Chronic Traumatic Encephalopathy

Etiology

Repeated head injury is crucial in the genesis of CTE, with a strong causal relationship established between repeated trauma and the condition.[3] Repeated head injury exposure is the only known unifying factor and is present in 97% of patients among the more than 600 CTE cases reported in the literature.[3] Computational models and animal studies involving Musk oxen and bighorn sheep—both with gyrencephalic brains (with sulci) and engaged in combative headbutting—have shown positive correlations between repeated head injury and CTE.[3] 

An association exists between cognitive reserve, demographic factors (eg, early age of first exposure), and exposure metrics (eg, cumulative head impact index) with the severity of future neurological sequelae.[1][6] A consistent dose-response relationship has been validated between cumulative years of playing contact sports, such as American football and ice hockey, and both the onset and severity of CTE.[3] Additionally, the APOE epsilon-4 allele has been shown to predict an increased risk of developing cognitive decline following repeated head impacts.[1]

Epidemiology

Approximately 4 million sports-related concussions are reported annually in the United States alone.[1] The incidence of sport-related neurological conditions among boxers is reported to be 17%. In a study conducted by the Mayo Clinic Brain Bank, CTE pathology was found in 32% of athletes who participated in contact sports. Similarly, in the largest case series of 177 former professional football players, CTE was diagnosed in up to 87% of the patients.[1] A recent study has also revealed significant neuropathological evidence of CTE among football players who donated their brains for research.[7]

Pathophysiology

Tau protein regulates the assembly of tubulin into microtubules, thereby maintaining the structural integrity of axons. Tau phosphorylation mediates tau's binding to microtubules. Tau proteins dissociate from microtubules in axons due to calcium influx and glutamate hyperexcitotoxicity. Calcium influx activates caspases, while glutamate hyperexcitotoxicity causes cytoskeletal failure. These disruptions lead to kinase-mediated hyperphosphorylation, misfolding, and aggregation of tau, which is then proteolytically cleaved by calpains and caspases.[8][9] These processes, including tau phosphorylation, misfolding, shortening, and aggregation, contribute to NFT deposition.[9] 

TAR DNA-binding protein 43 (TDP-43) inclusions and amyloid-β deposition are also observed in CTE. Perivascular polarization of astroglial aquaporin-4 impairs glymphatic clearance.[9] The combination of excessive protein deposition and reduced clearance aggravates the neurodegenerative process. Oxidative stress, neuroinflammation, and glutaminergic toxicity contribute significantly to CTE pathogenesis. Chronic inflammation disrupts the ubiquitin-proteasome pathway, while microglial priming leads to immune-excitotoxic responses and persistent neurodegeneration.[9] 

Immuno-excitotoxicity is critical in the pathogenesis of CTE. Repeatedly primed microglia, after a repetitive head injury, fail to transition from a neuro-destructive mode to a reparative mode. This failure exacerbates the inflammatory insult to the brain by providing a favorable milieu amidst glutamate toxicity.[10] Excitotoxicity also generates reactive oxygen and nitrogen species.[9] Repeated head injury causes axonal degeneration and microtubular disintegration, leading to tau oligomerization. This oligomerization progresses to the formation of NFTs, affecting neuronal crosstalk and networking. This disruption eventually results in tau propagation, which triggers inflammatory cascades and ultimately impairs blood-brain barrier permeability.[11]

Histopathology

Gross examination reveals features of regional atrophy, most commonly in the frontal lobe, along with ventriculomegaly, wasting of the corpus callosum, and characteristic fenestration of the septum pellucidum. The regions of atrophy parallel high concentrations of glutamate receptors, thereby connoting excitotoxicity's role in the entity's pathogenesis.[1]

Microscopically, the predominant findings include the deposition of NFTs and neuropil threads. In CTE, NFTs are deposited perivascularly at the sulcal depths and are exclusively neuronal.[3][12] 4R isomers are predominant in stages I and II, while 3R isomers are more prevalent in stages III and IV.[3] Perivascular tau deposition within the sulcal depths is a critical criterion for diagnosing CTE, according to the first consensus from the NINDS and NIBIB.[1] The presence of neuronal p-tau is significantly associated with age, years of repeated head injury exposure, and the severity of CTE.[3]

The following 4 histomorphologic phenotypes have been associated with CTE:

• Type 1: NFTs and neuropil threads are present only in the cerebral cortex and brainstem.
• Type 2: Type 1 features along with amyloid-β deposition.
• Type 3: NFTs and neuropil threads are found exclusively in the brainstem.
• Type 4: NFTs and neuropil threads in the cortex, subcortex, brainstem, and basal ganglia, with the cerebellum being spared.[13]

The Understanding Neurologic Injury in Traumatic Encephalopathy (UNITE) study, funded by the NINDS, also described patchy and perivascular deposits of NFTs in astrocytes and at the depths of the sulci.[14] As established by the NINDS panel consensus, the pattern of p-tau in CTE is distinct from other neurodegenerative conditions.[14] Hallmarks include the superficial distribution of NFTs in layers II and III, patchy distribution of NFTs, and a perivascular pattern within the depths of the cortical sulci.[3] Brainstem p-tau pathology is considered a supportive feature of CTE.[3] P-tau spares the calcarine cortex even in the advanced stage.[9]

History and Physical

The medical history typically includes some form of repetitive head trauma, often involving individuals who participate in contact sports or serve in the military. A thorough neurologic examination is crucial, with a particular emphasis on mental status assessment.[1] Younger individuals are more likely to present with mood and behavior symptoms, while older individuals commonly exhibit cognitive impairment and executive dysfunction.[3] Cognitive symptoms increase the odds of CTE by 3.6-fold.[14] During longitudinal follow-up, patients with a history of recurrent concussions tend to have a higher burden of cognitive, sleep, and neuropsychiatric symptoms but not migraine symptoms.[2] 

As described by Browne, the disease process begins with affective disturbances, followed by a stage of social instability and behavioral changes, with subtle features of early Parkinsonism. This eventually progresses to a third stage characterized by cognitive dysfunction, dementia, and full-blown Parkinsonism.[15] These changes have been attributed to the disease's impact on the Papez circuit.[16] 

The research diagnostic criteria describe 4 subtypes of CTE, including:

• Behavioral or mood variant
• Cognitive variant
• Mixed variant
• Dementia form [1]

Evaluation

Montenegro et al proposed the following clinical diagnostic criteria for CTE:

• A history of multiple head impacts
• Exclusion of other clinical mimics
• Symptomatology present for at least 12 months
• A minimum of 1 core and 2 supportive elements present[17]

The core elements comprise cognitive symptoms (eg, episodic memory, executive function, and attention), behavioral (eg, verbal or physical aggression), and mood symptoms (eg, feeling depressed or hopeless).[14] As CTE can only be definitively diagnosed through postmortem neuropathologic findings, the NINDS consensus developed guidelines to aid in the clinical identification of TES.[4]

The 4 primary diagnostic criteria proposed by the NINDS consensus for TES include:

• Substantial exposure to repeated head injury
• Core clinical features such as cognitive impairment (eg, episodic memory and executive functioning) and neurobehavioral dysregulation (eg, explosiveness, impulsivity, rage, violent outbursts, and emotional lability) with a progressive course
• Clinical features not fully accounted for by other disorders [3]

However, these criteria have a high risk of false positives, with nearly 54% of cognitively normal individuals receiving a consensus diagnosis. Additionally, there is a lack of spatial correlation between TES and head injury exposure.[18] The degree of depression is the only significant predictor of a positive TES diagnosis.[18] 

Although CTE is confirmed through postmortem autopsy, the diagnosis is facilitated by immunohistochemistry for p-tau.[6][11] Recent advances in imaging armamentarium and fluid biomarkers can also provide valuable input to support the diagnosis.[11][19][20] Growing evidence supports the role of the regional tau standardized uptake value ratio in flortaucipir positron-emission tomography (PET) and florbetapir PET for facilitating diagnosis,[14] although the specificity remains poorly documented.[21] Specific prototypical patterns or regional volume differences have not been identified in PET imaging.[22]

A significant correlation has been observed only in the superior frontal region and among individuals aged 60 or older.[23] Furthermore, off-target binding in the hippocampus and thalamus complicates the interpretation of imaging results.[21] Other important radiological features include concurrent cavum septum pellucidum and reduced fractional anisotropy in the corpus callosum and medial temporal white matter.[14][22] Magnetic resonance imaging (MRI) and PET imaging are essential for ruling out other clinical mimics.[22]

Potential fluid biomarkers for CTE include glial fibrillary acidic protein (GFAP), neurofibrillary light chain (NfL), total tau, neuron-specific enolase (NSE), ubiquitin C-terminal hydrolase-1 (UCHL-1), S100B, myelin basic protein (MBP), microtubule-associated protein-2 (MAP-2), brain-derived neurotrophic factor (BDNF), microRNA, and microvesicles and exosomes.[14][24][25] However, plasma biomarkers do not correspond well with cerebrospinal fluid measures in cases of late repetitive head injury, thereby minimizing their efficacy.[26] Therefore, consensus on the role of fluid biomarkers in managing CTE has yet to be established. However, a recent pivotal finding of a characteristic hydrophobic cavity within the β-helix of tau filaments from CTE has opened new avenues for identifying early diagnostic targets (see Image. Chronic Traumatic Encephalopathy).[27]

Treatment / Management

Currently, a definitive treatment for CTE does not exist; therefore, multispectral supportive measures are the mainstay of management.[1] Amantadine and guanfacine may offer benefits for cognitive and working memory deficits. Cognitive improvement can be supported through cognitive rehabilitation therapy, a Mediterranean diet, and aerobic exercise.[14] Occupational rehabilitation should also be encouraged. Depression requires careful management due to the potential risk of suicidality.

Antioxidants such as ascorbic acid, N-acetylcysteine, alpha-tocopherol (ie, vitamin E), carotenoids, and omega-3 fatty acids have been used to counteract reactive oxygen species and reactive nitrogen species. Salsalate, which inhibits the acetylation process before the phosphorylation of the paired helical filament-6 motif and thereby suppresses microglial activation, is under research.[11] Ongoing research also focuses on tau acetylation, tau phosphorylation, and immunotherapy, such as using adeno-associated virus vectors to deliver anti-p-tau antibodies.

The best modality for minimizing the incidence of CTE is through strict adherence to preventive measures and safe practices.[14] Establishing mandatory provisions for a safe playing environment and strictly upholding "return-to-play" policies are paramount.[12]

Differential Diagnosis

In addition to a single traumatic brain injury, conditions with clinical features that mimic CTE include:[28][29]

• Alzheimer disease.
• Frontotemporal lobar degeneration.
• Lewy body disease.
• Cerebral amyloid angiopathy.
• Parkinsonism.
• Age-related tau astrogliopathy, characterized by subpial "thorn-shaped astrocytes" with purely astrocytic perivascular p-tau pathology, is observed. Moreover, 47% of these lesions are restricted to the midbrain, whereas current criteria for CTE require at least 1 pathognomonic cortical lesion.
• Limbic-predominant age-related TDP-43 encephalopathy with neuropathologic changes associated with hippocampal sclerosis.
• Bulbar amyotrophic lateral sclerosis.
• Primary age-related tauopathy (PART).[3][30]

The characteristic finding that helps differentiate CTE from other tauopathies, such as Alzheimer and Lewy body dementia, is the perivascular deposition of tau-immunoreactive astrocytes within the sulcal depths of superficial cortical layers.[11] Additionally, the dimensions of NFTs in CTE are larger and are associated with co-localized aggregates of TDP-43.[11] Concurrent neurodegenerative diseases are observed in almost 40% of CTE cases.[3] However, CTE remains a unique tauopathy—both ultrastructurally and microscopically.[3] 

The tau filament in CTE features a unique β-helix region with a hydrophobic cavity.[14][27] CTE exhibits higher levels of p-tau in the CA2 and CA3 regions of the hippocampus compared to CA1 and subiculum in Alzheimer disease. Similarly, CA3 and CA4 regions have significantly higher p-tau burden in CTE than PART.[3]

Pertinent Studies and Ongoing Trials

NEurodegeneration: Traumatic Brain Injury as Origin of the Neuropathology (NEwTON)

NEwTON is a prospective study recruiting patients at risk for developing CTE.[31] Similarly, the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE)'' research project aims to provide newer insights into CTE's pathogenesis and natural history.[32]

Staging

The following 4 stages of CTE are described according to the distribution of NFTs and associated clinical signs and symptoms:

• Stage I: Perivascular deposits of NFTs in the sulcal depths characterized by headache and loss of concentration.
• Stage II: Stage I features plus NFTs within the nucleus basalis of Meynert and locus coeruleus, with mood swings and short-term memory loss.
• Stage III: Stage II features plus atrophy, wasting of the corpus callosum, septal abnormalities, ventriculomegaly, depigmentation of the substantia nigra, and widespread deposition of p-tau, characterized by cognitive impairment, executive dysfunction, and visuospatial abnormalities.
• Stage IV: Stage III features plus further atrophy, gliosis, and hippocampal sclerosis, characterized by profound memory loss and florid parkinsonian features.[1]

McKee described the following 4 pathological stages of CTE:

• Stage I: Perivascular p-tau deposits in the sulci, primarily within the superior dorsolateral and inferior frontal cortices.
• Stage II: Mild ventricular enlargement and changes in the septum pellucidum.
• Stage III: Progressive ventricular enlargement, mild frontal and temporal atrophy, and NFT deposits within the olfactory bulb, entorhinal cortex, hippocampus, amygdala, and mammillary bodies.
• Stage IV: Diffuse cortical atrophy and complete depigmentation of the locus coeruleus and substantia nigra.[6]

Prognosis

The incidence of mortality among former players has been observed to be 3 times higher than their healthy counterparts. Furthermore, studies have demonstrated a link between CTE and the development of early-onset Parkinsonian dementia.[33]

Complications

CTE is progressive in approximately 68% of patients. In a small subgroup with predominantly behavioral or mood symptoms, the condition may remain stable for years before progressing to other stages after a latency of 11 to 14 years.[1] The neurodegenerative process sequentially progresses through stages of social instability and behavioral changes before advancing to dementia.[1] Additionally, there is an increased risk of suicide among these subsets of patients.