Study Finds Potentially Treatable Cause of Dementia Following Stroke

The development of dementia following a stroke may be due to chronic inflammation in the brain that could be treated with a medication used for rheumatoid arthritis and some cancers, according to a study published in the Feb. 4 issue of the Journal of Neuroscience

Of the 800,000 Americans each year who survive a stroke, nearly one-third develop dementia within a year. Very little is known about inflammation in the brain after stroke, or why some stroke patients develop dementia, a severe decline in mental ability such as memory or thinking skills that can interfere with daily life.

University of Arizona College of Medicine – Tucson researcher Kristian Doyle, PhD, is first author on the study, “B-Lymphocyte-mediated delayed cognitive impairment following stroke,” which was conducted when he was a post-doctoral scholar in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine, Calif., under the mentorship of the study’s principal investigator Marion S. Buckwalter, MD, PhD, Stanford assistant professor of neurology and neurosurgery.

“We provide the first evidence here that chronic inflammation in the brain after stroke can cause delayed onset of cognitive impairment or dementia,” said Dr. Doyle, who joined the UA in 2013 as assistant professor of immunobiology and neurology at the UA College of Medicine – Tucson and as a member of the University of Arizona Center on Aging and UA BIO5 Institute. “We demonstrated that B-lymphocytes are required to produce the delayed onset of cognitive impairment after stroke. Taken together, these results have tremendous implications for people who have dementia after stroke.

“We also demonstrated that the accumulation of B-lymphocytes in the brain after stroke could be prevented with the murine version of the FDA-approved anti-B lymphocyte drug Rituximab, a drug used for other diseases associated with B-lymphocytes, including rheumatoid arthritis, non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. This raises the possibility that Rituximab could be of benefit to a large number of stroke patients.” More research would be needed before clinical trials could begin, Dr. Doyle noted.

“In many ways, this discovery has the potential to turn the field (and treatment of stroke patients) upside down. If, as implicated by this study, the immune system ends up doing further damage to the stroke-injured brain for weeks following stroke, then our therapeutic targets must be re-examined and changed accordingly,” said Janko Nikolich-Žugich, MD, PhD, chairman of the UA Department of Immunobiology, co-director of the UA Center on Aging, Elizabeth Bowman Professor in Medical Research at the UA College of Medicine – Tucson and a member of the UA BIO5 Institute.

In addition to Drs. Doyle and Buckwalter, study contributors included researchers at Stanford University School of Medicine; the Neurosciences Institute and Department of Biochemistry and Molecular Biology of the Universitat Autonoma de Barcelona, Spain; and the Department of Pathology and Neurological Sciences, Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Also contributing was UA research scientist Thuy-Vi V. Nguyen, PhD, with the UA immunobiology and neurology departments and UA Center on Aging, who previously was a senior scientist with the Department of Neurology and Neurological Sciences at Stanford University School of Medicine.

For more information about the study, please see Stanford University Medical School of Medicine’s news release.

This work was supported by National Institutes of Health grants R01NS067132, R21NS078571, K99NR013593 and P30AG10161; National Institute on Aging grant R01AG017917, as well as the Jean Perkins Foundation and the Horngren Family Alzheimer’s Research Fund.

About Dr. Doyle

Kristian Doyle, PhD, joined the University of Arizona in 2013 as assistant professor of immunobiology and neurology at the UA College of Medicine – Tucson and as a member of the UA Center on Aging and UA BIO5 Institute. The Doyle lab investigates the role of the immune system in causing dementia after stroke. Dr. Doyle earned his doctorate in 2007 from Oregon Health & Science University in Portland, where he developed novel therapeutics for stroke in the laboratory of Mary Stenzel-Poore, PhD. He then trained as a postdoctoral scholar at Stanford University under the mentorship of Marion Buckwalter, MD, PhD, researching the role of TGFbeta signaling after stroke and developing a model of post-stroke dementia. Dr. Doyle was awarded an American Federation of Aging Research Fellowship in 2009, an Anita Roberts Young Scientist Scholarship in 2010 and a K99/R00 faculty transition award from the National Institute of Nursing Research in 2012.

About the UA Department of Immunobiology

The Department of Immunobiology, one of the five basic science departments at the UA College of Medicine – Tucson, conducts cutting-edge research in the development, function and regulation of the immune system in health and disease. Areas of study include the biology of microorganisms and their interaction with the immune system over the lifespan of the individual. Department faculty seek to improve and regulate the function of the immune system to reduce and prevent illness and death from infectious and autoimmune diseases and cancer. The department educates medical and other health sciences students, physicians and scientists in all areas of immunobiology and microbiology. For more information, please visit the website.

About the University of Arizona Center on Aging

The mission of the UA Center on Aging (ACOA) at the UA College of Medicine – Tucson is to promote long and healthy lives of older adults through coordinated programs in research, education, outreach and patient care. Established in 1980 as one of a network of Long Term Care Gerontology Centers authorized by the Older Americans Act, the ACOA was approved by the Arizona Board of Regents as a Center of Excellence at the Arizona Health Sciences Center in 1991. For more information, please visit the center’s website.