Steven M. Greenberg, MD, PhD: Updates in Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy is a disease that is caused by the accumulation of β-amyloid deposits in cerebral vessels and is common among elderly individuals. At the American Neurological Association’s 145th Annual Meeting, Steven M. Greenberg, MD, PhD, gave a talk on recent research and treatment advances in cerebral amyloid angiopathy. After Dr Greenberg’s presentation, Neurology Learning Network caught up with him about the key advances in this area.

Dr Greenberg is the director of the Hemorrhagic Stroke Research Program, vice chair of Faculty Development and Promotions, and holds the John J. Conway Endowed Chair in Neurology at Massachusetts General Hospital in Boston.

Neurology Learning Network: What have been some key recent research advances in the pathogenesis, clinical care, and features of cerebral amyloid angiopathy?

Dr Greenberg: During my talk at the ANA Meeting, I said that I wish my field of amyloidosis had the same problems as transthyretin (TTR) amyloidosis, because we have not yet seen the exciting advances that are now being seen in TTR amyloidosis. Building on the same kinds of biological approaches that have been developed for TTR amyloidosis, there is a lot of promise for the amyloid that we studied, which is the amyloid that deposits in blood vessels and the brain. From a practical standpoint, it is on the wrong side of the blood‑brain barrier. It is inside the central nervous system rather than outside, making it harder for drug therapies to access the amyloid.

Some of the same approaches, which potentially include interventions like small molecules to decrease aggregation or RNA‑interference type approaches to prevent formation of amyloid, are viable strategies for cerebral amyloid angiopathy. We have a good set of biomarkers in place to be able to perform the kinds of clinical studies that have proven so fruitful in TTR amyloidosis.

NLN: Could you discuss the effects of amyloidosis on the cerebrovascular system?

Dr Greenberg: In the case of cerebral amyloid angiopathy, the walls of blood vessels break down, and that can lead to 1 of 2 outcomes. One is, if they break down enough to allow rupture of the vessel wall, then hemorrhagic strokes occur, which are the deadliest form of stroke.

The other more subtle, but also clinically important, way that amyloid angiopathy damages the brain is through loss of normal vessel function. Loss of normal reactivity to stimulation occurs, and the ability of the blood vessels to deliver blood to areas that have higher demand in the brain is impaired in cerebral amyloid angiopathy. That probably leads to a death by a thousand cuts with one small area of damage after another—either microinfarction or microbleeding—that over time results in cognitive impairment.

It is not quite of the same magnitude as the kind of impairment from Alzheimer disease. It is a somewhat lesser contributor, but still quite a major contributor—part of this broader problem of vascular contributions to cognitive impairment and dementia that we know is a major part of the cognitive decline problem. It is a double whammy to normal blood vessel function in the brain.

NLN: Could you discuss the treatment landscape for this patient population, as well as any potential options on the horizon?

Dr Greenberg: Treatments for cerebral amyloid angiopathy are still on the horizon, and I strongly believe that clinical trials will move forward in this field of amyloidosis. My colleagues and I will try to walk on the road that has been so well laid out by the TTR field.

NLN: What key takeaways on these topics do you hope to leave with neurologists and neurology providers?

Dr Greenberg: From a cerebral amyloid angiopathy standpoint, the key takeaways for neurologists are that this is a disease that can be diagnosed with pretty high accuracy during life, which was not always the case in the past. It can be diagnosed by the presence of multiple strictly lobar hemorrhagic lesions, meaning large hemorrhages, microbleeds, convexity subarachnoid hemorrhage, or cortical superficial siderosis. When these are observed in strictly lobar, cortical, or subcortical locations, with high accuracy you can say that is cerebral amyloid angiopathy.

The steps you can take are related to limiting exposure to antithrombotic agents with careful consideration of the risk vs the benefit, treating blood pressure, and recommending lifestyle changes like discouraging heavy alcohol use because of evidence that that raises bleeding risk.

These are practical implications to making the diagnosis of cerebral amyloid angiopathy. There is also a form of an autoimmune response to amyloid angiopathy called cerebral amyloid angiopathy‑related inflammation, for which there are good treatments available.

The other message is that I hope that when we are having this conversation in the future, it will be about disease‑modifying treatments with a proven impact on this disease.

—Christina Vogt

Greenberg SM. Recent advances in amyloidosis: a disease you can't afford to miss. Cerebral amyloid angiopathy. Talk presented at: American Neurological Association 2020 Virtual Meeting; October 4-9, 2020.