Dr Atri comments on observation of amyloid related imaging abnormalities (ARIA) seen with many Alzheimer’s disease treatments and shares his thoughts on management of ARIA.
Marwan Sabbagh, MD: As a follow up, we’re starting to see this phenomenon now as ARIA [amyloid-related imaging abnormalities]. Can you comment a bit more about amyloid-related imaging abnormalities as a safety signal?
Alireza Atri, MD, PhD: This is not something that’s unknown. This was first known with bapineuzumab, which was one of the monoclonals, as Dr Cohen mentioned. One of the things that’s really helped us is choosing the right population and the correct dose at the correct stage. We’ve gone higher doses. We’ve confirmed that they have amyloid pathology. We’ve gone to clinically earlier stages where potentially you can change the trajectory more. But in the past, the difference with the other drugs was that they didn’t remove amyloid, or sufficiently. We don’t understand amyloid-related imaging abnormalities very well. We break it down to an E and an H. The E can be edema or effusions that could be in the parenchyma or the sulci. And the H could be a bit of microhemorrhages. And they have to do with some kind of vascular dysfunction. And the risks are associated with having APOE4 [apolipoprotein E] if you’re homozygous it’s more than if it’s heterozygous with baseline presence of cerebral amyloid angiopathy. Individuals who have leaked already have little, almost like little bruises that you can see on the brain because of theMRI are more at risk. People [who] have more white matter disease are more at risk.This requires, in these studies, a careful examination of the MRI with inclusion criteria and exclusion criteria. For most of these trials, individuals who had 5 or more microhemorrhages were not included. This has been an important thing for the field because the field has been cautious about it and it's probably caused a lot of complications because of that safety. But what we’ve learned is oftentimes if you have MRI monitoring and you have a protocol, you can manage this quite well over time. And they’re early and usually asymptomatic.
Marwan Sabbagh, MD: And most of them are asymptomatic.
Alireza Atri, MD, PhD: Yes. Most of them are asymptomatic. Most of them are not severe or serious. However, it doesn’t mean that it can’t become.
Marwan Sabbagh, MD: But they can’t. Right.
Alireza Atri, MD, PhD: They can’t become that. And that’s important to know. We look back and think about, for example, clot busters, where we were with tPA [tissue plasminogen activator] and everything else back in the 90s. And how we learned. It took a while to learn to manage that. We’re learning very well how to do that in the context of the clinical trial. Eventually when these drugs are more available, that’s something that requires proficiency, coordination, and monitoring. It’s probably something that happens earlier than later but it can be recurrent. That’s the one caveat is the safety part, which I would say will require our colleagues to be vigilant and work and communicate closely. And that’s part of a patient-centered discussion also when you’re thinking about risk and benefits to disclose to patients.
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