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A brain scan-blood panel method accurately estimated brain degeneration in human participants and in animal subjects exposed to repetitive, low-level blasts, showing promise for earlier detection of brain damage in war veterans. The study, published in Molecular Psychiatry, also suggested that neurofilament light chain (Nf-L) measurements could become a key biomarker for tracking traumatic brain injury (TBI).
Many young otherwise healthy veterans who have suffered blast-related TBIs have yet to recover, said co-senior author Gregory Elder, MD, professor of neurology and psychiatry at the Icahn School of Medicine at Mount Sinai, in a statement. “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.” Elder led the animal model in the study, whereas Sam Gandy, MD, PhD, director of the Center for Cognitive Health and NFL Neurological Care at the Icahn School of Medicine at Mount Sinai, conducted the human model in 17 test subjects: 10 war veterans and seven comparison subjects.
The goal of the study was to accumulate as much information as possible about the neuropsychological, neuroimaging, and neurochemical changes after TBI, Gandy explained to CLN Stat. “Each species added different pieces to the puzzle. With humans, we have only the clinical presentation; we have no way of knowing what sort of force or number of TBIs they endured. With rats, we could control conditions very carefully and observe dose-response changes that we could never see in humans.”
For clinical labs, the impact blood Nf-L levels will have on clinical and commercial applications is the big takeaway from this study and others the authors are involved in, Gandy said. Labs should expect to see this and other biomarkers reported from various body fluids, he added. “A surprise is that a ubiquitous neuronal protein like neurofilament gives such a sensitive signal but without much specificity at all. If your brain is sick and your blood brain barrier is leaky, your blood is likely to show elevated levels of neurofilament.”
The research team used positron emission topography (PET) that employs a [18F]AV1451 tagged ligand called flortaucipir that sticks to tangles inside nerve cells. Tangles develop in Alzheimer’s and various other dementias, including chronic traumatic encephalopathy (CTE), Gandy said. Gandy’s team was the first to report of its possible use in CTE, after it was developed for use in Alzheimer’s.
Clumping of tau brain protein and leakage of Nf-L from the brain into the blood are two factors that signal neurodegeneration. Five of 10 veterans studied showed excessive retention of [18F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, an area in which tau protein clumping occurs after TBI. The researchers also discovered elevated Nf-L levels in the plasma of veterans with excess [18F]AV1451 retention.
For the rat model, they exposed the animals to a level of blast exposure comparable to a mild TBI or a subclinical blast exposure in humans. Subjected to repetitive, low-level blasts, the animals ended up accumulating abnormal tau in nerve cells and around blood vessels in astrocyte cells, which help support nerve cells.
The team has been conducting other, parallel studies, including a trial of 25 athletes. “We are writing that paper now,” Gandy said. With new drugs in the pipeline, “we need as many ways as possible to standardize injuries and to measure responses. We plan more trials like this, but in coming trials we will test new drugs as well.”