Table 1.

Neuroimaging-to-Autopsy Case Series of Nine Participants from the University of California, San Francisco Memory and Aging Center with Clinical Impairment and History of Repetitive Head Trauma

P#	Exposure	Exposure duration (years)	Symptom duration (years)	Early symptoms	Late symptoms	TES diagnosisa	Consensus diagnosis during lifeb	Age at death	CTE stage/ level	ABC score	Primary and contributing neuropathological findings	Other incidental neuropathological findings
1	Am. football	17	13	Irritability Explosivity Social withdrawal Depression Memory Executive dysfunction	Parkinsonism Seizures	Probable CTE	n/a	72	IV / High	A0B?C0	CTE* Limbic TDP-43 with hippocampal sclerosis L subiculum infarcts	Limbic AGD Mild arteriolosclerosis. ARTAG
2	Am. football	24	9	Mood	Memory Executive dysfunction Seizures	Probable CTE	Amnestic, multi-domain dementia due to AD and vascular	74	III / High	A1B1C0	CTE* Limbic TDP-43 with hippocampal sclerosis	Limbic AGD Mild arteriolosclerosis ARTAG Infiltrating glioma Low ADNC
3	Am. football	23	8	Memory Visuospatial Word-finding Depression Anxiety	n/a	Probable CTE	Amnestic, multi-domain dementia due to AD	79	I / Low	A3B3C3	High ADNC* Limbic TDP-43 with hippocampal sclerosis	CTE Lymphocytic leukemia Mild arteriolosclerosis Limbic AGD
4	Am. football Motocross/ racecar driver	8 (Am. football) +5 (racecar driving with ≥3 TBI)	8	Apathy Loss of empathy Disinhibition Compulsions	Memory Language	Probable CTE	bvFTD	49	None	A0B2C0	FTLD-tau (CBD)* FTLD-TDP43 (U) with hippocampal sclerosis	Limbic AGD
5	Am. football	12	9	Apathy Irritability Depression	Visuospatial Memory	Probable CTE	Non-amnestic, multi-domain dementia due to AD	58	None	A3B3C3	High ADNC*	Limbic AGD Mild arteriolosclerosis Mild CAA LBD (amygdala) ARTAG
6	Boxing Military Bicycle crash with subdural hematoma	≥12 professional boxing (≥100 bouts)	7	Memory Inattention	Worsening memory Word-finding Depression (mild) Irritability (mild)	Possible CTE	Amnestic, multi-domain MCI (non-AD)	81	None	A0B2C0	PART*	Vascular brain injury Limbic AGD ARTAG
7	Am. football Boxing Military	≥20 military (unknown sport duration)	13	Memory Executive dysfunction	Parkinsonism	Uncertain TES (unknown exposure duration)	Amnestic, multi-domain dementia due to AD	84	III / High	A3B3C3	High ADNC* CTE Limbic TDP-43 with hippocampal sclerosis	Limbic AGD Moderate CAA LBD (Braak IV) Subdural hematoma White matter rarefaction
8	Am. football 2 late-life mTBIs (falls)	N/A	11	Social withdrawal Loss of empathy Hyperorality Compulsions Delusions	Loss of semantic knowledge	Uncertain TES (unknown exposure duration)	Right temporal variant of svPPA	70	Nonec	A1B2C1	FTLD-TDP Type C* “Focal traumatic tau astrogliopathy” c	Limbic AGD Thalamic infarcts Moderate arteriolosclerosis Low ADNC
9	Am. football Wrestling	N/A	12	Disinhibition Loss of empathy Apathy Repetitive behaviors Sweet food preference	Fasciculations Unsteadiness Breathing changes L > R hand tremor Dysphagia	Uncertain TES (may be fully explained by other disorder)	bvFTD with MND	59	IV / High	A0B?C0	FTLD-TDP Type B with MND*	CTE Limbic AGD Mild arteriolosclerosis ARTAG ATAC

All participants underwent comprehensive neurological and neuropsychological evaluations before death. Autopsies were performed through the University of California, San Francisco Neurodegenerative Disease Brain Bank. Head trauma exposure histories and symptom details were derived from antemortem evaluations that included detailed clinical histories and neurological examinations. “Early” and “Late” symptoms refer to participant- and informant-reported symptom trajectories or neurological examination findings (e.g., parkinsonism, fasciculations). Reported memory and/or executive dysfunction symptoms are bolded if objective neuropsychological testing in these domains was >1.5 standard deviations below the mean of healthy controls. Presence or absence of chronic traumatic encephalopathy and Alzheimer disease pathology along with staging were reported separately for each patient. “Primary and Contributing Neuropathological Findings” are neuropathological findings thought to contribute most to the patient's antemortem clinical symptoms. “Other Incidental Neuropathological Findings” were present but thought to have contributed minimally to clinical symptoms, per the reviewing neuropathologist, based on autopsy findings and available antemortem clinical data.

TES, traumatic encephalopathy syndrome; CTE, chronic traumatic encephalopathy; ABC, Amyloid phase/Braak stage of neurofibrillary tangles/CERAD neuritic plaque score (per NIA-AA guidelines for describing AD neuropathological changes); TDP, transactive response DNA-binding protein of 43 kDa; AGD, argyrophilic grain disease; ARTAG, age-related tau astrogliopathy; AD, Alzheimer disease; ADNC, Alzheimer disease neuropathological change²¹; TBI, traumatic brain injury; bvFTD, behavioral variant frontotemporal dementia; FTLD, frontotemporal lobar degeneration; CBD, corticobasal degeneration; CAA, cerebral amyloid angiopathy; LBD, Lewy body disease; MCI, mild cognitive impairment; svPPA, semantic variant of primary progressive aphasia; MND, motor neuron disease; ATAC, argyrophilic thorny astrocytes in clusters; U, unclassifiable.

^* Primary neuropathological diagnosis designated by the reviewing neuropathologist based on the expected role played by the disease in the patient's clinical syndrome.

^a TES Diagnosis was determined via investigator consensus (BA, JT) and represents the provisional level of certainty for chronic traumatic encephalopathy pathology through retroactive application of the most recently proposed traumatic encephalopathy syndrome (TES) diagnostic criteria.¹ The TES criteria were applied blinded to neuropathological diagnosis and available neuroimaging or other biomarker data (e.g., Alzheimer disease biomarkers) because these data do not factor into the 2021 TES diagnostic criteria.

^b Formal application of evolving traumatic encephalopathy syndrome (TES) diagnostic criteria was not systematically applied by consensus conference throughout the time span that these patients were evaluated at our center. The “Consensus Diagnosis During Life” reflects consensus clinical diagnosis for the patient at the time of study visit and also takes into account available biomarkers collected through research for the patient (structural magnetic resonance imaging, positron emission tomography neuroimaging, and/or cerebrospinal fluid biomarkers).

^c Patient had a severe, focal tauopathy in fronto-temporal-limbic regions overlapping with features of ARTAG. Given the distribution of the astrogliopathy and the patient's relatively young age of symptom onset (59) and death (70), these findings were fthought by the reviewing neuropathologist to most likely have been associated with previous repetitive head trauma, but would not meet diagnostic criteria for chronic traumatic encephalopathy because of absence of clear neuronal involvement.