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Neurotrauma: 2024 update 

David S. Priemer1,2, Daniel P. Perl1,2 

1 The Department of Defense/Uniformed Services University Brain Tissue Repository, Bethesda, MD, USA 

2 Department of Pathology, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD, 
USA 

Corresponding author: 
Daniel P. Perl · Department of Pathology · F. Edward Hébert School of Medicine · Uniformed Services University (USU) · 4301 Jones 
Bridge Rd · Bethesda, MD 20814 · USA 
daniel.perl@usuhs.edu 

Submitted: 09 September 2024 · Accepted: 03 October 2024 · Copyedited by: João Gama · Published: 23 October 2024 

Abstract 

2023 was an important year for research in traumatic brain injury (TBI), particularly as it concerned interests in 
neuropathology. After reviewing the literature, we present the advancements that we felt were of particular 
importance to the neuropathology community. Highlighted are articles that report upon: (1) the first large-cohort 
assessment for the neuropathology of intimate partner violence, (2) the assessment of chronic traumatic 
encephalopathy (CTE) in young athletes, (3) the observation of cortical sulcal depth vascular changes in CTE, (4) 
a proposal for a tau immunohistochemical panel to evaluate complex cases of CTE in the context of multiple 
tauopathies, (5) the relationship of TBI and/or CTE with TDP-43 pathology, (6) repetitive TBI inducing pathology 
in C9orf72-transgenic mice, (7) radiologic patterns of head and neck injury following vehicular underbody blast 
exposure, (8) chronic alterations in brain metal content following repetitive impact TBI, (9) neurovascular unit 
injury following low-level blast exposure, and finally (10) an assessment of Muhammad Ali’s clinical history 
leading to the conclusion that he suffered from young-onset, idiopathic Parkinson Disease. We close our writing 
with in memoriam to Dr. Byron A. Kakulas, a renowned figure in the neuropathology of spinal cord injury who 
we lost in 2023. 
 

Keywords: Traumatic brain injury, Chronic traumatic encephalopathy, TDP43, Neurovascular, Intimate partner violence, Blast 

Introduction 

The year 2023 was an especially fruitful year in 
the study of traumatic brain injury (TBI), particularly 
as it concerned aspects of neuropathology, demon-
strating that interest in the field remains robust. 
Many notable studies were published, providing 
many impactful advancements in knowledge. After 

conducting a thorough review of the literature re-
garding neurotrauma over the year of 2023, herein 
we present and summarize the discoveries that we 
felt were of particular importance and relevance to 
the neuropathology community. We conclude our 
review with memoriam to the life of Dr. Byron A. 
Kakulas, a pioneer in the neuropathology of spinal 
cord injury, who died in 2023 at the age of 90. 

Review 

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https://creativecommons.org/publicdomain/zero/1.0/
mailto:daniel.perl@usuhs.edu


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The neuropathology of intimate part-
ner violence 

While the large focus of research on the 
chronic neuropathologic effects of repetitive TBI has 
been dedicated to contact sports athletes and, to a 
lesser degree, military service, there are other 
circumstances in which repetitive TBI and its long-
term sequelae must be investigated. One important 
setting is intimate partner violence (IPV), as it is a 
remarkably common global phenomenon of increas-
ing medical research interest (Figure 1) and as pre-
vious, highly-cited anecdotal reports have impli-
cated this exposure with risk of chronic traumatic 
encephalopathy (CTE).1-3 In 2023, authors Dams-
O’Conner and Folkerth et al. reported the compre-

hensive neuropathological examination and clinico-
pathological correlation of the first large case series 
of brains from victims of IPV.4 

The authors used a multi-prong approach to 
address this question. First, they prospectively 
identified a total of 14 brains from documented IPV 
cases which had come to the New York City Office of 
Chief Medical Examiner over a 24-month period. 
These cases were comprehensively examined neu-
ropathologically, and all available medical records, 
medicolegal records, and data available from post-
mortem interviews from next-of-kin were reviewed. 
The fourteen prospectively gathered cases were 
supplemented by the retrospective review of neuro-
pathological material from 70 additional cases 
derived from additional victims of IPV.

 

Figure 1. Total PubMed listings regarding intimate partner violence (IPV) and related terms, by year. 

Medical research interest in IPV has grown substantially in recent years, particularly in the most recent decade, as is easily demonstrated 
by the dramatic increases in annual publications for IPV and related terms (domestic violence, domestic abuse) indexed by PubMed. 
Within the box are the proportions of the total number of publications regarding a given term that have been published within the last 
decade, i.e. though the first publication listed in PubMed utilizing the term IPV appeared in 1976, 63.5 % of the total studies using this 
term have emerged only in the last decade. 

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The fourteen prospectively gathered cases, as 
could be expected, had complex histories associated 
with IPV, including known TBI in six cases, non-fatal 
strangulation in four, epilepsy in seven, and some 
history of cerebrovascular, neurological, or psychiat-
ric condition (related to IPV or otherwise) in thir-
teen. In this group, evidence of prior TBI, such as old 
contusions or subdural membranes, was identified 
in eight cases, and evidence of more recent injuries 
was identified in six. Amyloid Precursor Protein 
(APP) immunohistochemistry demonstrated evi-
dence of axonal injury in regions susceptible to 
diffuse traumatic axonal injury in nine cases; further, 
these regions were highlighted by perivascular or 
parenchymal microgliosis (CD68 immunohisto-
chemistry) and/or iron deposition (Perls stain) in 
twelve cases, many of which were in the absence of 
hypertensive arteriolosclerotic disease. 

This study illustrates that the complexity of IPV 
translates to the variable development of different 
corresponding neuropathologies, most of which are 
related to direct anatomic disruptions from trauma 
such as hemorrhage, contusion, and axonal injury. 
Importantly, and despite high rates of neuropsychi-
atric symptomatology in the cohort, comprehensive 
examination did not reveal evidence of CTE in any of 
the 14 cases. This finding was corroborated in the 
second portion of the study analyzing 70 archival 
cases of IPV, which similarly did not reveal a single 
case of CTE. Therefore, this study also suggests that 
TBI sustained in the context of IPV, similar to that 
sustained in other non-athletic contexts wherein 
impact TBI occurs but is less predictable and cer-
tainly less repetitive,5 is often of an insufficient dose 
and/or mechanism to produce CTE neuropathology. 
Moreover, this data further suggests that CTE does 
not provide a “catch-all” or common denominator 
accounting for high proportions of chronic neuro-
psychiatric sequalae following TBI. As such, we also 
feel that this study serves as an important oppor-
tunity to urge caution regarding the overinterpreta-
tion of isolated cases reports in our research prac-
tices, particularly as it concerns diseases with high 
public interest such as CTE. 

CTE in young contact sports athletes 

The large majority of CTE cases have been char-
acterized in older age groups and/or in athletes with 

long careers, particularly those with an elite level of 
sport participation.6 However, a lingering question 
concerns development of CTE at young ages and the 
risk of developing CTE from lower level athletic 
exposures (e.g., high school sports). Among the 
most impactful studies with respect to public aware-
ness in 2023 was written by Dr. Ann Mckee and col-
leagues, titled “Neuropathologic and Clinical Find-
ings in Young Contact Sport Athletes Exposed to 
Repetitive Head Impacts”.7 

The study describes the neuropathologic eval-
uation for CTE, with use of the “McKee” staging 
system to assess severity,8 in a convenience sample 
of 152 donated brains from former contact sports 
athletes and who were under the age of 30 years at 
death (range = 13–29 years). The majority of the 
series (60.5 %) had a history of participation in 
American football, with the average duration of 
football play being 10.29 years, and the average age 
at which football participation began being 9.25 
years. Of the 152 cases, 128 were classified as 
“amateur athletes” that did not play at a semipro-
fessional or professional level but rather played in 
youth, high school (most frequent), or up to colle-
giate levels. The authors report that CTE was present 
in 63 of 152 cases (41.4 %), the large majority 
(95.2 %) of which had minimal/mild pathology 
(McKee stages I or II). 45 of the 63 CTE cases were 
from amateur athletes. Consistent with what has 
been observed and reported in the literature,6 the 
brains with CTE were from individuals who were 
significantly older, and had significantly longer dura-
tions of play than those without CTE. However, the 
youngest individual reportedly diagnosed with CTE 
in this study was 17 years old. 

The authors of the study have made an im-
portant contribution with the largest series of 
athletes in this young age group to be assessed for 
CTE pathology, and identifying pathologic features 
at a relatively high frequency. However, apart from 
the largely unavoidable limitations of ascertainment 
bias in a convenience sample derived from a brain 
bank dedicated to TBI research, there are a number 
of concerns with this study that we care to highlight. 
First, though McKee et al state that evaluation for 
CTE in this study was done in accordance with the 
most recent National Institute of Neurological Disor-
ders and Stroke/National Institute of Biomedical  

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Imaging and Bioengineering (NINDS/NIBIB) consen-
sus criteria,9 there is no detail provided with respect 
to the extent or manner of sampling that was per-
formed in these cases. In addition, the authors 
provide their interpretation of the pathognomonic 
lesion of CTE as occurring “typically”, and “most 
frequently” at the depth of a cortical sulcus, which 
stands in notable contrast to the NINDS/NIBIB 
consensus document which states that a pathogno-
monic lesion of CTE must be at a sulcal depth by 
definition.9 This raises concern about how these 
cases were being diagnosed, as an especially liberal 
approach may very well have led to over-diagnosing 
CTE in these mildly affected cases. Accordingly, it 
will be hard to relate the data reported here to other 
published studies. 

It is also important to express concern with 
how the lay media has approached this study. 
Indeed the publication garnered nationwide media 
attention, which involved the publication of several 
anecdotal stories involving very young athletes 
who had died by suicide, with the implication that 
contact sports participation and CTE were contribu-
tory, if not causal.10-12 These media articles were 
written in this manner despite the fact that the 
study published by McKee et al identified no corre-
lation with clinical symptoms (including neurocogni-
tive and psychiatric symptoms) or cause of death 
(including suicide) with CTE when compared to cases 
without CTE, which itself is consistent with other 
recently published data.13 

How media outlets may ultimately choose to 
interpret scientific articles is often out of our 
control. However, as neuropathologists who may 
concern ourselves with CTE or other neurologic 
 disorders that are within the public eye, we must be 
especially careful with how we communicate to the 
media and the lay public at large when given the 
opportunity, so as to avoid mischaracterization 
and/or unnecessary hyperbolizing of our findings. 

Evidence of vascular injury and 
remodeling at sulcal depths in CTE 

Next, we would like to highlight the collective 
efforts of two separate studies, both largely focused 
out of the Boston University CTE center and the Vet-
erans Administration Healthcare system in Boston, 

which have identified evidence of chronic vascular 
injury and remodeling concentrated at sulcal depths 
in cases of CTE, demonstrating evidence that vascu-
lar insults may be intricately tied to the disease. 

First, in a study that investigated the theory 
that microvascular and associated blood brain bar-
rier damage at sulcal depths may be involved in the 
pathogenesis of CTE, authors Kirsch et al. published 
a large immunohistochemical and immunoassay-
based study using brain tissues from cohorts which 
included high stage CTE, low stage CTE, and CTE-neg-
ative controls with and without history of repetitive 
TBI.14 Most of those with a history of repetitive TBI 
were exposed via contact sports. A total of 156 cases 
were included in the immunoassay portion of the 
study, which quantified markers of vascular injury 
and inflammation, including intercellular adhesion 
molecule 1 (ICAM1), vascular cellular adhesion mol-
ecule 1 (VCAM1), and C-Reactive Protein (CRP) in 
samples from the dorsolateral frontal region; the 
authors proceeded to measure for associations 
between these quantifications and extent of repeti-
tive TBI exposure (years of contact sports played), 
evidence of microgliosis, and p-tau pathology. 
A smaller sampling of 57 cases with high stage CTE, 
low stage CTE, and no CTE were evaluated histolog-
ically via immunohistochemistry with antibodies 
including for ICAM1, albumin, p-tau (AT8), and 
microglia (Iba1, CD68). The authors found that quan-
tified levels of ICAM1, VCAM1, and CRP were signif-
icantly increased in CTE cases versus CTE-negative 
cases, and generally increased with CTE severity. 
Further, these elevated levels were statistically 
associated with duration of repetitive TBI exposure, 
increased microglial density, and overall p-tau bur-
den. In CTE cases, particularly in high stage cases, 
histologic examination revealed dramatic co-locali-
zation of ICAM1 and AT8 at sulcal depths. Whether 
these increases relate to repetitive impact TBI expo-
sure, p-tau aggregation, or a combination of both 
remains an important question. However, all cases 
wherein there was a history of repetitive TBI demon-
strated extravascular albumin staining in both gray 
and white matter, in contrast to none of the of the 
cases without a history of repetitive TBI, suggesting 
chronic compromise to vascular integrity and the 
blood-brain barrier following this exposure. 

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In the second study, authors Rosen et al. im-
aged vascular microstructure in passively cleared 
(SHIELD tissue processing) and tomato lectin-
stained dorsolateral frontal samples from 41 total 
cases, including donors with high stage CTE, low 
stage CTE, and no CTE (44 % of which had repetitive 
TBI history) using fluorescence microscopy.15 Again, 
the majority of the CTE cases corresponded to TBI 
from contact sports participation. Among the 
factors evaluated in different cortical regions (e.g. 
sulcal depth versus gyral crest) included assess-
ments for vessel branch density (the number of 
vessel branches per volume of the image stack), and 
vessel fraction volume (the volume of blood vessels 
per volume of the image stack). First, CTE cases 
demonstrated evidence of vascular remodeling 
characterized by significantly increased vascular 
branch density at the sulcal depths compared to 
non-CTE controls. Further, there were statistically 
significant differences in both vessel branch density 
and vessel fraction volume at sulcal depths versus 
the gyral crest in CTE cases that were not observed 
in controls. Finally, AT8 staining density correlated 
positively with vessel fraction volume at the sulcus, 
though this was independent of CTE status. 

These two studies collectively demonstrate 
that chronic vascular injury is an important compo-
nent of repetitive, mild TBI and its predilection to 
sulcal depths with remarkable correlation with p-tau 
deposition in CTE offers a tantalizing theory for CTE 
pathogenesis. Indeed, vascular/blood-brain-barrier 
injury from TBI could induce insufficient delivery of 
nutrients (including oxygen) and removal of waste 
products, and promote a malnourished/hypoxic, 
pro-inflammatory, and even neurodegenerative 
environment in which p-tau can accumulate. Fur-
ther, while authors Rosen et al. postulate that the 
changes in vascular branching and volume at sulcal 
depths in CTE may be accounted for by atrophy in 
the sulcus relative to the gyral crest, it has also been 
demonstrated that chronic vascular insufficiency 
triggers pro-angiogenic proteins, such as vascular 
endothelial growth factor.16,17 Nonetheless, it can-
not be stated with certainty whether the processes 
of vascular injury and remodeling are pathogenically 
linked to CTE rather than being co-occurring/parallel 
processes in locations susceptible to impact TBI.18 
More research is needed. 

Assessing multiple concurrent tauopa-
thies in the setting of CTE: a way 
forward? 

The second, and still the most recent, 
NINDS/NIBIB consensus for the neuropathological 
diagnosis of CTE made important strides regarding 
diagnostic approach, in that it refined the definition 
of the pathognomonic lesion for CTE.9 Specifically, 
the newest consensus definition of CTE defines it as 
a disease of perivascular neuronal tau deposition at 
sulcal depths, with or without glial tau; the defini-
tion was adjusted in part to allow for a more careful 
delineation of CTE from age-related tau astrogliopa-
thy (ARTAG), which as the name suggests is limited 
to tau accumulation in astrocytes but also tends to 
be limited to superficial cortex when it involves 
sulcal depths. Beyond the discernment of ARTAG, 
the consensus paper stated that the interpretation 
of CTE in the context of other multiple, concurrent 
neurodegenerative diseases is a matter of future 
consideration, and specifically made “no assertion” 
in this regard. However, especially in brains from 
older individuals with CTE, co-pathologies which 
include other tauopathies (e.g. Alzheimer disease 
[AD], primary age-related tauopathy, progressive 
supranuclear palsy [PSP], etc.) are common,8,19 and 
this creates a dilemma in neuropathology practice. 
Though multiple co-occurring tauopathies can 
certainly be diagnosed (Figure 2), given the degree 
of overlap between CTE distribution and that of 
other tauopathies, distinguishing (i.e. determining 
which p-tau aggregates belong to which disease) 
and thus staging any individual tauopathy in this 
circumstance under current guidance can be ex-
traordinarily difficult, if not impossible. Importantly, 
this issue also precludes many aspects regarding the 
clinicopathological correlation of CTE and the clinical 
validation of pathological staging criteria. 

While we hope for a third NINDS/NIBIB 
Consensus effort in the near future that could begin 
to address this unresolved issue, in 2023 authors 
Sorrentino et al. investigated a solution and wrote a 
brief manuscript detailing a study in which they used 
an immunohistochemical panel of multiple antibod-
ies for p-tau on diagnostic material from a small 
series of cases of AD, CTE, PSP, and controls.20 Anti-
bodies utilized in the panel included AT8 (p-tau at 

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Figure 2. Chronic traumatic encephalopathy (CTE) overlap with 
Alzheimer disease. 

CTE neuropathology overlapping with Alzheimer neuropatho-
logic change in the brain of a 72 year-old man with a history of 
repetitive impact-type traumatic brain injury. A: AT8 immuno-
histochemical stain (scale bar = 4 mm) performed on a sample 
from the orbitofrontal cortex demonstrating phosphorylated 
tau aggregation throughout the cortex in a pattern consistent 
with Alzheimer disease, overlapped by sulcal depth aggrega-
tions corresponding to CTE. B: AT8 immunohistochemical stain 
(scale bar = 200 µm) performed on a sample from the dorsolat-
eral prefrontal cortex demonstrating extensive perivascular 
phosphorylated tau aggregation; this was identified at a sulcal 
depth. C: 4G8 immunohistochemical stain (scale bar = 4 mm) 
performed on a sample from the orbitofrontal cortex demon-
strating florid involvement by Aβ plaques. 

S202 and T205), AT180 (p-tau at T231), PHF1 (p-tau 
at S396 and S404), and MC1, which is an antibody 
specifically raised against p-tau in AD.21 The authors 
found little discernable difference in cases of AD, 
CTE, and PSP labeled with AT8, AT108, and PHF1. 
However, interestingly, MC1 immunostaining was 
minimal to absent in cases of CTE and PSP in com-
parison to the strong staining identified in the AD 
case as rated subjectively and also calculated by 
assessment of p-tau inclusions per three 10x micro-
scopic fields (p = ≤ 0.0002). 

In this study, the authors demonstrate 
evidence that the conformation of p-tau in AD is suf-
ficiently different so as to potentially allow the 
differentiation of AD from other tauopathies, 
importantly CTE, through the use of MC1 immuno-
histochemistry. This study, though small, therefore 
provides promise for a simple and practical means 
to potentially address major diagnostic issues con-
cerning CTE when concurrent with multiple tauopa-
thies. More investigation with mixed cases is 
needed, particularly given that, at the time of this 
writing, the discussion regarding mixed neuro-
degenerative pathologies in brains from individuals 
exposed to repetitive TBI continues to grow.22 

The relationship between TBI, CTE, 
and TDP43 pathology 

TDP43 pathology has been described in a rela-
tively small number of mostly advanced CTE cases, 
including descriptions of neocortical deposits 
(sometimes at sulcal depths, coincident with CTE 
pathognomonic lesions) as well as deposits in limbic 
structures, sometimes coincident with hippocampal 
sclerosis (HS).23-27 As it concerns CTE with concurrent 
limbic TDP43 pathology and HS, the precise relation-
ship between these entities has been uncertain, as 
has been how limbic TDP43 pathology and HS may 
differ in the context of CTE versus that of aging alone 
(i.e., the impact of TBI on these lesions). In 2023, 
authors Nicks et al. published a large cohort study to 
begin to address this gap in knowledge.28 

The authors began with a 401-case cohort of 
cases with CTE and known TBI history, predomi-
nantly from contact sports participation (mostly 
American football). The mean age of the cohort was 
62.2 years, with a range of 20–100 years. The 

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authors found evidence of TDP43 pathology in 
43.3 % of the CTE cases, and HS in 23.4 % of cases. 
Regardless of whether or not HS was identified, 
TDP43 pathology was most common in the limbic 
regions (93 % of TDP43-positive cases), and less 
so in the examined frontal cortex (47 % of TDP43-
positive cases, including 7 % which only had TDP43 
accumulations in the frontal cortex in the absence of 
limbic pathology). Perhaps expectedly, the most 
numerically significant factor between CTE cases 
with and without HS was age; the average age in the 
CTE group with HS was 77 years (range 52–100), and 
without HS was 57.7 (range: 20–91). Interestingly, 
however, another statistically significant factor that 
emerged in the study was duration of contact sport 
participation, which was significantly longer in the 
CTE group with HS as opposed to without (p=0.029). 

As a means of comparison, the group also 
assessed differences between the CTE cohort and a 
33-donor cohort diagnosed with HS related to aging, 
without a history of TBI and without CTE (average 
age = 86.6 years). Among the notable observations 
was that the CTE group with HS had a substantially 
greater proportion of cases with TDP43 inclusions 
within both limbic and frontal regions (41.5 %) in 
comparison to the group with HS but no CTE 
(18.2 %), which was particularly interesting given 
that the CTE group had an average age of death that 
was 10 years younger than the HS group without 
CTE. Also interesting was that the distribution of 
TDP43 pathology in the hippocampus differed 
between the groups. In the CTE group with HS, the 
CA1 region and dentate gyrus were statistically less 
likely to be involved by any TDP43 pathology, and 
the CA2 region was more severely involved TDP43 
pathology. 

With this study, the authors demonstrate a 
high rate of TDP43 pathology in aged individuals 
with CTE, and provide evidence that CTE, and/or 
repetitive TBI, may exacerbate or accelerate age-re-
lated TDP43 pathology with or without HS, and/or 
may be a risk factor for the development of inde-
pendent, and perhaps different, TDP43 pathology. 
The latter notion becomes particularly interesting 
when considering another 2023 article which identi-
fied TDP43 inclusions in the inner nuclear layer of 
6/8 retinas from cases with CTE, and in only 1/8 of 

the age-matched controls.29 We are excited to see 
what the future holds for these new developments. 

Repetitive TBI elicits pathology in 
C9orf72 transgenic mice 

In our continued efforts to understand the link 
between amyotrophic lateral sclerosis (ALS) and 
frontotemporal dementia, the identification of 
C9orf72 hexanucleotide gene expansion as the most 
common genetic association between these disor-
ders was a landmark discovery.30,31 Interestingly, 
links between repetitive TBI and ALS have also been 
suggested, and bolstered by evidence epidemiologi-
cally, which itself includes demonstrations that a 
history of multiple TBIs is associated with a three-
fold increased risk of ALS, and that incidence and 
mortality from ALS is nearly four times higher in 
professional American football players in compari-
son with the general population.32-34 Questions 
surrounding how TBI may impact development of 
pathology in the setting of a known genetic risk for 
frontotemporal dementia/ALS should therefore be 
explored. 

In a 2023 article published in Brain, authors 
Kahriman et al. investigated the effect of repeated, 
mild TBI on producing pathology in a transgenic 
hemizygous and homozygous C9orf72 expansion 
mouse model.35 The authors experimented on 63 
total mice, including transgenic and non-transgenic 
lines, 34 of which were subjected to repetitive, mild, 
closed-head TBI using a weight-drop impact model 
and 29 of which were sham. The TBI model delivered 
over 5 consecutive days, and the brains were 
removed for neuropathologic examination 52 weeks 
following exposure. In the interim period, mice were 
subjected to a variety of neurologic and behavioral 
testing. 

Alterations in neurologic and behavioral testing 
during the long survival period were observed in the 
transgenic, TBI-subjected mice, which included but 
were not limited to significantly reduced grip 
strength, and behaviors that were similar to some 
phenotypes of human ALS. Neuropathologic findings 
in these mice were also particularly striking. Histo-
logical examination included chromogenic immuno-
histochemistry and immunofluorescent staining for 

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antibodies including TDP43, glial fibrillary acidic pro-
tein (GFAP), Iba1 and CD68, neurofilament (SMI-
312), synaptophysin (a pre-synaptic marker) and 
PSD-95 (a post-synaptic marker), and neuronal 
markers NeuN, Tuj1 (Beta-III tubulin), and MAP2. 
Examination revealed that brains from the TBI-ex-
posed, transgenic mice suffered significantly more 
neuronal loss in the cortex along with axonal and 
synaptic marker loss and evidence of widespread 
microglial activation in comparison with controls. 
These findings were seen coincidently with dramatic 
cytoplasmic mislocalization of TDP43 in the remain-
ing neurons of the cortex, which was not observed 
in either the non-transgenic mice which sustained 
TBI or the transgenic sham mice following the 
52-week survival period. With these findings, the 
authors demonstrate evidence that repetitive TBI is 
sufficient to initiate, exacerbate, and accelerate the 
development of frontotemporal dementia/ALS-like 
pathology in the setting of genetic predisposition 
with C9orf72 expansion in a mouse model. The find-
ings are most informative with regard the relation-
ship of TBI and ALS, and also have implications with 
regard to development and implementation of 
therapy for TDP43 pathology and/or TBI. 

Patterns of head and neck injury in 
fatal underbody blast exposures 

TBI is considered a “signature wound” of mod-
ern warfare, and blast exposure is acknowledged 
as the most common source of TBI in the military 
context.36,37 Among the more common causes of 
military blast-related morbidity and mortality is 
so-called underbody, or “mounted” blast exposure. 
Underbody blast exposure, which became notable 
due to the increased use of improvised explosive 
devices in the most recent wars in the Middle East, 
is sustained when an explosive is detonated under a 
vehicle. This causes the vehicle, its contents/occu-
pants to be propelled upwards in a rapid accelera-
tion event that further includes impacts between 
vehicle occupants and other occupants, vehicle con-
tents, and/or the inner walls of the vehicle. The 
precise mechanism(s) by which fatal central nervous 
system injuries occur in this context, and/or constel-
lations that these injuries tend to occur in, have 
been poorly understood. 

Ashworth et al. studied post-mortem com-
puted tomography scans of 46 underbody blast 
fatalities which occurred from 2007–2013 among 
British military personnel.38 The authors identified 
that the most common pathology identified within 
or of the cranium was subarachnoid hemorrhage 
(80.4 % of total cases), followed by skull fracture 
(63 %, including 10.9 % of cases with an “eggshell” 
pattern of skull fracture reflecting direct head 
impact), 4th ventricular hemorrhage (63 %), and 
contusions (28.3 %). Other injuries observed less 
frequently included subdural hematoma, epidural 
hematoma, brainstem hemorrhage, and pneumo-
cephalus. Radiologic evidence of diffuse axonal 
injury was uncommon (1 case). Examination of the 
spine frequently revealed fractures, being most 
common in the lower spine (lumbar fractures in 
52.2 % of cases, sacral in 50 %), followed by the 
thoracic and cervical. In examining the constellation 
of injuries to the central nervous system and its 
surroundings, together with secondary injuries to 
other regions (e.g. thorax, abdomen, limbs), the 
authors hypothesized five categories/patterns of 
potential head and neck injury in fatal underbody 
blasts. Briefly, these constellations are published as 
follows: 

1. Multiple-level spinal injuries in addition to 
skull fracture: Frequent association of frac-
tures at the C0-C1 junction and three or more 
vertebral fractures at other spinal levels, along 
with base-of-skull and brainstem injuries. 
Often coincident with injuries to the thorax and 
abdomen. The proposed mechanism is upward 
compression of the axial skeleton due to up-
ward force of the blast. 

2. Peri-mesencephalic hemorrhage: Peri-mesen-
cephalic hemorrhage, as characterized by 
hemorrhage in the 4th ventricle, lateral ventri-
cles, and/or posterior fossa. The proposed 
mechanism is increased jugular pressure and 
secondary non-aneurysmal, peri-mesence-
phalic bleeding. 

3. Spinal (cervical) fractures and brainstem 
injury: Proposed tertiary blast injury, that is 
blunt force injuries occurring as a result of the 
person being accelerated by the blast and im-
pacting objects, leading to flexion/extension 

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and rotational forces about the neck, and 
resulting C1 and condylar fractures. 

4. Contusions with injury to C0-C1: Injury, includ-
ing contusions, at C0-C1 combined with 
abdominal or thoracic injury. 

5.  “Eggshell” skull fractures: Eggshell pattern of 
skull fracture on the convexity of the skull, 
owing to direct impact, most likely with the 
vehicular cabin ceiling. 

The information in this study may be particu-
larly important to medical examiners and/or neuro-
pathologists who practice in a forensic setting. 
Further, the article may also serve to emphasize the 
growing utility of post-mortem imaging in diagnostic 
practice. Beyond the scope of neuropathology, 
understanding mechanisms by which the central 
nervous system can be injured in various settings of 
blast exposure is critical for diagnosis and care, 
including triage efforts, and also for the develop-
ment of protective measures and mitigation. 

Chronically altered brain metal 
homeostasis following repetitive im-
pact TBI 

Alterations in the content and metabolism of 
metals including iron, zinc, and copper have been 
identified in the context of aging and Alzheimer dis-
ease, as well as Parkinson’s disease, and have been 
implicated with misfolding of pathogenic proteins in 
neurodegeneration.39-43 While a small number of 
studies have reported iron accumulation following 
repeated traumatic brain injury,44-46 there has been 
little investigation with regard to alterations in iron 
regulatory proteins and the potential association of 
metal dysregulation with neurodegeneration in the 
context of TBI. Paul Adlard’s laboratory had previ-
ously shown altered brain metals following a single 
impact TBI, and demonstrated increased iron levels 
in the subacute period following repeated impact 
TBI, in mice.47,48 As a follow-up, they investigated 
chronic alterations in metal content, iron regulatory 
proteins, and neurodegenerative proteins in a 
mouse model of mild, repetitive impact TBI with 
prolonged survival within a study they published in 
2023.49 

The authors subjected groups of three-month-
old mice to either single or repeated (five instances, 
each 48 hours apart) mild, closed-head impact TBI, 
and compared to corresponding sham controls. In 
order to demonstrate evidence of ongoing genetic 
changes following TBI, RNA sequencing and differ-
ential gene expression analysis was performed on 
ipsilateral and contralateral cerebral hemispheres 
from mice sacrificed following 6 months of survival. 
In the mice with 12 months of survival, ipsilateral 
and contralateral cortical samples were subjected to 
metal analysis using inductively coupled plasma-
mass spectrometry (ICP-MS) and Western blot anal-
ysis using a list of antibodies related to iron regula-
tory proteins, to tau and tau regulatory proteins, 
and to amyloid precursor protein. 

The authors identified significant alterations in 
metal content and regulatory proteins in the mouse 
brains exposed to repetitive TBI. First, they found 
increases in ferritin and divalent metal transporter 1 
(DMT1, a cytosolic iron transport protein), and a 
decrease in transferrin receptor in the ipsilateral 
cortex. This signature would typically imply iron ex-
cess; however, these findings were observed in the 
context of a downward trend in total iron content, 
suggesting perhaps that iron had previously been 
elevated but then restored with a regulatory 
response. Conversely, in the contralateral cortex of 
mice exposed to repetitive TBI, there were no signif-
icant differences in iron regulatory proteins and 
rather there was an increase in iron content, which 
could suggest iron regulatory failure on the contra-
lateral side. This was also coincident with increases 
in total zinc and copper on the contralateral side, 
which was not observed on the ipsilateral side. It is 
unclear what may account for the differences 
between the hemispheres, but nonetheless the 
authors do demonstrate chronic alterations in brain 
metals and related metabolism following repeated 
TBI. Interestingly, there were no significant tran-
scriptional or translational changes in tau or tau 
regulatory proteins found in either hemisphere 
following repeated TBI with 6- and 12- months of 
survival, respectively. Given the lack of this associa-
tion, and the association between the measured 
metals and adverse neurologic sequelae/neuro-
degeneration, the authors posit that many of the 
significantly increased neurobehavioral deficits that 

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were observed in the repeated TBI mice during the 
survival period were at least partially contributed to 
by metal excess. As such, the authors suggest that 
chelation therapy following repeated TBI exposure 
as a means to potentially prevent long-term adverse 
outcomes is worthy of further investigation. 

Blast exposure damages the neurovas-
cular unit in mice 

Between the years 2000 and 2023, there were 
almost 500,000 individuals with new diagnoses of 
TBI among United States military personnel rec-
orded by the Defense Health Agency of the United 
States Department of Defense, the overwhelming 
majority (82.2 %) of which were classified as mild 
TBI.50 One aspect of the military experience that is 
particularly unique in comparison to the civilian pop-
ulation is exposure to repetitive blast overpressures 
in the context of both live combat and in training 
circumstances. Of increasing recognition is the 
potential of so-called “low-level blast exposure” 
(LLB), i.e. that which may be generated by firing 
heavy weapons, breaching exercises, or other low-
intensity explosives, to produce mild TBI or subclini-
cal damage to the brain with potential chronic impli-
cations.51-53 However, our understanding of the 
pathophysiology of such injury is still in develop-
ment. The neurovascular unit is a functional unit of 
the brain that is critical in the management of cere-
bral blood flow and maintenance of the blood-brain 
barrier, being composed of the delicate and complex 
interplay of endothelial cells and their tight junc-
tions, perivascular astrocytes (particularly astrocytic 
endfeet), pericytes, basement membranes, and 
finally adjacent microglia and neurons. Certainly, in-
sults to the neurovascular unit are implicated in a 
wide variety of neurological disease states.54 In 
2023, authors Li et al. tested a hypothesis that LLB 
could induce ultrastructural abnormalities of the 
neurovascular unit using a mouse model.55 

The authors exposed a group of anesthetized 
mice to a single open-field LLB, during which no 
head or body movements were observed. Among 
the several studies performed on the brain tissues 
following sacrifice, examination of ultrastructure 
by transmission electron microscopy (EM) in mice  

sacrificed 7 and 30 days following LLB exposure pro-
duced many of the most interesting findings, reveal-
ing a myriad of changes which suggest injury to 
multiple constituents of the neurovascular unit. In 
summary, the statistically significant findings in 
comparison to controls included drop-out of peri-
cyte surface area and associated coverage of endo-
thelial cells at 30 days survival, endothelial swelling 
at 7 days survival with loss and/or discontinuity of 
tight junctions at both 7 and 30 days survival, thick-
ening of basement membranes at 7 and 30 days 
survival, swelling of astrocytic endfeet at 7 and 30 
days survival, and finally detachments of astrocytic 
endfeet with one another as well as with basement 
membranes. The above changes were coincident 
with marked luminal constriction relative to controls 
at 7 days survival, and dilation at 30 days survival, 
potentially indicating the presence and reversal of 
vasospasm. Many unquantified morphological 
changes were also observed in comparison to 
controls, including vacuolization of numerous neu-
rovascular unit constituents (pericytes, endothelial 
cells, basement membranes, astrocytic endfeet) 
potentially indicative of cellular edema, detach-
ments between endothelial cells and bulging of 
endothelial cytoplasm into the lumen, and bulging 
and fragmentation of basement membranes. 

With these findings, the authors demonstrate 
evidence of significant neurovascular unit damage 
and loss of structural integrity of the blood-brain 
barrier in the short and intermediate survival period 
that follows just a single LLB exposure in mice. This, 
of course, may have profound implications with 
regard to military Service Members who may expe-
rience many multitudes of these exposures, and at 
short intervals, throughout the length of a career. 
Certainly, studies with long-term survival and neuro-
behavioral analysis are necessary to determine the 
potential chronicity of these changes, or to deter-
mine how these changes may evolve over time. 
Human autopsy studies with this research question 
are also paramount. Nonetheless, this study serves 
as an indication that blast overpressure exposure in 
the military context, no matter how low the inten-
sity, should be monitored and minimized where 
possible. 

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Muhammad Ali had young-onset, 
idiopathic Parkinson disease 

On June 3rd, 2016 Muhammad Ali died of 
sepsis. Famously, Ali denied autopsy owing to his 
Muslim faith. During approximately 34 years preced-
ing his death, Ali suffered from a progressive parkin-
sonian movement disorder that was and has 
remained among the most widely discussed anec-
dotes in neurodegeneration. Particularly acceler-
ated by the resurgence of dementia pugilistica as 
CTE, speculation regarding the role of Ali’s illustrious 
boxing career on his manifestation of parkinsonism 
has escalated. Indeed, many lay media depictions 
have, at least, made implications of a strong role of 
TBI,56,57 with one lay book that even speculates 
CTE.58 Continuing with what has become a theme in 
this writing, we provide the readership one last 
precautionary message regarding overinterpreta-
tion and undue speculation on individual cases and 
bring to awareness an article published in 2023 that 
provides for us a succinct, yet comprehensive medi-
cal account of Ali’s clinical course. This leads to an 
important conclusion: in the absence of an autopsy, 
all of the information available to us indicates that 
Muhammad Ali suffered from classic, early-onset, 
idiopathic Parkinson disease.59 

Neurologists Michael Okun, Helen Mayberg, 
and Mahlon DeLong, all of whom were involved in 
Muhammad Ali’s clinical care at Emory University, 
give us an account of the two decades of clinical 
follow-up with Ali at the institution to support their 
conclusion. In brief, below is a bulleted summary: 

 Unlike what is currently understood regarding 
the course of CTE, from which clinical manifes-
tations tend to emerge after a latent period 
that most often extends into the retirement 
years of former athletes,60 Muhammad Ali’s 
symptomatology began while he was still active 
and in his mid-to-late 30’s. Notably, during Ali’s 
final fight in 1981, decreased movement on his 
left was demonstrable on the video footage. 

 Following Ali’s retirement, slowed movement 
on the left side became more apparent on 
televised interviews, and a rest tremor of the 
left hand emerged during an interview in 1991. 

 As the years progressed, neurologists observed 
chronic and progressive symptoms including 
the classic parkinsonian rest tremor in the left 
hand, slowing of motor function/bradykinesia, 
cogwheel rigidity, softer and dysarthric speech 
that eventually became hypotonic, micro-
graphic writing (verified by signatures over 
time), masked facies, and characteristic sleep 
dysfunction. The motor symptoms were asym-
metric but became more generalized over 
time. Serial cognitive testing showed progres-
sive frontal and memory impairment. 

 Finally, Ali developed late-stage signs and 
symptoms that are classic of idiopathic Parkin-
son disease, including stooped posture, shuf-
fling gait, postural instability, falls. 

Though the natural history of Ali’s disease is 
quite characteristic for idiopathic Parkinson disease, 
several additional diagnostic findings provide fur-
ther support. First, fluorodeoxyglucose positron 
emission tomography (PET) and fluorodopa F18 PET 
scans performed in 1997 and 1998 demonstrated 
bilateral striatal activity and low striatal uptake, 
respectively, both of which are consistent with and 
classic for Parkinson disease in contrast to post-trau-
matic parkinsonism. Polysomnography to investi-
gate Ali’s sleep dysfunction revealed rapid-eye 
movement sleep behavioral disorder which, though 
not specific, is most classically associated with synu-
cleinopathies including Parkinson disease. Finally, 
the clinical feature that draws the most convincing 
contrast between Parkinson disease and post-trau-
matic parkinsonism or CTE is the fact that Ali’s symp-
toms were “clearly” and “substantially” responsive 
to levodopa. 

In summary, Muhammad Ali experienced a 
34-year chronic, progressive course that followed a 
classic natural history of Parkinson disease, with 
compatible (if not classical) imaging, and that was 
responsive to levodopa. This is unlike posttraumatic 
parkinsonism which can be transitory, often shows 
kinetic tremor, and is not characteristically respon-
sive to levodopa. Though in the absence of postmor-
tem examination it can never be stated with 
certainty if Ali did, in fact, have CTE neuropathologi-
cal changes, the available (and rather complete) 
clinical evidence strongly suggests that at least his 

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symptomatology was driven by early-onset, idio-
pathic Parkinson disease. 

In Memoriam: Dr. Byron A. Kakulas 

We would like to end this years’ listing to honor 
the legacy of Dr. Byron A. Kakulas. In January, 2023, 
Dr. Kakulas (Emeritus Professor, University of West-
ern Australia) died at age 90 in his native city, Perth, 
Western Australia. While he was mostly known for 
his work on muscular dystrophy, he was also a world 
authority on the neuropathology of spinal cord 
injury. His interest in spinal cord injury began early 
in his career in neuropathology and over the years 
he accumulated and studied a remarkably large 
number of anatomic specimens with this lesion. 

For those with interest in spinal cord injury, 
Sir Ludwig Guttmann is considered to be a towering 
figure in the history of its treatment. Guttmann was 
an early pioneer in changing the clinical outcome for 
spinal cord injury patients and, among other things, 
introduced sports participation in their rehabilita-
tion process. Perhaps the foremost acknowledg-
ment of one’s standing in the field of spinal cord 
research is to be asked to give the Ludwig Guttmann 
Memorial Lecture at the annual meeting of the 
International Spinal Cord Society. In September, 
2004, Byron Kakulas gave the Guttmann Lecture 
entitled: “Neuropathology: the foundation for new 
treatments in spinal cord injury”.61 We believe he is 
the only neuropathologist to be so honored. His 
lecture has been published and remains a remarka-
ble document, summarizing his findings and 
thoughts on the subject based on examining a total 
of 588 spinal cord injury cases! For those involved 
in studies of spinal cord injury who have not read 
this paper (and his others on the subject), it is highly 
recommended and shows Professor Kakulas’ 
immense talents as a neuropathologist, and his 
depth of knowledge and understanding of the sub-
ject. It is truly a classic paper and as he clearly 
demonstrates: “In the context of finding a cure for 
spinal cord injury, the first and foremost require-
ment is an in-depth knowledge of the disorder in 
neuropathological terms with the complexity of the 
spinal cord appreciated.” To read further on Profes-
sor Kakulas’ life and career in neuropathology, the 
reader is referred to his obituary published in Free 

Neuropathology (see https://doi.org/10.17879
/freeneuropathology-2023-4820).62 Byron Kakulas 
was a superb neuropathologist, a very creative 
scientist, a charismatic mentor to many, and a man 
who was devoted to his Greek heritage and to his 
loving extended family. He was also a cherished 
friend of one of the authors (DPP, Figure 3). He will 
be greatly missed. 

 

Figure 3. In memory of Dr. Byron Kakulas 

Dr. Kakulas (left) can be seen here along with his wife, Valerie 
(middle), and Dr. Daniel Perl (right). 

Conflicts of Interest Statement: 

The authors do not have any conflict of interest 
to declare. 

Funding Statement 

The work of the authors is supported by the 
DoD/USU Brain Tissue Repository and Neuropathol-
ogy Program, USU award #HU00012120007 (HJF 
award# 312159-1.00-66531). 

Disclaimer 

The information/content, conclusions, and/or 
opinions expressed herein do not necessarily repre-
sent the official position or policy of, nor should any 
official endorsement be inferred on the part of, 
Uniformed Services University, The Department of 
Defense, United States Uniformed Services, or the 
United States Government. 

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https://doi.org/10.17879/freeneuropathology-2023-4820

	Review
	Introduction
	The neuropathology of intimate partner violence
	CTE in young contact sports athletes
	Evidence of vascular injury and remodeling at sulcal depths in CTE
	Assessing multiple concurrent tauopathies in the setting of CTE: a way forward?
	The relationship between TBI, CTE, and TDP43 pathology
	Repetitive TBI elicits pathology in C9orf72 transgenic mice
	Patterns of head and neck injury in fatal underbody blast exposures
	Chronically altered brain metal homeostasis following repetitive impact TBI
	Blast exposure damages the neurovascular unit in mice
	Muhammad Ali had young-onset, idiopathic Parkinson disease
	In Memoriam: Dr. Byron A. Kakulas
	Conflicts of Interest Statement:
	Funding Statement
	Disclaimer
	References

