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Competing Interests: I declare no competing interests.

Background: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations., Methods: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy., Findings: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard., Interpretation: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations., Funding: US National Institutes of Health (R01 AG26484)., Competing Interests: Declaration of interests AC reports receiving funding from the Bodossaki Foundation and the Frechette Family Foundation and consulting fees from Imperative Care. MPF reports receiving funding from Biogen and Voyager Therapeutics. Gba reports receiving funding from the Rosetrees Trust, Alzheimer's Research UK, NIHR, and the Stroke Association. CC reports receiving funding from the French Ministry of Health and honoraria from Amgen, and participating in data safety monitoring, advisory, or steering committees for the University of Glasgow, University of Caen, Op2Lysis, AstraZeneca, Bristol Myers Squibb, and Biogen. MD reports receiving funding from Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology and the Vascular Dementia Research Foundation. JH reports receiving funding from the German Research Foundation and German Center for Neurodegenerative Diseases and tissue from Neurobiobank Munich. JL reports serving on a serving on an advisory board for Biogen and Mediaire. LP reports receiving honoraria from Daiichi Sankyo Ireland. FP reports receiving funding from the Alzheimer's Association (AARG-18-561699), participation on an Advisory Board for Roche, and leadership of the CAA Study Group of the Italia Society of Neurology-Dementia and the iCAB International Network. SR reports receiving funding from the German Research Foundation and brain tissue from Neurobiobank Munich. MAR reports receiving funding from the Wellcome Trust. JAS reports receiving funding from the US National Institutes of Health, consulting fees from Alnylam Pharmaceuticals, Apellis Pharmaceuticals, and Avid Radiopharmaceuticals, honoraria from Weil Cornell University, payment for expert testimony from the National Hockey League, support for travel from the US National Institutes for Health, serving on safety monitoring or advisory boards for the Framingham Heart Study, DISCOVERY, University of Kansas, Boston University, and University of California Irvine, and serving in leadership positions for the Alzheimer's Association and Foundation Alzheimer France. CSm reports receiving funding from the Medical Research Council UK. LS reports receiving funding from the Hungarian Academy of Sciences and Ministry for Innovation and Technology of Hungary from the source of the National Research. JMW reports receiving funding from the UK Dementia Research Institute funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK, and a leadership role for the European Stroke Organization SVD Guidelines. FAW reports receiving honoraria from Alexion Pharm. MEG reports receiving funding from Avid Radiopharmaceuticals, Pfizer, and Boston Scientific. AV reports receiving funding from the US National Institutes of Health and consulting fees from Alnylam Pharmaceuticals and Biogen Pharmaceuticals. RA-SS reports receiving funding from the UK Medical Research Council and the Stroke Association. EES reports receiving funding from the Canadian Institutes of Health Research, Brain Canada, and Biogen, and consulting fees from Biogen and Eli Lily. DJW reports receiving consulting fees from Alnylam and Novo Nordisk, honoraria from Bayer and Alexion, participation on a safety monitoring board for the OXHARP study, and serving in leadership for the British Association of Stroke Physicians. SMG reports receiving funding from the US National Institutes of Health, royalties from Up-To-Date, consulting fees from Eli Lily, and serving on data safety monitoring committees for Washington University, Bayer, Biogen, and Roche. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The shared role of amyloid-β (Aβ) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aβ generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aβ clearance, creating conditions for a self-reinforcing cycle of increased vascular Aβ, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aβ deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aβ immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aβ from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.

Rationale: The Boston criteria are used worldwide for the in vivo diagnosis of cerebral amyloid angiopathy and are the basis for clinical decision-making and research in the field. Given substantial advances in cerebral amyloid angiopathy's clinical aspects and MRI biomarkers, we designed a multicenter study within the International cerebral amyloid angiopathy Association aimed at further validating the diagnostic accuracy of the Boston and potentially improving and updating them., Aim: We aim to derive and validate an updated "version 2.0" of the Boston criteria across the spectrum of cerebral amyloid angiopathy-related presentations and MRI biomarkers., Sample Size Estimates: Participating centers with suitable available data (see Methods) were identified from existing collaborations and an open invitation to the International Cerebral Amyloid Angiopathy Association emailing list. Our study sample will include: (1) a derivation cohort - Massachusetts General Hospital (MGH), Boston cases from inception to 2012 (∼150 patients); (2) temporal external validation cohort - MGH, Boston cases from 2012 to 2018 (∼100 patients); and (3) geographical external validation cohort - non-Boston cases (∼85 patients)., Methods and Design: Multicenter collaborative study. We will collect and analyze data from patients' age ≥ 50 with any potential sporadic cerebral amyloid angiopathy-related clinical presentations (spontaneous intracerebral hemorrhage, transient focal neurological episodes and cognitive impairment), available brain MRI ("index test"), and histopathologic assessment for cerebral amyloid angiopathy ("reference standard" for diagnosis). Trained raters will assess MRI for all prespecified hemorrhagic and non-hemorrhagic small vessel disease markers of interest, according to validated criteria and a prespecified protocol, masked to clinical and histopathologic features. Brain tissue samples will be rated for cerebral amyloid angiopathy, defined as Vonsattel grade ≥2 for whole brain autopsies and ≥1 for cortical biopsies or hematoma evacuation. Based on our estimated available sample size, we will undertake pre-specified cohort splitting as above. We will: (a) pre-specify variables and statistical cut-offs; (b) examine univariable and multivariable associations; and (c) then assess classification measures (sensitivity, specificity etc.) for each MRI biomarker individually, in relation to the cerebral amyloid angiopathy diagnosis reference standard on neuropathology in a derivation cohort. The MRI biomarkers strongly associated with cerebral amyloid angiopathy diagnosis will be selected for inclusion in provisional (probable and possible cerebral amyloid angiopathy) Boston criteria v2.0 and validated using appropriate metrics and models., Study Outcomes: Boston criteria v2.0 for clinical cerebral amyloid angiopathy diagnosis., Discussion: This work aims to potentially update and improve the diagnostic test accuracy of the Boston criteria for cerebral amyloid angiopathy and to provide wider validation of the criteria in a large sample. We envision that this work will meet the needs of clinicians and investigators and help accelerate progress towards better treatment of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly. Matrix metalloproteinases (MMPs) have been implicated in blood-brain barrier disruption and ICH pathogenesis. In this study, we determined the levels MMP-2 and MMP-9 in plasma and their brain expression in CAA-associated hemorrhagic stroke. Although MMP-2 and MMP-9 plasma levels did not differ among patients and controls, their brain expression was increased in perihematoma areas of CAA-related hemorrhagic strokes compared with contralateral areas and nonhemorrhagic brains. In addition, MMP-2 reactivity was found in β-amyloid (Aβ)-damaged vessels located far from the acute ICH and in chronic microbleeds. MMP-2 expression was associated to endothelial cells, histiocytes and reactive astrocytes, whereas MMP-9 expression was restricted to inflammatory cells. In summary, MMP-2 expression within and around Aβ-compromised vessels might contribute to the vasculature fatal fate, triggering an eventual bleeding., (© 2011 The Authors. Brain Pathology © 2011 International Society of Neuropathology.)

Background: Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly., Objective: To analyze β-amyloid (Aβ) species in plasma in order to uncover biological markers that may contribute to improve the diagnosis of CAA in life., Methods: We determined the level of Aβ(1-40), Aβ(N-40), Aβ(1-42) and Aβ(N-42) in plasma of CAA-related ICH patients (n = 29) and healthy controls (n = 21) using xMAP® technology. Hemorrhages were identified and classified using a CT scan and brain MRI. Patients were clinically classified as probable or possible CAA according to the Boston criteria., Results: We found that plasma full-length Aβ(1-42) and truncated fragments Aβ(N-42) were higher in probable CAA patients than in controls (p < 0.001 and p = 0.046, respectively), and full-length Aβ(1-40) was selectively elevated in probable CAA compared to possible cases (p = 0.015) and controls (p = 0.005). In addition, plasma Aβ(N-42) levels were also higher in patients that presented multiple lobar macrohemorrhages compared to patients that had one symptomatic hemorrhagic event (p = 0.022), indicating that a certain degree of CAA severity is necessary to show increased Aβ fragments in peripheral circulation., Conclusion: Our results suggest that specific Aβ fragments in plasma might be considered as potential biomarkers for the diagnosis of CAA., (Copyright © 2012 S. Karger AG, Basel.)

Cerebral amyloid angiopathy (CAA) is a well-established cause of lobar intracerebral hemorrhage (ICH). The aim of the authors was to investigate the influence of clinical characteristics and genetic variants in the ACE, LRP, MMP9, Tafi, VEGFA, CYP11B2, A2M and APOE on ICH recurrence in a cohort of CAA-related ICH patients. Sixty patients were enrolled and new symptomatic ICHs in the 36 mo following the index event were recorded. Leukoaraiosis degree, microbleeds count and variants in the APOE and ACE were associated with ICH recurrence. The rs4311 variant of the ACE was an independent risk factor (p = 0.001), resisting Bonferroni correction. Moreover, carriers of ε2 of the APOE and TT of the rs4311 of the ACE reached 100% recurrence before 18 mo (p < 0.001). Finally, ACE protein level was measured in serum of controls and depended on the rs4311 genotypes, TT carriers presenting higher level than CC carriers (p = 0.012). These results suggest that variants in the ACE are associated with CAA-related ICH recurrence, possibly by modulating ACE protein level., (Copyright © 2011 Elsevier Inc. All rights reserved.)