Chronic traumatic encephalopathy-neuropathologic change in a routine neuropathology service: 7-year follow-up

Abstract

To follow our 2016 study of chronic traumatic encephalopathy neuropathologic change (CTE-NC) in our forensic autopsy service, we prospectively screened all cases with clinical histories of multiple concussions, persistent post-head injury symptoms, or ≥3 hospital investigations for head injuries from 2016 to 2022 inclusive using hyperphosphorylated tau (p-tau) immunostaining. The cases had routine brain sampling plus 4-6 additional lateral hemisphere samples. When “pathognomonic” CTE-NC lesions were identified, additional p-tau immunostaining was done for CTE-NC staging. Of ∼1100 adult brains aged 18–65 years examined, 85 were screened, and 16 were positive for CTE-NC (2 women, 14 men, ages 35–61 years, median 47 years). Alcohol abuse was documented in 14 of 16 (8 in combination with other substances); 5 had developmental brain anomalies (2 presumed genetic, 3 from acquired perinatal insults). Widespread p-tau deposits (high CTE-NC) were found in 7 of 16. Old brain contusions were present in 9 of 16, but CTE-NC did not colocalize. Of particular interest were (1) a man with FGFR3 mutation/hypochondroplasia and life-long head banging, (2) a woman with cerebral palsy and life-long head banging, and (3) a man with bilateral peri-Sylvian polymicrogyria, alcohol abuse, and multiple head injuries. Thus, CTE-NC occurs in association with repeated head trauma outside contact sports. Substance abuse is a common determinant of risk behavior. The utility of diagnosing mild-/low-stage CTE-NC in this population remains to be determined.

INTRODUCTION

Chronic traumatic encephalopathy (CTE) is a neurologic disorder associated with characteristic patterns of hyperphosphorylated tau (p-tau) accumulation in the brain accompanied by a cognitive decline in some individuals (i.e. traumatic encephalopathy syndrome [TES]) (1–3). Because the relationship between CTE and TES remains unclear (4), herein we use the term CTE neuropathologic change (CTE-NC) to explicitly address the histologic features alone (5, 6), recognizing that for some authors CTE is the pathologic change. CTE-NC has been most commonly described in contact sport athletes (7). The main risk factor seems to be repeated mild head injury (8), while APOEε4 genotype might also impart increased risk (9). In 2016, we investigated 111 consecutive brains from persons 18–60 years submitted routinely to our forensic autopsy service for p-tau-immunoreactive CTE-NC (10). In 34 cases, we observed very mild CTE-NC, which we considered to be less than what McKee et al had originally described as stage 1 (11). Based upon existing criteria at the time (12), we diagnosed CTE stage 1 in 3 cases and CTE stage 2 in 2 cases. In a similar community study of 180 autopsy cases in Australia (age 18–101 years), the authors found CTE-NC in only 4 cases (13). Since our 2016 study, we have continued to examine cases using a flexible decision and screening algorithm followed by the use of the updated consensus diagnostic criteria for CTE-NC (1). We believe that it is still important to study a population beyond professional athletes (14). Herein we report our observations.

MATERIALS AND METHODS

This prospective study was performed at the Health Sciences Centre in Winnipeg, Manitoba, Canada from 2016 to 2022 inclusive. The study was performed in accordance with departmental tissue use guidelines and was approved for postmortem clinical record review and neuropathological examination by the Health Research Ethics Board at the University of Manitoba (protocol numbers H2019:504 and H2013:217). Based upon our prior experience (10), we expected that people with multiple head injuries (including concussions) documented by history including, but not restricted to, emergency room visits and hospital admissions would be most likely to have pathology. During the study period, we completed brain examinations on approximately 1100 adults aged 18–65 years (this includes a decline during the COVID-19 pandemic period). In our Medical Examiner system, death investigators interview family members and persons knowledgeable of the decedent to obtain moderately detailed information about the medical and trauma history. Furthermore, the complete provincial imaging record can be quickly reviewed for the history of computed tomography (CT) or magnetic resonance imaging of the brain following head injury. Eighty-five cases had a clinical history of multiple concussions, persistent post-head injury symptoms, or ≥3 hospital investigations for head injuries. As before, we recorded age, sex, history of head injuries (including involvement in contact sports) either provided by family members or from the provincial imaging records, history of psychiatric/neurologic disease, and details of substance abuse. One additional case not described in the “Results,” the brain of an 82-year-old former professional football player was sent on a family request for examination by Dr. G. Kovacs at the University of Toronto. He was found to have CTE-NC (high), Alzheimer disease neuropathologic changes (A3B3C3), limbic-predominant age-related TDP-43 encephalopathy-neuropathological change (LATE-NC, stage 2 out of 3), and widespread age-related tau astrogliopathy (ARTAG).

Most brains were fixed in 10% buffered formalin for 12–28 days, although a few were fixed for only 2 days prior to slicing to accommodate family desires. All brains were sampled widely (12–18 regions total) including paramedian frontal, bilateral lateral frontal (at the level of anterior basal nuclei), bilateral lateral frontal (at the level of optic chiasm), lateral temporal, lateral parietal, hippocampus/medial temporal, amygdala, thalamus, midbrain, pons, medulla, and cerebellum. We took into account the recommendation of the first consensus meeting; “if there is a high index of suspicion of CTE … taking extra sections of frontal and temporal cortices, and hypothalamus including the mammillary body” (12). Fixed brain samples were dehydrated and embedded in standard 3 × 2 × 0.3 cm paraffin blocks, sectioned at 5-µm thickness, and stained with hematoxylin and eosin. Hyperphosphorylated tau (p-tau) immunostaining was performed with the AT8 mouse monoclonal antibody (MN1020, ThermoFisher; dilution 1/3000) using the Dako EnVision + Dual Link System-HRP followed by counterstaining with hematoxylin. This was initially done on 3–5 lateral cerebral samples that included sulci, along with the hippocampus/medial temporal region. If CTE-NC was identified in any section, additional immunostains were performed to complete the 2021 consensus diagnostic criteria (1). We routinely screen autopsy brains from persons >65 years old with Bielschowsky stains to determine if formal evaluation for Alzheimer-type pathology is warranted. In the cases <65 years, additional samples were stained with modified Bielschowsky silver stain and β-amyloid immunostain to evaluate for Alzheimer disease-type changes (15) only if p-tau-immunoreactive deposits were present. We used the 2021 consensus definition of the CTE-associated p-tau lesion; “an accumulation of abnormal p-tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern” (1). CTE-NC p-tau deposits were distinguished from ARTAG (16), early tau-only lesions (17), and primary age-related tauopathy (PART) (18), according to the published literature. The majority of cases were reviewed by all three authors. The approximate size, location, and pattern of CTE-NC p-tau deposits were recorded, as were other p-tau patterns.

RESULTS

Case details that we considered triggers for screening included a history of multiple head injuries with or without post-concussion symptoms, or ≥3 CT scans of the brain for head injuries that occurred on separate occasions. During the study period, 85 adult cases were subjected to p-tau immunostaining, and 69 were negative for CTE-NC. Among those negative for CTE-NC were 5 cases aged <35 years with family concerns about chronic post-concussion symptoms and normal brain imaging.

Sixteen cases, age 35–61 years (median 46.5 years; 2 women, 14 men) had CTE-NC p-tau immunoreactivity ranging from a single small focus to widespread abnormalities (see details in the Table). Using the second consensus criteria (1), 9 of 16 were categorized as low CTE-NC and 7 of 16 as high CTE-NC. Their head injury histories ranged from 3 documented mild head injuries with CT scans showing no focal lesions (cases 1, 10, 14) to a case with 2 severe traumatic brain injuries plus >15 mild head injuries (case 2). Chronic structural brain abnormalities included old contusions in 9 cases and diffuse atrophy (attributed to substance abuse or prior brain damage) in 5 cases. Evidence of recent mild to severe traumatic brain injury (TBI) was present in 7 of 16 cases at the time of death. In one case not included in the series, a single field (∼1cm) of diffuse neuropil p-tau immunoreactivity with neurofibrillary tangle (NFT) was present at the site of an old contusion; it lacked the perivascular and sulcal pattern of CTE-NC (Supplementary Data). Immunoreactivity for p-tau was also occasionally found in granular eosinophilic bodies adjacent to old contusions or in an ARTAG-like pattern at sites of superficial siderosis (Supplementary Data).

Table.

Cases with CTE-neuropathologic change arranged by ascending age

Case #	Age (years) sex	Clinical history	Head injury and brain imaging history	Death circumstance	Brain weight; neuropathology findings	p-tau findings/CTE level
1	35 M	Alcohol and drug abuse	3 CT scans: assaulted with baseball bat to face, fell, punched/fell	Blunt head trauma 23 days before death; craniotomy for large subdural hematoma (homicide)	1386 g; subacute SDH, craniotomy, contusions, swelling, herniations; old contusion cerebellum	Three small (<1 mm) CTE-NC foci at depths of frontal and temporal lobe sulci; CTE low
2	35 M	Alcohol abuse, alcohol withdrawal seizures/post-traumatic epilepsy	22 CT scans: assaults and seizure-related falls; 2 severe TBI—epidural hematoma + temporal lobe contusion at 19 years; temporal ICH + IVH at 30 years	Blunt head trauma (homicide)	1330 g; large acute SDH and contusions; old contusions	Two small (<2 mm) CTE-NC perivascular foci in inferior and lateral aspects of the frontal lobes (not associated with contusions); NFT in many loci; CTE high
3	37 M	Solvent abuse since teenage years, alcohol abuse, HIV	>10 CT scans: falls and assaults	Acute blunt head injury (homicide)	1215 g; subdural and subarachnoid hemorrhage, severe acute hypoxic ischemic brain damage, solvent/toluene leukoencephalopathy; old brain contusions (frontal temporal)	Four small (<0.5 mm) CTE-NC perivascular foci in inferior, lateral, and medial aspects of cerebrum (not associated with contusions); CTE low
4	42 M	Chronic alcohol and solvent abuse; suicidal ideation	3 CT scans: 18 and 8 years prior to death, skull fracture, previous assaults	Sudden death, complications of chronic alcoholism	1465 g; no old contusions or gross atrophy; negative for toluene leukoencephalopathy	Three small (<1 mm) CTE-NC foci at depths of cerebral sulci; CTE low
5	44 F	Chronic alcohol abuse	12 CT scans: multiple falls and assaults while intoxicated; 2 severe TBI—brain contusion 10 years prior to death, subdural hematoma 3 years prior to death	Smoke inhalation, house fire	1290 g; old contusion, resolved subdural hemorrhage, mild cerebral atrophy	Two CTE-NC foci, one 3–4 mm at depth of medial temporal sulcus, and one 1.5 mm at depth of sulcus near amygdala; CTE low
6 (see Figure 1)	44 M	Short limb dwarfism (hypochondroplasia with heterozygous FGFR3 c.1620C>G, p. Asn540Lys mutation), cognitive delay, blind from retinal detachments, seizures	Regular head banging since 3 years age	Hypertrophic cardiomyopathy and congestive heart failure	1540 g; dysmorphic temporal lobes and hippocampi; resolved subdural hemorrhage	Eleven separate large (>1 cm) CTE-NC foci in cerebral cortex; NFT and neuropil threads throughout disorganized hippocampi/entorhinal; NFT in thalamus, amygdala, hippocampus; periventricular and subpial ARTAG in 5 foci; CTE high
7	46 M	Alcohol, cocaine, methamphetamine, and marijuana use; schizophrenia	8 CT scans: multiple assaults, brain contusion 2 years prior to death	Undetermined (alcohol + cardiomegaly + acute minor trauma)	1579 g; resolved subdural hematoma, old frontotemporal contusions	Three small (500–750 µm) and one large (>2 cm) CTE-NC foci around blood vessels at depths of sulci in 4 separate lateral cortical sites, 1 entorhinal focus; abundant NFT throughout hippocampus; ARTAG near a contusion; CTE low
8 (see Fig. 2)	46 F	Cerebral palsy with spastic diplegia and cognitive delay secondary to perinatal hypoxia, suspected FASD	Chronic head banging	Choked on food	1220 g; hydrocephalus ex vacuo; unilateral thalamus internal capsule atrophy (perinatal ischemic damage); no senile plaques on Bielschowsky stain; sparse beta-amyloid-immunoreactive plaques in frontal neocortex	Small CTE-NC foci around blood vessels near 5 separate sulci; NFT in hippocampus, entorhinal cortex, dentate gyrus, amygdala, frontal and inferior parietal neocortex; periventricular ARTAG; CTE high
9	47 M	Seizure disorder since infancy, long-time abuse of solvents and alcohol, Wernicke-Korsakoff syndrome	19 CT scans (and >70 ER visits): many falls and seizures, no focal or hemorrhagic lesions ever identified on CT scan	Probable seizure + dilated cardiomyopathy	1440 g; mild enlargement of lateral ventricles; acute hypoxic-ischemic neuron changes; negative for toluene leukoencephalopathy	Small CTE-NC foci around vessels at depths of sulci in 6 separate regions; scattered NFT in 7 separate lateral neocortical regions, medial temporal/hippocampus/dentate, midbrain, locus ceruleus; CTE high
10	50 M	Chronic alcoholism and frequent falls	3 CT scans: most recent brain for head trauma 9 years prior to death—no focal abnormality	Acute SDH with minimal external evidence of head trauma	1420 g; 200 mL subdural hematoma with herniations; negative for beta-amyloid plaques or blood vessels	Single small (1 mm) CTE-NC focus at base of middle frontal sulcus; PART involving medial temporal structures; CTE low
11 (see Fig. 3)	50 M	Chronic alcohol and solvent abuse	11 CT scans: multiple falls and assaults; brain contusions 9 years prior to death, progressive atrophy beginning 8 years prior to death	Sepsis secondary to scalp wound infection	1155 g; atrophy; severe solvent (toluene) leukoencephalopathy; old frontal/temporal contusions, resolved subdural hemorrhage	Small (up to 2 mm) CTE-NC foci at 3 separate lateral sulcus locations; rare NFT in 6 separate lateral neocortical regions, medial temporal, hippocampus, substantia nigra, periaqueductal gray matter, locus ceruleus; CTE high
12	51 M	Hypoxic brain damage at birth (breech presentation and cord prolapse), cognitive delay, seizure disorder; chronic alcohol abuse; diabetes mellitus type 2	6 CT scans: minor head injuries associated with intoxication (falls)	Alcohol toxicity/hypothermia	1415 g; old small frontal-temporal contusion; focal (5 mm) subcortical demyelination (query osmotic); negative for beta-amyloid	Small (0.5–3 mm) CTE-NC foci at depths of 3 separate lateral surface sulci; subpial ARTAG in 2 foci; abundant NFT in entorhinal region (PART); CTE low
13	52 M	Chronic alcohol + other drug abuse; seizures	Severe TBI >30 years prior to death with contusions and craniotomy for evacuation of SDH; multiple CT scans after seizure-related falls	Accidental head trauma + cardiac arrest + hypothermia; survived 17 days in coma after resuscitation with severe hypoxic-ischemic brain damage	1220 g; subacute contusions, small SDH, SAH; old contusions with atrophy; negative for beta-amyloid plaques	Small (2 mm) CTE-NC foci in 2 neocortical sites and near mammillary bodies; ARTAG in 6 sites: subpial, subependymal, and adjacent to old contusion; rare NFT in multiple neocortical sites, amygdala, entorhinal, hippocampus; CTE low
14	52 M	Headaches and several assaults	2 CT scans and 1 MRI: no focal lesions	Acute blunt head trauma (homicide)	1475 g; acute trauma with skull fracture, SDH, many contusions, IVH; negative for beta-amyloid	One small CTE-NC focus in frontal sulcus; small foci of subpial and periventricular ARTAG; rare NFT in temporal cortex; CTE low
15	54 M	Abusive head trauma at 10 months age, mild hydrocephalus (shunt nonfunctioning), cognitive delay, chronic alcohol abuse	3 CT scans: multiple assaults and falls; brain contusion 6 years prior to death	Undetermined (minor blunt head trauma + intoxication)	1900 g; small acute SDH and SAH; bilateral chronic calcified subdural fluid collections; old temporal contusion; negative for beta amyloid	Six small CTE-NC foci; 2 small subpial foci of ARTAG; NFT in parahippocampal entorhinal cortex, amygdala, CA1/CA4 sectors of hippocampus, thalamus, subthalamus; CTE high
16	61 M	Daily alcohol abuse for decades, poorly controlled seizures with onset in adulthood presumed to be related to. alcohol use, phenytoin often sub-therapeutic	>20 CT scans over 2 decades: falls and seizures; ventriculomegaly, absent septum pellucidum, diffuse cerebral atrophy, no focal traumatic lesions; in retrospect, MRI 9 years before death showed gyral anomaly in Sylvian regions	Multifactorial natural—ischemic heart disease + metastatic carcinoma in mediastinum (unknown primary)	1465 g; bilateral symmetric periSylvian (opercular) polymicrogyria; absent septum pellucidum; unilateral hippocampal neuron loss; microscopic deposits of metastatic carcinoma; negative for beta-amyloid	One large (1 cm) CTE-NC focus at depth of frontal sulcus and several smaller (1 mm) foci; diffuse abundant NFT in hippocampi and entorhinal (PART); ARTAG in small subpial (including polymicrogyria regions) and subependymal foci; (amygdala and mammillary bodies not sampled by forensic pathologist); CTE high

ARTAG, age-related tau astrogliopathy; CA, cornu ammonis; CT, computed tomography; CTE, chronic traumatic encephalopathy; FASD, fetal alcohol spectrum disorder; HIV, human immunodeficiency virus; IVH, intraventricular hemorrhage; MRI, magnetic resonance image; NFT, neurofibrillary tangle(s); PART, primary age-related tauopathy; SAH, subarachnoid hemorrhage; SDH, subdural hematoma/hemorrhage; TBI, traumatic brain injury.

There tended to be a relationship between the number of documented head injuries and the magnitude (or absence) of CTE-NC. However, the trend was not strong enough to predict in an individual the presence of CTE-NC. The most extreme example of a negative case was a 34-year-old woman with >10 years of drug and alcohol abuse and 27 ER encounters with CT scans of the head following assaults or fall-related head injuries (including 4 that showed small subdural or subarachnoid blood collections). p-tau immunostaining on 11 brain blocks showed not a single NFT.

Among the 16 cases with CTE-NC, 6 had alcohol abuse alone, 4 had alcohol and other drug abuse, and 4 had alcohol abuse combined with inhalational solvent abuse. Three cases had a history of brain damage during the perinatal period or infancy, and 2 had structural brain abnormalities from a genetic (or presumed genetic) cause; among these 5, 2 had behavioral disturbances associated with repeated head banging over decades. Epilepsy (excluding those with alcohol withdrawal seizures) was present in 3 of 16 cases. None of the cases had a clinical diagnosis of dementia, but cognitive decline might have been overlooked or not mentioned on the assumption that it was attributable to severe substance abuse. Contact sport participation was not a notable factor in any of the cases.

Three cases are illustrated to highlight the various pathologies associated with multiple TBIs and high-level CTE-NC. Case 6 was a 44-year-old man with near life-long repeated head banging stemming from behavioral abnormalities related to a brain malformation caused by FGFR3 mutation (Fig. 1). Case 8 was a 46-year-old woman with near life-long repeated head banging following perinatal hypoxic brain damage (Fig. 2). Case 11 was a 50-year-old man with multiple falls and assaults associated with severe substance abuse disorder (Fig. 3). Case 16 was a 61-year-old man with chronic alcohol abuse, bilateral peri-Sylvian microgyria, and chronic seizure disorder with multiple falls (Supplementary Data).

Figure 1.

(Case 6): A 44-year-old man with hypochondroplasia due to heterozygous FGFR3 p. Asn540Lys mutation, dysmorphic temporal lobes, seizures, cognitive delay, regular head banging since 3 years of age, and blindness from retinal detachments. CTE-NC high. (A) Computed tomography scan (horizontal slice, slightly tilted) performed approximately 1 year prior to death showing calcification in retina and enlargement of temporal horn of lateral ventricle. (B) Photograph showing dysmorphic left temporal lobe. (C) Photomicrograph (solochrome cyanin + eosin stain, whole mount image) showing dysmorphic hippocampus at the same level. (D) Photomicrograph (p-tau immunostain + hematoxylin counterstain, whole mount image) of left orbital surface of frontal lobe showing extensive cortical deposition of p-tau (brown). (E) Photomicrograph (p-tau immunostain + hematoxylin counterstain, ×40 magnification) showing CTE-NC (brown) including NFTs and perivascular glial/neuropil labeling at depth of sulcus along the right lateral temporal lobe.

Figure 2.

(Case 8): A 46-year-old woman with cerebral palsy and cognitive delay secondary to perinatal hypoxia and chronic head banging. CTE-NC high. (A) Photograph showing coronal brain slice with asymmetric ventricle enlargement (ex vacuo) and atrophic right basal nuclei. (B) Photomicrograph (solochrome cyanin + eosin stain, ×12.5 magnification) showing right putamen (at same level) with status marmoratus. (C) Photomicrograph (p-tau immunostain + hematoxylin counterstain, ×12.5 magnification) of right anterior temporal cortex (near amygdala) with extensive deposition of p-tau (brown). (D) Photomicrograph (p-tau immunostain + hematoxylin counterstain, ×40 magnification) showing CTE-NC (brown) including NFTs and perivascular neuropil labeling at the depth of a sulcus along the right lateral frontal lobe.

Figure 3.

(Case 11): A 50-year-old man with chronic alcohol and solvent abuse (toluene inhalation), history of multiple falls and assaults, brain contusions 9 years prior to death, and progressive atrophy beginning 8 years prior to death. CTE-NC high. (A) Photograph showing coronal brain slice with symmetric ventricle enlargement (ex vacuo) and atrophic right temporal lobe at site of old contusion (arrow). (B) Photomicrograph (solochrome cyanin + eosin stain, ×100 magnification) showing ill-defined hypomyelination (arrow) around a frontal lobe blood vessel. (C) Photomicrograph (hematoxylin + eosin stain, ×600 magnification, partial polarization) showing birefringent inclusions (characteristic of toluene leukoencephalopathy; arrow) adjacent to blood vessel in corpus callosum. (D) Photomicrograph (p-tau immunostain + hematoxylin counterstain, ×12.5 magnification) of lateral frontal cortex with deposition of p-tau at depths of sulci (brown; arrows). (E) Photomicrograph (p-tau immunostain + hematoxylin counterstain, ×100 magnification) showing CTE-NC (brown) including NFTs and perivascular neuropil labeling at depth of sulcus along the lateral frontal lobe.

DISCUSSION

In this follow-up study of CTE-NC in a community population, we confirm several of our previous findings (10). First, CTE-NC appears with some regularity in individuals who are not involved in contact sports but who have sustained repeated head injuries. Second, we found that substance abuse, and alcohol in particular, is common in the population. At the very least, substance abuse predisposes to activities that can result in multiple head injuries (e.g. fighting and falling). The high prevalence of solvent leukoencephalopathy in this series reflects the pattern of substance abuse in our jurisdiction (19) and is likely not a specific risk factor for CTE-NC. We had previously speculated that substance abuse might be an independent biological risk factor for CTE-NC (10). However, this concept was not supported by the study of a similar community population in Australia (13).

Despite the frequent co-existence of CTE-NC and brain contusions, we did not observe definite anatomical colocalization of the lesions. The pathophysiology of CTE-NC is hypothesized to be related to repeated mechanical strain deformation along the sulci (20). A supplemental hypothesis we put forth is that maintained cerebral blood flow is necessary for CTE-NC to develop; in a contusion, the brain tissue and vasculature are both disrupted thereby preventing the gradual development of CTE-NC. Considering the lack of a good animal model so far, this will be difficult to test.

Because the pathognomonic CTE-NC lesion is more likely to appear on lateral surfaces of the cerebral hemispheres, a 2-step diagnostic approach is possible in the forensic setting, wherein finances are usually constrained. Immunostaining for p-tau was done on a few lateral cortex samples followed, if necessary, by more extensive p-tau immunostaining to identify NFTs in other brain regions (1). The Australian study similarly screened 2 lateral neocortical regions and the hippocampus for p-tau immunoreactivity (13).

A few of the cases are worth discussing in some detail. Two of them (case 6 and case 8) had childhood-onset behavioral and cognitive abnormalities that were associated with decades of repeated head banging. One had cerebral palsy secondary to perinatal hypoxia and the other had brain abnormalities secondary to a mutation in FGFR3, which is associated with temporal lobe dysgenesis (21, 22). Head banging and other stereotypic self-injurious behaviors are not uncommon in children with intellectual disabilities (e.g. in up to 10% of children with autism spectrum disorder) (23–26) and may continue into adulthood (27). Head banging has previously been associated with ocular pathology (28–30), mild brain atrophy on imaging (31), and intracranial hemorrhage (32–34). Case 6 had gone blind from retinal detachments. Head banging has also previously been described as a risk factor for CTE and other forms of neurofibrillary degeneration (11, 35–38). As in contact sports, behavioral head banging is associated with hundreds or thousands of sub-concussive impacts. As a complement to cases in the current study, we did p-tau immunostaining on 3 children and 2 adults with more limited histories of head banging; none had CTE-NC (Supplementary Data). Three other individuals (case 9, case 12, case 15) had neurological disorders with onset in infancy and substance abuse disorder and multiple head injuries in adulthood. Perinatal brain damage or brain malformation can predispose to behavioral changes that increase the risk of multiple TBIs. However, there is no evidence that such changes on their own act as an independent biological risk factor for CTE-NC. There are no systematic studies of long-term survivors of perinatal hypoxia or abusive brain trauma. Anecdotally, we did not detect p-tau immunoreactivity in 3 cases of severe brain damage due to abusive brain trauma in infancy followed by persistent neurological deficits.

Case 16 with periSylvian polymicrogyria had the obvious risk factor of repeated falls secondary to epileptic seizures. Bilateral periSylvian polymicrogyria is often caused by mutations in the tubulin family of genes (39). Unfortunately, we could not get permission to obtain a genetic diagnosis. Tau protein binds tubulin heterodimers to stabilize microtubules (40). While tau phosphorylation decreases the binding affinity to tubulin (41), we could not find published evidence that a mutation in one of the microtubule proteins predisposes to tau phosphorylation.

Although 7 of 16 cases had high CTE-NC according to the current consensus criteria (1), only 1 of our cases (Case 6) had large p-tau deposits that would be comparable to stage 3 as illustrated in McKee et al in 2013 (11). Authors of the second consensus wrote, “the proposed assessment scheme for CTE severity is provisional” (1). We found the scheme relatively easy to use, and we accept that the definition of “pathognomonic lesion of CTE” is reasonably reproducible. However, we have the impression that the low/high CTE staging scheme overvalues the presence of scattered neurofibrillary deposits in a wide range of brain regions while undervaluing a measured (or estimated) volumetric span of CTE-NC neocortical deposits. As we argued previously (10), for application in the forensic setting, a clearer discussion of the 2-dimensional size, frequency, and distribution of CTE-NC p-tau aggregates would be helpful. We are comfortable reporting “chronic traumatic encephalopathy-neuropathologic change”, with an explanatory comment, in the setting of forensic autopsy neuropathology consultations. Given our uncertainty about how small, but “pathognomonic,” p-tau deposits might contribute to brain dysfunction, we typically would not render a diagnosis of CTE unless it was severe, however. Non-expert readers of the reports might not appreciate, despite an explanation, that “encephalopathy” in this context refers to the neuropathologic change and not the clinical syndrome.

Our study has several limitations. Unlike some of the professional contact sport athletes described in many studies, we have only limited information about the head injury frequency in our cases. While the number of CT scans serves as a useful surrogate for head injuries that precipitate a visit to the hospital, we have no way of knowing if this was all of their head injuries or merely a small fraction in a population of substance abusers with frequent fights and falls. Furthermore, because historical information sought about the deceased is focused on the circumstance of death, our information about casual/amateur involvement in contact sports (e.g. ice hockey, which is popular in our province), is limited. Many of our subjects had severe substance abuse disorders with associated homelessness and detachment from family; early social history was often difficult to obtain. Our reports are purely observational; the sample size is too small and the historical details too imprecise to conduct a multivariate data analysis to determine what factors other than repeated head trauma predispose to CTE-NC. We do not have detailed longitudinal information about the cognitive status of the individuals; thus, we cannot comment on dementia associated with either CTE-NC (i.e. TES) or alcohol consumption (42). The presence of brain contusions and occasional surgical interventions puts many in our population into the moderate-to-severe TBI category. It remains unclear how the magnitude and frequency of brain trauma interact, and to what extent they are directly causative of CTE-NC. Finally, we have not attempted to study in detail the elderly, who are more likely to have multiple contributors to p-tau pathology.

We conclude that CTE-NC occurs with some regularity in adults with multiple head injuries that may be associated with chronic head banging or frequent fights and falls. Developmental pathologies and substance abuse are associated with these cases, but it remains to be determined if they are simply determinants of risk behavior or actual biological aggravating factors. Knowing that CTE-NC can occur in people with little or no contact sport exposure is important information with respect to developing public health messages. But the value of making this diagnosis in individual cases is unclear because of the difficulty of linking it to a clinical syndrome. In our opinion, the current recommendation for diagnosing CTE requires some modification to accommodate the non-research, forensic neuropathology domain.

FUNDING

No funding is reported.

CONFLICT OF INTEREST

The authors have no duality or conflicts of interest to declare.

SUPPLEMENTARY DATA

Supplementary Data can be found at academic.oup.com/jnen.