News from the Society for Neuroscience's 2011 Meeting in Washington, DC.
Alzheimer’s Vaccine Triggers Brain Inflammation When Brain Amyloid Burden Is High
Patients in the early stages of Alzheimer’s disease will likely benefit most from vaccine therapies now being tested in a number of human clinical trials, according to researchers.
Their study is the first to show that mice with a large brain burden of amyloid protein—representative of many patients now receiving immunization—were much more likely to experience significant brain inflammation. In contrast, mice with less amyloid in their brains did not experience this side effect and showed a significant benefit from the vaccine.
Inflammation was found in a small subset of patients with Alzheimer’s disease enrolled in ongoing vaccine trials, said the study’s lead investigator, R. Scott Turner, MD, PhD, Director of the Georgetown University Memory Disorders Program in Washington, DC.
While patients often do not know they have this side effect and have no symptoms, the swelling can be seen on MRI scans that are routinely performed on patients enrolled in these trials, Dr. Turner said. “Excessive inflammation, however, is counter-productive because it will limit the benefits of the vaccine treatment, and in a few cases, will cause new problems,” he said.
The study shows that excessive inflammation occurs in brains that have a high burden of amyloid, suggesting that benefits from the vaccine will most likely be found in those with a lower amyloid burden. The study also provides clues as to how and why the inflammation occurs, Dr. Turner said. Such studies defining inflammatory mechanisms in the brain are not possible in Alzheimer’s patients undergoing these treatments.
Active immunization involves injecting amyloid protein in patients so they can mount an antibody response. Passive immunization involves infusing monoclonal antibodies intravenously so they can attack amyloid build-up in the brain. Inflammation is an expected part of the body’s immune response in both of these vaccine strategies, but excessive inflammation can be harmful, Dr. Turner said. He undertook the study in a mouse model of Alzheimer’s disease to understand if amyloid burden plays an important role in the degree of inflammation generated in response to passive immunization treatments.
Given the study findings, he said that the vaccines now being tested in patients with Alzheimer’s disease may work better in patients with mild cognitive impairment. Consistent with this notion, a new clinical trial testing active immunization in patients with mild cognitive impairment and a positive amyloid PET scan is now recruiting volunteers.
“We may find that in the future, we will have to tailor immunization therapies based on amyloid burden in individual patients,” Dr. Turner said. For example, in order to minimize the risk of excessive inflammation in brain, the antibody dosage with passive immunization treatments may be limited in those individuals with a higher amyloid burden.
Ultrathin Flexible Brain Implant Offers Unique Look at Seizures
Researchers have developed a flexible brain implant that may one day be used to treat epileptic seizures. In animal studies, the researchers used the device—a type of electrode array that conforms to the brain’s surface—to take an unprecedented look at the brain activity underlying seizures.
“Someday, these flexible arrays could be used to pinpoint where seizures start in the brain and perhaps to shut them down,” said Brian Litt, MD, the principal investigator and an Associate Professor of Neurology at the University of Pennsylvania School of Medicine in Philadelphia.
“This group’s work reflects a confluence of skills and advances in electrical engineering, materials science, and neurosurgery,” said Story Landis, PhD, Director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the work. “These flexible electrode arrays could significantly expand surgical options for patients with drug-resistant epilepsy.”
In an animal model, the researchers saw spiral waves of brain activity not previously observed during a seizure. Similar waves are known to ripple through cardiac muscle during ventricular fibrillation.
“If our findings are borne out in human studies, they open up the possibility of treating seizures with therapies like those used for cardiac arrhythmias,” said Dr. Litt. Epilepsy surgery could become more analogous to ablation procedures for cardiac arrhythmias. In these procedures, electrodes are used to detect aberrant electrical circuits in the heart, which are then interrupted by making tiny lesions in the muscle. A stimulating electrode array might one day be designed to suppress seizure activity, working like a pacemaker for the brain, Dr. Litt said.
The arrays currently used to record seizure activity in patients being considered for surgery consist of electrodes attached to a rubbery base about the thickness of a credit card. These arrays are placed on the surface of the brain, but they are not flexible enough to mold to the brain’s many folds. The electrodes are widely spaced and allow for only limited brain coverage.