Neuropathology in Consecutive Forensic Consultation Cases with a History of Remote Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is widely assumed to be causal in neurodegenerative disease, based on epidemiological surveys demonstrating an increased risk of Alzheimer disease (AD) following TBI, and on recent theories surrounding repetitive head movement. We tested this assumption by evaluating 30 consecutive forensic examinations in which neuropathology consultation was sought, and in which a history of remote TBI was uncovered during the course of the investigation. In this series, there was a high frequency of psychiatric co-morbidities (100%), remote contusion (90%), and seizures (63%). Extent of proteinopathy showed no differences with age-matched controls. A subset of the cases showed focal geographic tauopathy that correlated with older age at autopsy, but had no correlation with clinical signs, and was minimal in comparison with the encephalomalacia secondary to trauma. The results suggest that cerebral contusion and post-traumatic epilepsy may be over-represented in civilian TBI, while structural brain damage from trauma is the predominant cause of morbidity following TBI. We found no evidence that TBI initiates a progressive proteinopathy.

Keywords

Alzheimer’s disease Amyloid-β contusion epilepsy neurodegenerative disease phosphorylated tau traumatic brain injury

INTRODUCTION

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the civilian population. In 2013, there were approximately 2.5 million TBI-related ED visits, approximately 282,000 TBI-related hospitalizations, and 56,000 TBI-related deaths in the United States [1]. One population based study indicated that 37% of people hospitalized with TBI required assistance of another person in physical and/or cognitive activities of daily living [2]. In another study, among 288,009 hospitalized TBI survivors in the United States in 2003, an estimated 124,626 developed a long term disability, with an estimated cost of $2 billion for rehabilitative and supportive services in the year following discharge [3]. Falls and motor vehicle accidents predominated among the TBI mechanisms.

Although sport-related TBI is matter of intensive investigation, morbidity and mortality in this setting is comparatively small [4, 5]. Factors such as subconcussion, repetition, and delayed onset changes are often raised in terms of changes in brain tissue immunohistochemistry [6 –8], but are difficult to extrapolate to the civilian TBI population outside of sport. Evidence of TBI is generally inferred from the sport history [9, 10], rather than by a distinct neurological injury or pathological evidence of trauma. Given these and other uncertainties [11 –14], geographic p-tau aggregates are in need of further study not only in the sport construct but in the setting of civilian TBI.

Decedents presenting to medical examiner’s offices for post-mortem examination may be informative with respect to civilian TBI. Evidence of TBI history may be uncovered by death scene investigators or medical record review, which while potentially limited in terms of details of medical evaluation, would not suffer from selection bias inherent in case material sought by researchers or families. Further studies on this population may therefore be warranted. In this study, we examine neuropathological findings in consecutive decedents with a history of TBI who presented for forensic autopsy and were subsequently referred for neuropathological consultation. Included in the analyses is assessment for proteinopathy.

MATERIALS AND METHODS

Case selection

This study was presented to the Institutional Review Board at Western Michigan University Homer Stryker MD School of Medicine (WMed), and was exempted from full board review. All control samples were obtained with informed consent of next-of-kin. Protocol number 20111080. We searched forensic autopsy cases with accompanying neuropathology consultation from the Office of the Medical Examiner at WMed from 2016 to 2018, for any cases with a TBI history that was uncovered as part of the death scene investigation and/or by the forensic pathologist assigned to the case. For cases in which a history of remote TBI was uncovered, further data was collected including autopsy reports, any available medical records, death certificates, and when available, time between TBI and death in years. Cases of pediatric TBI were excluded, as were cases of acute TBI resulting in death.

Gross brain examination

All brains were fixed in 10% neutral buffered formalin and examined by a neuropathologist following fixation (RJC). Following fixation, external brain and dura were examined, the Circle of Willis and proximal branches were dissected, the cerebral hemispheres were sectioned in the coronal plane, the brainstem was sectioned in the axial plane, and the cerebellar hemispheres were sectioned in the sagittal/parasagittal plane. External and sectioned brain were photographed.

Histology

Representative sections of neocortex from all cerebral lobes, medial temporal allocortex, deep gray matter, midbrain, pons, rostral medulla, caudal medulla, cerebellar hemisphere, dura mater, and pituitary gland were processed through graded ethanol and xylene solutions, embedded in paraffin, sectioned at 5 microns, and stained with hematoxylin and eosin.

Immunohistochemistry

Antibodies to p-tau (AT8), amyloid-β, and TPD-43 were used for immunohistochemistry following standard antigen retrieval procedures (see Table 1), and immunostained using a Thermo Scientific 480S IHC Autostainer. Following H&E interpretation, immunohistochemical assessments generally followed the 2016 NINDS/NIBIB recommendations for sport-implicated geographic tauopathy [15], and modified NIA-AA 2012 consensus guidelines for assessment of AD neuropathologic change [16]. The CERAD component of the NIA-AA 2012 consensus guidelines was modified with the use primarily of Aβ immunohistochemistry to assess Aβ burden and plaque frequency, otherwise semiquantitated into sparse, moderate, and frequent per schematic illustrations in the original CERAD publication [17]. We chose this approach as we were interested in proteinopathy, and because the “neuritic plaque” is not precisely defined. Modified CERAD plaque scores were obtained in this fashion by examination of the four neocortical areas, with the score reflecting the most abundant areas. The Braak stage [18] was obtained by examination of hippocampal formation, subiculum, entorhinal cortex, and inferior temporal neocortex bilaterally, along with four neocortical areas (superior/middle frontal gyrus, superior/middle temporal gyrus, inferior parietal lobule, calcarine cortex). Paraffin sections from all paraffin blocks were immunostained for p-tau (AT8) to approximate the preliminary NINDS/NIBIB recommendations. Sections from selected paraffin blocks were additionally immunostained for TPD-43. In order to compare proteinopathy burden with the general population, Braak and modified CERAD plaque scores obtained using similar methodology and consent criteria were compared to control donors with no TBI history.

Table 1

Antibodies

Antibody	Clone	Vendor	Dilution	Antigen retrieval
Phospho-tau	AT8	Thermo Scientific	1:250	ThermoScientific Dewax and HIER L Buffer 20 min 98°C
Amyloid-β	BAM01	Thermo Scientific	1:50	95% Formic Acid 30 min
TDP-43	TARDBP	ThermoFisher Scientific	1:50	95% Formic Acid 30 min

For control samples, p-tau and Aβ burdens were assessed by immunohistochemistry similar to the remote TBI cases, with immunohistochemistry for Aβ performed on the four neocortical areas noted above, and p-tau immunohistochemistry performed on the above four neocortical areas plus hippocampal formation and adjacent medial temporal lobe.

RESULTS

Demographic and clinical information

30 decedents were identified in the neuropathology consultation files with “traumatic brain injury” indicated in the available case information. History of contact sport was not considered a surrogate for TBI history. 26 (87%) were men and 4 (13%) were women. The average age was 52.3±15.6 years, with a range of 21 to 92 years. Where information was available, 13 out of 21 (62%) had a history of drug and/or alcohol abuse, 17 out of 27 had a history of “seizures” (one of which had seizures since birth), 4 out of 22 had a history of cognitive impairment or dementia not otherwise specified, 15 out of 15 had a history of psychiatric problems (including depression and major depressive disorder, suicidality, bipolar disorder, general anxiety disorder, post-traumatic stress disorder, and schizophrenia; see Table 2). The interval between TBI and death ranged from 9 months to 41 years (average: 11±11 years; data available in 15 cases). One decedent likely sustained head injury from sport (motocross). One decedent sustained TBI from a blast injury while on active duty in the military and a subsequent fall with epidural hematoma during civilian life. The remaining subjects sustained accidental TBI in civilian life outside of sport.

Table 2

Demographic, clinical, and pathological information

	Age	Sex	Abuse	Sz	Psych	Other neuro	Age at neurotrauma exposure*	CTE path	Braak	CERAD	Remote Contusion(s)	Diameter (cm)
Case 1	42	F	No	Y	?		21	No	0	0	N
Case 2	47	M	A	Y	Anx, BPD		?	NA	NA	NA	Y	1.5
Case 3	33	M	D	N	?	s/p EDH	32	NA	NA	NA	Y	2.5
Case 4	69	M	Unk	N	Suicidal		?	NA	NA	NA	Y	6.3
Case 5	56	M	A/D	Y	?		36	NA	NA	NA	Y	6.5
Case 6	37	M	No	N	?		?	NA	NA	NA	Y	9.3
Case 7	51	M	A	Y	Anx, Dep		45	NA	NA	NA	Y	2
Case 8	56	M	A/D	Y	Schiz		51	NA	NA	NA	Y	5
Case 9	54	M	A	N	?		52	No	2	Mod	Y	7
Case 10	62	M	Unk	?	?		?	Yes	2	0	Y	3.2
Case 11	40	M	D	Y	PTSD, Dep	s/p crani	31–34	No	0	0	Y	2.5
Case 12	69	M	Unk	?	?	ALS	?	Yes	1	0	Y	5.4
Case 13	59	M	Unk	Y	?	Dementia	?	Yes	3	0	Y	6
Case 14	36	M	D	N	?		?	No	0	0	Y	9.8
Case 15	49	F	No	Y	?	Aneurysm clip	33	Yes	1	0	Y	0.9
Case 16	41	M	Unk	Y	Dep		?	No	0	0	Y	17.6
Case 17	66	M	A	Y	Dep		?	Yes	3	Sp	Y	0.5
Case 18	54	M	A	Y	MDD, GAD		?	NA	NA	NA	Y	?
Case 19	55	M	Unk	Y	?		?	NA	NA	NA	Y	11
Case 20	60	M	No	N	Dep		56	Yes	0	0	Y	11.5
Case 21	70	M	No	Y	?	Dementia	60	Yes	4	Sp	Y	8.8
Case 22	92	M	Unk	Y	?		52	NA	NA	NA	Y	?
Case 23	78	M	No	N	Dep, Del, suicidal, GAD	Dementia	?	NA	NA	NA	Y	?
Case 24	69	M	Unk	?	Schiz, OCD, GAD		?	Yes	3	Sp	N
Case 25	40	F	No	Y	BPD		38	No	0	0	Y	7
Case 26	31	M	A	Y	?		21–23	No	0	0	Y	3.5
Case 27	63	M	No	Y	?	Dementia	22	Yes	1	0	Y	?
Case 28	21	F	D	N	Suicidal, GAD, Dep		?	No	0	0	N
Case 29	37	M	D	N	BPD, Schiz		36	No	0	0	Y	5
Case 30	60	M	Unk	N	Dep		?	?	?	?	N

A, alcohol; ALS, amyotrophic lateral sclerosis; anx, anxiety; BPD, bipolar disorder; dep, depression; D, drugs; EDH, epidural hematoma; F, female; GAD, general anxiety disorder; M, male; MDD, major depressive disorder; mod, moderate; N, no; NA, not available; PTSD, post-traumatic stress disorder; schiz, schizophrenia; sp, sparse; unk, unknown; Y, yes.

Neuropathology

The most remarkable gross pathological finding in this series was the high frequency of remote contusion (Fig. 1), noted by gross examination in 27 out of 30 decedents (90%). Aggregate diameter of damaged brain in individual cases ranged from 0.5 cm to 17.6 cm. Subjects described as having “dementia” had contusions (2 cases, 6 cm aggregate diameter and 8.8 cm aggregate diameter), and penetrating shotgun injury (published previously as a case report [19]). One subject with cognitive impairment including memory loss did not have a contusion, but did have chronic subdural hematoma, atrophic fornices, atrophic mamillary bodies, remote microhemorrhages in the substantia nigra, and a fenestrated septum pellucidum.

Fig.1

Multiple remote contusions are present in the left temporal lobe and left frontal lobe. The decedent was a 70-year-old man with a history of “dementia” after a fall approximately 10 years prior to death. The same subject had Braak stage IV neurofibrillary change, and CERAD sparse neuritic plaque pathology, which by itself is an insufficient explanation for dementia. The temporal relationship between the head trauma and the dementia instead indicates that brain damage from trauma is the relevant pathological substrate.

Immunohistochemistry

Immunohistochemistry was performed on cases in which paraffin blocks were available (n = 19) (Figs. 2–4). Assigning a value of 1 to 6 for Braak scores ranging from I to VI indicated an average Braak score of 1.26 overall. Assigning a value of 1, 2, and 3 to sparse, moderate, and frequent respectively, the average modified CERAD score across the group was 0.42. The age range for those cases with immunohistochemistry ranged from 21 to 78 years, with a mean of 52 years, ±15 years (standard deviation). Braak and modified CERAD data from control samples age 50 and above (immunostains are not obtained in control samples under the age of 50 per protocol) showed an average Braak/modified CERAD of 0.97/0.22, 2.14/0.58, and 2.87/0.84, for decedents in their 50 s (n = 90), 60 s (n = 78), and 70 s (n = 38), respectively. Average Braak and modified CERAD for TBI samples involving decedents age 50 and older (mean age 63.5±8.1 years) was 2.18 and 0.73, respectively. These averages are not significantly different from an age-matched control sample of decedent’s in their seventh decade (mean age 64.1±3.1 years, n = 78) (unpaired student t-test; p = 0.93 for Braak; p = 0.63 for modified CERAD). The Braak and modified CERAD data are therefore, not surprisingly, age-related rather than trauma-related.

Fig.2

Tau immunostains in A and B show irregular p-tau aggregates, predominantly but not solely astrocytic. Irregular neocortical p-tau along with neuritic plaque pathology is present in C, and an additional irregular collection of p-tau aggregates in neurons, astrocytes, and cell processes around small blood vessels and accentuated at sulcal depths is present in D. These features are consistent with a preliminary required criterion for sport-implicated geographic tauopathy according to a recent consensus effort [15]. This case was interesting in that the decedent was a 78-year-old man with memory impairment who additionally had remote microhemorrhages in the substantia nigra, chronic subdural hematoma, septal fenestrations, dilated third ventricle with convex thalami, and atrophic mammillary bodies. There was no sport history although he did have a history of frequent falls, falls off a horse, and motor vehicle accidents. Overall, this case demonstrated many features of dementia pugilistica described in the classical study by Corsellis et al. [32]. There was also Braak stage IV neurofibrillary change, and CERAD moderate plaque pathology. Although the extent of proteinopathy in this case may be deemed sufficient explanation for dementia, the multiple additional brain lesions most likely played a role in the decedent’s neurological status. The fact that he was living independently also indicates a level of reserve even in the face of extensive pathological lesions.

Fig.3

The same subject as in Fig. 2 showed abundant perivascular, astrocytic p-tau in areas of temporal subcortical white matter (A), and abundant p-tau in the medial temporal lobe including the amygdala, anterior hippocampal formation, and entorhinal cortex (B). Patchy p-tau aggregates in the midbrain substantia nigra, cerebral peduncles, cranial nerve nuclei, subependymal glia, and subpial areas indicate an abundance of subcortical p-tau (C). Although there is substantial overlap between sport-implicated geographic p-tau aggregates and that of age-related tau astrogliopathy, such an extent and irregular distribution may be interpreted as more advanced pathology and repetitive head trauma-related. On the other head, p-tau pathology in the lumbar spinal cord (D), while geographic or sport-implicated p-tau-like in its irregularity or patchiness, is difficult to ascribe to head trauma by virtue of its presence in the lower spinal cord.

Fig.4

Superficial cortical lamina p-tau, and relatively abundant CA-2 p-tau with focal CA-4 p-tau within dendritic processes, in this 70-year-old man also depicted in Fig. 1, are among the supportive criteria for sport-implicated geographic p-tau aggregates. As noted above, this decedent’s dementia is more clearly related to structural brain damage or extensive frontotemporal contusion.

With respect to NIA-AA consensus guidelines for AD assessment, none of the 19 cases had changes corresponding to “high” AD neuropathologic change. Three of 19 cases had changes corresponding to “intermediate” AD neuropathologic change, including the presence of neuritic plaques as defined by p-tau AT8 immunohistochemistry. Two of 19 cases had changes corresponding to “low” AD neuropathologic change. The remaining fourteen cases had changes corresponding to “no” AD neuropathologic change. Two decedents with “dementia” in the clinical history had no AD neuropathologic change, while one decedent with dementia had intermediate AD neuropathologic change along with abundant cerebral contusions. One 78-year-old decedent with memory impairment and heterogeneous neuropathology (chronic subdural hematoma, septal fenestration, atrophy the fornices and mamillary bodies, remote microhemorrhages in the substantia nigra, and lacunar infarct) also had intermediate AD pathology. This decedent was living independently shortly before death.

All paraffin blocks were examined for geographic p-tau aggregates according to NINDS-NIBIB consensus recommendations. Although these recommendations are “preliminary” and may overlap with aging-related pathology depending on how strict criteria are applied [14] we interpreted cases according to the specific wording of the consensus recommendations for the required criterion and supportive criteria. These criteria were applied blindly with respect to all clinical data.

10 of 19 decedents were thus interpreted as having geographic t-tau aggregates consistent with the required criterion described. The pathology was generally limited in extent, in comparison with the structural brain damage. The mean age of decedents with geographic p-tau aggregates was 64.5±7.8 years (standard deviation). The average Braak stage was 2.2 and the average modified CERAD score was 0.6 in this group. These averages are similar to an average Braak of 2.14 and average modified CERAD of 0.58 in our control sample without TBI of decedents in their 60 s (n = 78, average age of 64.1±3.1 years). The time period between trauma and autopsy examination ranged from 4 years to 41 years (data available in three cases).

Of the nine decedents without geographic p-tau aggregates, the average age was 38±8.9 years. The average Braak score was 0.22 and the average CERAD score was 0.22, although 8 of the 9 decedents were essentially devoid of p-tau and Aβ (Braak 0, modified CERAD 0), while one decedent had Braak stage II p-tau and modified CERAD moderate Aβ. Time from trauma to autopsy examination ranged from 1 year to 21 years (data available in 6 out of 9 cases). The only significant different between the group with geographic p-tau aggregates and the group without geographic p-tau aggregates was age, with the geographic p-tau aggregate group being significantly older (p < 0.0001; two-tailed student t test).

DISCUSSION

The frequency of contusions at autopsy in our civilian population with a history of “TBI” uncovered by death scene investigation was high. This suggests that structural brain damage is a common feature of civilian TBI. Although contusion is not a feature of most definitions of TBI, it has a tendency to occur in the aftermath of moderate or severe injury [20], and is associated with poor outcome in the setting of mild TBI [21]. The high frequency in this study is in line with the morbidity of civilian TBI in general.

Of note were cases in which the decedent suffered from antemortem “dementia” solely on the basis of mechanical damage to brain tissue. Two decedents with “dementia” had no AD neuropathologic change, while one decedent with dementia had intermediate AD pathology along with abundant cerebral contusions. A fourth subject with memory impairment and heterogeneous neuropathology also had intermediate AD pathology. Given the strong genetic influence of APOE genotype, it would be important to know whether subjects with intermediate AD pathology had one or two ɛ4 alleles before inferring a role for trauma in the occasional older subjects with moderate Aβ plaque and p-tau pathology.

Geographic p-tau aggregates were present in some decedents but were sparse and microscopic in comparison to the gross brain tissue destruction from trauma. Since there is at present no lower limit to sport-implicated geographic p-tau aggregates, the significance of isolated or patchy microscopic foci of geographic p-tau aggregates is unclear, as any putative clinical correlation may be obscured by the much more abundant tissue destruction from contusion. Importantly, contusion is a traumatic lesion by definition. Geographic p-tau deposition as a traumatic lesion instead has to be inferred from the sport history, and does not appear to be an absolute indicator of neurotrauma [22 –29].

In this series, overall p-tau burden as assessed by Braak staging, and amyloid burden assessed by modified CERAD plaque score, were not significantly different from age-matched controls, indicating no discernible relationship between TBI and AD pathology in this series. Taken together, our data suggest that dementia due to “TBI in situ” or mechanical damage to brain tissue may be under-appreciated. Large scale epidemiological studies examining dementia risk in the absence of neuropathological characterization may over-estimate AD dementia or otherwise dementia due to a supervening progressive proteinopathy as hypothesized. Our results instead indicate that neurodegenerative disease per se appears to have a marginal, if any, role in the long-term morbidity and mortality from civilian TBI. As further evidence of the predominant role of age over trauma in the appearance of geographic p-tau aggregates, the only detectable difference between those cases with such aggregates and those without, was the significantly younger mean age of the latter group.

The frequency of seizure disorders in this case material was striking. Although medical records are limited, the available data suggest post-traumatic epilepsy is prevalent in the civilian TBI population, and may be particularly common with temporal lobe contusion [30]. Given that the risk of sudden death is substantial in subjects with epilepsy [31], TBI history with an accompanying contusion, especially temporal lobe contusion, may be a common sequence in civilian TBI leading to reduced life expectancy. More studies are needed to fully elucidate the relationship between TBI-related contusion, post-traumatic epilepsy, and sudden death. Vigilance in diagnosis and monitoring of seizures in the aftermath of civilian TBI nevertheless seems warranted.

At present, three overall conclusions remain plausible: 1) mechanical damage to the brain from the acute event is responsible for the long-term morbidity and mortality of TBI; 2) proteinopathy as identified by immunohistochemistry is either absent or inconsequential as a long-term effect of TBI; and 3) genuine traumatic encephalopathy appears to be a static process over the long term, rather than neurodegenerative disease-like, either clinically or pathologically.

This study has clear limitations. The case numbers are overall small and heterogeneous, as are the numbers of cases with dementia due to TBI in situ. The TBI histories, while empirically evident in the high frequency of contusion, generally lack detail in terms of severity of the acute event. Detailed neuropsychiatric evaluation is not available in this case series, making it difficult to comment on the presence or absence of progressive clinical deterioration with certainty. On the other hand, given the lack of proteinopathy in this series, the mechanism of any identifiable disease progression would remain unclear. Finally, as noted above, epilepsy was common in this series. The series may therefore be skewed toward sudden-unexpected death in epilepsy, which likely differs from the spectrum of morbidities associated with civilian TBI in general.

In summary, we studied neuropathological details, including immunohistochemistry for proteinopathy, in consecutive decedents presenting for forensic autopsy and neuropathology consultation who also had a remote history of TBI. Cerebral contusions and post-traumatic epilepsy were present in the majority of study subjects, suggesting a sequence of TBI-related mortality that may be underappreciated. Our findings further suggest that mechanical brain tissue injury and a resulting static encephalopathy determines the long-term TBI morbidity, while neurodegenerative proteinopathy is specifically absent, notwithstanding clinically inconsequential, microscopic geography tauopathy in a subset of cases.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0782r1).

References

Taylor

, Bell

, Breiding

, Xu

(2017) Traumatic brain injury-related emergency department visits, hospitalizations, and deaths - United States, 2007 and 2013. MMWR Surveill Summ 66, 1–16.

Whiteneck

, Brooks

, Mellick

, Harrison-Felix

, Terrill

, Noble

(2004) Population-based estimates of outcomes after hospitalization for traumatic brain injury in Colorado. Arch Phys Med Rehabil 85, 73–81.

Selassie

, Zaloshnja

, Langlois

, Miller

, Jones

, Steiner

(2008) Incidence of long-term disability following traumatic brain injury hospitalization, United States, 2003. J Head Trauma Rehabil 23, 123–131.

Mueller

(2001) Catastrophic head injuries in high school and collegiate sports. J Athl Train 36, 312–315.

Nalliah

, Anderson

, Lee

, Rampa

, Allareddy

(2014) Epidemiology of hospital-based emergency department visits due to sports injuries. Pediatr Emerg Care 30, 511–515.

Bailes

, Petraglia

, Omalu

, Nauman

, Talavage

(2013) Role of subconcussion in repetitive mild traumatic brain injury. J Neurosurg 119, 1235–1245.

Gavett

, Stern

, McKee

(2011) Chronic traumatic encephalopathy: A potential late effect of sport-related concussive and subconcussive head trauma. Clin Sports Med 30, 179–188.

Stern

, Riley

, Daneshvar

, Nowinski

, Cantu

, McKee

(2011) Long-term consequences of repetitive brain trauma: Chronic traumatic encephalopathy. PM R 3(10 Suppl 2), S460–S467.

Omalu

, Dekosky

, Minster

RLIS

, Kamboh

, Hamilton

, Wecht

(2005) Chronic traumatic encephalopathy in a National Football League Player. Neurosurgery 57, 128–134.

10.

McKee

, Stern

, Nowinski

, Stein

, Alvarez

, Daneshvar

, Lee

H-S

, Wojtowicz

, Hall

, Baugh

, Riley

, Kubilus

, Cormier

, Jacobs

, Martin

, Abraham

, Ikezu

, Reichard

, Wolozin

, Budson

, Goldstein

, Kowall

, Cantu

(2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64.

11.

Casson

, Viano

(2019) Long-term neurological consequences related to boxing and American football: A review of the literature. J Alzheimers Dis 69, 935–952.

12.

Schwab

, Hazrati

(2018) Assessing the limitations and biases in the current understanding of chronic traumatic encephalopathy. J Alzheimers Dis 64, 1067–1076.

13.

Bieniek

, Blessing

, Heckman

, Diehl

, Serie

, Paolini MA

, Boeve

, Savica

, Reichard

, Dickson

(2019) Association between contact sports participation and chronic traumatic encephalopathy: A retrospective cohort study. Brain Pathol. doi: 10.1111/bpa.12757

14.

Forrest

, Kril

, Wagner

, Hönigschnabl

, Reiner

, Fischer

, Kovacs

(2019) Chronic traumatic encephalopathy (CTE) is absent from a european community-based aging cohort while cortical aging-related tau astrogliopathy (ARTAG) is highly prevalent. J Neuropathol Exp Neurol 78, 398–405.

15.

McKee

, Cairns

, Dickson

, Folkerth

, Dirk Keene

, Litvan

, Perl

, Stein

, Vonsattel

, Stewart

, Tripodis

, Crary

, Bieniek

, Dams-O’Connor

, Alvarez

, Gordon

(2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131, 75–86.

16.

Montine

, Phelps

, Beach

, Bigio

, Cairns

, Dickson

, Duyckaerts

, Frosch

, Masliah

, Mirra

, Nelson

, Schneider

, Thal

, Trojanowski

, Vinters

, Hyman

(2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol 123, 1–11.

17.

Mirra

, Heyman

, McKeel

, Sumi

(1991) The consortium to establish a registry for Alzheimer’s disease (CREAD). Part II. standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 46, 142–145.

18.

Braak

, Braak

(1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82, 239–259.

19.

Tribett

, Erskine

, Bailey

, Brown

, Castellani

(2019) Chronic traumatic encephalopathy pathology after shotgun injury to the brain. J Forensic Sci 64, 1248–1252.

20.

Bell

, Hackett

, Hall

, Pülhorn

, McMahon

, Bavikatte

(2018) Symptomatology following traumatic brain injury in a multidisciplinary clinic: Experiences from a tertiary centre. Br J Neurosurg 32, 495–500.

21.

Yue

, Winkler

, Puffer

, Deng

, Phelps

RRL

, Wagle

, Morrissey

, Rivera

, Runyon

, Vassar

, Taylor

, Cnossen

, Lingsma

, Yuh

, Mukherjee

, Schnyder

, Puccio

, Valadka

, Okonkwo

, Money

, The Track TBI Investigators (2018) Temporal lobe contusions are associated with impaired six-month functional recovery after mild TBI: A track-TBI study. J Neurotrauma 40, 972.981.

22.

Noy

, Krawitz

, Bigio

MR Del

(2016) Chronic traumatic encephalopathy-like abnormalities in a routine neuropathology service. J Neuropathol Exp Neurol 75, 1145–1154.

23.

Puvenna

, Engeler

, Banjara

, Brennan

, Schreiber

, Dadas

, Bahrami

, Solanki

, Bandyopadhyay

, Morris

, Bernick

, Ghosh

, Rapp

, Bazarian

, Janigro

(2016) Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy. Brain Res 1630, 225–240.

24.

Shively

, Edgerton

, Iacono

, Purohit

, Qu

, Haroutunian

, Davis

, Diaz-Arrastia

, Perl

(2017) Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain. Acta Neuropathol 133, 353–366.

25.

Fournier

, Gearing

, Upadhyayula

, Klein

, Glass

(2015) Head injury does not alter disease progression or neuropathologic outcomes in ALS. Neurology 84, 1788–1795.

26.

Gao

, Ramsay

, Twose

, Rogaeva

, Tator

, Hazrati

L-N

(2017) Chronic traumatic encephalopathy-like neuropathological findings without a history of trauma. Int J Pathol Clin Res 3, 1–4.

27.

Koga

, Dickson

, Bieniek

(2016) Chronic traumatic encephalopathy pathology in multiple system atrophy. J Neuropathol Exp Neurol 75, 963–970.

28.

Ling

, Holton

, Shaw

, Davey

, Lashley

, Revesz

(2015) Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases. Acta Neuropathol 130, 891–893.

29.

Iverson

, Luoto

, Karhunen

, Castellani

(2019) Mild chronic traumatic encephalopathy neuropathology in people with no known participation in contact sports or history of repetitive neurotrauma. J Neuropathol Exp Neurol 78, 615–625.

30.

Tubi

, Lutkenhoff

, Blanco

, McArthur

, Villablanca

, Ellingson

, Diaz-Arrastia

, Van Ness

, Real

, Shrestha

, Engel

, Vespa

, Agoston

, Au

, Bell

, Bleck

, Branch

, Buitrago Blanco

, Bullock

, Burrows

, Claassen

, Clarke

, Cloyd

, Coles

, Crawford

, Duncan

, Foreman

, Galanopoulou

, Gilmore

, Olli

, Harris

, Hartings

, Lawrence

, Hunn

, Jette

, Johnston

, Jones

, Kanner

, Monti

, Morokoff

, Moshe

, Mowrey

, O’Brien

, O’Phelan

, Pitkanen

, Raman

, Robertson

, Rosenthal

, Shultz

, Snutch

, Staba

, Toga

, Van Horn

, Vespa

, Willyerd

, Zimmermann

(2019) Early seizures and temporal lobe trauma predict post-traumatic epilepsy: A longitudinal study. Neurobiol Dis 123, 115–121.

31.

Saetre

, Abdelnoor

(2018) Incidence rate of sudden death in epilepsy: A systematic review and meta-analysis. Epilepsy Behav 86, 193–199.

32.

Corsellis

, Bruton

, Freeman-Browne

(1973) The aftermath of boxing. Psychol Med 3, 270–303.