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Mild traumatic brain injury (mTBI) includes concussion, subconcussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and pathological features that overlap with postconcussion ...

Chronic traumatic encephalopathy (CTE, previously called punch drunk and dementia pugilistica) has a rich history in the medical literature in association with boxing, but has only recently been recognized with other contact sports, such as football and ice hockey, as well as with military blast injuries. CTE is thought to be a neurodegenerative disease associated with repeated concussive and subconcussive blows to the head. There is characteristic gross and microscopic pathology found in the brain, including frontal and temporal atrophy, axonal degeneration, and hyperphosphorylated tau and TAR DNA-binding protein 43 pathology. Clinically, there are characteristic progressive deficits in cognition (memory, executive dysfunction), behavior (explosivity, aggression), mood (depression, suicidality), and motor function (parkinsonism), which correlate with the anatomic distribution of brain pathology. While CTE shares clinical and neuropathological traits with other neurodegenerative diseases, the clinical syndrome and the neuropathology as a whole are distinct from other neurodegenerative diseases. Here we review the CTE literature to date. We also draw on the literature from mild traumatic brain injury and other neurodegenerative dementias, particularly when these studies provide guidance for future CTE research. We conclude by suggesting seven essential areas for future CTE research.

There are growing concerns that cumulative repetitive head impact exposure through routine participation in contact and collision sports is associated with increased risk of long-term problems in memory and cognition, including the development of chronic traumatic encephalopathy (CTE). CTE is a distinctive neurodegenerative disease that occurs as a result of repetitive head impacts (RHI) including concussion and subconcussion. Like most neurodegenerative diseases, CTE can only be diagnosed by postmortem neuropathologic examination of brain tissue. Recently a panel of exerts concluded that CTE is a unique disorder with a pathognomonic lesion that can be reliably distinguished from other neurodegenerative diseases, such as Alzheimer's disease and frontotemporal lobar degeneration. The pathognomonic lesion of CTE consists of a perivascular accumulation of hyperphosphorylated tau protein in neurons and astrocytes in an irregular pattern, and is typically most prominent at the depths of the cerebral sulci. Clinically CTE is associated with violent behaviors, explosivity, a loss of control, depression, suicide, memory loss and cognitive changes. While the exact incidence and prevalence of CTE remain unknown, there is increasing evidence that CTE affects amateur atheletes as well as professional athletes and military veterans. Given the millions of contact sport athletes and military service members who are exposed to RHI each year, CTE has become a major public health concern. There is a critical need for identification of CTE during life, improved understanding of the epidemiology and pathobiology, and the development of effective prevention and treatment strategies for CTE.

Abstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs in association with repetitive traumatic brain injury experienced in sport and military service. In most instances, the clinical symptoms of the disease begin after a long period of latency ranging from several years to several decades. The initial symptoms are typically insidious, consisting of irritability, impulsivity, aggression, depression, short-term memory loss and heightened suicidality. The symptoms progress slowly over decades to include cognitive deficits and dementia. The pathology of CTE is characterized by the accumulation of phosphorylated tau protein in neurons and astrocytes in a pattern that is unique from other tauopathies, including Alzheimer's disease. The hyperphosphorylated tau abnormalities begin focally, as perivascular neurofibrillary tangles and neurites at the depths of the cerebral sulci, and then spread to involve superficial layers of adjacent cortex before becoming a widespread degeneration affecting medial temporal lobe structures, diencephalon and brainstem. Most instances of CTE (>85% of cases) show abnormal accumulations of phosphorylated 43 kDa TAR DNA binding protein that are partially colocalized with phosphorylated tau protein. As CTE is characterized pathologically by frontal and temporal lobe atrophy, by abnormal deposits of phosphorylated tau and by 43 kDa TAR DNA binding protein and is associated clinically with behavioral and personality changes, as well as cognitive impairments, CTE is increasingly categorized as an acquired frontotemporal lobar degeneration. Currently, some of the greatest challenges are that CTE cannot be diagnosed during life and the incidence and prevalence of the disorder remain uncertain. Furthermore, the contribution of age, gender, genetics, stress, alcohol and substance abuse to the development of CTE remains to be determined.

Abstract The association of military blast exposure and brain injury was first appreciated in World War I as commotio cerebri, and later as shell shock. Similar injuries sustained in modern military conflicts are now classified as mild traumatic brain injury (TBI). Recent research has yielded new insights into the mechanisms by which blast exposure leads to acute brain injury and chronic sequelae, including postconcussive syndrome, post-traumatic stress disorder, post-traumatic headache, and chronic traumatic encephalopathy, a tau protein neurodegenerative disease. Impediments to delivery of effective medical care for individuals affected by blast-related TBI include: poor insight into the heterogeneity of neurological insults induced by blast exposure; limited understanding of the mechanisms by which blast exposure injures the brain and triggers sequelae; failure to appreciate interactive injuries that affect frontal lobe function, pituitary regulation, and neurovegetative homeostasis; unknown influence of genetic risk factors, prior trauma, and comorbidities; absence of validated diagnostic criteria and clinical nosology that differentiate clinical endophenotypes; and lack of empirical evidence to guide medical management and therapeutic intervention. While clinicopathological analysis can provide evidence of correlative association, experimental use of animal models remains the primary tool for establishing causal mechanisms of disease. However, the TBI field is confronted by a welter of animal models with varying clinical relevance, thereby impeding scientific coherence and hindering translational progress. Animal models of blast TBI will be far more translationally useful if experimental emphasis focuses on accurate reproduction of clinically relevant endpoints (output) rather than scaled replication of idealized blast shockwaves (input). The utility of an animal model is dependent on the degree to which the model recapitulates pathophysiological mechanisms, neuropathological features, and neurological sequelae observed in the corresponding human disorder. Understanding the purpose of an animal model and the criteria by which experimental results derived from the model are validated are critical components for useful animal modeling. Animal models that reliably demonstrate clinically relevant endpoints will expedite development of new treatments, diagnostics, preventive measures, and rehabilitative strategies for individuals affected by blast TBI and its aftermath.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs in association with repetitive traumatic brain injury experienced in sport and military service. In most instances, the clinical symptoms of the disease begin after a long period of latency ranging from several years to several decades. The initial symptoms are typically insidious, consisting of irritability, impulsivity, aggression, depression, short-term memory loss and heightened suicidality. The symptoms progress slowly over decades to include cognitive deficits and dementia. The pathology of CTE is characterized by the accumulation of phosphorylated tau protein in neurons and astrocytes in a pattern that is unique from other tauopathies, including Alzheimer's disease. The hyperphosphorylated tau abnormalities begin focally, as perivascular neurofibrillary tangles and neurites at the depths of the cerebral sulci, and then spread to involve superficial layers of adjacent cortex before becoming a widespread degeneration affecting medial temporal lobe structures, diencephalon and brainstem. Most instances of CTE (>85% of cases) show abnormal accumulations of phosphorylated 43 kDa TAR DNA binding protein that are partially colocalized with phosphorylated tau protein. As CTE is characterized pathologically by frontal and temporal lobe atrophy, by abnormal deposits of phosphorylated tau and by 43 kDa TAR DNA binding protein and is associated clinically with behavioral and personality changes, as well as cognitive impairments, CTE is increasingly categorized as an acquired frontotemporal lobar degeneration. Currently, some of the greatest challenges are that CTE cannot be diagnosed during life and the incidence and prevalence of the disorder remain uncertain. Furthermore, the contribution of age, gender, genetics, stress, alcohol and substance abuse to the development of CTE remains to be determined.

Military personnel are often exposed to multiple instances of various types of head trauma. As a result, there has been increasing concern recently over identifying when head trauma has resulted in a brain injury and what, if any, long-term consequences those brain injuries may have. Efforts to develop equipment to protect soldiers from these long-term consequences will first require understanding the types of head trauma that are likely responsible. In this study, we sought to identify the types of head trauma most likely to lead to the deposition of tau, a protein identified as a likely indicator of long-term negative consequences of brain injury. To define the types of head trauma in a military population, we applied a factor analysis to interviews from a larger cohort of 428 Veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders. Three factors were identified: Blast Exposure, Symptom Duration, and Blunt Concussion. Sixteen male Veterans from this study and one additional male civilian (aged 25–69, mean 35.2 years) underwent simultaneous positron emission tomography/magnetic resonance imaging using a tracer that binds to tau protein, the ligand T807/AV-1451 (Flortaucipir). Standard uptake value ratios to the isthmus of the cingulate were calculated from a 20-minute time frame 70 min post-injection. We found that tracer uptake throughout the brain was associated with Blast Exposure factor beta weights, but not with either Symptom Duration or Blunt Concussion. Associations with uptake were located primarily in the cerebellar, occipital, inferior temporal and frontal regions. The data suggest that in this small, relatively young cohort of Veterans, elevated T807/AV-1451 uptake is associated with exposure to blast neurotrauma. These findings are unanticipated, as they do not match histopathological descriptions of tau pathology associated with head trauma. Continued work will be necessary to understand the nature of the regional T807/AV-1451 uptake and any ...

Exposure to military blast and repetitive head impacts (RHI) in contact sports is associated with increased risk of long-term neurobehavioral sequelae and cognitive deficits, and the neurodegenerative disease chronic traumatic encephalopathy (CTE). At present, the exact pathogenic mechanisms of RHI and CTE are unknown, and no targeted therapies are available. Astrocytes have recently emerged as key mediators of the multicellular response to head trauma. Here, we investigated interface astrogliosis in blast and impact neurotrauma, specifically in the context of RHI and early stage CTE. We compared postmortem brain tissue from former military veterans with a history of blast exposure with and without a neuropathological diagnosis of CTE, former American football players with a history of RHI with and without a neuropathological diagnosis of CTE, and control donors without a history of blast, RHI exposure or CTE diagnosis. Using quantitative immunofluorescence, we found that astrogliosis was higher at the grey-white matter interface in the dorsolateral frontal cortex, with mixed effects at the subpial surface and underlying cortex, in both blast and RHI donors with and without CTE, compared to controls. These results indicate that certain astrocytic alterations are associated with both impact and blast neurotrauma, and that different astroglial responses take place in distinct brain regions.

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts. White matter rarefaction and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. In astrocytes, total cell numbers were indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and suggest that white matter alterations are a critical aspect of CTE neurodegeneration. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-021-02322-2.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. The current status of the epidemiology, challenges to its study, and novel study design options are discussed in this paper. We focus on recent results from large-scale population based prospective studies, case-control studies and population based registries, risk factors, and neuropathologic findings in chronic traumatic encephalomyelopathy. We identify areas of interest for future research, including time-trends in the incidence and prevalence of ALS; the meaning of lifetime risk; the phenotypic description of ALS; the definition of familial versus sporadic ALS, syndromic aspects of ALS; specific risk factors such as military service, life style factors such as smoking, the use of statins, and the presence of β-N-methylamino-L-alanine (BMAA), an excitotoxic amino acid derivative possibly produced by cyanobacteria found in almost every terrestrial and aquatic habitat; the emergence and disappearance of an endemic ALS in areas of the Pacific; and gene-environment interactions in the etiology of ALS. To move the epidemiology forward, we suggest using well-characterized cohorts of newly diagnosed ALS patients to identify risk and prognostic factors; storing biological material for future studies; building on the National ALS Registry as a resource of future studies; working in multidisciplinary consortia; and addressing the possible early life etiology of ALS.

Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increased number of NFTs across the pathological stages of CTE. However, molecular mechanisms underlying nbM neurodegeneration in the context of CTE pathology remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several gene ontology groups between CTE stages. Specifically, downregulation of the nicotinic cholinergic receptor subunit β-2 gene (CHRNB2), monoaminergic enzymes catechol-O-methyltransferase (COMT) and dopa decarboxylase (DDC), chloride channels CLCN4 and CLCN5, scaffolding protein caveolin 1 (CAV1), cortical development/cytoskeleton element lissencephaly 1 (LIS1), and intracellular signaling cascade member adenylate cyclase 3 (ADCY3) was observed in pS422-immunreactive nbM neurons in CTE patients. By contrast, upregulation of calpain 2 (CAPN2) and microtubule-associated protein 2 (MAP2) transcript levels was found in Stage IV CTE patients. These single-population data in vulnerable neurons indicate alterations in gene expression associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics, suggesting novel molecular pathways to target for drug discovery in CTE.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p-tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression, or therapeutic development. Disruption of alternative pre-mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data is available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post-mortem human brain tissue from individuals with a range of CTE stages (n=99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p-tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I-II), a 3R shift was observed in later stages (III-IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R-positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau ...

Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are signature injuries of the wars in Iraq and Afghanistan and have been linked to an increased risk of Alzheimer's disease (AD) and other dementias. A meeting hosted by the Alzheimer's Association and the Veterans' Health Research Institute (NCIRE) in May 2012 brought together experts from the U.S. military and academic medical centers around the world to discuss current evidence and hypotheses regarding the pathophysiological mechanisms linking TBI, PTSD, and AD. Studies underway in civilian and military populations were highlighted, along with new research initiatives such as a study to extend the Alzheimer's Disease Neuroimaging Initiative (ADNI) to a population of veterans exposed to TBI and PTSD. Greater collaboration and data sharing among diverse research groups is needed to advance an understanding and appropriate interventions in this continuum of military injuries and neurodegenerative disease in the aging veteran.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5 years after initial symptom onset, approximately 10% of patients with ALS live more than 10 years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n = 179), dichotomized into standard duration (<10 years) and long-duration (≥10 years). The ALS Functional Rating Scale-Revised (ALSFRS-R) was administered at study entry and semi-annually thereafter until death. Microglial density was determined in a subset of participants. Long-duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3 years (min/max = 10.1/42.2). Participants with long-duration ALS were younger at disease onset (P = 0.002), had a slower initial ALS symptom progression on the ALSFRS-R (P < 0.001) and took longer to diagnose (P < 0.002) than standard duration ALS. Pathologically, long-duration ALS was associated with less frequent TDP-43 pathology (P < 0.001). Upper motor neuron degeneration was similar; however, long-duration ALS participants had less severe lower motor neuron degeneration at death (P < 0.001). In addition, the density of microglia was decreased in the corticospinal tract (P = 0.017) and spinal cord anterior horn (P = 0.009) in long-duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long-duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long-duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive head impacts and has been associated with amyotrophic lateral sclerosis (ALS), a fatal, degenerative neuromuscular disorder. The Department of Veterans Affairs Biorepository Brain Bank (VABBB) is a tissue repository that collects antemortem disease progression data and postmortem central nervous system tissue from veterans with ALS. We set out to determine the frequency of co-morbid ALS and CTE in the VABBB cohort and to characterize the clinical, genetic, and pathological distinctions between participants with ALS only and those with both ALS and CTE (ALS+CTE). Of 155 participants, 9 (5.8%) had neuropathologically confirmed ALS+CTE. Participants with ALS+CTE were more likely to have a history of traumatic brain injury (p < 0.001), served during the first Persian Gulf War (p < 0.05), and to have more severe tau pathology within the frontal cortex and spinal cord (p < 0.05). The most common exposures to head impacts included contact sports (n = 5) and military service (n = 2). Clinically, participants with ALS+CTE were more likely to have bulbar onset ALS (p = 0.006), behavioral changes (p = 0.002), and/or mood changes (p < 0.001). Overall, compared with ALS in isolation, comorbid ALS+CTE is associated with a history of TBI and has a distinct clinical and pathological presentation.