New study sheds light on ALS mechanisms

Gary Boas
January 21, 2015


The ALS Ice Bucket Challenge that swept across the Internet last summer brought renewed public attention to amyotrophic lateral sclerosis (ALS) research. And while the proliferation of videos eventually slowed to a stop, the research it helped to spotlight continues to thrive.

A major, ongoing goal of ALS research is to determine the mechanisms behind the disease. In recent years, studies have implicated immune system cells within the central nervous system called microglia, activation of which can lead to neuroinflammation. Now, in a positron emission tomography (PET) study with human ALS patients, investigators in the Martinos Center for Biomedical Imaging at Massachusetts General Hospital report in vivo evidence of the involvement of these processes.

The findings, reported online in the journal Neuroimage: Clinical, could have significant impact on our understandings of ALS mechanisms as well as on future drug development.

The study was performed by members of the Hooker Research Group in the Martinos Center and colleagues in the Neurological Clinical Research Institute and the Department of Anesthesiology, both also at MGH.

Importantly, it was the first to look at glial activation in ALS patients using  the radioligand [11C]-PBR28; radioligands are agents injected into patients for PET and other neuroimaging applications. Because it exhibits higher specific binding to an inflammation-associated protein than older-generation radioligands, the recently developed [11C]-PBR28 was able to uncover important connections in the study subjects’ brains.

“We observed increased microglial activation in motor cortices and corticospinal tract in patients with ALS,” supporting a possible role of glial cells in the disease, said Nicole Zürcher, an investigator in the Hooker Research Group and first author of the study. “Furthermore, glial activation in the motor cortex was positively correlated with disease severity and upper motor neuron burden.”

The researchers also noted the potential of [11C]-PBR28 for monitoring the efficacy of treatments targeting neuroinflammation in ALS.

“PBR28 imaging could be used as a pharmacodynamic biomarker in early phase trials to confirm target engagement and inform dose selection of anti-inflammatory agents,” said Nazem Atassi, Associate Director of the Neurological Clinical Research Institute and co-senior author of the Neuroimage: Clinical paper.

“It will also be interesting to investigate if individuals with high glial activation in the brain measured using PET will be the ones to particularly benefit from anti-inflammatory treatments,” he added.

In the meantime, the researchers continue to explore ALS mechanisms using [11C]-PBR28. They are increasing the sample size of their cohort so they can look at different disease subgroups, for example. They are also beginning to study changes in glial activation over time as a function of ALS disease progression.