Solopova E, Romero-Fernandez W, Harmsen H, Ventura-Antunes L, Wang E, Shostak A, Maldonado J, Donahue MJ, Schultz D, Coyne TM, Charidimou A, Schrag M. Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer's disease. Nat Commun. 2023 Dec 12;14(1):8220. PubMed.
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Massachusetts General Hospital
The data presented in this case report continue to support the hypothesis that the mechanism underlying ARIA closely relates to CAA and likely shares many mechanistic links with CAA-related inflammation (CAA-ri). These findings emphasize the importance of accurately diagnosing concomitant CAA when considering administration of anti-amyloid immunotherapies.
Given the high resolution of postmortem MR imaging, it is not surprising that more microhemorrhages were observed post-mortem than in the in-vivo scans—this has previously been reported in patients with CAA (van Veluw et al., 2016). However, this difference does bring up an important issue regarding assessing for CAA prior to initiating anti-amyloid immunotherapies. While it is known that ~50 percent of patients with AD will have evidence of moderate to severe CAA at autopsy (Jäkel et al., 2021), it is notable that this patient met the MRI-based Boston Criteria (both the modified Boston Criteria and the recently published Boston Criteria 2.0, see Charidimou et al., 2022) for probable CAA prior to the initiation of treatment.
The recent clinical trials of passive immunization have kept exclusion criteria based on microbleeds relatively simple, excluding patients with > 4 microbleeds (on GRE sequences). However, enhancing this imaging and taking advantage of well-established MR-based imaging criteria for CAA may be a potential way to refine our understanding of ARIA risk and help patients/physicians make more informed decisions regarding their individualized risks/benefits of anti-amyloid immunotherapies.
For example, as suggested by the authors, susceptibility-weighted imaging sequences (more sensitive for microbleeds) could be used, and the location of microbleeds taken into consideration (as deep/non-lobar microbleeds are not associated with CAA). Hemorrhagic manifestations of CAA are considered very advanced stages of vessel pathology, occurring many years after initial vascular Aβ deposition (Koemans et al., 2023). Therefore, patients with evidence of lobar microbleeds are likely to have many other vessels with vascular amyloid and advanced pathology, a meaningful risk factor for ARIA.
Of note, earlier reports of patients who received active immunization with AN1792 also suggest relocation of parenchymal amyloid to the vasculature with anti-amyloid immunotherapy (Boche et al., 2008), likely an important exacerbating factor which could preferentially impact patients with pre-existing CAA given the hypothesized issues with perivascular amyloid clearance associated with this disease.
In addition to probable CAA, this patient notably had other known risk factors for ARIA, including two APOE4 alleles and recent initiation of anti-amyloid immunotherapy (similar to the case reported by Reish et al.). Given this emerging data, if the decision is made to use these therapies in these higher-risk groups, additional caution is warranted with a lower threshold for repeat MRIs in the setting of clinical symptoms (e.g. severe headache, seizure, focal neurological symptoms).
In terms of the inflammatory profile, the authors observed perivascular and transmural T-cell infiltration and identified macrophages/microglia associated with vascular amyloid. Similar findings have been observed in prior ARIA case reports including from Reish et al. (2023) and in older studies of active immunization with AN1792 (Nicoll et al., 2003). Additionally, similar neuropathological findings are observed in CAA-ri. A recent PET study also demonstrated microglial activation in the setting of CAA-ri (Piazza et al., 2022).
Notably, in a recent preclinical study using mouse models of AD, 3D6 (murine version of bapineuzumab) administration led to the formation of antibody immune complexes with vascular Aβ, which in turn led to perivascular macrophage activation (Taylor et al., 2023). While this case report does not differentiate between macrophage infiltration from the periphery vs. resident perivascular macrophages of the brain (or between macrophages and microglia), these findings again suggest the importance of perivascular macrophages in the vascular inflammation associated with ARIA.
Finally, the vascular inflammation observed in this case (and the case reported by Reish et al.) was severe, with transmural inflammation and multinucleated giant cells. While limited data exists, in cases of Aβ-related angiitis (ABRA), distinguished from CAA-ri by the presence of transmural inflammation, more aggressive immunosuppression is often considered (e.g., adding cyclophosphamide to IV steroids, echoing treatments used for primary angiitis of the CNS). More aggressive immunosuppression may be a consideration in treatment for severe ARIA in the future.
References:
van Veluw SJ, Charidimou A, van der Kouwe AJ, Lauer A, Reijmer YD, Costantino I, Gurol ME, Biessels GJ, Frosch MP, Viswanathan A, Greenberg SM. Microbleed and microinfarct detection in amyloid angiopathy: a high-resolution MRI-histopathology study. Brain. 2016 Dec;139(Pt 12):3151-3162. Epub 2016 Sep 19 PubMed.
Jäkel L, De Kort AM, Klijn CJ, Schreuder FH, Verbeek MM. Prevalence of cerebral amyloid angiopathy: A systematic review and meta-analysis. Alzheimers Dement. 2021 May 31; PubMed.
Charidimou A, Boulouis G, Frosch MP, Baron JC, Pasi M, Albucher JF, Banerjee G, Barbato C, Bonneville F, Brandner S, Calviere L, Caparros F, Casolla B, Cordonnier C, Delisle MB, Deramecourt V, Dichgans M, Gokcal E, Herms J, Hernandez-Guillamon M, Jäger HR, Jaunmuktane Z, Linn J, Martinez-Ramirez S, Martínez-Sáez E, Mawrin C, Montaner J, Moulin S, Olivot JM, Piazza F, Puy L, Raposo N, Rodrigues MA, Roeber S, Romero JR, Samarasekera N, Schneider JA, Schreiber S, Schreiber F, Schwall C, Smith C, Szalardy L, Varlet P, Viguier A, Wardlaw JM, Warren A, Wollenweber FA, Zedde M, van Buchem MA, Gurol ME, Viswanathan A, Al-Shahi Salman R, Smith EE, Werring DJ, Greenberg SM. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study. Lancet Neurol. 2022 Aug;21(8):714-725. PubMed.
Koemans EA, Chhatwal JP, van Veluw SJ, van Etten ES, van Osch MJ, van Walderveen MA, Sohrabi HR, Kozberg MG, Shirzadi Z, Terwindt GM, van Buchem MA, Smith EE, Werring DJ, Martins RN, Wermer MJ, Greenberg SM. Progression of cerebral amyloid angiopathy: a pathophysiological framework. Lancet Neurol. 2023 Jul;22(7):632-642. Epub 2023 May 23 PubMed.
Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C, Nicoll JA. Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. Brain. 2008 Dec;131(Pt 12):3299-310. PubMed.
Reish NJ, Jamshidi P, Stamm B, Flanagan ME, Sugg E, Tang M, Donohue KL, McCord M, Krumpelman C, Mesulam MM, Castellani R, Chou SH. Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with t-PA for Stroke. N Engl J Med. 2023 Jan 4; PubMed.
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.
Piazza F, Caminiti SP, Zedde M, Presotto L, DiFrancesco JC, Pascarella R, Giossi A, Sessa M, Poli L, Basso G, Perani D. Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies. Neurology. 2022 Sep 20;99(12):e1265-e1277. Epub 2022 Aug 8 PubMed.
Taylor X, Clark IM, Fitzgerald GJ, Oluoch H, Hole JT, DeMattos RB, Wang Y, Pan F. Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer's disease mice. Mol Neurodegener. 2023 Aug 30;18(1):59. PubMed.
View all comments by Mariel KozbergUniversity of Southampton School of Medicine
This study highlights the urgent need for a better understanding of the mechanism for the development of ARIA. Postmortem analysis showed severe cerebral amyloid angiopathy accompanied by perivascular inflammatory infiltrates. The findings offer support for the hypothesis that following immunotherapy against Aβ, the solubilized Aβ from plaques becomes entrapped in the pathways for intramural periarterial drainage (IPAD).
Apart from the urgent need to clarify the mechanisms of ARIA, there is an unmet need for determining the patient population with IPAD pathways that are not compromised and able to clear the solubilized Aβ from plaques with no risk of developing CAA or ARIA.
View all comments by Roxana CarareUniversity of Milano-Bicocca
This case further confirms the abundant evidence we published in the last years suggesting radiographic ARIA-E in immunotherapy trials is the downstream and, in some ways “late-stage,” manifestation of iatrogenic CAA-related inflammation (CAA-ri).
In the CAA-ri framework, we previously described a regional and temporal association between subacute radiographic ARIA-E and microglial activation, by in vivo PET. This association was specifically observed only within ARIA-E, while no or negligible microglial activation was observed within age-related white matter changes (ARWMC).
The neuropathological evidence reported here, of intense immunoreactivity for the microglial marker IBA1, is remarkably similar to our in vivo PET findings.
Moreover, as we formerly reported in CAA-ri, these peaks of increased microglial reactivity co-localized with ARIA-E were specifically observed only in patients with AD + CAA comorbid disease, while no co-localization between microglial and ARIA-E was observed in patients with CAA only, i.e., without AD co-pathology by means of positive ATN biomarkers.
Most intriguingly, all CAA-ri had raised CSF levels of anti-Aβ (auto)antibodies at (sub)acute presentation of ARIA-E, irrespective of ARIA-E clinical or radiological severity or their CAA severity or comorbidity with AD. The antibody concentration markedly reduced post-corticosteroid therapy, in parallel with the clinic-radiological resolution of ARIA-E, and markedly reduced microglial activation.
I am pleased to see that all of these findings can be in some way replicated here, in this case. This further reinforces our evidence that ARIA-E is the imaging manifestation of the complex (auto)immune biological mechanisms of CAA-ri.
In this framework, we do not need a new term to define the presentation of these ARIA-E side events, whether they are symptomatic or not, as they should be already called iatrogenic CAA-ri. Instead, the terms ARIA-E and ARIA-H should be used only to report the presence of these types of imaging abnormalities on MRI, avoiding any potential association with the presentation of clinical symptoms and/or clinical severity.
The term ARIA, in fact, was not intended for that. Indeed, it is quite clear that the MRI imaging severity of ARIA-E has no associations with its clinical severity at presentation or its prognosis after an ARIA-E index event has occurred.
In anticipation of a large use of monoclonal antibodies for AD immunotherapy in real-world clinical practice, precision medicine approaches will be key. The discovery and validation of additional fluid-based biomarkers of ARIA and CAA-ri to complement and overcome current limitations of MRI should represent an international priority.
References:
Piazza F, Caminiti SP, Zedde M, Presotto L, DiFrancesco JC, Pascarella R, Giossi A, Sessa M, Poli L, Basso G, Perani D. Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies. Neurology. 2022 Sep 20;99(12):e1265-e1277. Epub 2022 Aug 8 PubMed.
Kelly L, Brown C, Michalik D, Hawkes CA, Aldea R, Agarwal N, Salib R, Alzetani A, Ethell DW, Counts SE, de Leon M, Fossati S, Koronyo-Hamaoui M, Piazza F, Rich SA, Wolters FJ, Snyder H, Ismail O, Elahi F, Proulx ST, Verma A, Wunderlich H, Haack M, Dodart JC, Mazer N, Carare RO. Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's dise. Alzheimers Dement. 2024 Feb;20(2):1421-1435. Epub 2023 Oct 28 PubMed.
Zedde M, Pascarella R, Piazza F. CAA-ri and ARIA: Two Faces of the Same Coin?. AJNR Am J Neuroradiol. 2023 Feb;44(2):E13-E14. Epub 2023 Jan 12 PubMed.
Antolini L, DiFrancesco JC, Zedde M, Basso G, Arighi A, Shima A, Cagnin A, Caulo M, Carare RO, Charidimou A, Cirillo M, Di Lazzaro V, Ferrarese C, Giossi A, Inzitari D, Marcon M, Marconi R, Ihara M, Nitrini R, Orlandi B, Padovani A, Pascarella R, Perini F, Perini G, Sessa M, Scarpini E, Tagliavini F, Valenti R, Vázquez-Costa JF, Villarejo-Galende A, Hagiwara Y, Ziliotto N, Piazza F. Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy-Related Inflammation: A Multicenter Prospective Longitudinal Cohort Study. Neurology. 2021 Nov 2;97(18):e1809-e1822. Epub 2021 Sep 16 PubMed.
View all comments by Fabrizio PiazzaSt. Michael's Neurology and Pain Medicine
As we continue to struggle with the challenges of treating CAA-RI, the potential role of immunosuppressive therapy emerges as a critical area of focus.
For high-risk groups undergoing treatment with Leqembi, particularly those identified as probable cases of CAA-RI (Auriel et al., 2016), the implementation of early immunosuppressive therapy would be an important consideration. This approach warrants exploration through randomized clinical trials. In a retrospective study examining a cohort of patients with CAA-RI, data indicates that initiating immunosuppressive therapy early not only enhances the initial response to the disease but also appears to decrease the probability of its recurrence (Regenhardt et al., 2020).
The prevailing evidence suggests that an autoimmune response to Aβ drives CAA-RI. This hypothesis is substantiated by clinical and imaging similarities observed in ARIA, initially detected during bapineuzumab's clinical trials. ARIA manifests in two forms: ARIA-E, marked by either focal or widespread vasogenic edema visible on fluid-attenuated inversion recovery (FLAIR) imaging, and ARIA-H, characterized by cerebral microbleeds or cortical superficial siderosis, detectable in T2-weighted gradient-echo/susceptibility-weighted imaging (SWI) scans. These radiological signs are also common indicators of CAA-RI. Interestingly, almost half of the patients with ARIA-E also develop ARIA-H, and these conditions frequently co-occur in the same locations.
In several autoimmune types of vasculopathy, IL-6 plays a pathological role in the inflammatory response in both the vessel wall and the systemic circulation. Would Tocilizumab be a good agent to try? This is a humanized monoclonal antibody that competitively inhibits IL-6 by binding it to circulating and membrane-bound IL-6 receptors. The first reported randomized controlled trial on the efficacy of tocilizumab in giant cell arteritis, in addition to glucocorticoids, found it efficacious with a higher relapse-free survival (Villiger et al., 2016). I wonder if this observation could be mirrored in patients with complications of CAA-RI, although the exact inflammatory cascade behind CAA-RI remains unclear. Another report suggested administration of steroids with cyclophosphamide or azathioprine (Grasso et al., 2021).
Patients exhibiting rapid cognitive deterioration, headaches, seizures, or specific neurological deficits, alongside patchy or widespread hyperintensity in T2 or FLAIR sequences or showing clear signs of lobar microbleeds or cortical superficial siderosis in susceptibility-weighted imaging, likely indicate CAA-RI. In my view, these patients are prime candidates for prompt immunosuppressive treatment. Furthermore, individuals displaying elevated inflammatory markers or increased erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) levels are also at heightened risk for CAA-RI. They tend to be more susceptible to complications and might potentially benefit significantly from immunosuppressive therapies. In the absence of high-quality randomized trials, I am interested in the readership's opinions on the most effective management strategies for these patients.
References:
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.
Regenhardt RW, Thon JM, Das AS, Thon OR, Charidimou A, Viswanathan A, Gurol ME, Chwalisz BK, Frosch MP, Cho TA, Greenberg SM. Association Between Immunosuppressive Treatment and Outcomes of Cerebral Amyloid Angiopathy-Related Inflammation. JAMA Neurol. 2020 Jun 22; PubMed.
Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, Bütikofer L, Seitz M, Reichenbach S. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2016 May 7;387(10031):1921-7. Epub 2016 Mar 4 PubMed.
Grasso D, Castorani G, Borreggine C, Simeone A, De Blasi R. Cerebral amyloid angiopathy related inflammation: A little known but not to be underestimated disease. Radiol Case Rep. 2021 Sep;16(9):2514-2521. Epub 2021 Jul 3 PubMed.
View all comments by Mike Miguel PappollaTrueBinding
Immunization with fAβ42 (AN1792) results in a nearly complete absence of Aβ plaque deposits, both in mice that were vaccinated prior to the onset of amyloid deposition and in animals that were vaccinated after amyloid deposition was well underway. However, human clinical trials were halted due to a high incidence of meningioencephalitis that is presumably due to an auto inflammatory reaction to immunization with human Aβ. Overcoming the auto inflammatory side effects while maintaining an effective immune response is a hurdle that must be overcome for the development of a human vaccine for AD.
This study clearly shows the auto inflammatory side effects of lecanemab. Since the conformation dependent immune response to Aβ oligomer and Aβ fibril antigens are distinct while the immune response to the oligomer mimic antigens is common, this suggests that the increased incidence of micro hemorrhage may be due to sequence-specific antibodies that are common to the Aß containing antigens.
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