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Dallas Researchers Discover Early-Stage Alzheimer’s Disease Triggers Response Similar to Multiple Sclerosis
11/01/2013

DALLAS — Dallas researchers have discovered that the pre-clinical stage of Alzheimer’s disease — before patients experience significant memory loss and functional decline — causes almost the identical brain inflammatory response as the autoimmune disease that leads to multiple sclerosis.

Nancy Monson, Rong Zhang and Ann Stowe
Nancy Monson, Rong Zhang and Ann Stowe
Click photo to download hi-res image

Scientists from the Institute for Exercise and Environmental Medicine at Texas Health Presbyterian Hospital Dallas (IEEM) and UT Southwestern Medical Center have published their findings, “Elevated CNS inflammation in patients with preclinical Alzheimer’s disease,” in the current on-line edition of the Journal of Cerebral Blood Flow and Metabolism.

While the researchers say their paper does not necessarily show a link between multiple sclerosis and Alzheimer’s disease, it’s the first study to confirm that a massive brain inflammatory response is activated in patients with early-stage Alzheimer’s. The findings could potentially change the path of Alzheimer’s research and treatment options, and create the possibility of an early screening test for the debilitating brain condition.

“We were very surprised with our findings and think it could change the linear path of thinking of the amyloid hypothesis that has consumed Alzheimer’s research in recent years,” said Rong Zhang, Ph.D., senior author of the study and director of the IEEM’s cerebrovascular lab. “Up to now, we’ve always thought the plaque buildup in the brains of Alzheimer’s patients caused the activation of immune system-like fighter cells, microglia and astrocytes, but we were looking at people with late-stage disease and analyzing brain tissue during autopsies. Now we have to potentially think about it the other way around — that inappropriate immune-system activation early in the disease process leads to plaque accumulating in the brain and neuron death.”

The mirror-image immune responses in patients with MS and Alzheimer’s, both classified as neurodegenerative diseases, creates new questions, Zhang said.

“Should we look at Alzheimer’s as an autoimmune disease like MS? We can’t dismiss that and say, ‘no,’ ” he said. “The study has created a whole new set of puzzles to figure out. It certainly raises many more questions about the role of inflammation and how it could be a cause, not a result, of the disease.”

The researchers analyzed the cerebrospinal fluid of people with pre-clinical Alzheimer’s disease and those at the early stages of MS. The study subjects were people complaining of mild memory loss who were diagnosed with pre-clinical Alzheimer’s disease using widely accepted, standardized tests, including the Wechsler Memory Revised scale and other objective brain function tests. Up to 70 percent of patients determined to be pre-Alzheimer’s according to these criteria eventually develop Alzheimer’s disease within five years. The subjects with MS were diagnosed using the standard test for accurately diagnosing multiple sclerosis in its earliest stages.

The idea to use the spinal fluid to study brain inflammation in Alzheimer’s disease came during a lunch the two teams had last year to brainstorm ideas for better identifying biomarkers of Alzheimer’s disease, which is the most common cause of dementia in the United States. It affects one in 10 people over age 65 and nearly half of all individuals who reach age 85. More than four million Americans have Alzheimer’s disease, making it the fourth-leading cause of death in adults and resulting in billions of dollars annually in health care costs and immeasurable impact on those caring for loved ones with the progressive deterioration of brain condition.

“It’s exciting that our two teams were able to come together and make such an intriguing finding,” said Nancy Monson, Ph.D., first author of the study and an associate professor of neurology and neurotherapeutics at UT Southwestern. “Our discovery of an inflammatory response in the cerebrospinal fluid of pre-clinical Alzheimer’s patients could be a significant paradigm shift in research. Further studies raised by our teams’ work may lead to a breakthrough in the understanding of Alzheimer’s disease.”

She added: “We think our paper should be of great interest to Alzheimer’s disease researchers and neurologists, as well as the broader scientific community given its potential impact on diagnosis, prevention and treatment.”

The noticeable symptoms of Alzheimer’s disease are memory loss and other brain function problems. Definitive diagnosis is made during autopsies, which can show collections of amyloid plaques and neurofibrillary tangles in the cortex and other brain regions that control everything from short-term memory and problem solving to regions of the brain that control long-term memory and breathing in later stages. These plaques and tangles are actually clusters of misfolded amyloid and tau proteins, which affect the ability of neurons to transmit brain signals and cause neuronal death.

Traditionally seen as an amyloid protein overproduction or clearance issue, Alzheimer’s researchers have up to now analyzed spinal fluid of patients for protein markers, dismissing the cellular elements that carried information of brain inflammation.

“They were focusing on protein and other biomarkers tied to plaque and tangle buildup,” Zhang said. “The cellular elements of the spinal fluid were tossed away like debris. But we knew MS researchers found lots of valuable information in it, so we partnered with Nancy’s team to have a look and see if there was something going on in the immune systems of these early-stage patients.”

The MS study looks for signs of immune-system activation (inflammation) by measuring the number of T cells and other leukocytes, and amount of inflammatory cytokines in spinal fluid. Elevated levels of these disease-fighting “soldiers” mean the immune system is activated and reacting to a perceived problem. In multiple sclerosis, the immune system inappropriately over-activates and damages healthy cells, making it an autoimmune disease. The disease ends up killing healthy brain cells that affect motor function.

“This project is a fantastic outcome of the multidisciplinary, integrated approach towards medical problems we take at the IEEM, which has a unique and rich partnership with both the Alzheimer's Disease Center and Clinical Center for Multiple Sclerosis at UT Southwestern,” said Benjamin Levine, M.D., director of the IEEM and a professor of medicine and cardiology and a distinguished professor in exercise sciences at UT Southwestern Medical Center. “By finding evidence of active inflammation early on in Alzheimer’s disease, this observation sets the stage for novel pharmacologic and non-pharmacologic therapies.”

A paper earlier this year by the IEEM researchers showed that nerve fiber bundles in the brains of Masters athletes were found to be structurally superior than their sedentary counterparts, which may explain the impressive cognitive performance exhibited by the lifelong exercisers, Levine said. Those findings were published in the journal NeuroImage, adding to previous findings at the IEEM that has shown regional brain volume is also better preserved by lifelong exercise.

“The anti-inflammatory action of exercise may be one of the mechanisms by which it reduces, by up to 50 percent in some cases, the development of Alzheimer’s disease,” he added.

Inflammation markers in the brain of Alzheimer’s patients have been identified previously by scientists, even with some medical treatments including anti-inflammatory agents such as non-steroidal anti-inflammatory drugs. Those treatments have not shown significant promise, perhaps because they’ve been given too late in the disease process, Monson said.

“This work shows evidence that not only is something going on early in the disease process with these patients — it may or may not be related to bad protein production and accumulation in the brain. The immune system has been activated for some reason,” she said.

The study involved 11 aMCI (pre-clinical Alzheimer’s patients), 57 to 76 years old. For comparison, 23 MS patients, 20 to 69 years old, were given blood and spinal fluid tests (through funding from the National MS Society), though none were on medications for their conditions at the time of the tests. Researchers performed lumbar punctures to collect the spinal fluid samples.

The study was funded by the National Institutes of Health, which awarded the IEEM a four-year grant in 2009 to investigate the connection between exercise and brain function as people age. The patients selected for this study were part of the IEEM’s larger work on brain function, aging and exercise.

To inquire about participation in one of their studies, call 214-345-4629 or email THDIEEMBrain@TexasHealth.org.

About the Institute for Exercise and Environmental Medicine
The Institute for Exercise and Environmental Medicine (IEEM) was founded as a joint program between Texas Health Presbyterian Hospital Dallas and UT Southwestern Medical Center. Its mission is to promote basic and clinical research, education, and clinical practice in defining the limits to human functional capacity in health and disease, with the objective of improving the quality of life for human beings of all ages. The IEEM includes ten major laboratories tightly integrated and organized intellectually along the “oxygen cascade” — the path that oxygen must follow through the body from the external environment through the lungs, heart, skeletal muscles, and brain to perform cognitive function and physical activity. The IEEM is among the few research centers in the world that fosters the fusion of basic science and clinical medicine in a program designed specifically to study human physiology.

About Texas Health Presbyterian Hospital Dallas
Texas Health Presbyterian Hospital Dallas is an 898-bed acute care hospital and recognized clinical program leader, having provided compassionate care to the residents of Dallas and surrounding communities since 1966. U.S. News and World Report has ranked Texas Health Dallas among the nation’s best hospitals in digestive disorders, orthopedics, and neurology and neurosurgery. An affiliate of the faith-based, nonprofit Texas Health Resources system, Texas Health Dallas has approximately 4,000 employees and an active medical staff of more than 1,000 physicians. For more information, call 1-877-THR-WELL, or visit TexasHealth.org/Dallas.

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