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Neuropathological markers of AD in veterans with TBI
Tau, β-amyloid, and glucose metabolism
following service-related Traumatic Brain
Injury in Vietnam war veterans: The AIBLVETS study
Vincent Doré, Ph.D. 1,2,*, Tia L. Cummins, Ph.D. 1,3, *, Azadeh Feizpour, Ph.D. 1,3 ,
Natasha Krishnadas, M.D. 1,4 , Pierrick Bourgeat, Ph.D. 2 , Alby Elias, M.D. 1,5 , Fiona
Lamb, D. Psych 1 , Robert Williams 3 , Malcolm Hopwood, M.D. 5, Victor L. Villemagne,
M.D.1,6,7 , Michael Weiner, M.D. 8, Christopher C. Rowe, M.D. 1,6,9 , Alzheimer’s Disease
Neuroimaging Initiativea, AIBL Research Groupb
1
Department of Molecular Imaging & Therapy, Centre for PET, Austin Health,
Melbourne, Australia.
2
The Australian eHealth Research Centre, CSIRO, Brisbane, Australia
3
The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
4
Florey Department of Neurosciences and Mental Health, The University of Melbourne,
Australia
5
Department of Psychiatry, The University of Melbourne, Melbourne, Australia.
6
Department of Medicine, The University of Melbourne, Melbourne, Australia.
7
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
8
University of California, San Francisco, USA
9
The Australian Dementia Network (ADNeT)
*Equal contribution
a
Some data used in preparation of this article were obtained from the Alzheim er's
Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the
investigators within the ADNI contributed to the design and implementation of ADNI
and/or provided data but did not participate in analysis or writing of this report. A
complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
b
AIBL Research Group: https://aibl.csiro.au/about/aibl-research-team/
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
1
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Neuropathological markers of AD in veterans with TBI
Running title: Neuropathological markers of AD in veterans with TBI
Corresponding author: Vincent Doré
ORCID: 0000-0002-8051-0558
Address: Dept of Molecular Imaging & Therapy, Austin Hospital, LVL1 Harrold
STOKES Block, 145 Studley Road, 3084 Heidelberg, Victoria Australia
Tel: +61 (0)3 9496 3321
Email: Vincent.Dore@csiro.au
2
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Neuropathological markers of AD in veterans with TBI
Abstract
Traumatic Brain Injury (TBI) is common amongst military veterans and has been
associated with an increased risk of dementia. It is unclear if this is due to increased risk
for Alzheimer’s disease (AD) or other mechanisms. This case control study sought
evidence for AD, as defined by the 2018 NIA-AA research framework 1 , by measuring
tau, β-amyloid and glucose metabolism using positron emission tomography (PET) in
veterans with service-related TBI.
Seventy male Vietnam war veterans — 40 with TBI (aged 68.0±2.5 years) and 30 controls
(aged 70.1±5.3 years) — with no prior diagnosis of dementia or mild cognitive
impairment underwent β-amyloid (18 F-Florbetaben), tau ( 18 F-Flortaucipir) and
18
F-FDG
PET. The TBI cohort included 15 participants with mild, 16 with moderate, and 9 with
severe injury. β-amyloid level was calculated using the Centiloid (CL) method and tau
was measured by Standardized Uptake Value Ratios (SUVR) using the cerebellar cortex
as reference region. Analyses were adjusted for age and APOE-e4. The findings were
validated in an independent cohort from the ADNI-DOD study.
There were no significant nor trending differences in β-amyloid or tau levels or
18
F-FDG
uptake between the TBI and control groups before and after controlling for covariates.
The β-amyloid and tau findings were replicated in the ADNI-DOD validation cohort and
persisted when the AIBL-VETS and ADNI-DOD cohorts were combined (114 TBI vs 87
controls in total). These findings suggest that TBI is not associated with the later life
accumulation of the neuropathological markers of AD.
Keywords: Traumatic brain injury, TBI, Tau, β-amyloid,
18
F-FDG, positron emission
tomography, PET, brain imaging, Vietnam veterans
3
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Neuropathological markers of AD in veterans with TBI
Introduction
Military service is associated with an increased risk of traumatic brain injury (TBI), with
up to 10% of service personnel experiencing TBI in recent conflicts 2. TBI has been argued
to be a strong environmental risk factor for dementia and epidemiological studies report
a 2-4 fold increase in risk amongst veterans with moderate or severe TBI 3. TBI has been
classified as a modifiable risk factor for dementia 4 . However, the mechanism underlying
this increased dementia risk remains unclear. Some studies have reported strong
associations between TBI and non-AD forms of dementia but not with AD 5 or a weaker
association between TBI and AD than with vascular dementia and unspecified dementia 6,
while other studies report that TBI is related to higher relative risk of AD 7-9 or an earlier
age of mild cognitive impairment (MCI) onset 10. These latter epidemiologic studies have
two major limitations; First, they rely on self-report information regarding the history of
TBI, and second, the diagnosis of MCI or AD is largely based on medical record review
and there is a scarcity of biomarker or direct pathological evidence for this claim.
AD is characterised by dense β-amyloid (Aβ) plaques most abundant in the frontal cortex,
the cingulate gyrus, precuneus and lateral parietal and temporal regions 11 . The second
major pathological feature of AD is hyperphosphorylated tau, observed as neurofibrillary
tangles (NFTs), found in the transentorhinal areas, limbic and isocortical regions 12.
Animal studies have demonstrated acute effects of TBI on tau 13-15, amyloid precursor
protein (APP)16 and Aβ17. It is postulated that these changes in damaged axons contribute
to apoptosis and inflammation, indirectly leading to AD 18, 19 . Other mechanistic theories
posit that TBI reduces time-to-onset amongst those already at risk of AD, as evidenced
by accelerated AD related pathology amongst injured transgenic mice mod els expressing
mutations in APP, and tau 20 . In contrast, enriched levels of phospho-tau species following
TBI have been argued to be temporary, returning to baseline levels after just one day 21,
22
.
Human postmortem studies post TBI are limited and have not provided clear evidence
that TBI is associated with Alzheimer’s disease. β-amyloid as diffuse plaques have been
found in persons where brain tissue was obtained within hours of severe TBI 23, 24 . One
study of brains with ppostmortemevidence of moderate or severe TBI related to an event
ranging from one to 47 years earlier, identified neurofibrillary tangles and β -amyloid
plaques in approximately 30% of individuals, with a trend to more extensive distribution
than in age matched controls 25. However, in another postmortem study26 on three large
4
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Neuropathological markers of AD in veterans with TBI
community-based cohorts of 1500 brains found no association between TBI with loss of
consciousness and AD-like neuropathological features but did find an association with
neuropathologic changes related to Lewy body disease and Parkinson's disease.
Moderate-to-severe TBI survivors, within a year of injury, have been reported to exhibit
increased amyloid tracer binding in cortical grey matter and striatum, a pattern of
distribution broadly replicating that seen in carriers of mutations in the presenilin-1 (PS1)
gene, a driver of early onset AD 27. In contrast, a study of Aβ deposition with Pittsburgh
compound B (PiB) PET in 12 long term survivors of moderate to severe TBI who reported
cognitive impairment found no association between tracer uptake and severity of TBI 28.
In the DOD ADNI (www.adni.info.org) dataset, no effect of TBI history on AD
biomarkers were found 29,30.
The current tracers for tau PET detect the 3R/4R form of tau and do not show binding on
PET scans in non-AD tauopathies 31.
Fluorodeoxyglucose ( 18F-FDG) PET allows the measure of hypometabolism, a marker of
synaptic/neuronal impairment. Despite inconsistencies in time since injury, TBI severity,
age range and injury modality, studies have shown reductions in regional metabolism. A
general trend has emerged showing acutely increased glucose utilization in the days after
TBI, followed by hypometabolism lasting weeks to months 32-34. Reductions in regional
metabolism have been found in areas of the brain particularly sensitive to TBI, for
example in frontal and temporal regions 35-37, cerebellum, medial temporal lobe, parietal,
somatosensory and visual cortices 38,
39
. One group has hypothesised that impaired
cerebral glucose metabolism may contribute to promoting amyloidogenesis, abnormal tau
hyperphosphorylation and neurofibrillary degeneration, and therefore lead to AD -like
pathology40 . However, the observed depression in glucose metabolism only lasted for a
few weeks or months 32.
The main objective of the Australian Imaging Biomarkers and Lifestyle study of aging Veterans study (AIBL-VETS) was to investigate with a case-control study design if
Vietnam veterans with a history of TBI were more likely to demonstrate the
neuropathological markers of AD than controls. Consistent with the 2018 NIA -AA
Research Framework for a biological definition of AD 1, we investigated both β-amyloid
and tau biomarkers for AD pathology, and FDG as a marker of neurodegeneration.
5
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Neuropathological markers of AD in veterans with TBI
Materials and Methods
The AIBL-VETS study was designed to be compatible with the US Department of
Defense funded Alzheimer’s Disease Neuroimaging Initiative veterans study (DOD
ADNI) to allow independent validation of findings and pooling of data.
PARTICIPANTS
Ex-military service personnel, aged 60-85 years, with and without TBI, were recruited
through retired veteran organisations such as the Returned Services League and the
Vietnam Veterans Association of Australia, as well as the Older Veterans’ Psychiatry
Program located at Austin Health, Melbourne, Australia. Exclusion criteria included prior
diagnosis of Bipolar Affective Disorder, Schizophrenia, Dementia, Mild Cognitive
Impairment,
substance
abuse/dependence
within
the
last
five
years,
MRI
contraindication, major, unstable medical condition, and previous participation in clinical
trials involving an amyloid targeting therapy.
To be included in the TBI cohort, participants were required to have sustained at least
one TBI between the ages of 16-40 years. TBI severity was assessed based on criteria set
by the US Department of Defense and Department of Veterans’ affairs 41 (Table 1).
Medical records from the time of injury were not available. Given reliance on self -report,
and to ensure injuries were given accurate severity ratings (mild/moderate/severe), only
participants who were confident on the details of their injury were included. To be
included in the control group, participants met the same inclusion/exclusion criteria, but
were required to report no prior history of TBI nor Post-Traumatic Stress Disorder
(PTSD). Approval for this study was obtained from the Austin Health Human Research
Ethics Committee, the US Human Subjects Research Protection Office of the US Army
Medical Research and Material Command, and the Australian Department of Veterans
Affairs Ethics Committee. All participants provided consent prior to participating, and
there were no direct incentives offered for participation.
PROCEDURE & MATERIALS
All participants were screened over the phone to ensure they matched study criteria.
Those deemed suitable for the initial assessments were invited into the research center
to undergo psychiatric and neuropsychological assessment and an interview to obtain
detailed TBI history. Participants were asked to give a detailed account of events
6
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Neuropathological markers of AD in veterans with TBI
surrounding the injury, including age at injury, injury cause, presence and length of
unconsciousness, alteration of consciousness and post traumatic amnesia, as well as
information as to medical attention sought, and disruption of usual activities due to
injury. Based on this information, and in relation to the information included in Table 1,
each injury was classified as mild, moderate, or severe.
PSYCHIATRIC WELLBEING
The psychiatric evaluation consisted of several measures to assess PTSD severity, drug
and alcohol use, sleep quality and medical history. A PTSD diagnosis was allocated bas ed
on the Clinician Administered PTSD Scale (CAPS) 42 lifetime and current score. A
lifetime CAPS score of over 40 was indicative of previous PTSD, whilst a current CAPS
score of over 40 indicated current PTSD. The Addiction Severity Index-lite43 was used to
assess alcohol/substance use, and the Pittsburgh Sleep Quality Index (PSQI) 44, sleep
quality and disturbance. A score >5 on the PSQI was indicative of poor sleep quality.
OTHER MEASURES
Participants also self-reported years of education, military-service history, cigarette
smoking status and medical history. Comorbidities such as hypertension, ischemic heart
disease, stroke, diabetes, migraine, and sleep apnoea were determined via self -report in
an interview with the study psychiatrist. Apolipoprotein E (APOE) genotype was
determined by direct sequencing. The Wechsler Test of Adult Reading (WTAR) was also
assessed to provide a measure of premorbid intelligence. Participants also completed the
Combat Exposure Scale (CES) 45 to classify the level of wartime stressors experienced.
IMAGE ACQUISITION AND PROCESSING
Participants underwent tau, amyloid and 18 F-FDG PET, performed on separate days using
18
F-Flortaucipir,
18
F-Florbetaben, and
18
F-FDG respectively. All radiotracers were
produced on site, at Austin Health. The scans were acquired on a Siemens 128 mCT
PET/CT camera at the University of Melbourne. A 30-minute acquisition was performed
75-minutes post-injection of
minutes post injection of
18
18
F-Flortaucipir, and 20 minutes scans were acquired 90
F-Florbetaben and after 30 minutes uptake time while resting
quietly in a dimly lit room post-injection of
18
F-FDG. Low dose CT scan was used for
attenuation correction. There was no correction for partial volume effects. In a previous
paper, we reported no difference in hippocampal or grey matter volumes between the TBI
and control groups in this cohort 46.
7
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Neuropathological markers of AD in veterans with TBI
DOD ADNI validation cohort
Data and scans from the US Department of Defense Alzheimer’s Disease Neuroimaging
Initiative (DOD ADNI) database (adni.loni.usc.edu) were used to validate the Aβ and tau
PET findings. The primary goal of ADNI has been to test whether serial magnetic
resonance imaging (MRI), PET, as well as other biological,
clinical, and
neuropsychological assessment can be combined to detect and measure the progression
of preclinical, mild cognitive impairment (MCI) and early Alzheimer’s disease. For upto-date information see www.adni.info.org. In the DOD ADNI cohort, 57 normal control
(NC) and 74 TBI (16 mild TBI, 58 moderate-to-severe TBI) cognitively unimpaired
veterans underwent a
18
F-Florbetapir β-amyloid scan while 30 NC and 46 TBI (11 mild,
35 severe) had a 18 F-Flortaucipir tau scan (Supplementary Table 1). After download, these
scans were processed using the methods described below for the Australian veteran cohort
to provide compatible Centiloid and SUVR results.
IMAGE ANALYSIS
Reconstructed PET images were processed using CapAIBL, a previously validated tracer
uptake quantification software package 47. The standardised uptake value ratio (SUVR)
quantification process is described in-depth elsewhere
48
, however, in brief, an adaptive
atlas was automatically fitted to each Aβ PET image to match the Aβ PET retention
pattern. Each image was then spatially normalised to the best fitting atlas. Centiloid
values were then computed using the SPM8 mask and CapAIBL calibration equations
from Bourgeat, Doré et al. (2018) 49.
All tau and
18
F-FDG scans were normalised using the same CapAIBL software, but
instead of the Aβ analysis, multi-tau atlases 47 and a mean
18
F-FDG atlas were used.
Spatially normalised tau scans were sampled in three different composite regions, as per
earlier work 50: Mesial-temporal (Me), Temporoparietal (Te), and rest of neocortex (R).
The Me region comprised entorhinal cortex, hippocampus, parahippocampus and
amygdala, and the Te region comprised regions inferior and middle temporal, fusiform,
supramarginal and angular gyri, posterior cingulate/precuneus, superior and inferior
parietal, and lateral occipital. Rest of neocortex (R) was made up of dorsolateral and
ventrolateral prefrontal, orbitofrontal, gyrus rectus, superior temporal and anterior
cingulate. Glucose metabolism was also investigated in the neocortex region (a composite
region of frontal (dorsolateral, ventrolateral, and orbitofrontal), parietal (superior parietal
8
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Neuropathological markers of AD in veterans with TBI
and precuneus), lateral temporal (superior, middle, and inferior), lateral occipital lobe,
gyrus supra-marginalis, gyrus angularis and anterior and posterior cingulate.), in the
frontal, the Me and in the posterior cortical index (PCI) comprising the lateral temp oral,
parietal, and precuneus cortex.
For FTP and FDG, Standardised Uptake Values (SUV) were calculated for all brain
regions examined. The Standardised Uptake Value Ratio (SUVR) was the primary
outcome variable for the PET assessments and was generated by dividing the regional
SUVs by the cerebellar cortex SUV.
VISUAL READING OF IMAGES
All 18F-Florbetaben, 18 F-Flortaucipir and FDG images were also visually inspected. Each
image was assessed by a nuclear medicine specialist experienced in interpretation of these
scans. All
18
F-Florbetaben and FDG scans were rated as positive or negative, and
18
F-
Flortaucipir images were rated as either negative, equivocal, or positive.
DATA ANALYSIS
Power analysis was calculated from amyloid scans in age matched healthy controls from
the Australian Imaging Biomarkers Lifestyle study of aging (AIBL) and showed that to
observe a moderate effect size between groups (Cohen’s d ≥ 0.5), with 80% power, a total
of 62 participants would be required. Percentages were calculated for categorical
variables. Participant characteristics and demographics were compared between
individuals in the TBI cohort and the veteran control group using t-tests and the Wilcoxon
signed rank test (when variables were not normally distributed) for continuous variables
and Fisher’s exact test for categorical variables, as well as Cohen’s d to measure effect
sizes. Hierarchical regressions were used to investigate the influence of cova riates,
including age, APOE e4 status, years of education, premorbid intellectual functioning,
and lifetime PTSD severity. The Weschler Test of Adult Reading was used to provide an
estimate of IQ, and CAPS Lifetime score as a measure of lifetime severity o f PTSD.
Variables that had a significant effect on the outcome variable were then controlled for
in an analysis of covariance (ANCOVA). A p-value of less than 0.05 was deemed
statistically significant.
9
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Neuropathological markers of AD in veterans with TBI
Results
DEMOGRAPHICS
When compared to the control group, participants with a TBI had significantly fewer
years of education, lower levels of premorbid intellectual functioning, higher Body Mass
Index (BMI), higher PTSD, depression and distress scores, were more likely to endor se
previous diagnosis of sleep apnoea and more likely to carry the APOE -e4 allele (Table
2). Of the 40 TBI subjects, 12 met criteria for current PTSD. Of the TBI cohort, 15
participants had suffered mTBI, 16 moderate, and 9 severe. The 3 TBI groups did not
differ from each other in terms of demographics or medical comorbidities. Injuries were
sustained from a variety of mechanisms and further details are included in Figure 1. The
most common cause of injury, across all severities, was sports related, follow ed by motor
vehicle accidents. The average age at injury was 24.2 (±5.5), with the average time since
injury 44.1 (±5.3) years. The range for time since injury was 30-53 years.
POSITRON EMISSION TOMOGRAPHY
After examining demographic, medical, and psychiatric covariates, results from a series
of hierarchical linear regressions showed that only APOE had significant association with
18
F-Florbetaben SUVR. We have previously reported that PTSD was not associated with
PET findings in this AIBL-VETS cohort 58. A T-test on
18
F-Florbetaben SUVR showed
no difference between TBI and NC (Cohen’s d=0.31, p=0.2), despite the larger number
of APOE4 carriers in the TBI group. When considering only the APOE non -E4 carriers,
the Cohen’s d was 0.21 (p=0.44). After controlling for APOE using an ANCOVA, the
difference was even smaller between TBI and the NC cohort in
18
F-Florbetaben SUVR
(F=0.33, p>0.55). Similar results were found in the DOD ADNI cohort and when merging
the AIBL-VETS and DOD ADNI cohorts (Figure 2 B and C).
T-tests and ANCOVA on global and regional
18
F-Flortaucipir showed no significant
difference between controls and TBI subjects from the AIBL-VETS cohort
(Supplementary Figure 1), from the DOD ADNI cohort (Supplementary Figure 2) and
from the merging of both cohorts (Figure 3).
We found no significant difference in the
18
F-FDG SUVs from the cerebellum cortex
between the two groups, as reported in previous studies 51. This allowed us to analyse the
18
F-FDG SUVRs. No significant differences were found in the global and regional
quantification of FDG uptake between NC and TBI groups (Figure 4).
10
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Neuropathological markers of AD in veterans with TBI
EFFECT OF INJURY SEVERITY
To investigate the impact of injury severity, the TBI cohort was subdivided into mTBI
(n=15) and moderate-to-severe TBI (n=25) and we performed the analysis between NC
and the moderate to-severe TBI (Figure 1, lower row). We did not find any significant
covariate and there were no significant differences between NC and moderate-to-severe
TBI in centiloid values nor in tau SUVR (Supplementary Figure 3). Cohen’s d was of the
same order as the previous analysis (Cohen’s d>-0.30).
When visual classifications were analysed, no differences in Aβ or tau positivity rates
were found between TBI and control cohorts, even after removing the mild injuries from
the analysis.
Discussion
In this study, we employed amyloid, tau and
18
F-FDG PET, and APOE genotyping to
investigate the presence of the neuropathological hallmarks of AD in a homogenous
cohort of veterans three-to-five decades after TBI. The current study did not find evidence
of increased amyloid deposition amongst veterans with TBI, even in those with more
severe injuries. Our findings were replicated in the DOD ADNI validation cohort. This
result is in line with previous studies investigating the association between TBI and AD
pathology with post-mortem data26, 52 and with amyloid PET imaging 28, 30. Furthermore,
recent findings in clinically normal older adults confirm that in a longitudinal Aβ-PET
study (two Aβ-PET scans, 0.5 to 4 years apart), adults with mTBI did not have a
significantly higher rate of Aβ accumulation over time than those with no remote head
trauma53. Several other studies have reported association between TBI and amyloid
deposition24, 27 however time between TBI and in-vivo amyloid assessment was less than
1 year, or the association did not reach significance 25.
Using the MeTeR scale, the current study investigated tau accumulation in AD vulnerable
regions, nevertheless no significant differences in tracer uptake were found on two
different veteran cohorts (AIBL-VETS and DOD ADNI), even amongst those with
moderate-to-severe injuries. In contrast to our findings, a study using 11C-PBB3 tau tracer
found that patients with mild-repetitive or severe TBI had higher
11
C-PBB3 binding in
the neocortical grey and white matter than healthy control participants 54. Also in one postmortem study, a higher prevalence of subjects with NFT among TBI was reported but this
11
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Neuropathological markers of AD in veterans with TBI
was significant only in TBI subjects younger than 60 years old 25. No difference was
observed in a subsequent, much larger cohort 26.
We also report no difference in
18
F-FDG uptake. Previous studies reported low glucose
metabolism between several days and a few months after TBI 55. However, it was also
reported that the depression in glucose metabolism subsided after a few months 32.
In the 2020 Lancet report on dementia prevention 4, TBI was listed as a factor that can
contribute to increased dementia risk. However, no differentiation between AD and non AD dementia was performed. The normal level of Aβ deposition, tau aggregation and
glucose metabolism in TBI subjects compared with normal matched individuals does not
support the premise that TBI can be a risk factor for Alzheimer’s Disease. This suggests
that the observed increase in dementia risk may be due to other causes of dementia as has
been suggested, such as Dementia with Lewy Bodies 26 or frontotemporal dementia
(FTD)56, 57.
Low brain resilience or cognitive reserve leading to earlier clinical manifestation of
dementia for a given degree of neuropathology could also contribute to the consistently
reported increase in the prevalence of dementia in those with history of TBI. The
prevalence of AD is partially censored by deaths from other causes in the elderly so earlier
onset in those with TBI would also suggest higher prevalence. The AIBL -VETS TBI
cohort had many factors that could create low brain resilience or reserve. These include
diminished white matter integrity in those with moderate or severe TBI as previously
reported by the authors 46. The TBI cohort also scored significantly lower on the WTAR
measure of premorbid intellectual functioning than controls and as expected, higher on a
number of psychiatric measures. These included measures of anxiety, somatization,
obsessive compulsive behaviours, interpersonal sensitivity, depression, hostility,
paranoid ideation, psychoticism, in addition to lifetime and current PTS D symptomology.
Other health measures indicated that the TBI cohort have a significantly higher BMI than
controls, which may account also for the higher self-reported incidence of sleep apnoea
in this group. Prevalence of ischemic heart disease and diabetes, whilst not significantly
different to controls, was nearly doubled in the TBI cohort.
The results from the current study provide a unique perspective into the long -term effects
of TBI. Strengths of the study include: the reasonably large imaged cohort (114 TBI and
87 veteran controls when AIBL and ADNI cohorts were merged), homogenous TBI and
control participants by restricting the study to veterans of the Vietnam war, only including
12
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Neuropathological markers of AD in veterans with TBI
veterans three-to-five decades after injury, and using a range of biomarkers to investigate
the presence of neuropathological markers of AD. Our analysis was validated with the
independent DOD ADNI cohort.
Our study has some limitations. Medical records were not available to confirm TBI
severity, therefore, the study team were reliant upon self-report, which may have led to
an under or over-estimation of injury severity. In addition, sample sizes, while large for
a TBI PET study, restricted group separation by injury mechanism. This resulted in a
mixture of single and repetitive injuries in the mTBI group, and blast, penetrating and
other injury mechanisms amongst the moderate-to-severe TBIs. It was not possible to
exclude participants with TBI in addition to PTSD, and this may limit the applicability of
these findings to a number of other TBI cohorts.
In summary, the findings of this study suggest that TBI is not associated with the later
life accumulation of the neuropathological markers of AD.
Acknowledgements
Some of the data used in the preparation of this article was obtained from the Australian
Imaging Biomarkers and Lifestyle flagship study of aging (AIBL), and the Australian
Dementia Network (ADNeT) that receive funding support from the National Health and
Medical Research Council (NHMRC).
Data collection and sharing for this project was also funded by the Alzheimer's Disease
Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904)
and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI
is funded by the National Institute on Aging, the National Institute of Biomedical
Imaging and Bioengineering, and through generous contributions from the following:
AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon
Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.;
Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F.
Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE
Healthcare; IXICO Ltd.;Janssen Alzheimer Immunotherapy Research & Development,
LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity;
Lundbeck; Merck & Co., Inc.;Meso Scale Diagnostics, LLC.; NeuroRx Research;
13
medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272230; this version posted March 13, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
Neuropathological markers of AD in veterans with TBI
Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal
Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The
Canadian Institutes of Health Research is providing funds to support ADNI clinical sites
in Canada. Private sector contributions are facilitated by the Found ation for the National
Institutes of Health (www.fnih.org). The grantee organization is the Northern California
Institute for Research and Education, and the study is coordinated by the Alzheimer's
Therapeutic Research Institute at the University of Southern California. ADNI data are
disseminated by the Laboratory for Neuro Imaging at the University of Southern
California.
We also thank the participants who took part in the study and their families.
Authorship Contribution Statement
Vincent Doré: Methodology, Formal analysis, Writing - Original Draft, Tia L.
Cummins: Data Curation, Methodology, Formal analysis, Writing - Original Draft,
Azadeh Feizpour: Writing - Original Draft, Natasha Krishnadas: Writing - Review &
Editing, Pierrick Bourgeat: Formal analysis, Alby Elias: Data Curation, Fiona Lamb:
Data Curation, Robert Williams: Data Curation, Malcolm Hopwood: Writing Review & Editing, Victor V. Villemagne: Writing - Review & Editing, Michael
Weiner: Writing - Review & Editing, Christopher C. Rowe: Conceptualization,
Resources, Writing - Review & Editing
Author Disclosure Statement
Christopher C. Rowe has received research grants from NHMRC, Enigma Australia,
Biogen, Eisai and Abbvie. He is on the scientific advisory board for Cerveau
Technologies and has consulted for Prothena, Eisai, Roche, and Biogen Australia. Victor
Villemagne is and has been a consultant or paid speaker at sponsored conference sessions
for Eli Lilly, Life Molecular Imaging, GE Healthcare, IXICO, Abbvie, Lundbeck,
Shanghai Green Valley Pharmaceutical Co Ltd, and Hoffmann La Roche. The other
authors did not report any conflict of interest.
14
medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272230; this version posted March 13, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
Neuropathological markers of AD in veterans with TBI
Funding
The study was supported by grants from the National Health and Medical Research
Council (NHMRC) (award numbers APP1127007, APP10475151), the US Department
of Defense U.S. Army Medical Research and Materiel Command (award number
W81XWH-14-1-0418) and Piramal Imaging who marketed Florbetaben at the time of
the study. The funding sources had no input into the design of this study, the analysis of
data, or writing of the manuscript.
15
medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272230; this version posted March 13, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
Neuropathological markers of AD in veterans with TBI
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Neuropathological markers of AD in veterans with TBI
Tables
Table 1: Criteria used by Department of Defense and Veterans Affairs (VA/DoD) to
categorize head injury severity
Mild
Moderate
Severe
0 - 0.5 hrs
0.5 - 24 hrs
>24 hrs
Alteration of
A moment -
>24 hrs; severity
>24 hrs; severity
consciousness
24 hrs
based on other criteria
based on other criteria
Post-traumatic
0 - 1 day
1 - 7 days
>7 days
Glasgow Coma Scale 13 - 15
9 - 12
3-8
Structural Imaging
Normal/abnormal
Normal/abnormal
Loss of
consciousness
amnesia
Normal
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medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272230; this version posted March 13, 2022. The copyright holder for this
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It is made available under a CC-BY-ND 4.0 International license .
Neuropathological markers of AD in veterans with TBI
Table 2: AIBL-VETS Participant demographics
test statistic
NC
TBI
(n=30)
(n=40)
age, years
69.5 (4.6)
68.0 (2.5)
t=1.78 (66)
0.08
education, years
12.9 (3.0)
11.2 (2.6)
t=2.43 (66)
0.018*
0.61
111.8 (5.7)
104.6 (6.9)
t=4.55 (66)
<0.001*
1.12
10.0 (8.1)
13.8 (11.0)
t=-1.48 (58)
0.145
Mean (SD) or %
(degree of
p-value
freedom)
Effect size
(Cohen’s d)
Demographics
WTAR US predicted Full Scale
IQ
Combat Exposure Scale
age at TBI
24.2 (5.5)
APOE e4 carriers
Heterozygotes, %
7.1
40
0
0
Homozygotes, %
0.003*
Medical history
Hypertension
35.70%
50.00%
Fisher's exact test
0.24
ischemic heart disease
10.70%
20.00%
Fisher's exact test
0.31
Stroke
3.60%
0.00%
Fisher's exact test
0.23
Diabetes
10.70%
22.50%
Fisher's exact test
0.21
current smoking
3.60%
7.50%
Fisher's exact test
0.5
migraine
17.90%
27.50%
Fisher's exact test
0.36
sleep apnoea
11.50%
37.80%
Fisher's exact test
0.02*
0.62
27.0 (3.9)
30.4 (5.1)
t=-2.93 (66)
0.005*
0.73
Lifetime PTSD score
9.1 (8.6)
51.9 (27.6)
t=-8.07 (67)
<0.001*
1.95
Current PTSD score
6.5 (6.1)
29.1 (20.2)
t=-5.82 (67)
<0.001*
1.42
Depressive symptoms (GDS)
1.4 (1.7)
4.3 (3.7)
W=277
<0.001*
0.98
53.8 (13.6)
66.2 (13.9)
t=-3.63 (66)
0.001*
0.9
4.8 (4.5)
7.3 (4.2)
t=-2.05 (51)
0.045*
0.58
BMI
Psychiatric Evaluation
Psychological distress (SLC-90:
GSI)
Sleep disturbance (PSQI)
NC = Normal Control; TBI = Traumatic Brain Injury; APOE = Apolipoprotein E; BMI
= Body Mass Index; WTAR = the Wechsler Test of Adult Reading; PTSD = PostTraumatic Stress Disorder
26
medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272230; this version posted March 13, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
Neuropathological markers of AD in veterans with TBI
Figures
Figure 1: TBI characteristics. MVA – motor vehicle accident
27
medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272230; this version posted March 13, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
Neuropathological markers of AD in veterans with TBI
Figure 2: 18F-Florbetaben SUVRs for NC and TBI groups from AIBL-VETS and DOD
ADNI cohorts and both cohorts together. Top row – normal controls (NC) vs all TBI;
Bottom row– NC vs moderate or severe TBI
28
medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272230; this version posted March 13, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
Neuropathological markers of AD in veterans with TBI
Figure 3: 18 F-Flortaucipir SUVRs for NC and TBI groups from AIBL-VETS and DOD
ADNI cohorts merged together. Me – Mesial-temporal; Te – Temporal parietal; R - Rest
of neocortex.
29
medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272230; this version posted March 13, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
Neuropathological markers of AD in veterans with TBI
Figure 4: 18 F-FDG SUVRs for NC and TBI groups in AIBL-VETS. Me – Mesialtemporal; PCI – Posterior Cortical Index; Te – Temporal parietal; R- Rest of neocortex.
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