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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-142376 IOS Press

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Giorgio B. Boncoraglioa,1,∗ , Fabrizio Piazzab,c,1 , Mario Savoiardod , Laura Farinad , Jacopo C. DiFrancescob,e , Sara Prionif , Fabrizio Tagliavinif , Eugenio A. Paratia and Giorgio Giacconef a Department

of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy c The inflammatory Cerebral Amyloid Angiopathy and Alzheimer’s disease βiomarkers International Network (iCAβ) Coordinator d Department of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy e Department of Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy f Department of Neurodegenerative Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy b Department

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Abstract. Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare form of vasculitis associated with amyloid-␤ (A␤) deposition in vessel walls, has been proposed as a spontaneous human model of the amyloid-related imaging abnormalities (ARIA) occurring after anti-A␤ immunotherapy for the treatment of Alzheimer’s disease (AD). We describe a case of a patient with biopsy-proven CAA-ri and prodromal AD, confirmed by means of neuropsychological examination after 20 months followup, presenting with ARIA and high levels of cerebrospinal fluid anti-A␤ autoantibodies. This case further supports the analogies between the inflammatory response driven by anti-A␤ immunotherapy and that spontaneously occurring in CAA-ri.

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Accepted 30 November 2014 17

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Prodromal Alzheimer’s Disease Presenting as Cerebral Amyloid Angiopathy-Related Inflammation with Spontaneous Amyloid-Related Imaging Abnormalities and High Cerebrospinal Fluid Anti-A␤ Autoantibodies

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Short Communication

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Keywords: Alzheimer’s disease, amyloid-related imaging abnormalities, anti-A␤ autoantibodies, cerebral amyloid angiopathy, cerebral amyloid angiopathy-related inflammation, subarachnoid hemorrhage

INTRODUCTION 1 These

authors contributed equally to this work. to: Dr. Giorgio Boncoraglio, Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, via Celoria 11 – 20133 Milano, Italy. Tel.: +39 022394; Fax: +39 0270638217; E-mail: [email protected]. ∗ Correspondence

It was found that more than 17% of the patients with Alzheimer’s disease (AD) treated with bapineuzumab, the first clinically-used monoclonal anti-amyloid ␤ (A␤) antibody, was associated with the magnetic resonance imaging (MRI) appearance of sulcal and

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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hyperplasia, arterial hypertension, paroxysmal supraventricular tachycardia, and a previous episode of retinal ischemia. Medications included tamsulosin, dutasteride, doxazosin, propafenone, and aspirin. He began experiencing worsening fatigue and headache. One month later he presented acute left arm weakness. Brain computed tomography (CT) revealed right parietal subarachnoid hemorrhage (SAH) and an electrocardiogram showed supraventricular tachycardia. He was diagnosed as having cardioembolic stroke and aspirin was replaced with enoxaparin. The headache and left arm weakness were temporarily relieved but subsequently worsened and a second brain CT scan showed increased parietal-SAH. Enoxaparin was discontinued. MRI revealed right parietal and frontal sulcal siderosis (Figs. 1A–C) and leptomeningeal enhancement, together with some cortical microhemorrhages, thus suggesting carcinomatous meningitis. Two months after symptoms onset, the patient was admitted to our Institute with mild memory impairment, apraxia, left visual extinction, and mild left paresis. Brain MRI was unchanged. Electroencephalography showed right parieto-temporal slow waves, and cerebral angiography showed minimal capillary blush in the right parietal area without any segmental vasoconstrictions or other abnormalities. The patient’s CSF was xanthochromic, with 346 mg of proteins/dL and 21 cells/ ␮L (14 lymphocytes, no atypical cells); these findings were unchanged when the lumbar puncture was repeated five days later. The findings of routine blood tests, an autoantibody panel, electrocardiogram and whole body PET-CT were unremarkable. The patient’s headache and cognitive status rapidly worsened, and MRI revealed more marked and extensive sulcal post-contrast enhancement. Three weeks after admission, an open right parietal meningeal and brain biopsy ruled out malignancies but revealed CAA in the leptomeningeal and cortical vessels, with lympho-monocytic infiltration confined to the walls and peri-vascular spaces of amyloid-laden leptomeningeal vessels (Figs. 1D–G). Vascular wall disruption with focal fibrinoid necrosis was observed in the most severely affected meningeal vessels. Giant or multinucleated cells were not present. Immunohistochemistry revealed also the presence of numerous senile plaques and neurofibrillary changes (tangles, neuropil threads, dystrophic neurites in plaques) in the cerebral cortex (Figs. 1G–I). These findings were consistent with CAA-ri associated with AD pathology. Accordingly, further CSF analyses revealed very

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parenchymal hyperintensities, initially characterized as vasogenic edema [1, 2]. In order to highlight the importance of these severe adverse events, the Alzheimer’s Association Research Roundtable Workgroup has recently coined the term amyloid-related imaging abnormalities (ARIA) to describe the vasogenic edema and/or sulcal effusion observed in fluid-attenuated inversion recovery (FLAIR) MRI sequences, and the signal of hemosiderin deposits due to microhemorrhages and superficial siderosis found in T2∗ -weighted gradient echo (T2∗ -GRE) or susceptibility-weighted imaging sequences [2]. Although the pathogenesis of ARIA remains unknown, their association with the APOE ␧4 genotype and anti-A␤ antibody dosage is well documented [1–3]. Similar MRI abnormalities have been subsequently reported in relation to many other anti-amyloid drugs tested in AD patients and during active immunization with full length A␤ [4–6]. Our group has shown that they can occur in the case of cerebral amyloid angiopathy-related inflammation (CAA-ri), consisting in a vasculitis of the A␤-laden vessels [7, 8], which suggests that anti-A␤ antibodies, inflammation and vasogenic edema may be related to a transient vascular leakage at the sites of major A␤ removal. CAA-ri may therefore represent a spontaneous human model of the ARIA occurring in AD-treated patients mediated by a specific autoimmune reaction to perivascular A␤ deposited in the context of an aged and compromised cerebrovascular milieu [9, 10]. Although CAA is a very common age-related disease that is almost always found in patients with AD [11, 12], ARIA seem to be extremely rare in untreated AD patients (only two of a cohort of 2,141 cases described in the literature presented asymptomatic MRI-revealed vasogenic edema and microhemorrhages) [13]. We describe a case of prodromal AD, whose symptoms onset was characterized by spontaneous ARIA-like events. The high level of cerebrospinal fluid (CSF) anti-A␤ autoantibodies and histopathological findings of CAA-ri, further support analogies between the inflammatory response driven by anti-A␤ immunotherapy and those spontaneously occurring in CAA-ri [14, 15].

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G.B. Boncoraglio et al. / Spontaneous ARIA in Prodromal AD

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CASE REPORT A 78-year-old right-handed retired physician reported negative family history of neurological diseases, a regular and active lifestyle, benign prostatic

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G.B. Boncoraglio et al. / Spontaneous ARIA in Prodromal AD

Fig. 1. Neuroimaging and pathological findings. Brain MRI before biopsy: A) Axial T2∗ images showing sulcal superficial siderosis in the right parietal region (arrows) and rare cortical microbleeds. B) Post-contrast axial and coronal T1 images demonstrating marked leptomeningeal enhancement in the right cerebral hemisphere. C) Delayed post-contrast FLAIR images showing extensive contrast accumulation in the right subarachnoid spaces. Neuropathological findings of open meningeal and brain biopsy of the right parietal lobe: D) Hematoxylin & eosin staining revealed wall thickening and reduced lumens of the leptomeningeal and parenchymal vessels with lymphomonocytic infiltration and focal fibrinoid necrosis in the walls of the most severely affected meningeal vessels. E, H) The abnormal material on the vessel walls was intensely immunoreactive for A␤ protein (4G8 1:4000 immunostaining), and showed the optical and tinctorial properties of amyloid (yellow fluorescence after thioflavine S treatment) (G). F) There was lymphomonocytic infiltration in the perivascular space and walls (CD45 1:50 immunostaining) of amyloid-laden meningeal vessels, but not in those in the neuropil. Thioflavine S (G) and anti-A␤ antibody (4G8) (H) also revealed numerous A␤ deposits in the cortical neuropil, and there were abundant neurofibrillary changes (tangles, neuropil threads, clusters of dystrophic neurites) immunoreactive for phosphorylated tau (AT8 1:300 immunostaining) (I). The cerebral cortex and subcortical white matter showed severe astrogliosis and microglial activation. Bar in D = 100 ␮m. D, E, and F adjacent sections imaged using the same magnification. Bar in G = 50 ␮m. G, H, and I have the same magnification.

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We describe the case of a patient with biopsy-proven AD and CAA-ri, with spontaneous ARIA-like events at symptom onset, supported by evidence of increased CSF anti-A␤ autoantibody levels. This case is particular for various reasons. First of all, the neuroradiological findings were mainly characterized by sulcal hemosiderin deposits rather than microbleeds and white matter edema; although CAA-ri presenting with convexity-SAH and meningeal contrast enhancement has been previously described [16, 17], the enhancement was not as extensive as in our patient. Secondly, the inflammatory vascular changes were very severe and in some instances associated to fibrinoid necrosis, but were exclusively leptomeningeal, even if A␤ deposition in the form of senile plaque and CAA also involved the neuropil. There were also considerable neurofibrillary changes in the parietal cortex, which led to the final neuropathological diagnosis of fully expressed AD pathology, rather than barely CAA. Moreover, according to the Braak staging system [18], the involvement of parietal cortex by neurofibrillary changes indicates at least stage V, which is very rarely encountered in nondemented subjects [19]. It is therefore puzzling that our patient had not shown any sign of cognitive disturbances before the onset of the subacute neurological syndrome. Alternatively, this may have been an atypical focal cortical presentation of AD with neurofibrillary changes that does not follow the

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DISCUSSION

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low A␤42 (72 pg/mL, normal value >500), high total tau (698 pg/mL, normal value

Prodromal Alzheimer's disease presenting as cerebral amyloid angiopathy-related inflammation with spontaneous amyloid-related imaging abnormalities and high cerebrospinal fluid anti-Aβ autoantibodies.

Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare form of vasculitis associated with amyloid-β (Aβ) deposition in vessel walls, has be...
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