Advances to Know in Alzheimer's, Migraine, and Stroke

Bret S. Stetka, MD

April 23, 2015

This week, over 12,000 neurologists descended on the nation's capital for the American Academy of Neurology (AAN) 67th Annual Meeting. Tackling the entire program would be impossible, as there are over 2400 presentations and posters being presented in all, but at a Monday afternoon press conference, Natalia Rost, MD, MPH, associate professor of medicine at Harvard Medical School and vice chair of the AAN Scientific Committee, presented three studies that she felt stood out among the rest.

To start off, Rost reviewed a promising phase 1b randomized study of aducanumab,^[1] a monoclonal antibody being developed by Biogen Idec Inc with the hope that it will modulate the course of Alzheimer disease (AD). The compound targets aggregated beta-amyloid and was tested in 166 patients in the early phases of AD. Learning from the disappointing results of previous trials testing monoclonals in AD, the investigators enrolled patients very early in the disease course—those with either prodromal or mild AD. Using florbetapir PET scans, they also ensured that enrolled patients had a significant amyloid burden.

On the basis of before-and-after PET findings, the drug was found to reduce amyloid plaque burden in the brain as early as 6 months out from initiating therapy and also at 1 year. Furthermore, aducanumab treatment was associated with a slowing of cognitive decline. The primary safety and tolerability signals were amyloid-related imaging abnormalities–edema (ARIA-E), the incidence of which did significantly increase with treatment, especially in ApoE ε4 carriers. However, the compound was deemed safe and tolerable enough based on the findings that the investigators plan to move directly to a phase 3 trial.

Understanding Migraines

Next, Rost presented research exploring the pathophysiology of migraines.^[2] Past findings suggest that patients with migraines are hypersensitive to pain. Building on this work, a group of researchers used MRI scans to compare the cortical thickness of brain areas associated with pain processing in people with and without migraine. To mimic pain, heat stimulation was applied to 31 adults with migraine and 32 healthy controls.

Given the ratio of cortical thickness to pain threshold, the authors found that controls showed a negative correlation between pain threshold and cortical thickness in a number of brain regions, whereas those with migraine showed the reverse. In other words, on the basis of these findings, it appears that patients who have a higher tolerance to painful stimuli have lower cortical thickness in certain brain regions involved in pain processing, whereas those with migraines—and presumably a lower pain tolerance—have thicker cortices. This correlation was strongest in the left superior temporal and inferior parietal regions, areas involved in attention to painful stimuli, suggesting that perhaps absence of a normal correlation means that those with migraine can't shift attention away from pain.

During the question-and-answer portion of the press conference, a reporter asked whether the findings have any clinical implications at the moment. Rost commented that they might compel clinicians to consider therapies beyond the usual migraine suspects, such as cognitive-behavioral treatments like biofeedback, approaches that could help patients reorient their perception of pain.

A Stroke Debate Finally Settled?

Finally, Rost highlighted findings from the recent MR CLEAN trial,^[3] assessing the treatment of acute stroke. "There are very few game-changers that come during our lifetimes," she started out, "but as a stroke neurologist I think this study in particular is one of these."

The initial MR CLEAN data were published late last year. But given the potential clinical impact of the findings, Rost felt that they deserved more exposure at the AAN meeting. The study design was simple and the recruitment impressive: Within a few years, a team of Dutch researchers was able to include over 500 patients from a number of centers across The Netherlands. Patients treated with standard care—intravenous thrombolysis—were compared with those given standard care plus intra-arterial intervention, primarily using the latest-generation stent retrievers.

Patients who underwent mechanical thrombectomy had significantly better functional outcomes, defined as functional independence, compared with those who received only standard therapy. In Medscape's initial coverage of these results, study investigator Diederik Dippel, MD, from Erasmus MC University Medical Center in Rotterdam, commented, "Our study shows that intra-arterial treatment works. Patients are left with less handicap if they are treated with the endovascular approach."

When asked who would perform the presumed increased number of interventional procedures in light of the new findings, Rost acknowledged that use of interventional approaches was likely to increase. "However," she concluded, "there is a group of neuroendovascular specialists who are prepared to take it on."