ARTICLE IN BRIEF
In experiments using both mouse models of stroke and brain tissue samples from humans, investigators linked the delayed onset of post-stroke dementia to the persistent presence of B cells in the brain.
Why is the risk for developing dementia doubled for as much as a decade after a stroke? A new study suggests the answer may be B cells, which accumulate in both the mouse and human brain after stroke. Preventing that accumulation prevents post-stroke dementia in mice, investigators reported in the Feb. 4 issue of the Journal of Neuroscience.
“The risk of dementia after stroke is high,” said lead study author Marion Buckwalter, MD, PhD, an assistant professor of neurology and neurological sciences and neurosurgery at Stanford University School of Medicine in Palo Alto, CA. Dr. Buckwalter noted that between one-third and one-half of stroke patients eventually develop significant cognitive impairment, even after accounting for other risk factors, including high blood pressure and diabetes.
Antibodies have been found in the cerebrospinal fluid of stroke patients, and recent work has shown that spinal cord injury provokes a B cell response in mice. That led Dr. Buckwalter and first author Kristian Doyle, PhD, to ask whether B cells might also be involved in the response to stroke, and whether they may play a role in the development of dementia.
In most mouse models, stroke is induced by occluding the proximal middle cerebral artery, but that directly injures the hippocampus, Dr. Buckwalter explained. By moving more distally, she could lesion about a quarter of the affected hemisphere but still spare the hippocampus, leaving the mice cognitively intact in the immediate post-stroke period.
The team found that B cells were virtually undetectable in infarcted tissue one week after the stroke, but were prominent by seven weeks. They formed follicle-like structures, and many displayed markers of immunoglobulin-producing cells. Consistent with that, they found elevated levels of immunoglobulin A (IgA) and IgG, indicating that at least some of the B cells had become activated. T cells, required for B cell activation, were also found abundantly in the stroke lesion. “This is all telling us that an immune response is happening there,” Dr. Buckwalter said.
Immunoglobulins were also plentiful in the hippocampus, despite being outside the lesion, the team found; little was detected in the first week post-stroke, but then levels rose strongly by week seven. Their appearance in the hippocampus coincided with a deficit in long-term potentiation (LTP), the electrophysiologic hallmark of learning and memory, which declined by about 20 percent at seven weeks and 45 percent at 12 weeks post-stroke. Mice also performed worse over time on standard learning tests.
If the cognitive decline experienced by the mice was due to the B cell response, Dr. Buckwalter reasoned, then mice without B cells might be resistant. Indeed, stroke in a genetically B cell-deficient mouse did not lead to loss of LTP or poor hippocampal-based memory performance, despite the equivalent lesion size.
Next, the team showed that ablating B cells with an anti-CD20 antibody five days after the stroke also prevented the development of cognitive deficits. CD20 is a B cell-specific surface protein, and is the target for the US Food and Drug Administration-approved immunosuppressant drug rituximab.
Finally, they asked whether B cells are found in the brains of patients following stroke. They did immunostaining on post-mortem brain tissue from 21 subjects who had experienced an ischemic stroke and died with a diagnosis of non-Alzheimer's dementia, as well as nine control subjects with no stroke and no dementia. Dr. Buckwalter noted that the sites of stroke varied widely, and most spared the hippocampus. In controls, B cell density was about two cells per square centimeter compared with almost 13 cells per square centimeter in stroke subjects.
Dr. Buckwalter acknowledged that there is much work left to be done in humans to connect the dots between elevated B cell responses and the development of post-stroke dementia. “This cell type should not be in the normal human brain,” she said. The next step is to look more deeply at brains of those who died of stroke, to determine whether B cell levels and distribution at autopsy are associated with worse cognitive performance before death.
Should those studies confirm these initial findings, Dr. Buckwalter said, it is likely to advance the view that a chronic immune reaction, a form of autoimmunity, may contribute to post-stroke cognitive decline. “We speculate that plasma cells in the stroke core might be producing autoreactive antibodies, or antibodies that activate Fc receptors”— an antibody signaling target “and complement — and that those antibodies diffuse into the surrounding tissue and cause neurological dysfunction.”
“I think this is a very elegant study, which addresses an important issue in stroke,” said Kyra J. Becker, MD, a professor of neurology and neurological surgery at the University of Washington in Seattle. “The data are clear that people who suffer stroke have a higher risk of developing dementia, so the question is, what leads to cognitive decline? Showing that there is a B cell response that is delayed and is amenable to intervention is really exciting.”
If these results can be extended to confirm a contribution to dementia in humans, she said, the next question would be to determine the corresponding time window for autoimmunity development. On the one hand, the long delay between stroke and dementia in people may offer a long period in which to intervene. On the other hand, anti-B cell therapy comes with its own risks, especially in patients who have had stroke. “The evidence is pretty compelling that in stroke and other major insults to the body, there is a decrease in the ability of the peripheral immune system to respond to challenges, lasting weeks to months,” Dr. Becker said. “As a result, infection is the biggest issue in the post-stroke period,” making prolonged depletion of B cells potentially unwise.
“If there is a window of time when the autoimmune response is developing, and if you could somehow strategically limit the immune response during that period alone, you might be able to prevent these responses” that lead to dementia, she said. “But we need to know the time of highest risk.”
Whether or not that becomes possible, the results of the study strengthen the case for reconsidering the central nervous system as an immunologically privileged site. The alternative idea of the brain as a major immunologically responsive organ “is a relatively new concept, based mainly on animal studies so far,” said Costantino Iadecola, MD, director of the Brain and Mind Research Institute at Weill Medical College of Cornell University in New York. Dr. Buckwalter's study, he said, now makes it logical to look closely at the nature of the immune response in the post-stroke brain.
However, he pointed out that the antigens involved in promoting dementia may differ among patients, as might the contribution of the B cell response itself. When contemplating therapy, patient selection would be critical. “This is a case for precision medicine,” he said. “It may only be a minor contributor in some cases, but we haven't thought about it before, and now we need to look.”
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© 2015 American Academy of Neurology
•. Doyle KP, Quach LN, Solé M, et al. B-lymphocyte-mediated delayed cognitive impairment following stroke. J Neurosci
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