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1. Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study

Author

Taragano, F.E., Kril, J., Cavalieri, M., Jellinger, K.A., Kovacs, G.G., Engelborghs, S., Lafosse, C., Bertolucci, P.H., Brucki, S., Caramelli, P., de Toledo Ferraz Alves, T.C., Bocti, C., Fulop, T., Hogan, D.B., Hsiung, G.R., Kirk, A., Leach, L., Robillard, A., Sahlas, D.J., Guo, Q., Tian, J., Hokkanen, L., Jokinen, H., Benisty, S., Deramecourt, V., Hauw, J., Lenoir, H., Tsatali, M., Tsolaki, M., Sundar, U., Coen, R.F., Korczyn, A.D., Altieri, M., Baldereschi, M., Caltagirone, C., Caravaglios, G., Di Carlo, A., Di Piero, V., Gainotti, G., Galluzzi, S., Logroscino, G., Mecocci, P., Moretti, D.V., Padovani, A., Fukui, T., Ihara, M., Mizuno, T., Kim, S.Y., Akinyemi, R., Baiyewu, O., Ogunniyi, A., Szczudlik, A., Bastos-Leite, A.J., Firmino, H., Massano, J., Verdelho, A., Kruglov, L.S., Ikram, M.K., Kandiah, N., Arana, E., Barroso-Ribal, J., Calatayud, T., Cruz-Jentoft, A.J., López-Pousa, S., Martinez-Lage, P., Mataro, M., Börjesson-Hanson, A., Englund, E., Laukka, E.J., Qiu, C., Viitanen, M., Biessels, G.J., de Leeuw, F.-E., den Heijer, T., Exalto, L.G., Kappelle, L.J., Prins, N.D., Richard, E., Schmand, B., van den Berg, E., van der Flier, W.M., Bilgic, B., Allan, L.M., Archer, J., Attems, J., Bayer, A., Blackburn, D., Brayne, C., Bullock, R., Connelly, P.J., Farrant, A., Fish, M., Harkness, K., Ince, P.G., Langhorne, P., Mann, J., Matthews, F.E., Mayer, P., Pendlebury, S.T., Perneczky, R., Peters, R., Smithard, D., Stephan, B.C., Swartz, J.E., Todd, S., Werring, D.J., Wijayasiri, S.N., Wilcock, G., Zamboni, G., Au, R., Borson, S., Bozoki, A., Browndyke, J.N., Corrada, M.M., Crane, P.K., Diniz, B.S., Etcher, L., Fillit, H., Greenberg, S.M., Grinberg, L.T., Hurt, S.W., Lamar, M., Mielke, M., Ott, B.R., Perry, G., Powers, W.J., Ramos-Estebanez, C., Reed, B., Roberts, R.O., Romero, J.R., Saykin, A.J., Seshadri, S., Silbert, L., Stern, Y., Zarow, C., Skrobot, Olivia A., Black, Sandra E., Chen, Christopher, DeCarli, Charles, Erkinjuntti, Timo, Ford, Gary A., Kalaria, Rajesh N., O'Brien, John, Pantoni, Leonardo, Pasquier, Florence, Roman, Gustavo C., Wallin, Anders, Sachdev, Perminder, Skoog, Ingmar, Ben-Shlomo, Yoav, Passmore, Anthony P., Love, Seth, and Kehoe, Patrick G.

Published
2018
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2. The Vascular Impairment of Cognition Classification Consensus Study

Author

Taragano, F.E., Kril, J., Cavalieri, M., Jellinger, K.A., Kovacs, G.G., Engelborghs, S., Lafosse, C., Bertolucci, P.H., Brucki, S., Caramelli, P., de Toledo Ferraz Alves, T.C., Bocti, C., Fulop, T., Hogan, D.B., Hsiung, G.R., Kirk, A., Leach, L., Robillard, A., Sahlas, D.J., Guo, Q., Tian, J., Hokkanen, L., Jokinen, H., Benisty, S., Deramecourt, V., Hauw, J., Lenoir, H., Tsatali, M., Tsolaki, M., Sundar, U., Coen, R.F., Korczyn, A.D., Altieri, M., Baldereschi, M., Caltagirone, C., Caravaglios, G., Di Carlo, A., DI Piero, V., Gainotti, G., Galluzzi, S., Logroscino, G., Mecocci, P., Moretti, D.V., Padovani, A., Fukui, T., Ihara, M., Mizuno, T., Kim, S.Y., Akinyemi, R., Baiyewu, O., Ogunniyi, A., Szczudlik, A., Bastos-Leite, A.J., Firmino, H., Massano, J., Verdelho, A., Kruglov, L.S., Ikram, M.K., Kandiah, N., Arana, E., Barroso-Ribal, J., Calatayud, T., Cruz-Jentoft, A.J., López-Pousa, S., Martinez-Lage, P., Mataro, M., Börjesson-Hanson, A., Englund, E., Laukka, E.J., Qiu, C., Viitanen, M., Biessels, G.J., de Leeuw, F.-E., den Heijer, T., Exalto, L.G., Kappelle, L.J., Prins, N.D., Richard, E., Schmand, B., van den Berg, E., van der Flier, W.M., Bilgic, B., Allan, L.M., Archer, J., Attems, J., Bayer, A., Blackburn, D., Brayne, C., Bullock, R., Connelly, P.J., Farrant, A., Fish, M., Harkness, K., Ince, P.G., Langhorne, P., Mann, J., Matthews, F.E., Mayer, P., Pendlebury, S.T., Perneczky, R., Peters, R., Smithard, D., Stephan, B.C., Swartz, J.E., Todd, S., Werring, D.J., Wijayasiri, S.N., Wilcock, G., Zamboni, G., Au, R., Borson, S., Bozoki, A., Browndyke, J.N., Corrada, M.M., Crane, P.K., Diniz, B.S., Etcher, L., Fillit, H., Greenberg, S.M., Grinberg, L.T., Hurt, S.W., Lamar, M., Mielke, M., Ott, B.R., Perry, G., Powers, W.J., Ramos-Estebanez, C., Reed, B., Roberts, R.O., Romero, J.R., Saykin, A.J., Seshadri, S., Silbert, L., Stern, Y., Zarow, C., Skrobot, Olivia A., O'Brien, John, Black, Sandra, Chen, Christopher, DeCarli, Charles, Erkinjuntti, Timo, Ford, Gary A., Kalaria, Rajesh N., Pantoni, Leonardo, Pasquier, Florence, Roman, Gustavo C., Wallin, Anders, Sachdev, Perminder, Skoog, Ingmar, Ben-Shlomo, Yoav, Passmore, Anthony P., Love, Seth, and Kehoe, Patrick G.

Published
2017
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3. Histopathology of Cerebral Microinfarcts and Microbleeds in Spontaneous Intracerebral Hemorrhage.

Author

Jolink, W.M.T., Veluw, S.J. van, Zwanenburg, J.J.M., Rozemuller, A.J., Hecke, W. van, Frosch, M.P., Bacskai, B.J., Rinkel, G.J., Greenberg, S.M., Klijn, C.J.M., Jolink, W.M.T., Veluw, S.J. van, Zwanenburg, J.J.M., Rozemuller, A.J., Hecke, W. van, Frosch, M.P., Bacskai, B.J., Rinkel, G.J., Greenberg, S.M., and Klijn, C.J.M.

Abstract

01 april 2023, Item does not contain fulltext, In patients with spontaneous intracerebral hemorrhage caused by different vasculopathies, cerebral microinfarcts have the same aspect on MRI and the same applies to cerebral microbleeds. It is unclear what pathological changes underlie these cerebral microinfarcts and cerebral microbleeds. In the current study, we explored the histopathological substrate of these lesions by investigating the brain tissue of 20 patients (median age at death 77 years) who died from ICH (9 lobar, 11 non-lobar) with a combination of post-mortem 7-T MRI and histopathological analysis. We identified 132 CMIs and 204 CMBs in 15 patients on MRI, with higher numbers of CMIs in lobar ICH patients and similar numbers of CMBs. On histopathology, CMIs and CMBs were in lobar ICH more often located in the superficial than in the deep layers of the cortex, and in non-lobar ICH more often in the deeper layers. We found a tendency towards more severe CAA scores in lobar ICH patients. Other histopathological characteristics were comparable between lobar and non-lobar ICH patients. Although CMIs and CMBs were found in different segments of the cortex in lobar ICH compared to non-lobar ICH patients, otherwise similar histopathological features of cortical CMIs and CMBs distant from the ICH suggest shared pathophysiological mechanisms in lobar and non-lobar ICH caused by different vasculopathies.

Published
2023

4. A Causal Classification System for Intracerebral Hemorrhage Subtypes.

Author

Raposo, N., Zanon Zotin, M.C., Seiffge, D.J., Li, Q., Goeldlin, M.B., Charidimou, A., Shoamanesh, A., Jäger, H.R., Cordonnier, C., Klijn, C.J.M., Smith, E.E., Greenberg, S.M., Werring, D.J., Viswanathan, A., Raposo, N., Zanon Zotin, M.C., Seiffge, D.J., Li, Q., Goeldlin, M.B., Charidimou, A., Shoamanesh, A., Jäger, H.R., Cordonnier, C., Klijn, C.J.M., Smith, E.E., Greenberg, S.M., Werring, D.J., and Viswanathan, A.

Abstract

01 januari 2023, Item does not contain fulltext, OBJECTIVE: Determining the underlying causes of intracerebral hemorrhage (ICH) is of major importance, because risk factors, prognosis, and management differ by ICH subtype. We developed a new causal CLASsification system for ICH Subtypes, termed CLAS-ICH, based on recent advances in neuroimaging. METHODS: CLAS-ICH defines 5 ICH subtypes: arteriolosclerosis, cerebral amyloid angiopathy, mixed small vessel disease (SVD), other rare forms of SVD (genetic SVD and others), and secondary causes (macrovascular causes, tumor, and other rare causes). Every patient is scored in each category according to the level of diagnostic evidence: (1) well-defined ICH subtype; (2) possible underlying disease; and (0) no evidence of the disease. We evaluated CLAS-ICH in a derivation cohort of 113 patients with ICH from Massachusetts General Hospital, Boston, USA, and in a derivation cohort of 203 patients from Inselspital, Bern, Switzerland. RESULTS: In the derivation cohort, a well-defined ICH subtype could be identified in 74 (65.5%) patients, including 24 (21.2%) with arteriolosclerosis, 23 (20.4%) with cerebral amyloid angiopathy, 18 (15.9%) with mixed SVD, and 9 (8.0%) with a secondary cause. One or more possible causes were identified in 42 (37.2%) patients. Interobserver agreement was excellent for each category (kappa value ranging from 0.86 to 1.00). Despite substantial differences in imaging modalities, we obtained similar results in the validation cohort. INTERPRETATION: CLAS-ICH is a simple and reliable classification system for ICH subtyping, that captures overlap between causes and the level of diagnostic evidence. CLAS-ICH may guide clinicians to identify ICH causes, and improve ICH classification in multicenter studies. ANN NEUROL 2023;93:16-28.

Published
2023

6. Progressive White Matter Injury in Preclinical Dutch Cerebral Amyloid Angiopathy

Author

Shirzadi, Z., Yau, W.Y.W., Schultz, S.A., Schultz, A.P., Scott, M.R., Goubran, M., Mojiri-Forooshani, P., Joseph-Mathurin, N., Kantarci, K., Preboske, G., Wermer, M.J.H., Jack, C., Benzinger, T., Taddei, K., Sohrabi, H.R., Sperling, R.A., Johnson, K.A., Bateman, R.J., Martins, R.N., Greenberg, S.M., Chhatwal, J.P., and DIAN Investigators

Subjects
Cerebral Amyloid Angiopathy, Cross-Sectional Studies, Neurology, Humans, Hemorrhage, Neuroimaging, Neurology (clinical), Magnetic Resonance Imaging, White Matter, Cerebral Hemorrhage
Abstract

Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and14 years before the average age of first symptomatic hemorrhage. These results indicate that white matter disruption measures may be valuable cross-sectional and longitudinal biomarkers of D-CAA progression. ANN NEUROL 2022;92:358-363.

Published
2022

7. Histopathological correlates of haemorrhagic lesions on ex vivo magnetic resonance imaging in immunized Alzheimer's disease cases

Author

Scherlek, A.A., Kozberg, M.G., Nicoll, J.A.R., Perosa, V., Freeze, W.M., Weerd, L. van der, Bacskai, B.J., Greenberg, S.M., Frosch, M.P., Boche, D., and Veluw, S.J. van

Subjects
amyloid beta, siderosis, immunotherapy, cerebral amyloid angiopathy
Abstract

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 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.

Published
2022

8. Brain deep medullary veins on 7T MRI in Dutch-type hereditary cerebral amyloid angiopathy

Author

Harten, T.W. van, Heijmans, A., Rooden, S. van, Wermer, M.J.H., Osch, M.J.P. van, Kuijf, H.J., Veluw, S.J. van, Greenberg, S.M., Buchem, M.A. van, Grond, J. van der, and Walderveen, M.A.A. van

Subjects
Cerebral small vessel disease, magnetic resonance imaging, cerebral veins, hereditary cerebral amyloid angiopathy
Abstract

Background: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer's disease. So far, DMVs have not been evaluated in CAA. Objective: To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. Methods: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n = 8), symptomatic D-CAA mutation carriers (n = 8), and controls (n = 25). HemorrhagicMRImarkers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. Results: QuantitativeDMVparameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA.Conclusion: This study indicates that vascular amyloid-beta deposition does not affectDMVparameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA.

Published
2022

9. Normal cerebrospinal fluid concentrations of PDGFRβ in patients with cerebral amyloid angiopathy and Alzheimer's disease

Author

Kort, A.M. de, Kuiperij, H.B., Kersten, I., Versleijen, A.A.M., Schreuder, F.H.B.M., Nostrand, W.E. Van, Greenberg, S.M., Klijn, C.J.M., Claassen, J.A.H.R., and Verbeek, M.M.

Subjects
Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], Epidemiology, Health Policy, tau Proteins, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 150 000 MR Techniques in Brain Function, Peptide Fragments, Receptor, Platelet-Derived Growth Factor beta, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Cerebral Amyloid Angiopathy, Developmental Neuroscience, Alzheimer Disease, Humans, Cognitive Dysfunction, Neurology (clinical), Geriatrics and Gerontology, Biomarkers
Abstract

Contains fulltext : 287481.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-β (PDGFRβ) has been proposed as a biomarker of blood-brain barrier (BBB) breakdown. We studied PDGFRβ levels as a biomarker for cerebral amyloid angiopathy (CAA), amnestic mild cognitive impairment (aMCI), or Alzheimer's disease (AD). METHODS: CSF PDGFRβ levels were quantified by enzyme-linked immunosorbent assay in patients with CAA, patients with aMCI/AD, and in matched controls. In aMCI/AD we evaluated CSF PDGFRβ both by clinical phenotype and by using the AT(N) biomarker classification system defined by CSF amyloid (A), tau (T), and neurodegeneration (N) biomarkers. RESULTS: PDGFRβ levels were similar in CAA patients and controls (P = .78) and in aMCI/AD clinical phenotype and controls (P = .91). aMCI/AD patients with an AD+ biomarker profile (A+T+[N+]) had increased PDGFRβ levels compared to (A-T-[N-]) controls (P = .006). CONCLUSION: Our findings indicate that PDGFRβ levels are associated with an AD+ biomarker profile but are not a suitable biomarker for CAA or aMCI/AD clinical syndrome.

Published
2022

10. Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer's disease, but not in cerebral amyloid angiopathy

Author

De Kort, A.M., Kuiperij, H.B., Alcolea, Daniel, Kersten, I., Versleijen, A.A.M., Greenberg, S.M., Stoops, E., Schreuder, F.H.B.M., Klijn, C.J.M., Lleó, Alberto, Claassen, Jurgen A. H. R, Verbeek, M.M., and Universitat Autònoma de Barcelona

Subjects
medicine.medical_specialty, Amyloid, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], Neurology, Cognitive Neuroscience, Neurosciences. Biological psychiatry. Neuropsychiatry, Gastroenterology, Neuroprotection, All institutes and research themes of the Radboud University Medical Center, Cerebrospinal fluid, Neurotrophic factors, Internal medicine, mental disorders, Neuroleukin, Medicine, Senile plaques, Cerebral amyloid angiopathy, RC346-429, business.industry, Research, Alzheimer's disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Neuro-inflammation, Biomarker (medicine), Neurology (clinical), Neurology. Diseases of the nervous system, business, Alzheimer’s disease, Biomarkers, RC321-571
Abstract

Altres ajuts: BIONIC project (no. 733050822); "Memorabel," the research and innovation program for dementia, as part of the Dutch national "Deltaplan for Dementia"; the National Institutes of Health, USA (5R01NS104147-02); Dutch Heart Foundation (grant 2012 T077); ASPASIA grant from The Netherlands Organization for Health Research and Development, ZonMW (grant 015008048); senior clinical scientist grant of the Dutch Heart Foundation (grant 2019 T060); CIBERNED; Instituto de Salud Carlos III; Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, "Una manera de hacer Europa"; Generalitat de Catalunya; Fundació "La Marató TV3"; Fundació Bancària Obra Social La Caixa; Fundación BBVA; Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica (FUNDELA); Global Brain Health Institute; Fundació Catalana Síndrome de Down; Fundació Víctor Grífols i Lucas. Background: Neuroleukin (NLK) is a protein with neurotrophic properties and is present in a proportion of senile plaques and amyloid laden vessels. It has been suggested that NLK is part of a neuroprotective response to amyloid β-induced cell death. The aim of our study was to investigate the value of cerebrospinal fluid (CSF) NLK levels as a biomarker of vascular amyloid deposition in patients with cerebral amyloid angiopathy (CAA) and in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Methods: CSF NLK levels were quantified by ELISA in CAA patients (n = 25) and controls (n = 27) and in two independent samples of aMCI patients, AD patients, and controls: (1) From the Radboud University Medical Center (Nijmegen), we included n = 19 aMCI patients, n = 40 AD patients, and n = 32 controls. (2) From the Hospital of Sant Pau (Barcelona), we included n = 33 aMCI patients, n = 17 AD patients, and n = 50 controls. Results: CSF NLK levels were similar in CAA patients and controls (p = 0.95). However, we found an elevated CSF concentration of NLK in aMCI (p < 0.0001) and AD patients (p < 0.0001) compared to controls in both samples sets. In addition, we found a correlation of CSF NLK with CSF YKL-40 (age-adjusted-spearman-rank-coefficient = 0.82, p < 0.0001) in aMCI/AD patients, a well-known glial marker of neuro-inflammation. Conclusions: We found that CSF NLK levels are elevated in aMCI and AD patients compared to controls, but are not increased in CAA patients. CSF NLK levels may be related to an increased neuroinflammatory state in early stages of AD, given its association with YKL-40.

Published
2021

11. Presymptomatic Dutch-Type hereditary cerebral amyloid Angiopathy-Related blood metabolite alterations

Author

Chatterjee, P., Fagan, A.M., Xiong, C., McKay, M., Bhatnagar, A., Wu, Y., Singh, A.K., Taddei, K., Martins, I., Gardener, S.L., Molloy, M.P., Multhaup, G., Masters, C.L., Schofield, P.R., Benzinger, T.L.S., Morris, J.C., Bateman, R.J., Greenberg, S.M., Wermer, M.J.H., van Buchem, M.A., Sohrabi, H.R., Martins, R.N., Chatterjee, P., Fagan, A.M., Xiong, C., McKay, M., Bhatnagar, A., Wu, Y., Singh, A.K., Taddei, K., Martins, I., Gardener, S.L., Molloy, M.P., Multhaup, G., Masters, C.L., Schofield, P.R., Benzinger, T.L.S., Morris, J.C., Bateman, R.J., Greenberg, S.M., Wermer, M.J.H., van Buchem, M.A., Sohrabi, H.R., and Martins, R.N.

Abstract

Background:Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective:Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods:Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results:275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 0.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs = –0.527, p = 0.030). Conclusion:The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.

Published
2021

12. Off-label use of aducanumab for cerebral amyloid angiopathy

Author

Greenberg, S.M., Cordonnier, C., Schneider, J.A., Smith, E.E., Buchem, M.A. van, Veluw, S.J. van, Verbeek, M.M., Viswanathan, A., Werring, D.J., Greenberg, S.M., Cordonnier, C., Schneider, J.A., Smith, E.E., Buchem, M.A. van, Veluw, S.J. van, Verbeek, M.M., Viswanathan, A., and Werring, D.J.

Abstract

Item does not contain fulltext

Published
2021

13. Risk of intracranial haemorrhage and ischaemic stroke after convexity subarachnoid haemorrhage in cerebral amyloid angiopathy: international individual patient data pooled analysis.

Author

Hostettler I.C., Wilson D., Fiebelkorn C.A., Aum D., Ameriso S.F., Eberbach F., Beitzke M., Kleinig T., Phan T., Marchina S., Schneckenburger R., Carmona-Iragui M., Charidimou A., Mourand I., Parreira S., Ambler G., Jager H.R., Singhal S., Ly J., Ma H., Touze E., Geraldes R., Fonseca A.C., Melo T., Labauge P., Lefevre P.-H., Viswanathan A., Greenberg S.M., Fortea J., Apoil M., Boulanger M., Viader F., Kumar S., Srikanth V., Khurram A., Fazekas F., Bruno V., Zipfel G.J., Refai D., Rabinstein A., Graff-Radford J., Werring D.J., Hostettler I.C., Wilson D., Fiebelkorn C.A., Aum D., Ameriso S.F., Eberbach F., Beitzke M., Kleinig T., Phan T., Marchina S., Schneckenburger R., Carmona-Iragui M., Charidimou A., Mourand I., Parreira S., Ambler G., Jager H.R., Singhal S., Ly J., Ma H., Touze E., Geraldes R., Fonseca A.C., Melo T., Labauge P., Lefevre P.-H., Viswanathan A., Greenberg S.M., Fortea J., Apoil M., Boulanger M., Viader F., Kumar S., Srikanth V., Khurram A., Fazekas F., Bruno V., Zipfel G.J., Refai D., Rabinstein A., Graff-Radford J., and Werring D.J.

Abstract

Objective: To investigate the frequency, time-course and predictors of intracerebral haemorrhage (ICH), recurrent convexity subarachnoid haemorrhage (cSAH), and ischemic stroke after cSAH associated with cerebral amyloid angiopathy (CAA). Method(s): We performed a systematic review and international individual patient-data pooled analysis in patients with cSAH associated with probable or possible CAA diagnosed on baseline MRI using the modified Boston criteria. We used Cox proportional hazards models with a frailty term to account for between-cohort differences. Result(s): We included 190 patients (mean age 74.5 years; 45.3% female) from 13 centers with 385 patient-years of follow-up (median 1.4 years). The risks of each outcome (per patient-year) were: ICH 13.2% (95% CI 9.9-17.4); recurrent cSAH 11.1% (95% CI 7.9-15.2); combined ICH, cSAH, or both 21.4% (95% CI 16.7-26.9), ischemic stroke 5.1% (95% CI 3.1-8) and death 8.3% (95% CI 5.6-11.8). In multivariable models, there is evidence that patients with probable CAA (compared to possible CAA) had a higher risk of ICH (HR 8.45, 95% CI 1.13-75.5, p = 0.02) and cSAH (HR 3.66, 95% CI 0.84-15.9, p = 0.08) but not ischemic stroke (HR 0.56, 95% CI 0.17-1.82, p = 0.33) or mortality (HR 0.54, 95% CI 0.16-1.78, p = 0.31). Conclusion(s): Patients with cSAH associated with probable or possible CAA have high risk of future ICH and recurrent cSAH. Convexity SAH associated with probable (vs possible) CAA is associated with increased risk of ICH, and cSAH but not ischemic stroke. Our data provide precise risk estimates for key vascular events after cSAH associated with CAA which can inform management decisions.Copyright © 2021, The Author(s).

Published
2021

14. Peak Width of Skeletonized Mean Diffusivity as Neuroimaging Biomarker in Cerebral Amyloid Angiopathy

Author

Raposo, N., primary, Zanon Zotin, M.C., additional, Schoemaker, D., additional, Xiong, L., additional, Fotiadis, P., additional, Charidimou, A., additional, Pasi, M., additional, Boulouis, G., additional, Schwab, K., additional, Schirmer, M.D., additional, Etherton, M.R., additional, Gurol, M.E., additional, Greenberg, S.M., additional, Duering, M., additional, and Viswanathan, A., additional

Published
2021
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16. Advancing diagnostic criteria for sporadic cerebral amyloid angiopathy: Study protocol for a multicenter MRI-pathology validation of Boston criteria v2.0

Author

Charidimou, A., Frosch, M.P., Salman, R.A., Baron, J.C., Cordonnier, C., Hernandez-Guillamon, M., Linn, J., Raposo, N., Rodrigues, M., Romero, J.R., Schneider, J.A., Schreiber, S., Smith, E.E., Buchem, M.A. van, Viswanathan, A., Wollenweber, F.A., Werring, D.J., Greenberg, S.M., and Int CAA Assoc

Subjects
Pathology, medicine.medical_specialty, business.industry, diagnosis, diagnosis [Cerebral Amyloid Angiopathy], Reproducibility of Results, medicine.disease, pathology [Cerebral Amyloid Angiopathy], Magnetic Resonance Imaging, Sensitivity and Specificity, diagnostic imaging [Cerebral Amyloid Angiopathy], Neurology, cerebral microbleeds, Medicine, Humans, Cerebral amyloid angiopathy, ddc:610, business, Sporadic cerebral amyloid angiopathy, cortical superficial siderosis
Abstract

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.

Published
2019
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17. Brain atrophy in cerebral small vessel diseases: Extent, consequences, technical limitations and perspectives: The HARNESS initiative

Author

Guio, F. De, Duering, M., Fazekas, F., Leeuw, F.E. de, Greenberg, S.M., Pantoni, L., Aghetti, A., Smith, E.E., Wardlaw, J., Jouvent, E., Guio, F. De, Duering, M., Fazekas, F., Leeuw, F.E. de, Greenberg, S.M., Pantoni, L., Aghetti, A., Smith, E.E., Wardlaw, J., and Jouvent, E.

Abstract

Contains fulltext : 218849.pdf (Publisher’s version ) (Closed access)

Published
2020

18. Histopathology of diffusion-weighted imaging-positive lesions in cerebral amyloid angiopathy

Author

Telgte, A. ter, Scherlek, A.A., Reijmer, Y.D., Kouwe, A.J. van der, Harten, T. van, Duering, M., Bacskai, B.J., Leeuw, F.E. de, Frosch, M.P., Greenberg, S.M., Veluw, S.J. van, Telgte, A. ter, Scherlek, A.A., Reijmer, Y.D., Kouwe, A.J. van der, Harten, T. van, Duering, M., Bacskai, B.J., Leeuw, F.E. de, Frosch, M.P., Greenberg, S.M., and Veluw, S.J. van

Abstract

Contains fulltext : 220659.pdf (Publisher’s version ) (Closed access), 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+ 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.

Published
2020

19. Apolipoprotein D: a potential biomarker for cerebral amyloid angiopathy

Author

Kuiperij, H.B., Hondius, D.C., Kersten, I., Versleijen, A.A.M., Rozemuller, A.J., Greenberg, S.M., Schreuder, F., Klijn, C.J.M., Verbeek, M.M., Kuiperij, H.B., Hondius, D.C., Kersten, I., Versleijen, A.A.M., Rozemuller, A.J., Greenberg, S.M., Schreuder, F., Klijn, C.J.M., and Verbeek, M.M.

Abstract

Contains fulltext : 225773.pdf (Publisher’s version ) (Open Access), AIMS: We investigated the potential of apolipoprotein D (apoD) as cerebrospinal fluid (CSF) biomarker for cerebral amyloid angiopathy (CAA) after confirmation of its association with CAA pathology in human brain tissue. METHODS: The association of apoD with CAA pathology was analysed in human occipital lobe tissue of CAA (n = 9), Alzheimer's disease (AD) (n = 11) and healthy control cases (n = 11). ApoD levels were quantified in an age- and sex-matched CSF cohort of CAA patients (n = 31), AD patients (n = 27) and non-neurological controls (n = 67). The effects of confounding factors (age, sex, serum levels) on apoD levels were studied using CSF of non-neurological controls (age range 16-85 years), and paired CSF and serum samples. RESULTS: ApoD was strongly associated with amyloid deposits in vessels, but not with parenchymal plaques in human brain tissue. CSF apoD levels correlated with age and were higher in men than women in subjects >50 years. The apoD CSF/serum ratio correlated with the albumin ratio. When controlling for confounding factors, CSF apoD levels were significantly lower in CAA patients compared with controls and compared with AD patients (P = 0.0008). CONCLUSIONS: Our data show that apoD is specifically associated with CAA pathology and may be a CSF biomarker for CAA, but clinical application is complicated due to dependency on age, sex and blood-CSF barrier integrity. Well-controlled follow-up studies are required to determine whether apoD can be used as reliable biomarker for CAA.

Published
2020

20. The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice

Author

Banerjee, G., Carare, R., Cordonnier, C., Greenberg, S.M., Schneider, J.A., Smith, E.E., Buchem, M. van, Grond, J. van der, Verbeek, M.M., and Werring, D.J.

Subjects
mental disorders, nutritional and metabolic diseases, cardiovascular diseases, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Abstract

Contains fulltext : 182399.pdf (Publisher’s version ) (Open Access) Cerebral amyloid angiopathy (CAA) has never been more relevant. The last 5 years have seen a rapid increase in publications and research in the field, with the development of new biomarkers for the disease, thanks to advances in MRI, amyloid positron emission tomography and cerebrospinal fluid biomarker analysis. The inadvertent development of CAA-like pathology in patients treated with amyloid-beta immunotherapy for Alzheimer's disease has highlighted the importance of establishing how and why CAA develops; without this information, the use of these treatments may be unnecessarily restricted. Our understanding of the clinical and radiological spectrum of CAA has continued to evolve, and there are new insights into the independent impact that CAA has on cognition in the context of ageing and intracerebral haemorrhage, as well as in Alzheimer's and other dementias. While the association between CAA and lobar intracerebral haemorrhage (with its high recurrence risk) is now well recognised, a number of management dilemmas remain, particularly when considering the use of antithrombotics, anticoagulants and statins. The Boston criteria for CAA, in use in one form or another for the last 20 years, are now being reviewed to reflect these new wide-ranging clinical and radiological findings. This review aims to provide a 5-year update on these recent advances, as well as a look towards future directions for CAA research and clinical practice.

Published
2017
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21. Blood-brain barrier leakage and microvascular lesions in cerebral amyloid angiopathy

Author

Freeze, W.M., Bacskai, B.J., Frosch, M.P., Jacobs, H.I.L., Backes, W.H., Greenberg, S.M., and Veluw, S.J. van

Subjects
cognition, small vessel disease, immunohistochemistry, magnetic resonance imaging, blood-brain barrier
Abstract

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 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.

Published
2019

22. Clinical significance of cerebral microbleeds on MRI: A comprehensive meta-analysis of risk of intracerebral hemorrhage, ischemic stroke, mortality, and dementia in cohort studies (v1)

Author

Charidimou, A., Shams, S., Romero, J.R., Ding, J., Veltkamp, R., Horstmann, S., Eiriksdottir, G., Buchem, M.A. van, Gudnason, V., Himali, J.J., Gurol, M.E., Viswanathan, A., Imaizumi, T., Vernooij, M.W., Seshadri, S., Greenberg, S.M., Benavente, O.R., Launer, L.J., Shoamanesh, A., and Int META-MICROBLEEDS Initiative

Subjects
Antithrombotic, cerebral small vessel disease, cerebral microbleeds, magnetic resonance imaging, brain microbleeds, intracerebral hemorrahage
Published
2018

23. Amyloid imaging of dutch‐type hereditary cerebral amyloid angiopathy carriers

Author

Schultz, A.P., Kloet, R.W., Sohrabi, H.R., Weerd, L., Rooden, S., Wermer, M.J.H., Moursel, L.G., Yaqub, M., Berckel, B.N.M., Chatterjee, P., Gardener, S.L., Taddei, K., Fagan, A.M., Benzinger, T.L., Morris, J.C., Sperling, R., Johnson, K., Bateman, R.J., Gurol, M.E., Buchem, M.A., Martins, R., Chhatwal, J.P., Greenberg, S.M., Schultz, A.P., Kloet, R.W., Sohrabi, H.R., Weerd, L., Rooden, S., Wermer, M.J.H., Moursel, L.G., Yaqub, M., Berckel, B.N.M., Chatterjee, P., Gardener, S.L., Taddei, K., Fagan, A.M., Benzinger, T.L., Morris, J.C., Sperling, R., Johnson, K., Bateman, R.J., Gurol, M.E., Buchem, M.A., Martins, R., Chhatwal, J.P., and Greenberg, S.M.

Abstract

Objective To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular β‐amyloid (Aβ) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch‐type hereditary cerebral amyloid angiopathy (D‐CAA) mutation. Methods PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB‐PET in 19 D‐CAA mutation carriers (M+; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M−). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+, 8 M−). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aβ concentrations in 17 M+ and 11 M− participants who underwent lumbar puncture and compared the findings to PiB‐PET and CSF Aβ in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. Results D‐CAA M+ showed greater age‐dependent FLR PiB retention (p < 0.001) than M−, and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+, greater FLR PiB retention associated with reduced CSF concentrations of Aβ40 (r = −0.55, p = 0.021) but not Aβ42 (r = 0.01, p = 0.991). Despite comparably low CSF Aβ40 and Aβ42, PiB retention was substantially less in D‐CAA than ADAD (p < 0.001). Interpretation Increased PiB retention in D‐CAA and correlation with reduced CSF Aβ40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019;86:616–625

Published
2019

24. Immunotherapy with ponezumab for probable cerebral amyloid angiopathy

Author

Leurent, C., Goodman, J.A., Zhang, Y, He, P., Polimeni, J.R., Gurol, M.E., Lindsay, M., Frattura, L., Sohur, U.S., Viswanathan, A., Bednar, M.M., Klijn, C.J.M., Smith, E.E., Greenberg, S.M., Leurent, C., Goodman, J.A., Zhang, Y, He, P., Polimeni, J.R., Gurol, M.E., Lindsay, M., Frattura, L., Sohur, U.S., Viswanathan, A., Bednar, M.M., Klijn, C.J.M., Smith, E.E., and Greenberg, S.M.

Abstract

Contains fulltext : 207168.pdf (publisher's version ) (Open Access), Objective: Cerebral amyloid angiopathy (CAA) is caused by cerebrovascular deposition of beta-amyloid fragments leading to cerebrovascular dysfunction and other brain injuries. This phase 2, randomized, double-blind trial in patients with probable CAA assessed the efficacy and safety of ponezumab, a novel monoclonal antibody against Abeta 1-40. Methods: Thirty-six participants aged 55-80 years with probable CAA received intravenous placebo (n = 12) or ponezumab (n = 24). The change from baseline to Days 2 and 90 in cerebrovascular reactivity (CVR) was measured in the visual cortex as the natural log of the rising slope of the BOLD fMRI response to a visual stimulus. Safety and tolerability were also assessed. Results: The mean change from baseline to Day 90 was 0.817 (ponezumab) and 0.958 (placebo): a mean ratio of 0.852 (90% CI 0.735-0.989) representing a trend towards reduced CVR in the ponezumab group. This trend was not present at Day 2. There was one asymptomatic occurrence of amyloid-related imaging abnormality-edema in the ponezumab group. The total number of new cerebral microbleeds from baseline to day 90 did not differ between groups. The ponezumab group had a participant with nonfatal new cerebral hemorrhage with aphasia and a participant with subdural hemorrhage that site investigators deemed to be nondrug related. In the placebo group one participant had a fatal intracerebral hemorrhage and one participant had migraine with aura. Interpretation: Ponezumab was safe and well-tolerated. The ponezumab group showed a trend towards treatment effect at Day 90 that was opposite to the hypothesized direction. The prespecified efficacy criteria were thus not met.

Published
2019

25. Advances in stroke 2017.

Author

Goldstein L.B., Planas A.M., Yenari M.A., Greenberg S.M., Pantoni L., Amin-Hanjani S., Tymianski M., Dichgans M., Woo D., Reeves M., Thrift A., Kidwell C.S., Olivot J.M., Goyal M., Pierot L., Bennett D.A., Howard G., Ford G.A., Bernhardt J., Zorowitz R.D., Becker K.J., Keller E., Saposnik G., Strbian D., Goldstein L.B., Planas A.M., Yenari M.A., Greenberg S.M., Pantoni L., Amin-Hanjani S., Tymianski M., Dichgans M., Woo D., Reeves M., Thrift A., Kidwell C.S., Olivot J.M., Goyal M., Pierot L., Bennett D.A., Howard G., Ford G.A., Bernhardt J., Zorowitz R.D., Becker K.J., Keller E., Saposnik G., and Strbian D.

Published
2019

26. Clinical significance of cerebral microbleeds on MRI

Author

Charidimou, A. (Andreas), Shams, S. (Sara), Romero, J.R. (Jose Rafael), Ding, J. (Jie), Veltkamp, R. (Roland), Horstmann, S. (Solveig), Eiriksdottir, G. (Gudny), Buchem, M.A. (Mark) van, Gudnason, V. (Vilmundur), Himali, J.J. (Jayandra), Gurol, M.E. (Edip), Viswanathan, A. (Anand), Imaizumi, T. (Toshio), Vernooij, M.W. (Meike), Seshadri, S. (Sudha), Greenberg, S.M. (Steven), Benavente, O.R. (Oscar), Launer, L.J. (Lenore), Shoamanesh, A. (Ashkan), Charidimou, A. (Andreas), Shams, S. (Sara), Romero, J.R. (Jose Rafael), Ding, J. (Jie), Veltkamp, R. (Roland), Horstmann, S. (Solveig), Eiriksdottir, G. (Gudny), Buchem, M.A. (Mark) van, Gudnason, V. (Vilmundur), Himali, J.J. (Jayandra), Gurol, M.E. (Edip), Viswanathan, A. (Anand), Imaizumi, T. (Toshio), Vernooij, M.W. (Meike), Seshadri, S. (Sudha), Greenberg, S.M. (Steven), Benavente, O.R. (Oscar), Launer, L.J. (Lenore), and Shoamanesh, A. (Ashkan)

Abstract

__Background:__ Cerebral microbleeds can confer a high risk of intracerebral hemorrhage, ischemic stroke, death and dementia, but estimated risks remain imprecise and often conflicting. We investigated the association between cerebral microbleeds presence and these outcomes in a large meta-analysis of all published cohorts including: ischemic stroke/TIA, memory clinic, “high risk” elderly populations, and healthy individuals in population-based studies. __Methods:__ Cohorts (with > 100 participants) that assessed cerebral microbleeds presence on MRI, with subsequent follow-up (≥3 months) were identified. The association between cerebral microbleeds and each of the outcomes (ischemic stroke, intracerebral hemorrhage, death, and dementia) was quantified using random effects models of (a) unadjusted crude odds ratios and (b) covariate-adjusted hazard rations. Results: We identified 31 cohorts (n = 20,368): 19 ischemic stroke/TIA (n = 7672), 4 memory clinic (n = 1957), 3 high risk elderly (n = 1458) and 5 population-based cohorts (n = 11,722). Cerebral microbleeds were associated with an increased risk of ischemic stroke (OR: 2.14; 95% CI: 1.58–2.89 and adj-HR: 2.09; 95% CI: 1.71–2.57), but the relative increase in future intracerebral hemorrhage risk was greater (OR: 4.65; 95% CI: 2.68–8.08 and adj-HR: 3.93; 95% CI: 2.71–5.69). Cerebral microbleeds were an independent predictor of all-cause mortality (adj-HR: 1.36; 95% CI: 1.24–1.48). In three population-based studies, cerebral microbleeds were independently associated with incident dementia (adj-HR: 1.35; 95% CI: 1.00–1.82). Results were overall consistent in analyses stratified by different populations, but with different degrees of heterogeneity. __Conclusions:__ Our meta-analysis shows that cerebral microbleeds predict an increased risk of stroke, death, and dementia and provides up-to-date effect sizes across different clinical settings. These pooled estimates can inform clinical decisions and trials, further supp

Published
2018
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27. METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration: An initiative of the Joint Programme for Neurodegenerative Disease Research

Author

Dichgans, M., Wardlaw, J., Smith, E., Zietemann, V., Seshadri, S., Sachdev, P., Biessels, G.J., Fazekas, F., Benavente, O., Pantoni, L., Leeuw, F. de, Norrving, B., Matthews, P., Chen, C., Mok, V., During, M., Whiteley, W., Shuler, K., Alonso, A., Black, S.E., Brayne, C., Chabriat, H., Cordonnier, C., Doubal, F., Duzel, E., Ewers, M., Frayne, R., Hachinski, V., Ikram, M.A., Jessen, F., Jouvent, E., Linn, J., O'Brien, J., Oostenbrugge, R. van, Malik, R., Mazoyer, B., Schmidt, R., Sposato, L.A., Stephan, B., Swartz, R.H., Vernooij, M., Viswanathan, A., Werring, D., Abe, K., Allan, L., Arba, F., Bae, H.J., Bath, P.M.W., Bordet, R., Breteler, M., Choi, S., Deary, I., DeCarli, C., Ebmeier, K., Feng, L., Greenberg, S.M., Ihara, M., Kalaria, R., Kim, S., Lim, J.S., Lindley, R.I., Mead, G., Murray, A., Quinn, T., Ritchie, C., Sacco, R., Salman, R.A., Sprigg, N., Sudlow, C., Thomas, A., Boxtel, M. van, Grond, J. van der, Lugt, A. van der, Yang, Y.H., VISTA Collaboration, and METACOHORTS Consortiums

Subjects
Dementia, Neurodegeneration, Cerebrovascular disease, Survey, Cohorts, Small vessel disease
Published
2016

29. Current pharmacotherapy for Alzheimer's disease

Author

Lleo, A., Greenberg, S.M., and Growdon, J.H.

Subjects
Alzheimer's disease -- Diagnosis, Alzheimer's disease -- Drug therapy, Alzheimer's disease -- Product development, Alzheimer's disease -- Research, Health
Abstract

Five major categories of drugs used in the Alzheimer's disease (AD) treatment such as cholinergic treatment, antiglutamatergic treatment, vitamins and antioxidants and others are studied. Results show that the introduction of these drugs for AD in the past decade has been welcome but it does not detract from the need to improve symptomatic therapy and to develop neuroprotective drugs.

Published
2006

30. beta-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy

Author

Etten, E.S. van, Verbeek, M.M., Grond, J. van der, Zielman, R., Rooden, S. van, Zwet, E.W. van, Opstal, A.M. van, Haan, J., Greenberg, S.M., Buchem, M.A. van, Wermer, M.J., Terwindt, G.M., Etten, E.S. van, Verbeek, M.M., Grond, J. van der, Zielman, R., Rooden, S. van, Zwet, E.W. van, Opstal, A.M. van, Haan, J., Greenberg, S.M., Buchem, M.A. van, Wermer, M.J., and Terwindt, G.M.

Abstract

Contains fulltext : 170304.pdf (publisher's version ) (Closed access), OBJECTIVE: To investigate CSF biomarkers in presymptomatic and symptomatic mutation carriers with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a model for sporadic cerebral amyloid angiopathy, and to determine the earliest deposited form of beta-amyloid (Abeta). METHODS: HCHWA-D mutation carriers and controls were enrolled in the cross-sectional EDAN (Early Diagnosis of Amyloid Angiopathy Network) study. The HCHWA-D group was divided into symptomatic carriers with a previous intracerebral hemorrhage and presymptomatic carriers. CSF concentrations of Abeta40, Abeta42, total tau, and phosphorylated tau181 proteins were compared to those of controls of a similar age. Correlations between CSF biomarkers, MRI markers, and age were investigated with multivariate linear regression analyses. RESULTS: We included 10 symptomatic patients with HCHWA-D (mean age 55 +/- 6 years), 5 presymptomatic HCHWA-D carriers (mean age 36 +/- 13 years), 31 controls <50 years old (mean age 31 +/- 7 years), and 50 controls >/=50 years old (mean age 61 +/- 8 years). After correction for age, CSF Abeta40 and Abeta42 were significantly decreased in symptomatic carriers vs controls (median Abeta40 1,386 vs 3,867 ng/L, p < 0.001; median Abeta42 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Abeta40 3,501 vs 4,684 ng/L, p = 0.011; median Abeta42 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Abeta40 was associated with higher lobar microbleed count (p = 0.010), increasing white matter hyperintensity volume (p = 0.008), and presence of cortical superficial siderosis (p = 0.02). CONCLUSIONS: Decreased levels of CSF Abeta40 and Abeta42 occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both Abeta species as early steps in cerebral amyloid angiopathy pathogenesis. CSF Abeta40 and Abeta42 may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.

Published
2017

31. Genetic variants in CETP increase risk of intracerebral hemorrhage

Author

Anderson, C.D., Falcone, G.J., Phuah, C.L., Radmanesh, F., Brouwers, H.B., Battey, T.W., Biffi, A., Peloso, G.M., Liu, D.J., Ayres, A.M., Goldstein, J.N., Viswanathan, A., Greenberg, S.M., Selim, M., Meschia, J.F., Brown, D.L., Worrall, B.B., Silliman, S.L., Tirschwell, D.L., Flaherty, M.L., Kraft, P., Jagiella, J.M., Schmidt, H., Hansen, B.M., Jimenez-Conde, J., Giralt-Steinhauer, E., Elosua, R., Cuadrado-Godia, E., Soriano, C., Nieuwenhuizen, K.M. van, Klijn, C.J.M., Rannikmae, K., Samarasekera, N., Salman, R.A., Sudlow, C.L., Deary, I.J., Morotti, A., Pezzini, A., Pera, J., Urbanik, A., Pichler, A., Enzinger, C., Norrving, B., Montaner, J., Fernandez-Cadenas, I., Delgado, P., Roquer, J., Lindgren, A., Slowik, A., Schmidt, R., Kidwell, C.S., Kittner, S.J., Waddy, S.P., Langefeld, C.D., Abecasis, G., Willer, C.J., Kathiresan, S., Woo, D., Rosand, J., Anderson, C.D., Falcone, G.J., Phuah, C.L., Radmanesh, F., Brouwers, H.B., Battey, T.W., Biffi, A., Peloso, G.M., Liu, D.J., Ayres, A.M., Goldstein, J.N., Viswanathan, A., Greenberg, S.M., Selim, M., Meschia, J.F., Brown, D.L., Worrall, B.B., Silliman, S.L., Tirschwell, D.L., Flaherty, M.L., Kraft, P., Jagiella, J.M., Schmidt, H., Hansen, B.M., Jimenez-Conde, J., Giralt-Steinhauer, E., Elosua, R., Cuadrado-Godia, E., Soriano, C., Nieuwenhuizen, K.M. van, Klijn, C.J.M., Rannikmae, K., Samarasekera, N., Salman, R.A., Sudlow, C.L., Deary, I.J., Morotti, A., Pezzini, A., Pera, J., Urbanik, A., Pichler, A., Enzinger, C., Norrving, B., Montaner, J., Fernandez-Cadenas, I., Delgado, P., Roquer, J., Lindgren, A., Slowik, A., Schmidt, R., Kidwell, C.S., Kittner, S.J., Waddy, S.P., Langefeld, C.D., Abecasis, G., Willer, C.J., Kathiresan, S., Woo, D., and Rosand, J.

Abstract

Contains fulltext : 167830.pdf (Publisher’s version ) (Open Access), OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 x 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by approximately 2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 x 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.

Published
2016

32. The Vascular Impairment of Cognition Classification Consensus Study

Author

Skrobot, Olivia A., primary, O'Brien, John, additional, Black, Sandra, additional, Chen, Christopher, additional, DeCarli, Charles, additional, Erkinjuntti, Timo, additional, Ford, Gary A., additional, Kalaria, Rajesh N., additional, Pantoni, Leonardo, additional, Pasquier, Florence, additional, Roman, Gustavo C., additional, Wallin, Anders, additional, Sachdev, Perminder, additional, Skoog, Ingmar, additional, Taragano, F.E., additional, Kril, J., additional, Cavalieri, M., additional, Jellinger, K.A., additional, Kovacs, G.G., additional, Engelborghs, S., additional, Lafosse, C., additional, Bertolucci, P.H., additional, Brucki, S., additional, Caramelli, P., additional, Toledo Ferraz Alves, T.C., additional, Bocti, C., additional, Fulop, T., additional, Hogan, D.B., additional, Hsiung, G.R., additional, Kirk, A., additional, Leach, L., additional, Robillard, A., additional, Sahlas, D.J., additional, Guo, Q., additional, Tian, J., additional, Hokkanen, L., additional, Jokinen, H., additional, Benisty, S., additional, Deramecourt, V., additional, Hauw, J., additional, Lenoir, H., additional, Tsatali, M., additional, Tsolaki, M., additional, Sundar, U., additional, Coen, R.F., additional, Korczyn, A.D., additional, Altieri, M., additional, Baldereschi, M., additional, Caltagirone, C., additional, Caravaglios, G., additional, Di Carlo, A., additional, DI Piero, V., additional, Gainotti, G., additional, Galluzzi, S., additional, Logroscino, G., additional, Mecocci, P., additional, Moretti, D.V., additional, Padovani, A., additional, Fukui, T., additional, Ihara, M., additional, Mizuno, T., additional, Kim, S.Y., additional, Akinyemi, R., additional, Baiyewu, O., additional, Ogunniyi, A., additional, Szczudlik, A., additional, Bastos‐Leite, A.J., additional, Firmino, H., additional, Massano, J., additional, Verdelho, A., additional, Kruglov, L.S., additional, Ikram, M.K., additional, Kandiah, N., additional, Arana, E., additional, Barroso‐Ribal, J., additional, Calatayud, T., additional, Cruz‐Jentoft, A.J., additional, López‐Pousa, S., additional, Martinez‐Lage, P., additional, Mataro, M., additional, Börjesson‐Hanson, A., additional, Englund, E., additional, Laukka, E.J., additional, Qiu, C., additional, Viitanen, M., additional, Biessels, G.J., additional, Leeuw, F.‐E., additional, Heijer, T., additional, Exalto, L.G., additional, Kappelle, L.J., additional, Prins, N.D., additional, Richard, E., additional, Schmand, B., additional, Berg, E., additional, Flier, W.M., additional, Bilgic, B., additional, Allan, L.M., additional, Archer, J., additional, Attems, J., additional, Bayer, A., additional, Blackburn, D., additional, Brayne, C., additional, Bullock, R., additional, Connelly, P.J., additional, Farrant, A., additional, Fish, M., additional, Harkness, K., additional, Ince, P.G., additional, Langhorne, P., additional, Mann, J., additional, Matthews, F.E., additional, Mayer, P., additional, Pendlebury, S.T., additional, Perneczky, R., additional, Peters, R., additional, Smithard, D., additional, Stephan, B.C., additional, Swartz, J.E., additional, Todd, S., additional, Werring, D.J., additional, Wijayasiri, S.N., additional, Wilcock, G., additional, Zamboni, G., additional, Au, R., additional, Borson, S., additional, Bozoki, A., additional, Browndyke, J.N., additional, Corrada, M.M., additional, Crane, P.K., additional, Diniz, B.S., additional, Etcher, L., additional, Fillit, H., additional, Greenberg, S.M., additional, Grinberg, L.T., additional, Hurt, S.W., additional, Lamar, M., additional, Mielke, M., additional, Ott, B.R., additional, Perry, G., additional, Powers, W.J., additional, Ramos‐Estebanez, C., additional, Reed, B., additional, Roberts, R.O., additional, Romero, J.R., additional, Saykin, A.J., additional, Seshadri, S., additional, Silbert, L., additional, Stern, Y., additional, Zarow, C., additional, Ben‐Shlomo, Yoav, additional, Passmore, Anthony P., additional, Love, Seth, additional, and Kehoe, Patrick G., additional

Published
2016
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33. Effect of CTA Tube Current on Spot Sign Detection and Accuracy for Prediction of Intracerebral Hemorrhage Expansion

Author

Morotti, A., primary, Romero, J.M., additional, Jessel, M.J., additional, Brouwers, H.B., additional, Gupta, R., additional, Schwab, K., additional, Vashkevich, A., additional, Ayres, A., additional, Anderson, C.D., additional, Gurol, M.E., additional, Viswanathan, A., additional, Greenberg, S.M., additional, Rosand, J., additional, and Goldstein, J.N., additional

Published
2016
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35. Cerebral amyloid angiopathy burden associated with leukoaraiosis: A positron emission tomography/magnetic resonance imaging study

Author

Gurol, M.E., Viswanathan, A., Gidicsin, C., Hedden, T., Martinez-Ramirez, S., Dumas, A., Vashkevich, A., Ayres, A.M., Auriel, E., Etten, E. van, Becker, A., Carmasin, J., Schwab, K., Rosand, J., Johnson, K.A., and Greenberg, S.M.

Subjects
mental disorders
Abstract

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) 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

Published
2013

36. Cerebral microbleeds and cognitive functioning in the PROSPER study

Author

Es, A.C.G.M. van, Grond, J. van der, Craen, A.J.M. de, Westendorp, R.G.J., Bollen, E.L.E.M., Blauw, G.J., Greenberg, S.M., Buchem, M.A. van, and PROSPER Study Grp

Subjects
Brain Infarction, Male, medicine.medical_specialty, animal structures, Activities of daily living, Infarction, Audiology, Neuropsychological Tests, White matter, Executive Function, Memory, Risk Factors, Activities of Daily Living, medicine, Humans, Effects of sleep deprivation on cognitive performance, Cognitive skill, Prospective Studies, Prospective cohort study, Aged, Cerebral Hemorrhage, Aged, 80 and over, medicine.diagnostic_test, Reproducibility of Results, Magnetic resonance imaging, Cognition, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Physical therapy, Female, Neurology (clinical), Psychology, Cognition Disorders, Mental Status Schedule
Abstract

Objectives: Cerebral microbleeds (MBs) are an important indicator of cerebral small-vessel disease, and their prevalence increases with increasing age. Little is known about the functional consequences of MBs in the aging population. In this study we investigated whether the presence and location of MBs are associated with cognition in the PROSPER study. Methods: For 439 subjects the number and location (cortico-subcortical, deep white matter, basal ganglia, and infratentorial) of the MBs was recorded. Difference in cognitive performance between subjects with and without MBs was calculated by entering the variables sex, age, white matter hyperintensity volume, infarction, and MBs in a linear mixed model. Differences in cognition between subjects with and without one or more MBs at different anatomic locations were assessed using the same model. Results: We found that after correction for sex, age, white matter hyperintensity volume, and infarction, subjects with infratentorial MBs had a significantly lower score on the Immediate Picture-Word Learning test, Delayed Picture-Word Learning, and Instrumental Activities of Daily Living. Conclusions: Our data demonstrate that in elderly individuals at increased vascular risk, infratentorial MBs are associated with loss in cognitive functioning.

Published
2011

37. Outcome markers for clinical trials in cerebral amyloid angiopathy

Author

Greenberg, S.M. (Steven), Salman, R.A.S. (Rustam Al-Shahi), Biessels, G.J. (Geert Jan), Buchem, M.A. (Mark) van, Cordonnier, C. (Charlotte), Lee, J.-M. (Jin-Moo), Montaner, J. (Joan), Schneider, J.A. (Julie), Smith, E.E. (Eric), Vernooij, M.W. (Meike), Werring, D.J. (David), Greenberg, S.M. (Steven), Salman, R.A.S. (Rustam Al-Shahi), Biessels, G.J. (Geert Jan), Buchem, M.A. (Mark) van, Cordonnier, C. (Charlotte), Lee, J.-M. (Jin-Moo), Montaner, J. (Joan), Schneider, J.A. (Julie), Smith, E.E. (Eric), Vernooij, M.W. (Meike), and Werring, D.J. (David)

Abstract

Efforts are underway for early-phase trials of candidate treatments for cerebral amyloid angiopathy, an untreatable cause of haemorrhagic stroke and vascular cognitive impairment. A major barrier to these trials is the absence of consensus on measurement of treatment effectiveness. A range of potential outcome markers for cerebral amyloid angiopathy can be measured against the ideal criteria of being clinically meaningful, closely representative of biological progression, efficient for small or short trials, reliably measurable, and cost effective. In practice, outcomes tend either to have high clinical salience but low statistical efficiency, and thus more applicability for late-phase studies, or greater statistical efficiency but more limited clinical meaning. The most statistically efficient markers might be those that are potentially reversible with treatment, although their clinical significance remains unproven. Many of the candidate outcomes for cerebral amyloid angiopathy trials are probably applicable also to other small-vessel brain diseases.

Published
2014
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38. What is your diagnosis?

Author

VanderHart, D.J., Reese, D.J., Greenberg, S.M., VanderHart, D.J., Reese, D.J., and Greenberg, S.M.

Published
2014

39. CT angiography spot sign in intracerebral hemorrhage predicts active bleeding during surgery

Author

Brouwers, H.B., Raffeld, M.R., Nieuwenhuizen, K.M., Falcone, G.J., Ayres, A.M., McNamara, K.A., Schwab, K., Romero, J.M., Velthuis, B.K., Viswanathan, A., Greenberg, S.M., Ogilvy, C.S., Zwan, A. van der, Rinkel, G.J., Goldstein, J.N., Klijn, C.J., Rosand, J., Brouwers, H.B., Raffeld, M.R., Nieuwenhuizen, K.M., Falcone, G.J., Ayres, A.M., McNamara, K.A., Schwab, K., Romero, J.M., Velthuis, B.K., Viswanathan, A., Greenberg, S.M., Ogilvy, C.S., Zwan, A. van der, Rinkel, G.J., Goldstein, J.N., Klijn, C.J., and Rosand, J.

Abstract

Item does not contain fulltext, OBJECTIVE: To determine whether the CT angiography (CTA) spot sign marks bleeding complications during and after surgery for spontaneous intracerebral hemorrhage (ICH). METHODS: In a 2-center study of consecutive spontaneous ICH patients who underwent CTA followed by surgical hematoma evacuation, 2 experienced readers (blinded to clinical and surgical data) reviewed CTAs for spot sign presence. Blinded raters assessed active intraoperative and postoperative bleeding. The association between spot sign and active intraoperative bleeding, postoperative rebleeding, and residual ICH volumes was evaluated using univariable and multivariable logistic regression. RESULTS: A total of 95 patients met inclusion criteria: 44 lobar, 17 deep, 33 cerebellar, and 1 brainstem ICH; >/=1 spot sign was identified in 32 patients (34%). The spot sign was the only independent marker of active bleeding during surgery (odds ratio [OR] 3.4; 95% confidence interval [CI] 1.3-9.0). Spot sign (OR 4.1; 95% CI 1.1-17), female sex (OR 6.9; 95% CI 1.7-37), and antiplatelet use (OR 4.6; 95% CI 1.2-21) were predictive of postoperative rebleeding. Larger residual hematomas and postoperative rebleeding were associated with higher discharge case fatality (OR 3.4; 95% CI 1.1-11) and a trend toward increased case fatality at 3 months (OR 2.9; 95% CI 0.9-8.8). CONCLUSIONS: The CTA spot sign is associated with more intraoperative bleeding, more postoperative rebleeding, and larger residual ICH volumes in patients undergoing hematoma evacuation for spontaneous ICH. The spot sign may therefore be useful to select patients for future surgical trials.

Published
2014

40. Computed tomography angiography spot sign does not predict case fatality in aneurysmal subarachnoid hemorrhage with intraparenchymal extension

Author

Brouwers, H.B., Backes, D., Kimberly, W.T., Schwab, K., Romero, J.M., Velthuis, B.K., Klijn, C.J., Ogilvy, C.S., Regli, L., Greenberg, S.M., Rosand, J., Rinkel, G.J., Goldstein, J.N., Brouwers, H.B., Backes, D., Kimberly, W.T., Schwab, K., Romero, J.M., Velthuis, B.K., Klijn, C.J., Ogilvy, C.S., Regli, L., Greenberg, S.M., Rosand, J., Rinkel, G.J., and Goldstein, J.N.

Abstract

Item does not contain fulltext, BACKGROUND AND PURPOSE: Many patients with aneurysmal subarachnoid hemorrhage (SAH) with intraparenchymal extension develop early hematoma expansion, which is not explained by aneurysmal rerupture in half of cases. In patients with primary intracerebral hemorrhage, the computed tomography angiography (CTA) spot sign predicts hematoma expansion and poor outcome. We conducted a 2-center prospective cohort study to evaluate whether CTA spot sign predicts case fatality in aneurysmal subarachnoid hemorrhage with intraparenchymal extension. METHODS: We studied consecutive patients with aneurysmal subarachnoid hemorrhage with intraparenchymal extension. Two experienced readers, blinded to clinical data, analyzed CTAs for spot sign presence. We assessed the proportion of patients with the CTA spot sign and tested its association with in-hospital and 90-day case fatality, using univariable and multivariable logistic regression. RESULTS: In 32 of 236 patients (14%), we found at least 1 spot sign. Acute surgical hematoma evacuation with aneurysm occlusion occurred in 120 patients (51%). The overall in-hospital case fatality rate was 37%. The CTA spot sign was not associated with in-hospital (multivariable odds ratio, 0.51 [95% confidence interval, 0.06-3.26]) or 90-day (multivariable odds ratio, 0.59 [0.21-1.65]) case fatality. CONCLUSIONS: The found frequency of CTA spot signs is lower after aneurysmal than primary intracerebral hemorrhage and is not associated with in-hospital or 90-day case fatality in patients with aneurysmal subarachnoid hemorrhage with intraparenchymal extension.

Published
2013

42. Independent susceptibility markers for atrial fibrillation on chromosome 4q25

Author

Lubitz, S.A. (Steven), Sinner, M.F. (Moritz), Lunetta, K.L. (Kathryn), Makino, S. (Seiko), Pfeufer, A. (Arne), Rahman, R. (Rosanna), Veltman, C.E. (Caroline), Barnard, J. (John), Bis, J.C. (Joshua), Danik, S.P. (Stephan), Sonni, A. (Akshata), Shea, M.A. (Marisa), Del Monte, F. (Federica), Perz, S. (Siegfried), Muller, M. (Majon), Peters, A. (Annette), Greenberg, S.M. (Steven), Furie, K.L. (Karen), Noord, C. (Charlotte) van, Boerwinkle, E.A. (Eric), Stricker, B.H.Ch. (Bruno), Witteman, J.C.M. (Jacqueline), Smith, J.D. (Jonathan), Chung, M.K. (Mina), Heckbert, S.R. (Susan), Benjamin, E.J. (Emelia), Rosand, J. (Jonathan), Arking, D.E. (Dan), Alonso, A. (Alvaro), Kääb, S. (Stefan), Ellinor, P.T. (Patrick), Lubitz, S.A. (Steven), Sinner, M.F. (Moritz), Lunetta, K.L. (Kathryn), Makino, S. (Seiko), Pfeufer, A. (Arne), Rahman, R. (Rosanna), Veltman, C.E. (Caroline), Barnard, J. (John), Bis, J.C. (Joshua), Danik, S.P. (Stephan), Sonni, A. (Akshata), Shea, M.A. (Marisa), Del Monte, F. (Federica), Perz, S. (Siegfried), Muller, M. (Majon), Peters, A. (Annette), Greenberg, S.M. (Steven), Furie, K.L. (Karen), Noord, C. (Charlotte) van, Boerwinkle, E.A. (Eric), Stricker, B.H.Ch. (Bruno), Witteman, J.C.M. (Jacqueline), Smith, J.D. (Jonathan), Chung, M.K. (Mina), Heckbert, S.R. (Susan), Benjamin, E.J. (Emelia), Rosand, J. (Jonathan), Arking, D.E. (Dan), Alonso, A. (Alvaro), Kääb, S. (Stefan), and Ellinor, P.T. (Patrick)

Abstract

Background-: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. Methods and results-: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2×10) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. Conclusions-: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.

Published
2010
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43. Cerebrospinal fluid amyloid beta(40) is decreased in cerebral amyloid angiopathy.

Author

Verbeek, M.M., Kremer, H.P.H., Olde Rikkert, M.G.M., Domburg, P.H.M.F. van, Skehan, M.E., Greenberg, S.M., Verbeek, M.M., Kremer, H.P.H., Olde Rikkert, M.G.M., Domburg, P.H.M.F. van, Skehan, M.E., and Greenberg, S.M.

Abstract

Contains fulltext : 80131.pdf (publisher's version ) (Closed access), Cerebral amyloid angiopathy is caused by deposition of the amyloid beta protein in the cerebral vasculature. In analogy to previous observations in Alzheimer disease, we hypothesized that analysis of amyloid beta(40) and beta(42) proteins in the cerebrospinal fluid might serve as a molecular biomarker. We observed strongly decreased cerebrospinal fluid amyloid beta(40) (p < 0.01 vs controls or Alzheimer disease) and amyloid beta(42) concentrations (p < 0.001 vs controls and p < 0.05 vs Alzheimer disease) in cerebral amyloid angiopathy patients. The combination of amyloid beta(42) and total tau discriminated cerebral amyloid angiopathy from controls, with an area under the receiver operator curve of 0.98. Our data are consistent with neuropathological evidence that amyloid beta(40) as well as amyloid beta(42) protein are selectively trapped in the cerebral vasculature from interstitial fluid drainage pathways that otherwise transport amyloid beta proteins toward the cerebrospinal fluid.

Published
2009

44. Autologous anti-Aß antibodies in CAA-ri: New biomarker for detection of amyloid-related imaging abnormalities (ARIA) during Aß-disease modifying therapies for AD

Author

Piazza, F., primary, Greenberg, S.M., additional, Savoiardo, M., additional, Gardinetti, M., additional, Nitrini, R., additional, Sakaguchi, H., additional, Raicher, I., additional, Giaccone, G., additional, Chiapparini, L., additional, Brioschi, M., additional, Billo, G., additional, Colombo, A., additional, Lanzani, F., additional, Piscosquito, G., additional, Carriero, M., additional, Tagliavini, F., additional, Ferrarese, C., additional, and DiFrancesco, J.C., additional

Published
2013
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