Dataset Information

Association Between Immunosuppressive Treatment and Outcomes of Cerebral Amyloid Angiopathy-Related Inflammation.

ABSTRACT:

Importance

Cerebral amyloid angiopathy-related inflammation (CAA-ri), a distinct subtype of cerebral amyloid angiopathy, is characterized by an autoimmune reaction to cerebrovascular β-amyloid deposits. Outcomes and response to immunosuppressive therapy for CAA-ri are poorly understood.

Objective

To identify clinical, neuroimaging, laboratory, pathologic, or treatment-related associations with outcomes after an episode of CAA-ri.

Design, setting, and participants

A retrospective cohort study of prospectively identified individuals who presented from July 3, 1998, to November 27, 2017, with a median follow-up of 2.7 years (interquartile range, 1.0-5.5 years). The study included 48 consecutive patients with CAA-ri meeting diagnostic criteria who had at least 1 disease episode and subsequent outcome data. No patients refused or were excluded.

Exposures

Prespecified candidate variables were immunosuppressive therapies, cerebrospinal fluid pleocytosis, magnetic resonance imaging findings of recent infarcts or contrast enhancement, and histopathologic evidence of vessel wall inflammation.

Main outcomes and measures

Clinical improvement and worsening were defined by persistent changes in signs or symptoms, radiographic improvement by decreased subcortical foci of T2 hyperintensity or T1 enhancement, and radiographic worsening by increased subcortical T2 hyperintensity, T1 enhancement, or infarcts. Disease recurrence was defined as new-onset clinical symptoms associated with new imaging findings.

Results

The 48 individuals in the study included 29 women and had a mean (SD) age of 68.9 (9.9) years. Results of presenting magnetic resonance imaging revealed that 10 of 29 patients with CAA-ri (34%) had T1 contrast enhancement, 30 of 32 (94%) had subcortical T2 hyperintensity (22 of 30 [73%] asymmetric), 7 of 32 (22%) had acute or subacute punctate infarcts, and 27 of 31 (87%) had microbleeds. Immunosuppressive treatments after first episodes included corticosteroids (33 [69%]), cyclophosphamide (6 [13%]), and mycophenolate (2 [4%]); 14 patients (29%) received no treatment. Clinical improvement and radiographic improvement were each more likely in individuals treated with an immunosuppressive agent than with no treatment (clinical improvement: 32 of 34 [94%] vs 7 of 14 [50%]; odds ratio, 16.0; 95% CI, 2.72-94.1; radiographic improvement: 24 of 28 [86%] vs 4 of 14 [29%]; odds ratio, 15.0; 95% CI, 3.12-72.1). Recurrence was less likely if CAA-ri was treated with any immunosuppressant agent than not (9 of 34 [26%] vs 10 of 14 [71%]; hazard ratio, 0.19; 95% CI, 0.07-0.48). When controlling for treatment, no variables were associated with outcomes aside from an association between APOE ɛ4 and radiographic improvement (odds ratio, 4.49; 95% CI, 1.11-18.2).

Conclusions and relevance

These results from a relatively large series of patients with CAA-ri support the effectiveness of immunosuppressive treatment and suggest that early treatment may both improve the initial disease course and reduce the likelihood of recurrence. These results raise the possibility that early blunting of CAA-ri and the autoimmune response may have long-term benefits for the subsequent disease course.

SUBMITTER: Regenhardt RW

PROVIDER: S-EPMC7309570 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-β deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy-related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-β at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood-brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy-related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-β, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood-brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood-brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-β deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-β (Grade 0), and blood-brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2-4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood-brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood-brain barrier leakage as a potential trigger for subsequent perivascular inflammation.