An array of tests that combines functional
assessment with blood tests and brain scans promises more sensitive and
objective estimation of brain degeneration in human veterans exposed to
battlefield improvised explosive device (IED) blasts, according to research led
by doctors at the Icahn School of Medicine at Mount Sinai and the James J.
Peters VA Medical Center. The study was published in Molecular Psychiatry on
Tuesday, February 25, and featured on the journal's cover.
Traumatic brain injury (TBI) is associated
with acute brain destruction at the time of the injury and is also a risk
factor for developing neurodegenerative diseases later in life. It is estimated
that 10 to 20 percent of veterans returning from the conflicts in Iraq and
Afghanistan sustained mild TBI resulting from IED and other blast exposures.
The true prevalence may be even higher, given that many blast-related injuries
go undocumented. Symptoms of mild TBI frequently resolve in days to months
following injury, but in a subset of patients, symptoms persist and evolve into
a chronic syndrome. Veterans who had sustained TBIs may suffer subtle, yet
important, endocrine and neuropsychiatric dysfunction. Given the fact that
suicide rates have jumped substantially among young military veterans in recent
years, it is imperative to develop earlier, more objective and sensitive
methods to detect brain damage.
Using advanced methods of clinical
neuropsychological and neurocognitive assessment, brain imaging, and blood biomarker
measurement in veterans of the Middle East conflicts, together with modeling of
mild repeated blast injury in laboratory rats, the researchers found changes in
the brains and blood of those subjected to blasts. Specifically, they performed
neuroimaging and blood analysis of human veterans who were exposed to IED
blasts on the battlefield and on rats exposed to repetitive, low-level blasts
in a shock tube. All veterans reported histories of between 1 and 50 blast
exposures, and all had chronic behavioral and cognitive complaints.
Two chemical changes that occur during
neurodegeneration involve clumping of a brain protein called tau and leakage of
another protein called neurofilament protein-light chain (Nf-L) from the brain
into the blood. The research team used positron emission topography (PET) and
the [18F]AV1451 (flortaucipir) tau ligand, a molecule which produces a signal
by binding to a site on the tau protein that "lights up" on a PET
image, and found that 5 of the 10 veterans exhibited excessive retention of
[18F]AV1451 at the white/gray matter junction in frontal, parietal, and
temporal brain regions, a typical localization where tau protein clumps tend to
accumulate after TBI. In healthy brains, tau is essential for normal cell
functioning, helping stabilize the internal skeleton of nerve cells in the
brain, but when tau proteins build up and clump together, it causes the
internal skeleton to collapse and form twisted tau tangles that promote brain
cell damage.
As an additional biomarker, they measured
blood levels of Nf-L, since elevated levels of Nf-L have been reported in human
patients suffering from a variety of brain injuries, including mild TBI and
neurodegenerative diseases. They observed elevated levels of Nf-L in the plasma
of veterans displaying excess [18F]AV1451 retention. The human component of the
study was led by Sam Gandy, MD, Ph.D., Professor of Neurology, and Psychiatry,
and Director of the Center for Cognitive Health and NFL Neurological Care at
the Icahn School of Medicine at Mount Sinai, Attending Neurologist at the James
J. Peters VA Medical Center, and co-senior author of the paper.
In parallel, the research team examined a rat
model being studied by Gregory Elder, MD, Professor of Neurology, and
Psychiatry, at the Icahn School of Medicine at Mount Sinai, Chief of Neurology
at the James J. Peters VA Medical Center, and co-senior author of the paper.
The rat model was designed to mimic a level of blast exposure that would be
comparable to a mild TBI or a subclinical blast exposure in humans. Rats
exposed to this blast protocol exhibit a range of anxiety and behavioral traits
resembling post-traumatic stress disorder. Dr. Elder and colleagues found that
rats exposed to repetitive, low-level blasts accumulated abnormal tau in nerve
cells as well as around blood vessels in cells called astrocytes. Astrocytes
play important roles in supporting nerve cells and during inflammatory events.
"We are fortunate to have access to both
living humans and living rodent models so that we can conduct side-by-side
comparisons of the clinical and microscopic changes that are common to both
species related to traumatic brain injury," said Dr. Gandy. "As a
result of these parallel studies in veterans and in the Elder brain injury
model, we are well on our way to the first clinical trials wherein
first-in-class drugs will be evaluated for their safety and for their potential
clinical benefit in relieving the anxiety, depression, memory disorders, and
anger management issues that are associated with traumatic brain
injuries."
Previous research conducted by Dr. Gandy and
his colleagues identified some of the first PET images of protein aggregates in
the brains of living athletes and veterans with histories of TBI, consisting
primarily of either the tau protein or, alternatively, a protein called amyloid
beta. Amyloid beta is the main component of brain plaques associated with
Alzheimer's disease, while tau is the main constituent of neurofibrillary
tangles, which are hallmarks of the neurodegenerative diseases frontotemporal
dementia and chronic traumatic encephalopathy (CTE). For now, CTE can only
definitively be diagnosed postmortem, but one goal of this research conducted
by Drs. Gandy and Elder is to find methods for effective diagnosis while
patients are still alive.
"There are many young, otherwise healthy
veterans who have suffered blast-related TBIs, some of them years in the past,
who either aren't getting better or, in some cases, are getting worse,"
says Dr. Elder. "We don't know why or how to identify those at greatest
risk. The work in this study is a step towards answering those questions."
For this project, the human studies were
conducted by Dara Dickstein, Ph.D., Adjunct Assistant Professor of Neuroscience
at the Icahn School of Medicine at Mount Sinai.
Following blast exposure, the rats were
studied by Rita De Gasperi, Ph.D., Instructor in Psychiatry at the Icahn School
of Medicine at Mount Sinai and the James J. Peters VA Medical Center.
"This research supports the Alzheimer's
Drug Discovery Foundation mission by identifying biomarkers—like brain
neuroimaging—that can lead to earlier diagnosis of Alzheimer's and related
dementias, including CTE," said Dr. Howard Fillit, Founding Executive
Director and Chief Science Officer of ADDF, one of the study's financial
supporters. "CTE research is relatively new, but it is advancing rapidly.
Studies such as this one will advance our understanding of CTE, Alzheimer's and
other neurogenerative diseases, improve the rigor and efficiency of clinical
trials, and may ultimately provide screening tools to identify patients for the
trials and as a measurement to assess drug effect."
Source: https://medicalxpress.com/news/2020-02-brain-scan-blood-panel-trauma-battlefield.html
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