According to a recent study funded by the National Multiple Sclerosis Society, nearly one million people are now living with multiple sclerosis (MS) in the United States – more than double the last official estimate in 1976 and a validation that there is a much larger community of MS patients than previously thought in need of better treatments. Neurologists at NewYork-Presbyterian/Columbia’s Multiple Sclerosis Center are leading groundbreaking research initiatives aimed at developing a deeper understanding of the biological mechanisms of MS with the goals of slowing progression and finding a cure.
“We have not characterized in any meaningful detail individuals who are at risk of the disease and cannot yet predict who will eventually develop the disease; I think this is one of the big gaps that we need to address,” says Philip L. De Jager, MD, PhD, a neurologist and Chief of the Division of Neuroimmunology at NewYork-Presbyterian/Columbia. “Additionally, for those already diagnosed with MS, we still do not understand why – even when we control the inflammatory component of the disease – progressive brain atrophy is accelerated in certain patients and not in others. While it would be wonderful to stop the process altogether, the more modest goal of slowing down the progression of disability is potentially just as impactful and more achievable.”
For those already diagnosed with MS, we still do not understand why – even when we control the inflammatory component of the disease – progressive brain atrophy is accelerated in certain patients and not in others. While it would be wonderful to stop the process altogether, the more modest goal of slowing down the progression is potentially just as impactful and more achievable.
— Dr. Philip De Jager
But the best pathway to accomplishing this goal is contingent upon access to postmortem brain tissue. “With new technologies, we can look at the entire tissue at once to let the data speak to us. However, a scarcity of tissue samples from well-characterized MS-affected brains has limited our ability to better understand the origins and course of MS and to develop a broader range of effective, disease-modifying and symptomatic therapies,” says Dr. De Jager.
In 2020, Dr. De Jager, Claire Riley, MD, a neurologist and Co-Director of the Multiple Sclerosis Center at NewYork-Presbyterian/Columbia, and their colleagues at NewYork-Presbyterian/Columbia established the National MS Brain Bank in collaboration with investigators at the National Institute of Neurological Disorders and Stroke (NINDS) and the Yale School of Medicine. The National MS Brain Bank has been made possible, in part, through the generous support of the National Multiple Sclerosis Society. In just a few years, the MS Brain Bank has evolved from a regional initiative to an invaluable resource for scientists internationally in a shared commitment to cure MS.
The Mission of the National MS Brain Bank
The National MS Brain Bank is enrolling people with MS from across the country into a brain donation program prior to their death. “What distinguishes our program from most of the other brain banks around the world is that we are asking patients to participate in a study that tracks their MS and associated progression so that we can relate the course of their individual disease to pathology we see in the brain postmortem,” says Dr. De Jager.
What distinguishes our program from most of the other brain banks around the world is that we are asking patients to participate in a study that tracks their MS and associated progression so that we can relate the course of their individual disease to pathology we see in the brain postmortem.
— Dr. Philip De Jager
The Brain Bank team compiles clinical information, cognitive testing and imaging scans on an ongoing basis for each participant that they will link to in-depth characterization of brain tissue obtained from a postmortem autopsy. “Having worked in the Alzheimer's field, I saw the power of having thousands of brains to characterize at the molecular level, providing information and allowing for significant insights that are only possible through collaborative, large-scale efforts to gather data,” continues Dr. De Jager. “Collecting a large number of brains will give us the statistical power to answer our questions. Our goal initially is to enroll 1,000 individuals through the establishment of a consortium of investigators at other centers who are interested in this approach. Our long-term goal is to follow 5,000 to 10,000 patients. We want to establish the National MS Brain Bank as a community resource because today the best science derives from communities of investigators.”
MS Snapshot Study: Complementing the Goal of the Brain Bank
Why is MS progression gradual in some people, while in others it causes a rapid accumulation of disability and cognitive impairment? Dr. De Jager, Dr. Riley, and their colleagues seek to answer this question and many others through MS Snapshot, a prospective study enrolling participants with MS and those without MS who have agreed to donate their brain and spinal cord at their passing to the MS Brain Bank.
“The MS Snapshot study seeks to understand brain and spinal cord aging in healthy individuals and individuals with multiple sclerosis,” says Dr. De Jager. “By collecting data during the lives of participants and later on collecting brain tissue at their death gives us a rare opportunity to identify new tools that will enable investigators to understand which molecules in the brain made it more or less likely to achieve successful brain aging.”
The MS Snapshot study is conducted primarily online, with participants undergoing cognitive evaluations annually. Every 5 years, a wrist monitor measures the participant’s activity over a two-week period. A subset of participants is asked to come for in-person visits, biospecimen collection, and more detailed examinations of brain function. Compiling clinical history, neuroimaging data, disease features over time, and treatment information allows the study group to develop a comprehensive phenotype to incorporate with postmortem pathologic findings in the brain. Approximately 400 individuals are already enrolled in the study to date.
“There is wide heterogeneity in the clinical course of multiple sclerosis, which can differ substantially from what the radiology may suggest,” says Dr. Riley. “This is the clinico-radiologic paradox. By deeply phenotyping the individuals who participate in the prospective study and later donate their brains, we hope to unravel this paradox. Further, while MS research has often been dominated by non-Hispanic white participants, we seek to enroll a cohort of individuals with MS that reflects the tremendous diversity of our patient population and experience.”
The Overlap of MS and Alzheimer’s Disease
Dr. De Jager is a leader in understanding the role of inflammatory cells, such as microglia, and their important function in the development of pathologies of aging. “My specialty is in neuroimmunology, and the most common disorder in this field is multiple sclerosis. But I also work in the scientific arena of Alzheimer's disease,” says Dr. De Jager, who also serves as Deputy Director of Columbia’s Taub Institute for Research on Alzheimer's Disease and the Aging Brain. “Over the past 15 years, we have shown that there are many immune components in Alzheimer’s. While there is little evidence to date that the two diseases have shared mechanisms, much of the biology of these two neurodegenerative diseases remains unknown. In the context of MS, we have made great strides in managing the inflammatory phase of MS by controlling the influx of immune cells from the periphery into the brain.”
Over the past 15 years, we have shown that there are many immune components in Alzheimer’s. While there is little evidence to date that the two diseases have shared mechanisms, much of the biology of these two neurodegenerative diseases remains unknown. In the context of MS, we have made great strides in managing the inflammatory phase of MS by controlling the influx of immune cells from the periphery into the brain.
— Dr. Philip De Jager
The secondary, neurodegenerative component of MS resembles Alzheimer's disease in that it produces a chronic, unrelenting decline in function over time in certain patients. “What was initially described in the field of Alzheimer's in relation to brain resilience has now also been shown in MS,” adds Dr. De Jager. “Whether an individual has a neurologic disability from Alzheimer's or MS, the region of the brain that is activated to perform a function expands, essentially recruiting neighboring tissue to fulfill the task. In fact, the brain is quite good at compensating for and hiding deficits. But at some point this compensatory process in which other parts of the brain can be recruited to support the activity will fail. This is when you begin to see a chronic decline. Everyone’s brain shrinks as we get older, but with MS the inflammatory process leaves patients with fewer reserves and so those with MS appear to reach milestones of aging earlier than those who do not have MS.”
Everyone’s brain shrinks as we get older, but with MS the inflammatory process leaves patients with fewer reserves and so those with MS appear to reach milestones of aging earlier than those who do not have MS.
— Dr. Philip De Jager
The extent of commonalities between MS and Alzheimer’s disease notwithstanding, independently the two diseases can each cause dementia. “How do you tease out what is MS, what is Alzheimer's, and what is aging? Distinguishing aging from the ongoing neurodegenerative process in these patients is another fundamental complexity to be addressed,” says Dr. De Jager. “We do know that the patterns of cognitive decline are very different in MS and in Alzheimer's. Alzheimer’s has a very stereotypical pattern of brain atrophy in that it begins in one area of the brain, the hippocampus, then gradually spreads to other areas of the brain. This is why people with Alzheimer's disease have a very particular type of cognitive impairment, which is manifested by memory loss. While we do see similar manifestations in MS, the associated cognitive decline is not monomorphic in that some individuals, for example, may primarily have a language problem or an attention problem.”
Exploring the Molecular State of MS Donor Brains
Dr. De Jager notes that their current focus is on collecting donor brains and archiving them in the best possible manner. When brain tissue is received, within 24 hours, it is sent for rapid processing at the brain bank hub at NewYork-Presbyterian/Columbia. Here the tissue is frozen and preserved, enabling investigators to perform advanced molecular profiling at a later date. While the National MS Brain Bank team is at the beginning of the data generation phase, it has already begun to produce MRI data. For this component of the MS Brain Bank, a hemisphere (one-half) of the brain is sent for high resolution imaging to Daniel S. Reich, MD, PhD, Senior Investigator, Translational Neuroradiology Section, NINDS, and one of the principal investigators for the National MS Brain Bank.
“Dr. Reich and his group provide us with extremely high-resolution, very detailed images of the brain, enabling us to pinpoint and access lesions not visible to the naked eye,” explains Dr. De Jager. “In patients with MS, once the lesions cause their damage, the brain generally heals, leaving behind inactive scar tissue. However, some lesions are more pernicious and retain a rim of immune cells that seem to be active, further injuring the brain. With MRI analysis, we now have the potential to correlate this ring of pathogenic cells in people with chronically active lesions to worsening disability over time. We have terabytes of MRI data on over 50 brains, and we are in the process of making these data easily accessible to other investigators.”
With MRI analysis, we now have the potential to correlate this ring of pathogenic cells in people with chronically active lesions to worsening disability over time.
— Dr. Philip De Jager
The brain tissue also undergoes histological analysis in the laboratory of David Pitt, MD, at Yale who is the third principal investigator of the National MS Brain Bank. These images are digitized and can be linked to the images from the postmortem MRI to understand the biology behind the images of lesions on MRI.
“We not only need to understand what’s happening in the brain of someone who has had MS but also need to understand what is happening in the brain of someone who is healthy to uncover what is different about the MS brain,” notes Dr. De Jager. “By following patients over many years and monitoring how they progress, we can exponentially increase what we can learn from a pathological sample. All brain donations are helpful, but those that come with a history of the disease course are exceptionally valuable. The MS Brain Bank is a resource that will be widely available to scientists conducting MS research internationally. Providing them with high quality, well-preserved, and well-characterized samples of MS brains and spinal cords will pave the way for new fundamental insights that will lead us towards a cure.”
The MS Snapshot study and the National MS Brain Bank are guided by stakeholder advisors: a powerful group of dynamic individuals who help to shape the study and give voice to interests of patients and families who are impacted by the disease.
