Stanford study ties immune cells to delayed onset of post-stroke dementia

February 03, 2015

A single stroke doubles a person's risk of developing dementia over the following decade, even when that person's mental ability is initially unaffected. Why this delayed deterioration occurs has been a mystery. Now, Stanford University School of Medicine investigators think they have discovered a major reason for it.

In experiments using both mouse models of stroke and brain-tissue samples from humans, they linked the delayed onset of post-stroke dementia to the persistent presence, in the brain, of specialized immune cells that shouldn't be there at all.

The discovery could potentially translate into ways of identifying people at risk for dementia, allowing physicians time to try to stave off the disease. Drugs that can disable these immune cells are already available.

At roughly 800,000 new cases per year, stroke is the second-biggest cause of serious long-term disability in the United States, generating $74 billion annually in treatment and caretaking costs. Of the 7 million living stroke survivors nationwide, one-third either suffers from dementia, or will.

In a study to be published Feb. 4 in The Journal of Neuroscience, a team directed by Marion Buckwalter, MD, PhD, assistant professor of neurosurgery and of neurology and neurosciences, examined several mouse models of stroke, as well as human brain-tissue samples, and found strong evidence that antibody-producing cells called B cells play a key role in the delayed onset of dementia. Buckwalter is the study's senior author. The lead author is former postdoctoral scholar Kristian Doyle, PhD.

B cells help, usually

The antibodies that B cells produce are normally of great value to us. They circulate throughout blood and lymph, and bind to microbial invaders, gumming up the pathogens' nefarious schemes and marking them for destruction by other immune cells. Occasionally, B cells wrongly begin generating antibodies that bind to the body's own healthy tissues, causing certain forms of autoimmune disease, such as rheumatoid arthritis. Rituxan, a drug approved by the Food and Drug Administration for this condition, is actually an antibody itself: Its target is a protein found on the surface of every B cell. Use of this drug depletes B cells in the body, relieving the symptoms of rheumatoid arthritis and other B-cell-mediated disorders.

Like almost all other types of immune cells, B cells are virtually nonexistent in the brains of healthy people, whose outermost ramparts are mostly impervious to the cells and large molecules (like antibodies) freely circulating elsewhere. But the blood-brain barrier is not entirely unbreachable and is rendered much more permeable upon brain damage.

Two small reports from the last decade mentioned the puzzling presence of substantial numbers of immune cells in about 50 percent of the autopsied brains of people who had suffered strokes. This led Buckwalter to look more closely at the phenomenon.

Buckwalter is a team leader of Stanford's Stroke Collaborative Action Network, which is part of the Stanford Neurosciences Institute and coordinates stroke research efforts throughout the university. She was intrigued by those reports. So she and her colleagues embarked on a series of experiments in mouse models of stroke. Buckwalter's group fine-tuned their experimental procedures so that brain structures central to cognition in the mice would initially be left intact after a stroke.

"When we looked at the brains of these mice one week post-stroke, we saw a negligible presence of B cells in the stroke core," Buckwalter said. "But at seven weeks out, there were tons of them." The presence of B cells persisted at 12 weeks. The cells tended to cluster in or near the stroke core, where normal brain cells that succumbed to stroke-induced oxygen deprivation had died. No such B-cell infiltration was evident in the brains of mice subjected to a sham procedure in which their brains experienced no stroke.

The scientists also determined that the B cells had been actively producing antibodies and progressing through various stages of development that typify such cells once they've been activated by exposure to foreign material.

Drug stems cognitive loss

In tests of the mice's ability to store short-term memory--a key yardstick in assessing dementia--mice in which a stroke had been induced performed about as well a week later as mice in the control group did, indicating that key brain structures in the post-stroke mice were as yet unharmed. But by seven weeks, the post-stroke mice had developed substantial memory deficits. Mice in the control group hadn't.

When Buckwalter and her associates performed their experiments on post-stroke mice that were genetically altered to be incapable of generating B cells, they suffered no such delayed cognitive impairment.

So the investigators repeated their set of experiments on the same normal laboratory mice strain they'd previously been working with -- except that this time, beginning five days after stroke was induced and continuing biweekly for several weeks, the mice were given a mouse analog of Rituxan to deplete their B cells. This time, the post-stroke mice exhibited no signs of delayed cognitive loss.

Finally, the Stanford scientists examined autopsied brain sections from stroke cores of 21 stroke patients, all of whom had dementia. Among these, 12 contained suspiciously high numbers of B cells.

To see if a prominent B-cell presence in the brain might be a common occurrence in old age, even among healthy people, they looked at brain samples from nine age-matched patients with no history of stroke or dementia. In these brains, B cells were rare.

More work needed for a therapy

Buckwalter speculated that B cells entering a brain rendered accessible by a stroke may, upon exposure to intercellular substances released by dead or dying cells, become reactive to brain tissue, setting off a spiraling cycle of spreading cell injury and further B-cell activation. It's likely that this happens in only a fraction, albeit possibly a substantial one, of stroke patients, she cautioned, so it would be medically unsound to simply dose all stroke patients with a B-cell-depleting drug. But she suggested that a brain-penetrating, B-cell-tagging compound or antibody that was labeled for detection by, say, MRI could help identify candidates for such a therapy.

"We're not there yet. Much more work needs to be done to nail down who this happens to and what's the right drug timing and dosage," Buckwalter said. "But it's exciting to think that delayed-onset post-stroke dementia, which carries such an enormous cost to individuals and to society, is potentially treatable."
The study was supported by the National Institutes of Health (grants R01NS067132 and K99NR012593). Other Stanford co-authors are neurology professor Lawrence Steinman, MD; Frank Longo, MD, PhD, professor and chair of neurology; visiting scholar Montse Sole, PhD; research associate Thuy-Vi Nguyen, PhD; postdoctoral scholars Robert Axtell, PhD, Gilberto Soler-Llavia, PhD, and Sandra Jurado, PhD; and life science research assistants Jullet Han and Lisa Quach.

Information about Stanford?s Department of Neurology and Neurological Sciences and Department of Neurosurgery, which also supported the work, is available at and, respectively.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit The medical school is part of Stanford Medicine, which includes Stanford Health Care and Lucile Packard Children's Hospital Stanford. For information about all three, please visit

Stanford University Medical Center

Related Dementia Articles from Brightsurf:

The danger of Z-drugs for dementia patients
Strong sleeping pills known as 'Z-drugs' are linked with an increased risk of falls, fractures and stroke among people with dementia, according to new research.

The long road to dementia
Alzheimer's disease develops over decades. It begins with a fatal chain reaction in which masses of misfolded beta-amyloid proteins are produced that in the end literally flood the brain.

Why people with dementia go missing
People with dementia are more likely to go missing in areas where road networks are dense, complicated and disordered - according to new research from the University of East Anglia.

PTSD may double risk of dementia
People who have experienced post-traumatic stress disorder (PTSD) are up to twice as likely to develop dementia later in life, according to a new study by UCL researchers, published in the British Journal of Psychiatry.

Dementia education
School-based dementia education could deliver much needed empathy and understanding for older generations as new research from the University of South Australia shows it can significantly improve dementia knowledge and awareness among younger generations.

Building dementia friendly churches
A project to help church communities become more 'dementia friendly' has had a significant impact across the country.

A "feeling" for dementia?
A research team led by the DZNE concludes that personal perception can be an important indicator for the early detection of Alzheimer's disease.

New biomarker for dementia diagnosis
Medical researchers in the UK and Australia have identified a new marker which could support the search for novel preventative and therapeutic treatments for dementia.

Digital solutions for dementia care
Telehealth delivery of dementia care in the home can be as effective as face-to-face home visit services if carers and recipients take advantage of the technologies available, Australian researchers say.

Despite a marked reduction in the prevalence of dementia, the number of people with dementia is set to double by 2050 according to new Alzheimer Europe report
Today, at a European Parliament lunch debate, Alzheimer Europe launched a new report presenting the findings of its collaborative analysis of recent prevalence studies and setting out updated prevalence rates for dementia in Europe.

Read More: Dementia News and Dementia Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to