Auriel E, Charidimou A, Gurol ME, Ni J, Van Etten ES, Martinez-Ramirez S, Boulouis G, Piazza F, DiFrancesco JC, Frosch MP, Pontes-Neto OV, Shoamanesh A, Reijmer Y, Vashkevich A, Ayres AM, Schwab KM, Viswanathan A, Greenberg SM. Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy-Related Inflammation. JAMA Neurol. 2016 Feb;73(2):197-202. PubMed.

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  1. We feel that this paper by Steve Greenberg and colleagues is a very important contribution for two main reasons.

    1. Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a severe complication of cerebral amyloid angiopathy; it is characterized by progressive cognitive decline, seizures, and headaches. Many patients with CAA-ri respond to steroids, so making the diagnosis is a very important step. On the positive side, once the diagnosis is made, the patients can be treated and many will recover. Giving steroids to patients without CAA-ri, however, may result in complications from the steroid therapy with no therapeutic benefit. What the present paper does is take a group of biopsy-proven CAA-ri patients and show that the clinical and MRI findings are different from the group of patients with CAA and no related inflammation. If the diagnosis can be made with a high degree of certainty on clinical and MRI criteria alone, as suggested by this paper, this would avoid an invasive cerebral biopsy which would, in itself, add to the discomfort of the patient and increase the risk of complications. The authors put forward a strong case for using clinical and MRI criteria for diagnosing CAA-ri.

    2. Another important contribution is the comparison of imaging in CAA-ri with the results of the bapineuzumab trials that show clinical and imaging abnormalities similar to CAA-ri. MRI suggests that in both cases there is an increase in brain tissue fluid and this supports the hypothesis that there is impairment of drainage of interstitial fluid from the brain along the walls of arteries in both conditions (Weller et al., 2015). In patients treated with bapineuzumab, it appears that amyloid removed from brain tissue by the immunotherapy passes into the perivascular drainage pathways in artery walls and blocks those pathways. This results in a failure of fluid drainage from the underlying white matter and the corresponding changes on MRI. In the CAA-ri cases, it appears that the inflammatory reaction associated with amyloid in the vessel walls also impairs fluid drainage from the white matter. Thus, in addition to establishing firm diagnostic criteria for CAA-ri, the present paper brings into focus the physiological effects on the brain of CAA and CAA-ri that help us understand the pathological effects of increasing amyloid in vessel walls and the effects of inflammation. It would be interesting to see the MRI following steroid therapy in the CAA-ri patients to observe the timing and completeness of resolution of white-matter fluid retention. This would give some indication of how restoration of fluid flow correlates with resolution of pathological lesions in CAA-ri.

    The mechanisms behind the development of CAA-ri are not known. That in CAA-ri there are lymphocytes in the arterial wall rather than simply perivascular macrophages or lymphocytic perivascular cuffs suggests that it is possible that immune complexes may form in the walls of arteries, blocking the perivascular drainage of interstitial fluid and Aβ (Carare et al., 2013; Teeling et al., 2012). The presence of auto-antibodies against Aβ in the CSF of this group of patients further strengthens the hypothesis that immune complexes may form in the brains of some CAA patients, impeding the perivascular clearance of solutes along basement membranes and worsening the clinical presentation (Piazza et al., 2013). This valuable clinical study should form a platform for experimental studies into the pathophysiology of perivascular lymphatic drainage of solutes and how it interacts with the innate and adaptive immune responses.

    References:

    Weller RO, Hawkes CA, Kalaria RN, Werring DJ, Carare RO. White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol. 2015 Jan;25(1):63-78. PubMed.

    Carare RO, Teeling JL, Hawkes CA, Püntener U, Weller RO, Nicoll JA, Perry VH. Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer's disease. Acta Neuropathol Commun. 2013 Aug 9;1(1):48. PubMed.

    Teeling JL, Carare RO, Glennie MJ, Perry VH. Intracerebral immune complex formation induces inflammation in the brain that depends on Fc receptor interaction. Acta Neuropathol. 2012 Oct;124(4):479-90. Epub 2012 May 18 PubMed.

    Piazza F, Greenberg SM, Savoiardo M, Gardinetti M, Chiapparini L, Raicher I, Nitrini R, Sakaguchi H, Brioschi M, Billo G, Colombo A, Lanzani F, Piscosquito G, Carriero MR, Giaccone G, Tagliavini F, Ferrarese C, Difrancesco JC. Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: Implications for Amyloid-Modifying Therapies. Ann Neurol. 2013 Feb 11; PubMed.

    View all comments by Roxana Carare

  2. This paper by Auriel et al. addresses an important clinical problem. CAA with an inflammatory component is an aggressive and devastating disease, possibly autoimmune-based, but can be ameliorated by treatment with immunosuppression. Therefore, differentiating patients with CAA and no neuroinflammation from those with the inflammatory component is critical. Although diagnosis can be made with a brain biopsy, this is an invasive procedure with significant risks for the patient.

    Auriel et al. developed criteria that permit the diagnosis of CAA-ri with a high degree of sensitivity and specificity without a brain biopsy. Although further validation is needed in a larger group of patients, the study is an important first step in enabling physicians to swiftly identify CAA-ri and initiate treatment.

    Inasmuch as CAA-ri resembles the ARIA syndrome observed in patients undergoing immunotherapy for AD, the findings may be relevant also to AD patients who, due to this complication, cannot fully benefit from immunotherapy. It’s a bit of a stretch, but if CAA-ri is at the basis of ARIA, immunosuppression may be beneficial, allowing the affected patients to continue immunotherapy. On the flip side, ARIA is not as serious as CAA-ri, so treatment may not be warranted. Nevertheless, having the opportunity to prevent or treat ARIA would expand the number of patients who could benefit from immunotherapy.

    View all comments by Costantino Iadecola

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