U.S. veterans of the wars in Afghanistan and Iraq who suffered mild traumatic brain injury from exposure to explosive blasts were found to have changes in cerebrospinal fluid proteins that are typically seen in people who develop Alzheimer's disease, according to researchers at the University of Washington School of Medicine and VA Puget Sound Health Care System.
"While our research does not prove that veterans who experienced these injuries will develop Alzheimer's disease, it raises the possibility that they may be on a pathway leading to dementia," said Dr. Ge Li, the paper's first author and an associate professor of psychiatry and behavioral sciences at UW Medicine.
The study was published March 13 in the journal Neurology.
Previous research has found that sustaining a moderate to severe TBI increases a person's risk of developing Alzheimer's disease. It is not known, however, whether a mild TBI (mTBI) similarly increases this risk.
In the new study, the researchers analyzed protein levels in spinal fluid from 51 U.S. veterans of the wars in Afghanistan and Iraq. Each had suffered mTBIs from exposure to explosive blasts and had an average of 20 blast injuries. Those protein levels were compared with the protein levels of 85 veterans and civilians of similar age who had never sustained a TBI.
In this study, the veterans were considered to have experienced a TBI if they had an alteration or loss of consciousness from the blast. The TBIs were considered mild if the loss of consciousness lasted 30 minutes or less and there was no sign of brain damage on standard clinical MRI or CT scan. Such an injury is considered equivalent to a concussion.
The researchers examined protein levels in the veterans' cerebrospinal fluid, which flows around and through the brain and carries away waste materials. Two of the proteins measured compose the chief components of amyloid plaques, which aggregate in the brains of people with Alzheimer's. These proteins are called alpha-beta amyloid 40 and 42 (Aβ40, Aβ42).
The other proteins are versions of the tau protein. Normally, tau proteins are part of cells' cytoskeletons, which give cells their shape. But with Alzheimer's, these structures are changed, creating tangles within brain cells and killing them. This is the other hallmark of Alzheimer's.
With Alzheimer's disease, the levels of alpha-beta amyloid proteins in spinal fluid typically decrease. Researchers hypothesize that the proteins, instead of being flushed out into the spinal fluid and carried away as they normally would be, are deposited in amyloid plaques and remain in the brain. As the disease progresses, tau levels, in contrast, tend to be higher than normal, as the proteins are released from dying brain cells.
In the study, mTBI veterans in their late 40s and 50s had lower levels of beta-amyloid proteins, compared with the veterans and civilians who had not had such injuries.
Tau protein levels also were abnormal in the older mTBI veterans. Normally, tau levels rise as we age. But among the older middle-aged mTBI veterans, levels tended to remain the same, a finding that the normal brain clearance system may not be working as well in among the people with mTBI.
Among older mTBI veterans, having lower beta-amyloid 42 levels was also associated with doing less well on cognitive tests assessing verbal memory and fluency.
The decline in beta-amyloid proteins, in particular beta-amyloid 42, was concerning, said senior author Dr. Elaine Peskind, a UW research professor of psychiatry and director of the VA's Northwest Mental Illness Research, Education, and Clinical Center.
"A decline in beta-amyloid 42 is the earliest detectable change due to Alzheimer's that can be found in a cognitively normal person," she said. "The change can appear as much as 20 years before symptoms. So a person can have the pathology of Alzheimer's going on in their brain but still not have any symptoms — no problem with their memory or thinking functions — for as long as 20 years."
Peskind and her collaborators suspect the cause of the changes in the mTBI veterans' spinal fluid proteins is due to blast-related damage to a system in the brain, called the glymphatic system, that allows fluids to flow through the brain and carry away waste products. To find out, they have been funded by the National Institute of Neurological Diseases and Stroke to study the regulation and function of this system in veterans with these injuries.
