What are you trying to learn about Alzheimer’s?
Broadly, our group is interested in identifying new ways to diagnose Alzheimer’s disease earlier. Specifically, we focus on identifying imaging biomarkers, or changes in the shapes of brain regions that we can measure on an MRI. These markers can reveal what is happening at the molecular level during the onset of Alzheimer’s. Our goal is to start linking biomarkers to what we know is a key signature of the disease: the accumulation of two misfolded proteins, neurofibrillary tangles (NFTs) and amyloid plaques.
One challenge is that a definitive diagnosis of Alzheimer’s is not possible until autopsy. We’ve built a new technology, called Projective Large Deformation Diffeomorphic Metric Mapping (LDDMM), that allows us to reconstruct 3D maps of NFT density at high resolution using brain images from confirmed post-mortem cases. By reconstructing what the pathology of Alzheimer’s looks like, we can directly link what we see on an MRI of a living brain—how the regions are changing—to what we see in the confirmed cases.
Ultimately, we hope to understand the brain changes that trigger Alzheimer’s and how the disease progresses. What’s exciting is that ours is just one of many new technologies that are allowing researchers to look at structures we haven’t examined before.
What is the amygdala, and what is its connection to Alzheimer’s?
The amygdala is a region in the medial temporal lobe that is primarily associated with emotional responses. Most Alzheimer’s research to date has focused on other regions of the medial temporal lobe like the hippocampus, paying little attention to the amygdala.
Due to its homogenous shape, the amygdala is difficult to delineate on an MRI scan. That’s one reason that it hasn’t been as well-studied. Part of our work has involved developing an MRI segmentation technique to allow for more detailed study of the amygdala and its four subregions.
Using LDDMM, we observed that volume loss in the amygdala occurs in individuals who eventually develop dementia and Alzheimer’s over time. We can look at the extent to which some subregions are shrinking and others are not, and plan to investigate more into why this is happening. We think examining this region further may help fill some of the lingering gaps that exist in terms of knowing where the disease starts and how it travels through the circuits of the brain.
How is your approach to understanding Alzheimer’s unique?
Our long-term goal is to be able to identify the earliest pathological changes in Alzheimer’s disease at three different scales: tissue changes, molecular changes, and genetic changes.
We are collaborating with Meaghan Morris, an assistant professor in the Johns Hopkins Department of Pathology, to track changes in gene expression as Alzheimer’s progresses. So ideally, we will have the technology to identify a change on an MRI, confirm that change is linked to the buildup of Alzheimer’s-related proteins, and see what genes are expressed in these regions. Having this knowledge at various levels is going to be crucial for earlier diagnosis and for discovering new targets for potential treatments.
What do these findings mean for future research?
The amygdala is a newer player in the game, and that’s exciting. The purpose of our Brain review is to bring together all this research across institutions and across new technologies that have shown that, yes, the amygdala is important in the earliest stages of Alzheimer’s disease and shouldn’t be ignored.
We think it is useful to put together the pieces of the puzzle to bolster support for more work in this area—and there really are so many potential new avenues for research. For example, we now know that behavior and mood changes are common clinical symptoms. What is happening in the amygdala could explain why we are seeing depression, apathy, and anger early on with Alzheimer’s patients.
What’s next for your team?
We’re interested in doing more studies on the amygdala and how it is involved in Alzheimer’s. We are working with Marilyn Albert, a professor of neurology who leads the BIOCARD study, one of the largest Alzheimer’s studies in the world managed by the Johns Hopkins Alzheimer’s Disease Research Center. Participants don’t have Alzheimer’s, but we track them over time (15–20 years) and continue to monitor them to see how they age and develop mild cognitive impairment. We are currently growing the cohort that we are studying and gathering more data on imaging biomarkers.
We have an aging population at risk for Alzheimer’s, but we still don’t have a cure or even a definitive way to diagnose it. We hope that our future studies will uncover more evidence that the disease is possible to detect early, when treatments may be more effective.
