Chronic Traumatic Encephalopathy

Slide 1 · Chronic Traumatic

Encephalopathy

Neuropathology • mechanisms • diagnostic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain the relationship between repetitive head trauma and CTE pathology

Recognize the lesion distribution and associated tissue changes

Distinguish neuropathologic CTE from research criteria for TES

Appraise clinical uncertainty, comorbidity, and diagnostic limitations

Slide 3 · Three levels of interpretation

Repetitive head impacts: Exposure

Traumatic encephalopathy syndrome: Research clinical construct

CTE: Neuropathologic diagnosis at autopsy

These are distinct categories, not an obligatory sequence

Slide 4 · CTE is a distinctive chronic traumatic tauopathy

Classically described after repeated head trauma

Associated with a variable dementing or neurobehavioral syndrome

Distinguished by the location and cell types of abnormal tau deposits

Its neuropathologic diagnosis is not equivalent to a history of concussion

Slide 5 · Historical terminology: Dementia pugilistica

Older literature used “boxer’s dementia” or “dementia pugilistica”

The name reflected recognition in repeatedly exposed boxers

CTE now encompasses exposures beyond boxing

The historical term does not adequately describe the full pathologic spectrum

Slide 6 · Where repetitive head impacts occur

FEATURES / EVIDENCE

Contact and collision sport exposure

Military service with repetitive head trauma

INTERPRETATION / LIMITS

Occupational or civilian repetitive trauma

Exposure settings do not confer equal or individually predictable risk

Slide 7 · Repetitive exposure is not a neuropathologic diagnosis

A history of impacts may identify a risk-bearing population

Not every exposed individual develops CTE pathology

CTE cannot be confirmed by exposure history alone

Evidence must be evaluated at the population and individual levels

Slide 8 · Concussion and CTE should not be conflated

FEATURES / EVIDENCE

Concussion is an acute clinical syndrome after head injury

CTE refers to a chronic neuropathologic tauopathy

INTERPRETATION / LIMITS

Symptoms after a concussion may resolve without subsequent CTE

CTE-related pathology may follow years of cumulative exposure

Slide 9 · Impacts can occur without diagnosed concussion

Repetitive head impact exposure includes symptomatic and asymptomatic impacts

Concussion counts are therefore an incomplete exposure metric

Research criteria consider the nature and duration of exposure

No universal exposure-to-disease conversion factor is established

Slide 10 · Duration of exposure as a crude surrogate

Longer participation in repetitive-impact activity

Potentially higher cumulative frequency of impacts

Association with pathologic severity in autopsy series

Correlation does not yield an individual diagnostic threshold

Slide 11 · Why cumulative exposure is difficult to reconstruct

Activity duration does not encode number of impacts per year

Impact force and rotational mechanics vary

Recall-based concussion history can miss unrecognized events

A years-played measure is a proxy, not a physical dose

Slide 12 · Individual susceptibility remains incompletely defined

Uncertainty about who ultimately develops encephalopathy

An exposed population contains individuals with heterogeneous outcomes

Exposure associations should not be presented as destiny

Prediction requires validated longitudinal evidence

Slide 13 · Acute structural injury and chronic degeneration

FEATURES / EVIDENCE

Contusions: Immediate focal tissue destruction or hemorrhage

Diffuse axonal injury: Mechanical injury of white matter axons

INTERPRETATION / LIMITS

CTE: Delayed or progressive accumulation of characteristic tau lesions

A single scan cannot substitute for a neuropathologic tissue diagnosis

Slide 14 · Rotational acceleration can injure axons

Diffuse axonal injury may occur with marked angular acceleration

Axoplasmic flow changes produce axonal swellings

Susceptible sites include deep white matter and brainstem pathways

These acute observations provide context but are not CTE criteria

Slide 15 · Different time scales after head trauma

Impact and mechanical deformation

Acute neuronal, axonal, or vascular response

Variable recovery or persistent post-traumatic syndromes

In a subset, chronic neurodegenerative pathology may be found

Slide 16 · Clinical presentation is heterogeneous

CTE-associated cases have cognitive, behavioral, mood, and motor features

The relative prominence of these domains varies

Clinical symptoms are not specific to a single underlying proteinopathy

Pathologic and clinical descriptions must remain conceptually separate

Slide 17 · Cognitive manifestations: What is impaired?

Memory complaints may form part of the phenotype

Executive dysfunction can affect planning and organization

Cognitive decline may eventually interfere with daily functioning

The same domains are affected by several competing disorders

Slide 18 · Executive dysfunction in the TES construct

Reduced planning, flexible thinking, and inhibition may be reported

Consensus research criteria prioritize objective cognitive impairment

Episodic memory and executive function are specified core domains

Symptoms should represent a change from baseline

Slide 19 · Behavioral symptoms require careful characterization

Irritability or impulsivity may feature in reported histories

Altered emotional regulation can accompany frontal network dysfunction

Symptoms also occur in psychiatric and other neurologic illnesses

Behavior alone cannot confirm CTE pathology

Slide 20 · Neurobehavioral dysregulation in research criteria

TES criteria describe loss of behavioral or emotional control

Examples include explosive anger, impulsivity, and emotional lability

These are research constructs requiring progressive course and exposure

Assess them in context rather than labeling them pathognomonic

Slide 21 · Mood symptoms are diagnostically nonspecific

Anxiety and depressive symptoms have many potential causes

The 2021 TES consensus does not make mood symptoms alone a core criterion

Mood symptoms may be supportive or coexisting features

Psychiatric assessment remains important regardless of CTE concern

Slide 22 · Motor manifestations overlap with other disorders

Motor impairment can accompany reported CTE cases

Parkinsonian signs or gait abnormalities require broader differential diagnosis

Motor symptoms do not localize a specific tau lesion

Their presence warrants standard neurologic evaluation

Slide 23 · Clinical heterogeneity versus lesion specificity

FEATURES / EVIDENCE

Clinical cluster: Shared across many disorders

Neuropathologic lesion: Defined by abnormal tau topography

INTERPRETATION / LIMITS

Repetitive exposure raises suspicion but lacks tissue specificity

Clinical criteria are research-oriented; Tissue examination remains definitive

Slide 24 · Frontal and temporal cortical vulnerability

Repeated mechanical loading of the brain

Greatest stress and deformation near select sulcal regions

Predilection for frontal and temporal cortical pathology

A proposed mechanical link, not a complete molecular mechanism

Slide 25 · Global atrophy and ventricular enlargement

Reference schematic

Atrophic schematic

Schematic illustration — not an anatomical specimen

Grossly affected brains can be atrophic

Loss of tissue volume may accompany ventricular enlargement

Neither finding is unique to CTE

A brain-volume change alone cannot establish its etiology

Slide 26 · Gross morphologic patterns are supportive, not diagnostic

Cortical and other regional atrophy can be present

Enlarged ventricles can accompany overall parenchymal loss

Similar macroscopic findings occur in several neurodegenerative states

Microscopic lesion verification is indispensable

Slide 27 · Tau is the principal aggregating protein

Tau-containing neurofibrillary tangles

Tau aggregation is a broader feature of several tauopathies

The spatial organization of deposits distinguishes CTE

Total tau burden alone is not a CTE diagnostic criterion

Slide 28 · Neurofibrillary tangles represent abnormal tau accumulation

Abnormally phosphorylated tau is detected by immunohistochemistry

Intraneuronal aggregates can accompany degenerative neuronal injury

Tangles by themselves are not specific for CTE

Regional and microscopic relationships establish pathologic identity

Slide 29 · Why cortical sulcal depths matter

Schematic cortical fold

Sulcal depth

CTE lesions preferentially involve depths of cortical sulci

Robbins relates the distribution to impact-associated physical stress

A sulcus is an anatomic fold, not a tau-specific structure

Location must be combined with cellular and perivascular findings

Slide 30 · Perivascular clustering: An essential spatial clue

Small vessel

P-tau+ neurons

Schematic — not a histology image

Abnormal neuronal p-tau lies around small cortical vessels

The pattern is patchy rather than uniform

The defining focus lies in sulcal depths, including deeper cortical layers

A vessel alone is not sufficient without neuronal tau pathology

Slide 31 · Irregular distribution differs from diffuse tau deposition

The p-tau pattern is focal and spatially irregular

Low-power survey may reveal scattered cortical clusters

Diffuse or superficial tau staining alone is not equivalent to the lesion

Examine anatomic context before labeling deposits

Slide 32 · The pathognomonic lesion: Integrate three elements

Small vessel

P-tau+ neurons

Schematic — not a histology image

Neuronal phosphorylated tau aggregates

Perivascular accentuation around small vessels

Localization at the depth of a cortical sulcus

The lesion is judged as a tissue pattern, not a stain result

Slide 33 · 2021 consensus: Neuronal tau is required

Pathognomonic p-tau must involve neurons

Thorn-shaped astrocytes may or may not accompany the neuronal deposits

Purely astrocytic perivascular staining does not meet the definition

This refinement prevents confusion with aging-related tau astrogliopathy

Slide 34 · CTE lesion versus astrocytic sulcal tau

FEATURES / EVIDENCE

CTE: Perivascular neuronal p-tau at sulcal depths

ARTAG: Astrocytic tau can involve sulcal and subpial tissue

INTERPRETATION / LIMITS

Pure astroglial lesions without neuronal aggregates are insufficient

Similar location alone does not prove the same disease

Slide 35 · Consensus refinement in neuropathologic diagnosis

2015 panel defined a recognizable p-tau lesion

Subsequent independent blinded reviews tested reproducibility

2021 consensus emphasized neuronal involvement in deeper sulcal cortex

Diagnostic protocols standardized sampling and assessment

Slide 36 · Minimum pathologic threshold

The 2021 panel endorsed a single cortical pathognomonic lesion

The focus must meet location, cell-type, and vessel criteria

Additional tau deposits may support broader disease burden

Sampling and disease extent should be recorded separately

Slide 37 · Diagnostic lesion is not the same as severity

Identifying one defining focus answers whether CTE pathology is present

Extent elsewhere answers a different question: Distribution and burden

Severity schemes do not replace the core lesion requirement

Clinical impairment should not be inferred solely from one focus

Slide 38 · Phosphorylated tau immunostaining

Antibodies such as AT8 demonstrate phosphorylated tau deposits

Survey architecture at low magnification, then inspect cellular localization

Preserve awareness of cortical layers and sulcal geometry

Immunopositivity without correct pattern is insufficient

Slide 39 · A systematic sampling strategy

Cerebral cortical regions with sulci

Medial temporal structures and other relevant gray matter

Selected subcortical nuclei and brainstem

Expand sections when pathologic suspicion or differential requires it

Slide 40 · Focal pathology creates sampling limitations

A pathognomonic focus may occupy a restricted cortical region

Inadequate tissue sampling risks under-recognition

A negative limited panel does not equal proof of universal absence

Interpret the result in light of the sampling protocol

Slide 41 · Supportive cortical laminar findings

Tau tangles and pretangles may preferentially involve superficial cortex

Laminar distribution differs from classic Alzheimer patterns

This is supportive rather than the defining lesion

Interpret laminar findings alongside sulcal perivascular foci

Slide 42 · Hippocampal tau can provide supportive context

Consensus descriptions include involvement of CA2 and CA4

This contrasts with the commonly emphasized CA1/subiculum pattern in Alzheimer disease

Hippocampal findings alone are not diagnostic of CTE

Coexisting hippocampal disease can complicate attribution

Slide 43 · Subcortical disease in more extensive cases

P-tau involvement may extend into subcortical and brainstem nuclei

These regions are important when documenting widespread burden

Subcortical tau without a qualifying cortical lesion is not sufficient

Distribution and differential diagnosis remain central

Slide 44 · White matter rarefaction may accompany CTE

Loss or reduction of white matter substance

This is not equivalent to the defining cortical tau lesion

Axonal and myelin pathology may contribute to neurologic dysfunction

White matter change is not unique to chronic traumatic disease

Slide 45 · TDP-43 inclusions can coexist

Hippocampal neuronal TDP-43-positive inclusions

TDP-43 is a distinct aggregation-associated protein

Its presence is supportive in some cases, not required for CTE

Consider other TDP-43 proteinopathies and age-related co-pathology

Slide 46 · Hippocampal sclerosis is a possible associated lesion

Neuronal loss and gliosis can affect hippocampal regions

Clinical correlates may include memory dysfunction

Hippocampal sclerosis also occurs outside CTE

Do not infer a unique cause from this lesion alone

Slide 47 · Defining lesion versus accompanying changes

FEATURES / EVIDENCE

Defining: Cortical perivascular neuronal p-tau at sulcal depth

Accompanying: Atrophy and ventricular enlargement

INTERPRETATION / LIMITS

Accompanying: White matter rarefaction or hippocampal sclerosis

Possible co-pathology: TDP-43 or other age-related degeneration

Slide 48 · Aβ plaques: Interpret the Robbins statement carefully

Tau, not β-amyloid plaques, as the CTE signature

Aβ deposition is not part of the pathognomonic CTE lesion

Coexisting Alzheimer neuropathologic change can be present in an individual

Absence of Aβ should not be imposed as a universal exclusion criterion

Slide 49 · Mixed pathology changes clinicopathologic attribution

CTE pathology may occur with Alzheimer neuropathologic change

Multiple lesions can contribute to observed cognitive symptoms

Neuropathologic reporting should describe concurrent disorders

Avoid attributing all impairment to a single detected lesion

Slide 50 · CTE and Alzheimer disease: Lesion topology

FEATURES / EVIDENCE

CTE: Neuronal p-tau clustered around small vessels at sulcal depth

Alzheimer: Characteristic amyloid and tau pathology distributed by region

INTERPRETATION / LIMITS

Tangles occur in both, so tau positivity alone does not separate them

Co-pathology should be assessed rather than assumed absent

Slide 51 · CTE and ARTAG/PART: Common confusion

FEATURES / EVIDENCE

ARTAG: Astrocytic tau may be subpial or perivascular

PART: Neuronal tau pathology associated with aging, without requisite CTE geometry

INTERPRETATION / LIMITS

The 2021 CTE criterion demands perivascular neuronal tau in deep sulcal cortex

A tau-positive older brain therefore requires topographic assessment

Slide 52 · CTE and frontotemporal degeneration

Behavioral symptoms may overlap clinical FTLD syndromes

Tau and TDP-43 disorders can produce disparate molecular lesions

The CTE-defining cortical focus should be demonstrated independently

Clinical syndrome alone cannot differentiate the etiologies

Slide 53 · Low and high neuropathologic CTE

FEATURES / EVIDENCE

Consensus staging attempts to stratify severity of tissue involvement

Low burden: Fewer or more localized p-tau abnormalities

INTERPRETATION / LIMITS

High burden: Broader and more extensive regional involvement

These categories describe pathology and are not clinical dementia stages

Slide 54 · Cautions when interpreting neuropathologic staging

A stage depends on a defined protocol and sufficient sampling

Changing criteria over time limit naive comparison of published stages

Regional co-pathology may inflate apparent overall burden

Do not assume a direct one-to-one stage-to-symptom relationship

Slide 55 · Clinical phenotype versus pathology burden

FEATURES / EVIDENCE

A pathologic diagnosis concerns microscopic brain lesions

Symptoms reflect multiple functional networks and possible comorbidity

INTERPRETATION / LIMITS

The same symptom cluster can arise from different substrates

Clinical severity cannot replace histologic staging

Slide 56 · Traumatic encephalopathy syndrome is a research construct

TES criteria attempt to standardize a clinical syndrome

TES is not an in-life tissue-confirmed diagnosis of CTE

The criteria were developed primarily for research and require validation

Communicate uncertainty explicitly in clinical documentation

Slide 57 · TES research criteria: Stepwise logic

Substantial repetitive-head-impact exposure

Specified core cognitive or neurobehavioral features with progression

Symptoms not fully explained by an alternative condition

Then characterize the level of functional dependence

Slide 58 · TES core cognitive features

Episodic memory impairment and/or executive dysfunction

Neurobehavioral dysregulation may also meet the core feature definition

The symptom complex represents decline from prior functioning

Progression is part of the research case definition

Slide 59 · Progression and alternative explanations

Progressive course distinguishes TES criteria from many static sequelae

Assess primary psychiatric, sleep, substance-related, and other neurologic causes

Coexisting disorders do not automatically exclude TES

The question is whether they fully explain the clinical findings

Slide 60 · Functional dependence in TES research criteria

Functional levels range from independent to severe dementia

Function is a separate axis from anatomic lesion confirmation

Support needs and safety assessments remain clinically actionable

Severity labels do not determine CTE pathology without autopsy

Slide 61 · Disease-specific biomarkers remain unvalidated

No routinely established in-vivo biomarker can confirm CTE pathology

Existing amyloid or tau biomarkers target different biologic signals

MRI atrophy patterns are not pathognomonic

Research tools must not be presented as clinically definitive tests

Slide 62 · Clinical attribution is limited by common comorbidities

Depression, sleep disorders, medications, and substance use may affect cognition

Other neurodegenerative and vascular conditions can coexist

Focused examination and neuropsychology can characterize impairments

Neither a symptom checklist nor a scan proves CTE

Slide 63 · Brain-bank samples require selection-bias awareness

Autopsy donations are often nonrandom samples of exposed populations

Symptomatic cases and publicized histories may be overrepresented

Observed lesion frequencies need not equal population prevalence

Do not transform convenience-sample proportions into personal risk

Slide 64 · Association does not establish individual inevitability

Correlation between exposure duration and autopsy stage

Risk determinants and susceptible subgroups remain incompletely resolved

Effect estimates depend on sampling, exposure ascertainment, and follow-up

Population association is not a diagnostic certainty for one person

Slide 65 · A defensible clinical evaluation pathway

Document exposure chronology and specific complaints

Characterize cognitive, mood, behavioral, and motor domains

Evaluate alternative causes and functional impact

Use TES terminology carefully; Avoid claiming pathologic proof

Slide 66 · Clinical case: Symptoms after years of play

CLINICOPATHOLOGIC SCENARIO

A retired collision-sport participant reports worsening planning and irritability

Examination reveals executive deficits, but MRI is nonspecific

Question: Can CTE be diagnosed definitively during life?

What competing explanations must be evaluated?

Slide 67 · Clinical case debrief

FEATURES / EVIDENCE

A relevant exposure history raises the research question

The syndrome requires progression and alternative-cause assessment

INTERPRETATION / LIMITS

No established clinical test proves CTE tau pathology in life

Document observed deficits and diagnostic uncertainty

Slide 68 · Autopsy case: Focal p-tau at a sulcal depth

CLINICOPATHOLOGIC SCENARIO

AT8 reveals neuronal p-tau surrounding a small cortical vessel

The focus lies in deeper cortex at the depth of a sulcus

Elsewhere, sparse age-related astrocytic tau is present

Question: Which finding meets the defining criterion?

Slide 69 · Autopsy case debrief: The lesion is topographic

Small vessel

P-tau+ neurons

Schematic — not a histology image

Neuronal tau plus small-vessel relationship plus sulcal depth supports CTE

Unrelated astroglial tau does not substitute for the cortical lesion

Further sampling documents distribution and co-pathology

Interpretation requires an actual specimen, not the educational schematic

Slide 70 · Other long-term sequelae after traumatic brain injury

Posttraumatic epilepsy can follow injury

Posttraumatic hydrocephalus may follow disturbed CSF resorption

Infection risk can be increased after certain traumatic injuries

These outcomes are distinct from the CTE-defining tauopathy

Slide 71 · High-yield diagnostic distinctions

FEATURES / EVIDENCE

Repetitive head exposure: Risk history, not a neuropathologic diagnosis

TES: Research clinical criteria, not pathologic confirmation

INTERPRETATION / LIMITS

CTE: Perivascular neuronal p-tau at cortical sulcal depth

Atrophy, symptoms, and nonspecific tau cannot independently establish CTE

Slide 72 · Knowledge check: Identify a genuine CTE lesion

A: Isolated diffuse hippocampal tau tangles

B: Perivascular neuronal p-tau at the depth of a cortical sulcus

C: Purely astrocytic subpial p-tau with no neuronal lesion

D: Cortical atrophy with no qualifying tau focus

Slide 73 · Knowledge check: Rationale

FEATURES / EVIDENCE

Correct pattern: Perivascular neuronal p-tau at sulcal depth

Hippocampal tau and atrophy are not site-specific lesion criteria

INTERPRETATION / LIMITS

Astrocyte-only tau can represent ARTAG

The diagnostic unit is the combined histologic architecture

Slide 74 · Selected references

Robbins, Cotran & Kumar. Pathologic Basis of Disease, 11th ed. Chapter 28 (2026)

Second NINDS/NIBIB neuropathologic CTE consensus. J Neuropathol Exp Neurol (2021)

NINDS TES consensus criteria. Neurology (2021)

McKee et al. Acta Neuropathol (2023); CTE state-of-science review (2025)