A conversation with Christopher D. Anderson, MD, MMSC, Assistant Professor of Neurology, Harvard Medical School, Director or Acute Stroke Services at Massachusetts General Hospital, Faculty in the Center for Genomic Medicine and Associate Member at the Broad Institute.
Interviewed by Rachel Forman, MD, vascular neurology fellow, Massachusetts General Hospital.
They will be discussing the article “Genetics of Cerebral Small Vessel Disease,” published in the January 2020 issue of Stroke.
Dr. Forman: First of all, thank you for taking the time to sit down with me and discuss this important topic. How did this article come to fruition?
Dr. Anderson: This feature is part of a larger set of articles on cerebral small vessel disease (SVD) that was submitted as a group, and the genetics of SVD is a specific consideration that sheds a lot of light on the pathogenesis of the disease. I think it merited its own exploration as part of this issue.
Dr. Forman: Can you expand on the categorization of SVD into arteriosclerosis and amyloidosis?
Dr. Anderson: As it stands, these days SVD is subcategorized into amyloid-related and hypertensive or SVD-related. You can think of SVD as an arteriolar process that arises from the perforating arteries of the deep structures and is categorized by lipohyalinosis and sometimes perivascular necrosis. This is really pathologically distinct from the amyloid-related disease, which tends to be on the other side of the brain out in the cortical surface and the sub-cortical structures and is characterized by the classic apple green birefringent amyloid-related disease that results in this arteriopathy. This can co-exist often with SVD and certainly seems to be accelerated by the concurrent presence of SVD, but genetically at least, has a relatively distinct set of risk factors.
Dr. Forman: It was interesting to see how many patients with cryptogenic stroke have alpha-GAL mutations (0.5%); what do we do with this information?
Dr. Anderson: There is an increasing amount of literature on the utility of genotyping individuals with cryptogenic or even non-cryptogenic strokes looking for familial syndromes, and certainly in the setting of things like Fabry’s disease, there are distinct features that one can look for and even criteria that one can use to determine whether or not genetic testing is appropriate. I think the jury is still out on whether or not there is utility for strokes in individuals that have familial clustering, how close that familial clustering needs to be, and what form of genetic testing is appropriate (i.e., genetic panels, exome sequencing, whole genome sequencing), and how do you annotate the features of those results such that you can give meaningful data back to the patients, and how does that ultimately change the way that you manage. I think we are at the dawn of a new era to determine those salient characteristics.
Dr. Forman: How do we incorporate all of this information into clinical practice as far as ordering genetic testing?
Dr. Anderson: You always want to have a genetic counselor involved when you are considering these in a clinical environment. The presence or absence of some of these genetic variants may increase the risk, but is not deterministic in many of these conditions. The degree to which that information then informs upon the need for familial testing or testing of children of patients that are affected becomes challenging issues to dissect, and it is important to have an expert at your disposal to help navigate.
Dr. Forman: The paper mentions that CADASIL is the most common among monogenic SVD. What is the status of NOTCH3-targeted medications?
Dr. Anderson: There are therapeutic agents in pre-clinical testing, and it is not clear which or if any will ultimately make it to beneficial outcomes in the human level, but the work is ongoing and very exciting.
Dr. Forman: What is the take-home message of your paper?
Dr. Anderson: The goal for our paper was really to illustrate the number of molecular pathways that are relatively distinct, but certainly inter-related, that share in a common final pathway the genesis of SVD either through arteriolar hypertensive disease or amyloid-related disease and that the more we learn about the genetics of these conditions, the better we understand the biology that underlies them. It is hoped that by continuing to understand and dissect the genetic architecture of SVD, that new treatment targets will be elucidated that can then be targeted. This is the basis of a lot of our research that we do to understand both the established genetic risk factors for these conditions, as well as the search for new ones.
Dr. Forman: What are the next steps in the field of cerebrovascular genetics?
Dr. Anderson: The goal is to amass larger and larger populations of patients with well-characterized SVD, both episodic in the form of intracerebral hemorrhage and small vessel ischemic stroke, as well as populations with white matter hyperintensities and other radiographic features of SVD, and perform genetic testing on these populations to increase the power of discovery for variants in this field.
Dr. Forman: Thank you very much.
Disclosures: Dr. Forman works at the same institution as Dr. Anderson; however, she is not involved in this area of research.