{"id":14735,"date":"2026-06-12T06:00:00","date_gmt":"2026-06-12T10:00:00","guid":{"rendered":"https:\/\/cov19longhaulfoundation.org\/?p=14735"},"modified":"2026-05-24T11:27:59","modified_gmt":"2026-05-24T15:27:59","slug":"severe-cerebral-amyloid-angiopathy-related-inflammation-caa-ri-associated-with-vaccination","status":"publish","type":"post","link":"https:\/\/cov19longhaulfoundation.org\/?p=14735","title":{"rendered":"Severe cerebral amyloid angiopathy related inflammation (CAA-ri) associated with vaccination"},"content":{"rendered":"\n

Michael Tang\u00a01<\/a><\/sup>,\u00a0Jane Kim\u00a02<\/a><\/sup>,\u00a0Kui Kai Lau\u00a03<\/a><\/sup>,\u00a0Koon Ho Chan\u00a03<\/a><\/sup>, PMID:\u00a039094435<\/strong>, DOI:\u00a010.1016\/j.jneuroim.2024.578406<\/a><\/p>\n\n\n\n

Abstract<\/h2>\n\n\n\n

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rapid but reversible autoimmune encephalopathy where spontaneous autoantibody reaction against amyloid beta deposited in cerebral blood vessels produces characteristic neuroinflammatory changes such as vasogenic edema and microhemorrhages on MRI. The term amyloid-related imaging abnormalities (ARIA) is sometimes used to describe these changes but are more often reserved for similar MRI signal abnormalities seen after administration of anti-amyloid immunotherapy, using treatment exposure as an antecedent. It is unclear if there is any biological basis for this dichotomized distinction. We report a case of severe CAA-ri after exposure to SARS-CoV-2 vaccine and performed a literature review of CAA-ri related to vaccination. CAA-ri precipitated by immunogenic triggers other than anti-amyloid therapy would lend support to the hypothesis that ARIA seen on MRI may represent the same disease underpinned by a shared anti-A\u03b2 autoantibody response irrespective of etiology. A thorough history should be taken before labelling CAA-ri as spontaneous.<\/p>\n\n\n\n

Introduction<\/h2>\n\n\n\n

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a spontaneous autoimmune reaction from which A\u03b2 autoantibodies target cerebrovascular deposits of amyloid beta, resulting in neurovascular inflammation and amyloid-related imaging abnormalities (ARIA) on MRI. It was initially thought to occur only in a subset of patients with CAA, but findings from the iCA\u03b2 International Network cohort showed CAA-ri is prevalent in those with coexisting Alzheimer’s Disease (AD), implicating it as part of a wider inflammatory spectrum in A\u03b2 pathologies related to aging (Antolini et al., 2021).<\/p>\n\n\n\n

Individuals treated with anti-amyloid immunotherapy may also develop ARIA. The clinical characteristics, neuroimaging features, and association with APO\u03b54 in these patients closely resemble those with CAA-ri. Significant overlap between the two raises the hypothesis that both are driven by the same pathophysiological processes (Antolini et al., 2021; Hampel et al., 2023; Piazza et al., 2022). The only difference is whether the A\u03b2 autoantibodies are naturally occurring or iatrogenically induced.<\/p>\n\n\n\n

We report a case of severe CAA-ri who developed symptoms 48 h after administration of an inactivated dose of SARS-CoV-2 vaccination, suggesting that vaccine may also be an immunogenic trigger capable of inducing CAA-ri and consequent ARIA. We also provide a literature review of CAA-ri associated with vaccines.<\/p>\n\n\n\n

A 67-year-old gentleman was observed by his relative to have progressive bradyphrenia, forgetfulness, and altered behavior over a span of 48 h after his 3rd dose of SARS-CoV-2 vaccination (Coronavac). He has an unremarkable past medical history. He was globally aphasic and failed to follow any instructions, but otherwise remained hemodynamically stable and afebrile. Initial plain CT Brain did not show any abnormality, but his CSF revealed lymphocytic pleocytosis (Table 1). An urgent MRI Brain showed only faint left temporal lobe signal abnormality, suspicious for early meningoencephalitis. He was started on empirical ceftriaxone and acyclovir.<\/p>\n\n\n\n

However, interval CSF assessment on day 7 and day 11 post-admission showed persistent pleocytosis and raised protein, while new signal abnormalities in the right medial temporal lobe, inferior temporal gyrus, and bilateral medial frontal lobe appeared on MRI (Fig. 1B). Extensive microbiological workup and autoimmune encephalitis panel were unrevealing at this juncture.<\/p>\n\n\n\n

Since the patient deteriorated without any signs of infection, a 5-day course of intravenous immunoglobulin (IVIG) was administered for presumed immunological etiology. The effects were remarkable, with CSF showing acellularity on day 18. Nevertheless, the efficacy of IVIG was ephemeral and CSF showed reemergence of leukocytosis on day 25. By day 36, MRI showed significant deterioration in the extent of FLAIR hyperintensities along with mild increase in microbleeds (Fig. 1C). He was placed on intravenous methylprednisolone (1000 mg) for 3 days concomitant with a second 5-day course of IVIG. After completion of intravenous steroids, he was started on oral prednisolone 60 mg with the addition of azathioprine 25 mg daily 12 days later.<\/p>\n\n\n\n

Despite a total of 22 days of high dose steroids and 9 days of azathioprine, MRI Brain on day 60 showed continued to show deterioration of FLAIR hyperintensities. Moreover, there was significant progression of microbleeds and superficial siderosis bilaterally (Fig. 1D). Therefore, his immunosuppression was further intensified to high dose intravenous cyclophosphamide (CTX) 900 mg monthly planned for 6 cycles, concurrent with gradual tapering of steroids at a rate of 5 mg every 2 weeks. He was bridged to mycophenolate mofetil (MMF) 250 mg BD for maintenance after completion of his CTX.<\/p>\n\n\n\n

Under this regime, his MRI Brain showed mild improvement of white matter abnormalities on day 180, but there were already neurological sequelae of chronic inflammation such as global cerebral atrophy (Fig. 1E). Moreover, his treatment was complicated by left hip chronic osteomyelitis which warranted complete cessation of immunosuppression and a 12-week course of antibiotics. Upon discharge, he was able to regain most of his cognitive function and scored 20\/30 on the Montreal Cognitive Assessment. He was able to perform most basic activities of daily living but could not restore complete independence mainly due to a functional limitation arising from his left hip osteomyelitis.<\/p>\n\n\n\n

After searching the PubMed database using the key terms \u201cCAA-related inflammation\u201d or \u201camyloid-beta related angiitis\u201d with either \u201cvaccine\u201d or \u201cvaccination\u201d, ours is the fourth reported case of CAA-ri associated with vaccination. The three previous case reports were all vaccines against SARS-CoV-2 (Kizawa and Iwasaki, 2022; Rossato et al., 2021; Yamakawa et al., 2022). All cases were reported within the last 3 years. Please refer Table 2 for a comparison of key characteristics across the cases.<\/p>\n\n\n\n

Our case is unique in that it was the first associated with the use of inactivated virus vaccine, and the first that did not respond to steroid monotherapy. Inactivated vaccines are less immunogenic, but the inflammatory response in our patient was paradoxically the most robust (Lim et al., 2021). Since the patient’s symptoms only developed after three doses of vaccination, we postulate that unlike mRNA vaccines, even small but cumulative antibody responses may adequately cross an immunogenic threshold to precipitate overt disease.<\/p>\n\n\n\n

One potential mechanism underpinning vaccine associated CAA-ri may be due to the overactivation of microglial response triggered by the vaccine spike protein because of molecular mimicry. The spike protein of SARS-CoV-2 has been shown to be a key driver of microglial NLRP3 inflammasome activation (Albornoz et al., 2023). Microglial activity is also implicated in both anti-amyloid therapy and CAA-ri, where in the latter microglia is localized to regions affected by ARIA, and are associated with higher levels of anti-A\u03b2 autoantibodies (Piazza et al., 2022).<\/p>\n\n\n\n

In our patient, amyloid PET was performed on day 397 which showed amyloid deposits in the posterior cingulate, bilateral prefrontal, and bilateral parietal regions commonly associated with Alzheimer’s disease. However, it was absent in regions that had strong CAA-ri activity (Fig. 1F). This finding supports two reported observations. First, severity of ARIA had been found to be more pronounced in patients with both CAA and Alzheimer’s disease (Piazza et al., 2022). Second, CAA-ri development adheres to the vascular wall disturbance (VWD) model in which anti-A\u03b2 attempts to remove A\u03b2 aggregates at a rate exceeding that of intrinsic vascular repair processes (Kelly et al., 2024). The end product is a disruption of vascular integrity and exaggerated activation of immune cells which leads to edema and inflammation respectively (Aldea et al., 2022). Therefore, it is expected that regions with the highest CAA-ri activity would show minimal residual PET activity after its resolution. This finding is consistent with previous case reports showing reduced PET activity in previously active areas (Carmona-Iragui et al., 2016; Yang et al., 2023).<\/p>\n\n\n\n

Although our patient fulfilled all 5 clinico-radiological criteria required to diagnose probable CAA-ri with 82% sensitivity and 97% specificity, we were unable to obtain consent for a brain biopsy to reach a definitive diagnosis (Auriel et al., 2016; Chung et al., 2011). Furthermore, the lack of biopsy precluded pathological subtyping of disease into CAA-ri and amyloid-beta related angiitis (ABRA) based on the absence or presence of transmural or intramural granulomatous inflammation and angiodestruction of the cortical and leptomeningeal vessels respectively. Our interpretation of disease severity was largely based on clinical signs and symptoms and MRI features. We would like to highlight that the terminology used to define the pathological subtypes is remarkably heterogeneous within the literature. CAA-ri is often used interchangeably with inflammatory cerebral amyloid angiopathy (iCAA), with either being the collective term for this group of disease(de Souza and Tasker, 2023; Wu et al., 2021). Iatrogenic CAA related to A\u03b2 seed transmission after neurosurgical intervention is also denoted as iCAA, further complicating the nomenclature (Banerjee et al., 2022). A standardized nomenclature is desperately needed for effective communication of individual disease entity.<\/p>\n\n\n\n

Our case was unconventional in that it was refractory to standard treatment, which usually entails high dose intravenous steroids followed by a tapering course of oral steroids. Nonsteroidal immunosuppressants such as cyclophosphamide are usually reserved for severe or recurrent cases and are given at 2\u20134 week intervals (Antolini et al., 2021; Regenhardt et al., 2020). We switched to combined cyclophosphamide and steroids early based on the recalcitrant inflammatory features on MRI but even 4 cycles of treatment only conferred mild radiological improvement (Fig. 1E).<\/em> At this point, the brain already showed significant cerebral atrophy with widening of sulci. We wonder whether early aggressive treatment to halt the inflammation could have prevented such volume loss.<\/p>\n\n\n\n

In conclusion, there is emerging evidence that vaccine is capable of eliciting neuroinflammatory responses resembling those seen in CAA-ri and treatment-related ARIA. Although we cannot establish a causal relationship, it is provocative against the traditional assumption that ARIA is either spontaneous and anti-amyloid therapy related. Our case report is hypothesis generating and more research is needed to understand its underlying biology.<\/p>\n","protected":false},"excerpt":{"rendered":"

Michael Tang\u00a01,\u00a0Jane Kim\u00a02,\u00a0Kui Kai Lau\u00a03,\u00a0Koon Ho Chan\u00a03, PMID:\u00a039094435, DOI:\u00a010.1016\/j.jneuroim.2024.578406 Abstract Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rapid but reversible autoimmune encephalopathy where spontaneous autoantibody reaction against amyloid beta deposited […]<\/p>\n","protected":false},"author":2,"featured_media":14979,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1395,58,840,252,253],"tags":[],"class_list":["post-14735","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-amyloid-angiopathy","category-brain","category-inflammasome","category-inflammation","category-inflammation-2"],"_links":{"self":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/14735","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=14735"}],"version-history":[{"count":5,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/14735\/revisions"}],"predecessor-version":[{"id":14977,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/14735\/revisions\/14977"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/media\/14979"}],"wp:attachment":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=14735"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=14735"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=14735"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}