It used to be that clinicians could only diagnose inflammation related to cerebral amyloid angiopathy by sticking a needle in the brain and taking a biopsy. Seem unpleasant? Clinicians don’t like it much either. Now, scientists led by Steven Greenberg at Massachusetts General Hospital, Boston, have devised non-invasive diagnostic criteria for this relatively rare condition. They are based on clinical symptoms and magnetic resonance imaging (MRI). In patients who had pathologically confirmed CAA-related inflammation (CAA-ri), the criteria identified the disorder with high specificity and sensitivity, the scientists report in the December 28 JAMA Neurology online. Since this condition responds well to immunosuppressive therapy, these guidelines will allow doctors to more easily treat affected patients.
“These criteria diagnosed people with CAA-ri without false positives, which is what we really wanted to avoid,” said Greenberg. “We don’t want to treat unaffected individuals if we can help it.”
“Differentiating patients with CAA from those with the inflammatory component is critical,” wrote Costantino Iadecola of Weill Cornell Medical College, New York, who was not involved in the study (see full comment below). Iadecola said he believes further validation is needed in a larger group of patients, but added, “the study is an important first step enabling physicians to swiftly identify CAA-ri and initiate treatment.”
CAA-ri is closely related to ARIA-E, the inflammation sometimes seen in AD patients treated with antibodies to Aβ (Werring and Sperling, 2013; Jul 2011 conference news). In CAA, Aβ builds up on the walls of arteries in the brain. Some patients show no symptoms, but others suffer intracranial bleeds or dementia. In addition, a small fraction of patients get CAA-ri, which can cause swelling, headaches, seizures, and stroke. Most of these symptoms resolve with immunosuppressive drugs such as high-dose corticosteroids. These drugs can cause psychosis and hyperglycemia, so doctors prescribe them judiciously. For the patients most likely to benefit, clinicians currently resort to brain biopsies, which are unpopular with patients. Can they get diagnosed another way?
Previously proposed diagnostic criteria based on clinical and radiological characteristics specified that patients would have a headache that persisted for days to weeks, seizures, and/or focal neurological deficits, and be less alert or exhibit behavioral changes. MRI should show evidence of patchy swelling, multiple microbleeds, and intracranial hemorrhage. All this must occur in the absence of cancer, infection, or other known causes (Chung et al., 2011).
Greenberg and colleagues refined these criteria. They propose that the headaches and behavioral problems could occur over months to years, and specify that swelling should be asymmetrical and extend outward toward the surface of the brain (Linn et al., 2010). They also include cortical superficial siderosis among the types of bleeding. In their experience, this type of iron deposition underneath the pia mater occurs more frequently in people with CAA-ri.
In the current study, first author Eitan Auriel tested these criteria in patients who died with CAA and were autopsied. Combing through the medical records of Massachusetts General Hospital and the University of Milano-Bicocca, Monza, Italy, the researchers came up with 17 patients with autopsy-confirmed CAA-ri and 37 with non-inflammatory CAA over18 years. Fourteen of the 17 CAA-ri patients met the proposed criteria for probable disease, while only one person with non-inflammatory CAA did. That patient may actually have had CAA-ri, wrote the authors, as his records showed he had recovered on a short course of heavy-duty immunosuppressive drugs. Overall, the criteria had a specificity of 97 percent and sensitivity of 82 percent for detecting CAA-ri.
“The authors put forward a strong case for using clinical and MRI criteria for diagnosing CAA-ri,” said Roy Weller, University of Southampton, U.K. (see full comment below). “If the diagnosis can be made with a high degree of certainty, this would avoid an invasive cerebral biopsy, which would in itself add to the discomfort of the patient and increase the risk of complications.” Greenberg noted that MRIs are less than clear-cut for some patients, who will still require a biopsy. Even as Greenberg continues to collect data on the effectiveness of these guidelines and encourages other groups to help validate them, he claims the current data is sufficient to put the criteria into clinical practice now. He did acknowledge that this retrospective study of a small group of autopsy patients likely reflects the most severe cases, and agreed that it remains to be seen how well these criteria will generalize to all CAA-ri patients.
These new criteria may help physicians managing ARIA-E in AD immunotherapy trials, once any such therapy is approved. “If AD immunotherapy is effective, then understanding how to predict, detect, and treat ARIA will be a major focus of putting that therapy into practice,” Greenberg told Alzforum. Iadecola agreed. “If CAA-ri is the basis of ARIA, immunosuppression may allow affected patients to continue immunotherapy.” He noted that ARIA is less serious than CAA-ri, so not all cases of ARIA may require treatment. “Nevertheless, having the opportunity to prevent or treat ARIA would expand the number of patients who could benefit from immunotherapy,” he said.—Gwyneth Dickey Zakaib
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