Andreas Charidimou1, Matthew P Frosch2, Rustam Al-Shahi Salman3, Jean-Claude Baron4, Charlotte Cordonnier5, Mar Hernandez-Guillamon6, Jennifer Linn7, Nicolas Raposo8, Mark Rodrigues3, Jose Rafael Romero9, Julie A Schneider10, Stefanie Schreiber11, Eric E Smith12, Mark A van Buchem13, Anand Viswanathan1, Frank A Wollenweber14, David J Werring15, Steven M Greenberg1. 1. Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 2. C.S. Kubik Laboratory of Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. 3. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 4. Department of Neurology, Sainte-Anne Hospital, Université Paris Descartes, INSERM U894, Paris, France. 5. Department of Neurology, INSERM U1171-Degenerative and Vascular Cognitive Disorders, CHU Lille, University of Lille, Lille, France. 6. Neurovascular Research Laboratory, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 7. Department of Neuroradiology, University Hospital Carl Gustav Carus', Technische Universität Dresden, Dresden, SN, Germany. 8. Department of Neurology, Toulouse University Medical Center, Toulouse, France. 9. Department of Neurology, Boston University School of Medicine, MA and the Framingham Heart Study, MA, USA. 10. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA. 11. German Center for Neurodegenerative Diseases, Magdeburg, Germany. 12. Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Canada. 13. Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. 14. Institute for Stroke and Dementia Research, Ludwig Maximilians University, Munich, Germany. 15. Stroke Research Centre, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
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.
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.
Authors: Andreas Charidimou; Gregoire Boulouis; Matthew P Frosch; Jean-Claude Baron; Marco Pasi; Jean Francois Albucher; Gargi Banerjee; Carmen Barbato; Fabrice Bonneville; Sebastian Brandner; Lionel Calviere; François Caparros; Barbara Casolla; Charlotte Cordonnier; Marie-Bernadette Delisle; Vincent Deramecourt; Martin Dichgans; Elif Gokcal; Jochen Herms; Mar Hernandez-Guillamon; Hans Rolf Jäger; Zane Jaunmuktane; Jennifer Linn; Sergi Martinez-Ramirez; Elena Martínez-Sáez; Christian Mawrin; Joan Montaner; Solene Moulin; Jean-Marc Olivot; Fabrizio Piazza; Laurent Puy; Nicolas Raposo; Mark A Rodrigues; Sigrun Roeber; Jose Rafael Romero; Neshika Samarasekera; Julie A Schneider; Stefanie Schreiber; Frank Schreiber; Corentin Schwall; Colin Smith; Levente Szalardy; Pascale Varlet; Alain Viguier; Joanna M Wardlaw; Andrew Warren; Frank A Wollenweber; Marialuisa Zedde; Mark A van Buchem; M Edip Gurol; Anand Viswanathan; Rustam Al-Shahi Salman; Eric E Smith; David J Werring; Steven M Greenberg Journal: Lancet Neurol Date: 2022-08 Impact factor: 59.935
Authors: Marco Pasi; Lansing Sugita; Li Xiong; Andreas Charidimou; Gregoire Boulouis; Thanakit Pongpitakmetha; Sanjula Singh; Christina Kourkoulis; Kristin Schwab; Steven M Greenberg; Christopher D Anderson; M Edip Gurol; Jonathan Rosand; Anand Viswanathan; Alessandro Biffi Journal: Neurology Date: 2020-10-16 Impact factor: 9.910
Authors: Giovanna Viticchi; Eleonora Potente; Lorenzo Falsetti; Marco Burattini; Marco Bartolini; Laura Buratti; Giuseppe Pelliccioni; Mauro Silvestrini Journal: Neurol Sci Date: 2022-02-24 Impact factor: 3.830
Authors: Xiaoyue Zhu; Feng Xu; Michael D Hoos; Hedok Lee; Helene Benveniste; William E Van Nostrand Journal: Int J Mol Sci Date: 2020-01-01 Impact factor: 5.923