Background Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid beta in the cerebrovascular wall. The Boston... Show moreBackground Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid beta 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. Show less
Martinez-Ramirez, S.; Rooden, S. van; Charidimou, A.; Opstal, A.M. van; Wermer, M.; Gurol, M.E.; ... ; Viswanathan, A. 2018
Objective:To identify different white matter hyperintensity (WMH) patterns between 2 hemorrhage-prone cerebral small vessel diseases (SVD): cerebral amyloid angiopathy (CAA) and hypertensive... Show moreObjective:To identify different white matter hyperintensity (WMH) patterns between 2 hemorrhage-prone cerebral small vessel diseases (SVD): cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA).Methods:Consecutive patients with SVD-related intracerebral hemorrhage (ICH) from a single-center prospective cohort were analyzed. Four predefined subcortical WMH patterns were compared between the CAA and HA groups. These WMH patterns were (1) multiple subcortical spots; (2) peri-basal ganglia (BG); (3) large posterior subcortical patches; and (4) anterior subcortical patches. Their associations with other imaging (cerebral microbleeds [CMBs], enlarged perivascular spaces [EPVS]) and clinical markers of SVD were investigated using multivariable logistic regression.Results:The cohort included 319 patients with CAA and 137 patients with HA. Multiple subcortical spots prevalence was higher in the CAA compared to the HA group (29.8% vs 16.8%; p = 0.004). Peri-BG WMH pattern was more common in the HA- vs the CAA-ICH group (19% vs 7.8%; p = 0.001). In multivariable logistic regression, presence of multiple subcortical spots was associated with lobar CMBs (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.01-1.50, p = 0.039) and high degree of centrum semiovale EPVS (OR 2.43; 95% CI 1.56-3.80, p < 0.0001). By contrast, age (OR 1.05; 95% CI 1.02-1.09, p = 0.002), deep CMBs (OR 2.46; 95% CI 1.44-4.20, p = 0.001), total WMH volume (OR 1.02; 95% CI 1.01-1.04, p = 0.002), and high BG EPVS degree (OR 8.81; 95% CI 3.37-23.02, p < 0.0001) were predictors of peri-BG WMH pattern.Conclusion:Different patterns of subcortical leukoaraiosis visually identified on MRI might provide insights into the dominant underlying microangiopathy type as well as mechanisms of tissue injury in patients with ICH. Show less
Martinez-Ramirez, S.; Romero, J.R.; Shoamanesh, A.; McKee, A.C.; Etten, E. van; Pontes-Neto, O.; ... ; Viswanathan, A. 2015
Discussion: Strictly lobar MBs strongly predict CAA in non-ICH individuals when found in a hospital context. However, their diagnostic accuracy in the general population appears limited. (C) 2015... Show moreDiscussion: Strictly lobar MBs strongly predict CAA in non-ICH individuals when found in a hospital context. However, their diagnostic accuracy in the general population appears limited. (C) 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. Show less
Conclusions-Detecting even a single DWI lesion suggests an annual incidence of hundreds of new CMI. The cumulative effects of these lesions may directly contribute to small-vessel-related vascular... Show moreConclusions-Detecting even a single DWI lesion suggests an annual incidence of hundreds of new CMI. The cumulative effects of these lesions may directly contribute to small-vessel-related vascular cognitive impairment. Show less
Objective We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh compound B retention on positron emission tomography (PiB PET)... Show moreObjective We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh compound B retention on positron emission tomography (PiB PET) would correlate with the extent of magnetic resonance imaging (MRI) white matter hyperintensities (WMH; or leukoaraiosis) in patients with high vascular amyloid deposition (cerebral amyloid angiopathy [CAA]) but not in patients with high parenchymal amyloid deposition (Alzheimer disease [AD]; mild cognitive impairment [MCI]) or in healthy elderly (HE) subjects. Methods Forty-two nondemented CAA patients, 50 HE subjects, and 43 AD/MCI patients had brain MRI and PiB PET. Multivariate linear regression was used to assess the independent association between PiB retention and white matter disease volume, controlling for age, gender, apolipoprotein E genotype, and vascular risk factors within each group. Results CAA patients were younger than HE and AD subjects (68 +/- 10 vs 73.3 +/- 7 and 74 +/- 7.4, p < 0.01) but had higher amounts of WMH (median = 21 vs 3.2 and 10.8 ml, respectively, p < 0.05 for both comparisons). Global PiB retention and WMH showed strong correlation (rho = 0.52, p < 0.001) in the CAA group but not in HE or AD. These associations did not change in the multivariate models. Lobar microbleed count, another marker of CAA severity, also remained as an independent predictor of WMH volume. Interpretation Our results indicate that amyloid burden in CAA subjects (with primarily vascular amyloid) but not AD subjects (with primarily parenchymal amyloid) independently correlates with WMH volume. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia and highlights the possible utility of amyloid imaging as a marker of CAA severity. Ann Neurol 2013;73:529-536 Show less
