang G, Zhang L (2019) VEGF-C induces alternative activation of microglia to promote recovery from traumatic brain injury. J Alzheimers Dis 68, 1687-1697.

[40] Chen ST, Siddarth P, Merrill DA, Martinez J, Emerson ND, Liu J, Wong KP, Satyamurthy N, Giza CC, Huang SC, Fitzsimmons RP, Bailes J, Omalu B, Barrio JR, Small GW (2018) FDDNP-PET tau brain protein binding patterns in military personnel with suspected chronic traumatic encephalopathy. J Alzheimers Dis 65, 79-88.

[41] Amen DG, Willeumier K, Omalu B, Newberg A, Raghavendra C, Raji CA (2016) Perfusion neuroimaging abnormalities alone distinguish National Football League Players from a healthy population. J Alzheimers Dis 53, 237-241.

[42] Ho L, Zhao W, Dams-O’Connor K, Tang CY, Gordon W, Peskind ER, Yemul S, Haroutunian V, Pasinetti GM (2012) Elevated MCP-1 concentration following traumatic brain injury as a potential “predisposition” factor associated with an increased risk for subsequent development of Alzheimer’s disease. J Alzheimers Dis 31, 301-313.

[43] Finan JD, Udani SV, Patel V, Bailes JE (2018) The influence of the Val66Met polymorphism of brain-derived neurotrophic factor on neurological function after traumatic brain injury. J Alzheimers Dis 65, 1055-1064.

The long-term effects of repetitive head trauma on the brain have often been studied in boxers and American football players. The medical literature on this topic was reviewed in order to compare the findings related to boxing with those related to football. The evidence gathered from this review indicates that there are significant differences between the clinical and neuropathological descriptions of the chronic brain damage reported in retired boxers compared to those reported in retired football players. Differing biomechanics of head impacts in the two sports may help explain the different clinical and neuropathological consequences of participation in boxing versus football.

Extensive exposure of boxers to neurotrauma in the early 20th century led to the so-called punch drunk syndrome, which was formally recognized in the medical literature in 1928. “Punch drunk” terminology was replaced by the less derisive ‘dementia pugilistica’ in 1937. In the early case material, the diagnosis of dementia pugilistica required neurological deficits, including slurring dysarthria, ataxia, pyramidal signs, extrapyramidal signs, memory impairment, and personality changes, although the specific clinical substrate has assumed lesser importance in recent years with a shift in focus on molecular pathogenesis. The postmortem neuropathology of dementia pugilistica has also evolved substantially over the past 90 years, from suspected concussion-related hemorrhages to diverse structural and neurofibrillary changes to geographic tauopathy. Progressive neurodegenerative tauopathy is among the prevailing theories for disease pathogenesis currently, although this may be overly simplistic. Careful examination of historical cases reveals both misdiagnoses and a likelihood that dementia pugilistica at that time was caused by cumulative structural brain injury. More recent neuropathological studies indicate subclinical and possibly static tauopathy in some athletes and non-athletes. Indeed, it is unclear from the literature whether retired boxers reach the inflection point that tends toward progressive neurodegeneration in the manner of Alzheimer’s disease due to boxing. Even among historical cases with extreme levels of exposure, progressive disease was exceptional.

Chronic traumatic encephalopathy (CTE) is considered to be a progressive neurodegenerative disease caused by mild traumatic brain injury (mTBI). Recently there has been a significant amount of media attention surrounding the commonness of CTE in professional athletes, particularly American football, based on several postmortem case series. However, despite the persuasive claims made by the media about CTE, research on the disease and the effects of mTBI in general remain in its infancy. Commonly cited case series studying CTE are limited by methodological biases, pathological inconsistencies, insufficient clinical data, and a reliance on inherently biased postmortem data. These case series do not allow for the collection of any epidemiological data and are not representative of the general population. The exaggerated assumptions and assertions taken from these studies run the risk of creating a self-fulfilling prophecy for individuals who believe they are at risk and have the potential to negatively influence sports-related policymaking. This review outlines the status and limitations of recent CTE case series and calls for future prospective, longitudinal studies to further characterize the pathological and clinical hallmarks of CTE.

There is tremendous recent interest in chronic traumatic encephalopathy (CTE) in former collision sport athletes, civilians, and military veterans. This critical review places important recent research results into a historical context. In 2015, preliminary consensus criteria were developed for defining the neuropathology of CTE, which substantially narrowed the pathology previously reported to be characteristic. There are no agreed upon clinical criteria for diagnosis, although sets of criteria have been proposed for research purposes. A prevailing theory is that CTE is an inexorably progressive neurodegenerative disease within the molecular classification of the tauopathies. However, historical and recent evidence suggests that CTE, as it is presented in the literature, might not be pathologically or clinically progressive in a substantial percentage of people. At present, it is not known whether the emergence, course, or severity of clinical symptoms can be predicted by specific combinations of neuropathologies, thresholds for accumulation of pathology, or regional distributions of pathologies. More research is needed to determine the extent to which the neuropathology ascribed to long-term effects of neurotrauma is static, progressive, or both. Disambiguating the pathology from the broad array of clinical features that have been reported in recent studies might facilitate and accelerate research—and improve understanding of CTE.

There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau’s binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the “tau prion”. Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by the presence of abnormally phosphorylated tau protein in the depths of one or more cortical sulci. Controversy over the risk of CTE and neurologic disorders later in life among contact sport athletes has taken hold in the public spotlight, most notably in American football. Players, parents, coaches, and legislators have taken action based on the commonly held notion that contact sports invariably lead to neurodegenerative disorders. However, to fully understand the science behind this assumed association, a critical appraisal of the evidence is warranted. With regards to CTE in sports, the objectives of the current report are to: 1) describe the history of CTE, 2) review current CTE definitions, 3) critically evaluate the empiric data, divided into all contact sports and exclusively American football, and 4) summarize notable themes for future research.

This work critically reviews chronic traumatic encephalopathy (CTE), with a specific focus on the single criterion necessary and sufficient for diagnosis. Herein, CTE is compared to other well-established neurodegenerative entities including Alzheimer’s disease and dementia with Lewy bodies. Each neurodegenerative disorder is reviewed in five pertinent areas: 1) historical perspective, 2) guideline formation process, 3) clinical diagnostic criteria, 4) pathological diagnostic criteria, and 5) validation of previously described diagnostic criteria (e.g., sensitivity and specificity). These comparisons indicate that CTE is a disease in the earliest stages of formation and has yet to undergo rigorous development and refinement similar to other neurodegenerative diseases. Suggested future revisions to the diagnostic criterion of CTE include establishing a lower threshold for accumulation of pathology, as well as accounting for the presence of concomitant neuropathology and comorbid neurodegenerative disorders. Currently, while initial efforts have been attempted, agreed upon antemortem clinical criteria do not exist. As has been the scientific standard with similar neurodegenerative disorders, antemortem diagnostic guidelines should first be refined through subcommittees of neuroscientists from diverse institutional backgrounds with a subclassification of levels of diagnostic certainty (possible, probably, and definite). Validation studies should then assess the predictive value and accuracy of proposed antemortem diagnostic criteria in relation to potential pathological criteria.

It is presently unknown whether military service members are at risk for chronic traumatic encephalopathy (CTE) or Alzheimer’s disease (AD) pathology, due to traumatic brain injury (TBI). Studies with respect to AD have had mixed results with respect to mild TBI, although an increased risk of clinical AD with moderate and severe TBI is more consistently demonstrated. No studies to date have demonstrated a longitudinal progression from TBI to autopsy. We therefore initiated a cross-sectional survey of former military service members. 18 brain specimens have been examined to date that had extensive sampling, with an additional 64 specimens with limited sampling. The mean age was 68.4 years across all cases. Of these 82 cases, 26% were combat veterans. 13% noted a TBI history, either on active duty or in civilian life. 53% had a history of psychiatric problems, including 20% with post-traumatic stress disorder (PTSD). 17% reported neurological problems. No cases had CTE pathology. Assessment for proteinopathy by Braak staging and modified CERAD plaque scores showed averages of 2.41 and 0.78, respectively, which was essentially identical to age-matched controls (2.46 and 0.77, respectively). In the extensively sampled cases, there was no relationship between p-tau in the amygdala and psychiatric signs, including PTSD.ThesedatasuggestthatmilitaryserviceperseisnotariskfactorforCTEpathologyorneurodegenerativeproteinopathy. More research is needed to study the relationship, if any, between TBI and neurodegenerative proteinopathy.

There is a long history linking traumatic brain injury (TBI) with the development of dementia. Despite significant reservations, such as recall bias or concluding causality for TBI, a summary of recent research points to several conclusions on the TBI-dementia relationship. 1) Increasing severity of a single moderate-to-severe TBI increases the risk of subsequent Alzheimer’s disease (AD), the most common type of dementia. 2) Repetitive, often subconcussive, mild TBIs increases the risk for chronic traumatic encephalopathy (CTE), a degenerative neuropathology. 3) TBI may be a risk factor for other neurodegenerative disorders that can be associated with dementia. 4) TBI appears to lower the age of onset of TBI-related neurocognitive syndromes, potentially adding “TBI cognitive-behavioral features”. The literature further indicates several specific risk factors for TBI-associated dementia: 5) any blast or blunt physical force to the head as long as there is violent head displacement; 6) decreased cognitive and/or neuronal reserve and the related variable of older age at TBI; and 7) the presence of apolipoprotein E ε4 alleles, a genetic risk factor for AD. Finally, there are neuropathological features relating TBI with neurocognitive syndromes: 8) acute TBI results in amyloid pathology and other neurodegenerative proteinopathies; 9) CTE shares features with neurodegenerative dementias; and 10) TBI results in white matter tract and neural network disruptions. Although further research is needed, these ten findings suggest that dose-dependent effects of violent head displacement in vulnerable brains predispose to dementia; among several potential mechanisms is the propagation of abnormal proteins along damaged white matter networks.

Traumatic brain injury (TBI) is the most common form of head injury and is a leading cause of death worldwide. Due to the vast variability in the types and severity of trauma, the cellular consequences of head injury are not completely understood. The development of reliable models of TBI will aid in understanding the molecular consequences of head trauma, and they will assist in identifying biological surrogate markers of the degree of damage and prognosis. In doing so, effective therapeutic strategies can be applied. Current in vivo experimental models yield important information, but they too have a significant amount of variation. The goal of this review is to re-evaluate the use of these in vivo models of TBI and assess whether they correlate with the consequence of TBI in humans from the perspective of tau, an axonal microtubule-stabilizing protein. We present and discuss the current models of traumatic head injury, and we focus on those that assess changes in tau. We evaluate reports of TBI in humans that measured changes in tau and that were detectable in serum and cerebrospinal fluid, and as a pathological consequence in brain tissue.

Traumatic brain injury (TBI) is widely assumed to be causal in neurodegenerative disease, based on epidemiological surveys demonstrating an increased risk of Alzheimer disease (AD) following TBI, and on recent theories surrounding repetitive head movement. We tested this assumption by evaluating 30 consecutive forensic examinations in which neuropathology consultation was sought, and in which a history of remote TBI was uncovered during the course of the investigation. In this series, there was a high frequency of psychiatric co-morbidities (100%), remote contusion (90%), and seizures (63%). Extent of proteinopathy showed no differences with age-matched controls. A subset of the cases showed focal geographic tauopathy that correlated with older age at autopsy, but had no correlation with clinical signs, and was minimal in comparison with the encephalomalacia secondary to trauma. The results suggest that cerebral contusion and post-traumatic epilepsy may be over-represented in civilian TBI, while structural brain damage from trauma is the predominant cause of morbidity following TBI. We found no evidence that TBI initiates a progressive proteinopathy.

Background:

Findings are inconsistent regarding the role of traumatic head injury in the subsequent development of neurologic outcomes.

Objective:

Examine the relationship between head injury and later cognitive impairment.

Methods:

A sample of 3,123 Japanese-American men was assessed for history of head injury and evaluated for cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). For a subsample of 676 respondents, neuropathologic results from those with and without head injury were compared.

Results:

Although the crude model showed an association between history of head injury and later severe cognitive impairment, the relationship lost significance in the adjusted model (OR = 1.320, CI: 0.90–1.93), regardless of time between injury and impairment. Similar to cognitive impairment, hippocampal sclerosis was observed significantly more in the brains of respondents with a history of head injury in the crude model, but the relationship weakened in the adjusted model (OR = 1.462, CI: 0.68–3.12). After adjustment, decedents with a head injury demonstrated marginally higher brain weight (OR = 1.003, CI: 1.00–1.01).

Conclusion:

We did not find a relationship between head injury and subsequent cognitive decline in this cohort. The neuropathology results also displayed no strong association between history of head injury and specific brain lesions and characteristics. These results support other findings in prospective cohorts. However, they could be influenced by the demographic make-up of the sample (male Japanese-Americans) or by the observation that the majority reported only a single head injury.

The authors describe a case of a 55-year-old woman who was diagnosed with Alzheimer’s disease 1.5 years after a car accident in which she experienced a mild concussion. Extensive history taking disclosed no cognitive changes prior to the car accident. The case is discussed in view of the inflammation hypothesis regarding Alzheimer’s disease and the role of the apolipoprotein E4 genotype of the patient.

Traumatic brain injuries (TBI) have received widespread media attention in recent years as being a risk factor for the development of dementia and chronic traumatic encephalopathy (CTE). This has sparked fears about the potential long-term effects of TBI of any severity on cognitive aging, leading to a public health concern. This article reviews the evidence surrounding TBI as a risk factor for the later development of changes in brain structure and function, and an increased risk of neurodegenerative disorders. A number of studies have shown evidence of long-term brain changes and accumulation of pathological biomarkers (e.g., amyloid and tau proteins) related to a history of moderate-to-severe TBI, and research has also demonstrated that individuals with moderate-to-severe injuries have an increased risk of dementia. While milder injuries have been found to be associated with an increased risk for dementia in some recent studies, reports on long-term brain changes have been mixed and often are complicated by factors related to injury exposure (i.e., number of injuries) and severity/complications, psychiatric conditions, and opioid use disorder. CTE, although often described as a neurodegenerative disorder, remains a neuropathological condition that is poorly understood. Future research is needed to clarify the significance of CTE pathology and determine whether that can explain any clinical symptoms. Overall, it is clear that most individuals who sustain a TBI (particularly milder injuries) do not experience worse outcomes with aging, as the incidence for dementia is found to be less than 7% across the literature.

Background:

Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson’s disease, and Alzheimer’s disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB).

Objective:

The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB.

Method:

Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer’s Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer’s Disease Center visit) was associated with earlier DLB symptom onset.

Results:

Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects.

Conclusions:

Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted.

Background:

Traumatic brain injury (TBI) is the most established environmental risk factor for Alzheimer’s disease (AD), but it is unclear if TBI is specifically associated with early-onset AD (EOAD).

Objective:

To evaluate the relationship between TBI and EOAD (<65 years).

Methods:

We identified 1,449 EOAD, 4,337 late-onset AD (LOAD), and corresponding EOAD-matched and LOAD-matched normal controls (NC) in the National Alzheimer’s Coordinating Center Uniform (NACC) database and compared the prevalence of any history of TBI as well as measures of cognition, function, behavior, and neuropathology. For validation, we determined TBI prevalence among 115 well-characterized clinic patients with EOAD.

Results:

Part A: The prevalence of any TBI in the NACC-database EOAD participants (13.3%) was comparable to that observed in the clinic EOAD patients (13.9%) but significantly higher than in the NACC-database LOAD participants (7.7%; p < 0.0001) and trended to higher compared to EOAD-matched NC (11.1%; logistic regression p = 0.053). Part B: When we compared EOAD patients with documented non-acute and non-residually impairing TBI to EOAD without a documented history of prior TBI, those with TBI had significantly more disinhibition. Part C: Autopsies did not reveal differences in AD neuropathology based on a history of TBI.

Conclusions:

These findings suggest, but do not establish, that TBI is a specific risk factor for EOAD and may lead to disinhibition, a feature that often results from the frontal effects of head injury. This study recommends further research on the effects of TBI in EOAD in larger numbers of participants.

Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer’s disease (AD) are also implicated in the central autonomic nervous system (ANS) regulation. For example, deficits in central cholinergic function in AD could likely lead to autonomic dysfunction. We recently developed a simple, readily applicable evaluation for monitoring ANS disturbances in response to traumatic brain injury (TBI). This ability to monitor TBI allows for the possible detection and targeted prevention of long-term, detrimental brain responses caused by TBI that lead to neurodegenerative diseases such as AD. We randomly selected and extracted de-identified medical record information from subjects who have been assessed using the ANS evaluation protocol. Using machine learning strategies in the analysis of information from individual as well as a combination of ANS evaluation protocol components, we identified a novel prediction model that is effective in correctly segregating between cases with or without a documented history of TBI exposure. Results from our study support the hypothesis that trauma-induced ANS dysfunctions may contribute to clinical TBI features. Because autonomic dysfunction is very common in AD patients it is possible that TBI may also contribute to AD and/or other forms of dementia through these novel mechanisms. This study provides a novel prediction model to physiologically assess the likelihood of subjects with prior history of TBI to develop clinical TBI complications, such as AD.

This study examined whether history of traumatic brain injury (TBI) is associated with increased risk and earlier onset of mild cognitive impairment (MCI). Subjects with MCI (n = 3,187) and normal cognition (n = 3,244) were obtained from the National Alzheimer’s Coordinating Center database. TBI was categorized based on lifetime reported TBI with loss of consciousness (LOC) without chronic deficit. Logistic regression was used to examine TBI history as a predictor of MCI, adjusted for demographics, apolipoprotein E-ε4 (ApoE4), a composite vascular risk score, and history of psychiatric factors. ANCOVA was used to examine whether age at MCI diagnosis and estimated age of onset differed between those with (TBI+) and without (TBI–) a history of TBI. TBI history was a significant predictor (p < 0.01) and associated with increased odds of MCI diagnosis in unadjusted (OR = 1.25; 95% CI = 1.05–1.49) and adjusted models, accounting for age, education, ApoE4, and a composite vascular score (OR = 1.32; 95% CI = 1.10–1.58). This association, however, was largely attenuated (OR = 1.14; 95% CI = 0.94–1.37; p = 0.18) after adjustment for reported history of depression. MCI was diagnosed a mean of 2.3 years earlier (p < 0.001) in the TBI+ group, and although TBI+ subjects had an estimated mean of decline 1.7 years earlier, clinician-estimated age of onset failed to differ (p = 0.13) when gender and psychiatric factors were controlled. This is the first report of a possible role for TBI as a risk factor in MCI, but its association may be related to other factors such as gender and depression and requires further investigation.

Given the increasing rate of death by suicide in the United States, it is imperative to examine specific risk factors and to identify possible etiologies of suicidal behavior in at-risk clinical subpopulations. There is accumulating evidence to support an elevated risk of death by suicide in individuals with a history of traumatic brain injury (TBI). In this review article, after defining terms used in suicidology, we discuss the associations of TBI with death by suicide, suicide attempt, and suicidal ideation. A model for repetitive TBIs, leading to chronic traumatic encephalopathy, is also discussed as a neuroinflammatory process, with discussion about its possible link with suicide. The review concludes with an overview of interventions to prevent suicidal behavior.

We explored whether changes in the expression profile of peripheral blood plasma proteins may provide a clinical, readily accessible “window” into the brain, reflecting molecular alterations following traumatic brain injury (TBI) that might contribute to TBI complications. We recruited fourteen TBI and ten control civilian participants for the study, and also analyzed banked plasma specimens from 20 veterans with TBI and 20 control cases. Using antibody arrays and ELISA assays, we explored differentially-regulated protein species in the plasma of TBI compared to healthy controls from the two independent cohorts. We found three protein biomarker species, monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-binding protein-3, and epidermal growth factor receptor, that are differentially regulated in plasma specimens of the TBI cases. A three-biomarker panel using all three proteins provides the best potential criterion for separating TBI and control cases. Plasma MCP-1 contents are correlated with the severity of TBI and the index of compromised axonal fiber integrity in the frontal cortex. Based on these findings, we evaluated postmortem brain specimens from 7 mild cognitive impairment (MCI) and 7 neurologically normal cases. We found elevated MCP-1 expression in the frontal cortex of MCI cases that are at high risk for developing Alzheimer’s disease. Our findings suggest that additional application of the three-biomarker panel to current diagnostic criteria may lead to improved TBI detection and more sensitive outcome measures for clinical trials. Induction of MCP-1 in response to TBI might be a potential predisposing factor that may increase the risk for development of Alzheimer’s disease.

Traumatic brain injury (TBI) is a leading cause of death and disability among children and young adults in the United States. In this study, we explored whether changes in the gene expression profile of peripheral blood mononuclear cells (PBMC) may provide a clinically assessable “window” into the brain, reflecting molecular alterations following TBI that might contribute to the onset and progression of TBI clinical complications. We identified three olfactory receptor (OR) TBI biomarkers that are aberrantly down-regulated in PBMC specimens from TBI subjects. Down-regulation of these OR biomarkers in PBMC was correlated with the severity of brain injury and TBI-specific symptoms. A two- biomarker panel comprised of OR11H1 and OR4M1 provided the best criterion for segregating the TBI and control cases with 90% accuracy, 83.3% sensitivity, and 100% specificity. We found that the OR biomarkers are ectopically expressed in multiple brain regions, including the entorhinal-hippocampus system known to play an important role in memory formation and consolidation. Activation of OR4M1 led to attenuation of abnormal tau phosphorylation, possibly through JNK signaling pathway. Our results suggested that addition of the two-OR biomarker model to current diagnostic criteria may lead to improved TBI detection for clinical trials, and decreased expression of OR TBI biomarkers might be associated with TBI- induced tauopathy. Future studies exploring the physiological relevance of OR TBI biomarkers in the normal brain and in the brain following TBI will provide a better understanding of the biological mechanisms underlying TBI and insights into novel therapeutic targets for TBI.

Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results.

Alzheimer’s disease, traumatic brain injury, and chronic traumatic encephalopathy represent conditions that have a profound socioeconomic impact for both the individual and the wider community. They are all characterized by specific protein aggregation that results in synaptic dysfunction, neuronal death, and consequent cognitive decline and memory loss. In this review, we present evidence to support the notion that the common pathologies found in all conditions, and indeed their associated cognitive deficits, may be linked by zinc (Zn²⁺) ion dyshomeostasis. Elucidation of this hypothesis may present new therapeutic avenues for these devastating conditions.

Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.