Tarun Singhal, MD, MBBS, is a neurologist and nuclear medicine physician at Brigham and Women’s Hospital (BWH) whose research bridges physics, chemistry, and biology to develop new imaging tools to better understand neurological diseases.
For many of these diseases, including multiple sclerosis and Alzheimer’s disease, brain inflammation is a hallmark feature that actively contributes to the disease progression.
Over the last decade, Singhal and his team have worked to develop better ways to visualize brain inflammation.
They have developed specific markers for inflammatory cells, which they can measure with an imaging technique called Positron Emission Tomography (PET).
At the same time, Howard L. Weiner, MD, co-director of the Ann Romney Center for Neurologic Diseases at BWH and colleagues have been developing a new drug to reduce brain inflammation called Foralumab.
The drug, which can be administered with a nasal spray and was originally developed for patients with multiple sclerosis, is now being explored to reduce inflammation in other diseases such as Alzheimer’s disease.
Now, in an image published in the “Interesting Image” section of Clinical Nuclear Medicine, these two developments are intersecting for the first time, offering a peek into how nasal Foralumab treatment alters brain inflammation in a patient with Alzheimer’s disease.
Learn more in this Q&A with Singhal, where he lays out the groundwork leading up to this moment and how the new imaging technology could revolutionize drug development for diseases with brain inflammation.
Q: What made you want to study neurological diseases?
Alzheimer's disease is a huge problem worldwide, a huge societal burden and a huge economic burden. I think my own maternal grandmother in India had it, although she was never formally diagnosed.
Even before that, when I joined Mass General Brigham as a resident, I wrote in my personal statement that I want to help cure Alzheimer's disease. I think many people wrote that.
In that personal statement, I also quoted William Osler, who is an icon in medicine. He talked about physicians’ ambition to solve the problems that have perplexed us for ages, which guides me.
We are advancing technology, and contributing to further clinical developments across neurologic diseases now, and that’s very gratifying for me on multiple levels.
“To wrest from nature the secrets which have perplexed philosophers in all ages, to track to their sources the causes of disease, to correlate the vast stores of knowledge that they may be quickly available for the prevention and cure of disease—these are our ambitions” – William Osler
Q: Why are you interested in brain inflammation in the context of neurological disease?
The brain has these innate immune cells called microglia. Microglia have a supportive role under healthy circumstances, scanning the environment for any invaders, such as microorganisms or abnormal proteins.
They also support neurons in their normal functioning.
But under disease conditions, microglia tend to become abnormally activated and can cause injury to the neurons.
This state of neuroinflammation is not visible on regular MRI scans. It also doesn’t manifest like conventional inflammation—there won't be swelling or fever or pain.
This is a common mechanism that seems to happen across neurological diseases.
The emerging view is that this neuroinflammation not only a response to the underlying injury in each disease, but it actually contributes to the injury. If we can calm it down, it can prevent the propagation of that injury, ameliorate symptoms and maybe even modify the disease progression.
We wanted to develop a way to visualize this inflammation. So we started investigating a specialized dye that binds to these activated microglia in a person’s brain.
This dye is then detected when the patient undergoes a PET scan, which provides a visual indication of overall brain inflammation.
Q: Can you tell us about the image you’ve published? What does it show?
The image shows the brain of a 78-year-old man with moderate Alzheimer's disease who was treated with nasal Foralumab for three months.
Before treatment, the patient had an abnormal microglial PET signal, indicating higher than normal levels of inflammation, particularly in the regions that also had high amyloid burden—another hallmark feature of Alzheimer’s disease.
We used several analytical approaches and all of them showed the same result—that the patient had a reduction in inflammation after treatment with Foralumab.
The first panel (A) shows that overall inflammation is reduced throughout the brain following treatment.
In the second panel (B), we see the same effect looking at relative changes in inflammation—regions that had relatively high signal then became significantly lower after treatment.
When we focus in on regions where the patient has amyloid plaques (panel C), we found a significant reduction in microglial activation (shown in panel D).
From these measurements, it is very convincing that there was an imaging response to the treatment.
Further studies are nevertheless needed to confirm these findings in other individuals and with additional quantitative techniques.
Q: Can you describe the clinical trials born out of this work?
Building on our work developing the PET imaging technique to visualize inflammation in the brain, there is now Food and Drug Administration approval to use it in clinical trials for multiple sclerosis, Alzheimer’s disease and multiple system atrophy (a Parkinsonian condition) for the first time.
Visualizing brain inflammation is a groundbreaking technique that we can use to accelerate drug development by showing whether novel therapeutics can engage with their intended targets.
This paradigm shift in the field is a huge achievement for Brigham and Women’s Hospital—something that could have happened only here, leveraging the unique expertise, resourcefulness, and vision of all involved for over a decade now.
We believe that molecular PET imaging is currently underutilized in clinical trials design and novel drug development.
Our work paves the way for many other groups worldwide and essentially, the entire field to break silos, use PET imaging in a thoughtful and patient-centric manner, and for tackling not only neuroinflammation as a common pathway across diseases but also identify and target other novel mechanisms that can be harnessed to improve treatment and make our patients’ lives better.
Improving patients’ lives remains the center of all our endeavors in the NeuroPET program at Brigham and Women’s Hospital.
We are committed to advancing personalized and precision medicine across brain diseases in the service of that aspiration.
Subscribe to BenchMarks!
Subscribe to our monthly research newsletter and be the first to know what’s shaking in science at Mass General Brigham. From groundbreaking discoveries to the latest “you-heard-it-here-first” breakthroughs, we’ve got the updates that’ll keep your curiosity grooving.
Leave a Comment