How is chronic traumatic encephalopathy (CTE) diagnosed in a living patient, including recommended clinical evaluation and imaging studies?

Diagnosing Chronic Traumatic Encephalopathy (CTE)

CTE cannot be definitively diagnosed in living patients—the only confirmed diagnosis is through post-mortem neuropathologic examination demonstrating a unique pattern of hyperphosphorylated tau (p-tau) deposition. 1

Current Diagnostic Limitations

• Definitive diagnosis requires autopsy: CTE diagnosis can only be made by neuropathologic examination showing the pathognomonic lesion of perivascular accumulation of hyperphosphorylated tau as neurofibrillary tangles and dotlike neurites, preferentially at the depths of cortical sulci. 1, 2

• No validated in-vivo diagnostic method exists: A diagnosis of dementia due to CTE during life is not yet possible to make with certainty. 1

Clinical Evaluation: Traumatic Encephalopathy Syndrome (TES)

While you cannot diagnose CTE in living patients, you can evaluate for Traumatic Encephalopathy Syndrome (TES) using the 2021 NIH/NINDS Consensus Diagnostic Criteria, which requires ALL four of the following: 1

1. Substantial Exposure to Repetitive Head Impacts

• Contact sports participation (American football, boxing, rugby, ice hockey, soccer) 1, 3, 2
• Military service 1, 2
• Other causes of repeated head trauma 1

2. Core Clinical Features (at least one required):

• Cognitive impairment: Core deficits in episodic memory and/or executive function (potentially with other domain involvement) 1
• Neurobehavioral dysregulation: Poor regulation or control of emotions/behavior including explosiveness, impulsivity, rage, violent outbursts, having a "short fuse" (exceeding minor irritability), or emotional lability—not transiently occurring in context of life events like divorce, death, or financial problems 1

3. Progressive Course

• Symptoms must demonstrate progression over time 1

4. Exclusion of Alternative Diagnoses

• Clinical features are not fully accounted for by other neurologic, psychiatric, or medical conditions 1

Imaging Studies

Conventional Imaging Has Limited Utility for CTE Diagnosis

• MRI for subacute/chronic symptoms: MRI is recommended only in the presence of new, persistent, or worsening symptoms in patients with subacute to chronic traumatic brain injury. 4

• Structural MRI findings (non-specific for CTE): Studies have identified Evans index enlargement, cavum septum pellucidum presence/length, and regional brain atrophy, but these lack specificity for CTE. 5

• Advanced MRI techniques (research stage): Diffusion tensor imaging (DTI) showing axial diffusivity changes and free/intracellular water fraction alterations have been reported but require validation. 6, 7, 5

• CT has no role: CT is not useful for chronic TBI evaluation when assessing for CTE-related changes, as it lacks the soft-tissue contrast resolution needed to detect subtle findings. 8

Emerging Imaging Biomarkers (Not Yet Clinically Validated)

• Tau PET imaging: The most promising biomarker is tau-binding radionuclide PET signal, which is most specific to underlying CTE neuropathology and has differentiated suspected CTE from controls and Alzheimer disease patients in research settings. 5

• Other PET/SPECT: FDG-PET showing metabolic changes and SPECT perfusion abnormalities have been reported but lack specificity. 8, 5

Fluid Biomarkers (Research Stage Only)

Blood-based biomarkers are NOT recommended for clinical diagnosis: 1

• Plasma biomarkers (p-tau, TREM2, CCL11, neurofilament light [NfL], GFAP) are demonstrating potential for detecting disease-related proteins but require further validation in real-world populations. 1, 6, 7

• Appropriate use criteria do not recommend blood-based biomarkers as stand-alone biomarkers in clinical practice. 1

Critical Clinical Caveats

Do NOT Equate TES with CTE

• The 2021 diagnostic criteria for TES are meant primarily for research purposes and should be used cautiously in clinical and medicolegal settings, avoiding equivalence with a diagnosis of CTE. 1

• The 2014 TES criteria showed high sensitivity (97.3%) but very low specificity (20.2%), meaning many patients meeting criteria do not have CTE pathology. 1

Comorbid Pathology is Common

• Exposure to repetitive head impacts increases deposition of other pathologic proteins (β-amyloid, α-synuclein, TDP-43), raising risk for Alzheimer disease, Lewy body disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. 2

• Limited published CTE cases with objective neuropsychological data show cognitive deficits resembling Alzheimer dementia, but comorbid non-CTE neuropathologies are present in nearly all cases. 9

Clinical Presentation is Heterogeneous

• No consistent cognitive pattern exists, even for high CTE severity cases. 9

• Dementia-related diagnoses are prevalent (62%) in CTE cases, but diverse neuropsychological impairments occur. 9

Practical Clinical Approach

When evaluating a patient with suspected CTE-related symptoms:

1. Document detailed exposure history to repetitive head impacts (years of contact sport, military service, etc.) 1

2. Perform comprehensive neuropsychological assessment focusing on episodic memory, executive function, and behavioral dysregulation 1

3. Order brain MRI if new, persistent, or worsening symptoms exist to exclude other treatable conditions 4

4. Rule out alternative diagnoses including Alzheimer disease, frontotemporal dementia, Lewy body disease, psychiatric disorders, and other medical conditions 1, 9

5. Provide symptomatic treatment for cognitive and behavioral symptoms using evidence-based interventions that are etiologically agnostic 10

6. Communicate carefully with patients that definitive CTE diagnosis cannot be made during life and avoid using "CTE" terminology in clinical documentation 1

7. Consider referral to specialized dementia or concussion programs for patients with progressive symptoms 1, 10