Multiple Sclerosis: Rethinking How It Begins and Why It Progresses
Through two academic clinical and research centers dedicated to multiple sclerosis, faculty at Columbia University Vagelos College of Physicians and Surgeons and Weill Cornell Medicine are pursuing research that is yielding a better understanding of what triggers the disease, causes its progression, and furthers therapeutic options. Their expertise spans a spectrum of novel concepts that may prove pivotal to the care of patients.
Genomic Map Reveals Unexpected Findings
“This genomic mapping is not the end of MS genetics, but it is a major milestone and will be a reference for years to come that will inform the work of many investigators in the field of MS and beyond.”
— Dr. Philip L. De Jager
A study led by Columbia researchers on behalf of the International Multiple Sclerosis Genetics Consortium has overturned long held views on the cause of MS, an autoimmune disease in which the immune system attacks myelin, the protective sheath of the nerve cells in the brain and spinal cord. The study, the most comprehensive of its kind, showed that MS is triggered predominantly by dysregulated immune cells, both inside and outside the brain, that then cause damage to neurons, astrocytes, and other brain cells.
By analyzing the genomes of 115,803 individuals, including 47,429 MS patients and 68,374 healthy individuals, the researchers identified 233 genetic variants that contribute to the onset of MS. They then analyzed the downstream effects of these variants to determine the sequence of molecular events in each immune cell type that eventually perturb the function of these immune cells and make them attack the brain and spinal cord.
The genomic map revealed that MS begins with dysfunction in many different types of immune cells throughout the bloodstream and brain and not only in lymphocytes as had been thought. The array of dysfunctional cells, in combination, triggers a cascade of events that can lead to brain inflammation and, eventually, nerve cell death.
“There had been little or no evidence that neurons themselves are involved in triggering the disease,” explains study leader Philip L. De Jager, MD, PhD, Director of the Multiple Sclerosis Center at Columbia University Irving Medical Center. “It is now clear that MS is not caused by a single type of immune cell, namely lymphocytes, but rather by a broad dysfunction of the immune system. Lymphocytes are clearly important, but we now have good evidence that most immune cell types, such as natural killer cells, monocytes, and dendritic cells that move into the brain from the bloodstream, are also involved. We also found that the resident immune cells of the brain – the microglia – are involved. It’s a dysregulation of the entire immune system.”
Current MS treatments aim to stop brain inflammation after it has already started. According to Dr. De Jager, this new understanding of MS provides scientists with a better idea of what cells and molecules to target early in the disease, before the immune cells attack the brain, and that could lead to preventive treatments. “These findings will help us identify healthy individuals who are at high risk of developing MS. They are the most likely to experience a strong, dysregulated inflammatory response against the brain. They would benefit the most from preventive or early treatments with new medications that modulate the immune system in a specific fashion to minimize side effects.”
Read more at:
Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility: https://science.sciencemag.org/content/365/6460/eaav7188
A Novel Imaging Approach Focuses on Iron-Related Myelin Damage
“Differentiating MS lesions, especially chronic lesions, with quantitative susceptibility mapping may provide a biomarker for disease progression and a therapeutic target to reduce ongoing tissue damage.”
— Dr. Susan A. Gauthier
With longitudinal clinical and quantitative imaging data on some 5,000 brain MRIs of 2,000 patients with MS collected over nearly a decade, the Multiple Sclerosis Center at Weill Cornell Medicine, under the leadership of academic neurologist Susan A. Gauthier, DO, MPH, has established an unparalleled research platform — CollabDS (Collaborative Data Science) — for studies that can accelerate the development of new therapeutics.
“When I started this 11 years ago, I initially thought that I was just going to be storing conventional imaging, and using that imaging to help build predictive models of the disease,” says Dr. Gauthier. “However, as I met colleagues in radiology who were developing novel quantitative MRI sequences that could be applied to study MS, we started to collaborate and began to incorporate quantitative imaging sequences into the clinical arena. Through this collaboration, we can improve the pathological specificity of our standard clinical imaging protocol and with this, we can identify imaging features that may more accurately define an individual patients’ disease course.”
Dr. Gauthier, along with radiologists and physicists at Weill Cornell Medicine, developed a sophisticated MRI protocol that combines myelin water imaging, quantitative susceptibility mapping (QSM) to measure iron, diffusion tensor imaging to measure brain fiber tracts, and conventional MRI sequences. All of these images are acquired within the timeframe of a standard-of-care clinical MRI.
“Differentiating MS lesions, especially chronic lesions, with QSM may provide a biomarker for disease progression and a therapeutic target to reduce ongoing tissue damage,” notes Dr. Gauthier. “We are focusing our efforts on chronic lesions as these would otherwise be just considered a chronic scar on conventional MRI. QSM allows us to detect lesions that have a rim of iron-containing microglia, which are consistent with chronic active or slowly expanding MS lesions.” Dr. Gauthier and her colleagues were awarded several grants to develop and validate this biomarker, and were able to validate rim lesions utilizing PET imaging.
“PET can measure inflammation. We were able to demonstrate in an in vivo study that these lesions do have more inflammation, and confirm that QSM enables us to accurately identify chronic MS lesions with persistent inflammation,” says Dr. Gauthier. In a separate study, QSM was combined with their myelin imaging sequence and it was demonstrated that QSM rim lesions have more myelin damage. From both studies, it can be concluded that QSM provides “quantification of susceptibility changes related to iron-laden inflammatory cells and gives us the potential to identify chronic active MS lesions that are known to have ongoing demyelination.”
The researchers are now ready to implement this novel approach into clinical care, including incorporating QSM into the clinical imaging reports and providing the number of rim lesions present in a particular patient. “All of our definitions of disease stability are based upon conventional imaging or clinical measures,” adds Dr. Gauthier. “We now have to redefine disease stability and determine if our current treatments are affecting these lesions at all.”
CollabDS, the research platform established in 2011, continues to support critical studies by Dr. Gauthier and her colleagues, including a very recent study associating rim lesions with cognitive outcomes and clinical disability in which they found that only one rim lesion is needed to see an association with these outcomes and that having one rim lesion is also associated with more cortical thinning, a measure of neurodegeneration.
“All of these studies were possible because of our MRI database,” adds Dr. Gauthier. “QSM is enabling us to identify and quantify the extent of inflammation retained in a specific type of chronic lesion and this can lead to new therapeutic targets. Our goal is to improve disease prognosis and to provide a method to assess treatments targeting the central nervous system. Our MS center is one of the few that has the data and expertise to facilitate the translation of QSM to improve clinical care and treatment for patients with MS.”
Read more at:
Impact of lesion location on longitudinal myelin water fraction change in chronic multiple sclerosis lesions: https://onlinelibrary.wiley.com/doi/abs/10.1111/jon.12716
Quantitative susceptibility mapping of time-dependent susceptibility changes in multiple sclerosis lesions: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565472/
Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions: https://academic.oup.com/brain/article/142/1/133/5250435