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ARIA-Like Presentations in Cerebral Amyloid Angiopathy Inflammation Offer Aß Pathology Insights

Investigators observed a high prevalence of cerebral microbleeds, cortical superficial siderosis, and history of intracerebral hemorrhage, all well-established surrogate markers of cerebral amyloid angiopathy severity.

Findings from the largest longitudinal cohort registry of patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) highlighted the acute, transient, although potentially relapsing inflammatory nature of the disease. Investigators concluded that prompt management of the amyloid-related imaging abnormality (ARIA)-like inflammatory process has an impact on clinical outcomes, and that slow oral tapering-off method after intravenous (IV) corticosteroid pulse therapy helped prevent recurring relapses.

Senior author Fabrizio Piazza, MD, assistant professor, University of Milano, and colleagues evaluated the natural history and outcomes following treatment for spontaneous ARIAs among 113 inpatients meeting CAA-ri diagnostic criteria during January 2013 through March 2017. A predefined individual case-report form (CRF) that detailed demographic, genetic, pathologic, clinical and medication history, clinical features, MRI imagines, exposure to immunosuppressive therapy, and clinical and radiological outcomes at follow-up were systematically provided at time of each visit.

The baseline CRF was supplied at first-ever disease presentation. Follow-up CRF and MRI images were collected at each predefined visit at 3, 6, 12, and 24 months, and then annually. Twelve patients had a definite diagnosis of CAA-ri (10.6%), 81 probable (71.7%), and 20 possible (17.7%). In total, 36.3% had previous history of mild cognitive impairment or Alzheimer disease (AD), 33.6% had evidence of past intracerebral hemorrhage (ICH), and 37.1% were APOEe4 carriers.

At 3 months, most patients showed clinical recovery (70.3% [95% CI, 61.6-78.5]). The proportion of these patients increased to 80.2% (95% CI, 72.2-87.1) and 84.1% (95% CI, 76.2-90.6) from 3 to 6 months and from 6 to 12 months, respectively. Although slightly slower, the observed rate of radiological recovery was observed in 45.1% of participants at 3 months and 59.3% at 6 months follow-up. Clinical recovery (P = .49) and radiological recovery (P = .08) were not associated with specific diagnostic categories.

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After the first episode, 77% (n = 87) of patients received high dose corticosteroids as 5 IV boluses of 1-g/day methylprednisone, whereas 83.9% received 1-mg/kg oral prednisone daily with a slow tapering-off over several months. Despite not showing statistically significant effects on clinical recover after first-ever episode of CAA-ri (HR, 0.74 [95% CI, 0.39-1.42]; P = .37), recurrence was more likely if intravenous corticosteroid pulse therapy was suddenly stopped (HR, 4.68 [95% CI, 1.57-13.93]; P = .006).

"Our findings suggest that the spontaneous ARIA-like presentations occurring in CAA-ri could be part of the widely recognized inflammatory spectrum in Aß-drive pathologies of aging," the study authors wrote. "This opens the possibility that CAA-ri is not a rare manifestation restricted to a subset of CAA patients as originally thought. Furthermore, our results point to the importance of differential diagnosis for CAA-ri in the general AD population, in particular in patients exposed to immunotherapy, where it may be challenging to separate the natural incidence of spontaneous ARIA-like presentations from drug-related ARIA."

A total of 13 patients experienced new ICH, 8 of which (7.1% [95% CI, 3.6-13.8]) were within the first 3 months. A history of ICH prior to CAA-ri, as well as the occurrence of new ICH at follow-up, was more common in patients with cortical superficial siderosis than those without (cSS; 52.6% vs 14.3% [P <.0001]; and 19.3% vs 3.6% [P <.009], respectively).

Probability of relapse was 6.9% (95% CI, 2.9-15.8) within 3 months, 16.2% (95% CI, 9.3-27.6) within 12 months, and 38.3% (95% CI, 22.9-59.2) within 2 years from the ascertained recovery of the first-ever presentation. Each of these patients experienced more than 10 cerebral microbleeds at baseline. Among those who had clinical and radiological recovery (n = 90), 15 (16.7%) of patients had at least 1 CAA-ri relapse at 3-month follow-up from diagnosis.

"Given the precautions and warnings of potential ARIA side effects associated with such drugs, an increased understanding of the ARIA phenomena as well as increased knowledge about how to recognize, treat, manage, and separate the incidence of spontaneous ARIA-like events from drug-related ARIA will be critically important both for treating clinicians and the patient’s community,” Piazza et al wrote. “In order to optimize benefits and reduce potential risks to patients, reliable, timely accessible, and less costly biomarkers for the prediction, early diagnosis, response to therapy, and longitudinal monitoring of ARIA are urgently needed."

Antolini L, DiFrancesco JC, Zedde M, et al. Spontaneous ARIA-like events in cerebral amyloid angiopathy-related inflammation: a multicenter prospective longitudinal cohort study. Neurology. Published online September 16, 2021. doi:10.1212/WNL.00000000000012778