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
Scherlek, A.A.; Kozberg, M.G.; Nicoll, J.A.R.; Perosa, V.; Freeze, W.M.; Weerd, L. van der; ... ; Veluw, S.J. van 2022
Haemorrhagic amyloid-related imaging abnormalities on MRI are frequently observed adverse events in the context of amyloid beta immunotherapy trials in patients with Alzheimer's disease. The... Show moreHaemorrhagic amyloid-related imaging abnormalities on MRI are frequently observed adverse events in the context of amyloid beta immunotherapy trials in patients with Alzheimer's disease. The underlying histopathology and pathophysiological mechanisms of haemorrhagic amyloid-related imaging abnormalities remain largely unknown, although coexisting cerebral amyloid angiopathy may play a key role. Here, we used ex vivo MRI in cases that underwent amyloid beta immunotherapy during life to screen for haemorrhagic lesions and assess underlying tissue and vascular alterations. We hypothesized that these lesions would be associated with severe cerebral amyloid angiopathy. Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active amyloid beta immunization with AN1792 for Alzheimer's disease. Eleven matched non-immunized Alzheimer's disease cases from an independent brain brank were used as 'controls'. Formalin-fixed occipital brain slices were imaged at 7 T MRI to screen for haemorrhagic lesions (i.e. microbleeds and cortical superficial siderosis). Samples with and without haemorrhagic lesions were cut and stained. Artificial intelligence-assisted quantification of amyloid beta plaque area, cortical and leptomeningeal cerebral amyloid angiopathy area, the density of iron and calcium positive cells and reactive astrocytes and activated microglia was performed. On ex vivo MRI, cortical superficial siderosis was observed in 5/10 immunized Alzheimer's disease cases compared with 1/11 control Alzheimer's disease cases (kappa = 0.5). On histopathology, these areas revealed iron and calcium positive deposits in the cortex. Within the immunized Alzheimer's disease group, areas with siderosis on MRI revealed greater leptomeningeal cerebral amyloid angiopathy and concentric splitting of the vessel walls compared with areas without siderosis. Moreover, greater density of iron-positive cells in the cortex was associated with lower amyloid beta plaque area and a trend towards increased post-vaccination antibody titres. This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of haemorrhagic lesions observed in the context of amyloid beta immunotherapy. These findings suggest a possible role for cerebral amyloid angiopathy in the formation of haemorrhagic amyloid-related imaging abnormalities, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against amyloid beta with available in vivo MRI during life. Show less
Perivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel... Show morePerivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel disease (CSVD) and have been suggested to reflect dysfunctional perivascular clearance of soluble waste products from the brain. In this study, we investigated histopathological correlates of EPVS and how they relate to vascular amyloid-beta (A beta) in cerebral amyloid angiopathy (CAA), a form of CSVD that commonly co-exists with Alzheimer's disease (AD) pathology. We used ex vivo MRI, semi-automatic segmentation and validated deep-learning-based models to quantify EPVS and associated histopathological abnormalities. Severity of MRI-visible PVS during life was significantly associated with severity of MRI-visible PVS on ex vivo MRI in formalin fixed intact hemispheres and corresponded with PVS enlargement on histopathology in the same areas. EPVS were located mainly around the white matter portion of perforating cortical arterioles and their burden was associated with CAA severity in the overlying cortex. Furthermore, we observed markedly reduced smooth muscle cells and increased vascular A beta accumulation, extending into the WM, in individually affected vessels with an EPVS. Overall, these findings are consistent with the notion that EPVS reflect impaired outward flow along arterioles and have implications for our understanding of perivascular clearance mechanisms, which play an important role in the pathophysiology of CAA and AD. Show less
Telgte, A. ter; Scherlek, A.A.; Reijmer, Y.D.; Kouwe, A.J. van der; Harten, T. van; Duering, M.; ... ; Veluw, S.J. van 2020
Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+... Show moreSmall subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI-ex vivo MRI-histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI-/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls (p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of microinfarcts. Show less
Charidimou, A.; Frosch, M.P.; Salman, R.A.; Baron, J.C.; Cordonnier, C.; Hernandez-Guillamon, M.; ... ; Int CAA Assoc 2019
Objective Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid beta (A beta) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time... Show moreObjective Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid beta (A beta) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood. Methods We scanned intact formalin-fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions. Results In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole-brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of A beta-positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both A beta (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but A beta was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular A beta was almost always observed at the core of the lesion (91%, p < 0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%). Interpretation These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019;86:279-292 Show less
Background and Purpose-Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related... Show moreBackground and Purpose-Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions.Methods-Eleven CAA cases (median [IQR] age=69 years [65-79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68-92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere.Results-Our results demonstrated increased IgG positivity in the frontotemporal (P=0.044) and parietooccipital (P=0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions (P=0.005 and P=0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-beta-positive vessels (Spearman.=0.71, P=0.015 and Spearman.=0.73, P=0.011, respectively). Moreover, the percentage of fibrin and IgGpositive vessels, but not amyloid-beta-positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman.=0.77, P=0.005 and Spearman.=0.70, P=0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds.Conclusions-Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAArelated brain injury. Show less
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
Rutgers, K.S.; Remoortere, A. van; Buchem, M.A. van; Verrips, C.T.; Greenberg, S.M.; Bacskai, B.J.; ... ; Maarel, S.M. van der 2011
By phage display, llama-derived heavy chain antibody fragments were selected from non-immune and immune libraries and tested for their affinity and specificity for beta amyloid by phage-ELISA,... Show moreBy phage display, llama-derived heavy chain antibody fragments were selected from non-immune and immune libraries and tested for their affinity and specificity for beta amyloid by phage-ELISA, immunohistochemistry and surface plasmon resonance. We identified eight distinct heavy chain antibody fragments specific for beta amyloid. While three of them recognized vascular and parenchymal beta amyloid deposits, the remaining five heavy chain antibody fragments recognized vascular beta amyloid specifically, failing to bind to parenchymal beta amyloid. These heavy chain antibody fragments, selected from different libraries, demonstrated differential affinity for different epitopes when used for immunohistochemistry. These observations indicate that the llama heavy chain antibody fragments are the first immunologic probes with the ability to differentiate between parenchymal and vascular beta amyloid aggregates. This indicates that vascular and parenchymal beta amyloid deposits are heterogeneous in epitope presence/availability. The properties of these heavy chain antibody fragments make them potential candidates for use in in vivo differential diagnosis of Alzheimer disease and cerebral amyloid angiopathy. Continued use and characterization of these reagents will be necessary to fully understand the performance of these immunoreagents. (C) 2009 Elsevier Inc. All rights reserved. Show less
