Vascular cognitive impairment neuropathology guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment

doi:10.1093/brain/aww214 BRAIN 2016: 139; 2957–2969 | 2957 Vascular cognitive impairment neuropathology guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment Olivia A. Skrobot,1 Johannes Attems,2 Margaret Esiri,3 Tibor Hortobágyi,4,5 James W. Ironside,6 Rajesh N. Kalaria,2 Andrew King,7 George A. Lammie,8 David Mann,9 James Neal,10 Yoav Ben-Shlomo,11 Patrick G. Kehoe1 and Seth Love1 There are no generally accepted protocols for post-mortem assessment in cases of suspected vascular cognitive impairment. Neuropathologists from seven UK centres have collaborated in the development of a set of vascular cognitive impairment neuropathology guidelines (VCING), representing a validated consensus approach to the post-mortem assessment and scoring of cerebrovascular disease in relation to vascular cognitive impairment. The development had three stages: (i) agreement on a sampling protocol and scoring criteria, through a series of Delphi method surveys; (ii) determination of inter-rater reliability for each type of pathology in each region sampled (Gwet’s AC2 coefficient); and (iii) empirical testing and validation of the criteria, by blinded post-mortem assessment of brain tissue from 113 individuals (55 to 100 years) without significant neurodegenerative disease who had had formal cognitive assessments within 12 months of death. Fourteen different vessel and parenchymal pathologies were assessed in 13 brain regions. Almost perfect agreement (AC2 4 0.8) was found when the agreed criteria were used for assessment of leptomeningeal, cortical and capillary cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microhaemorrhage, larger haemorrhage, fibrinoid necrosis, microaneurysms, perivascular space dilation, perivascular haemosiderin leakage, and myelin loss. There was more variability (but still reasonably good agreement) in assessment of the severity of arteriolosclerosis (0.45–0.91) and microinfarcts (0.52–0.84). Regression analyses were undertaken to identify the best predictors of cognitive impairment. Seven pathologies—leptomeningeal cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space dilation and myelin loss—predicted cognitive impairment. Multivariable logistic regression determined the best predictive models of cognitive impairment. The preferred model included moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, moderate/severe arteriolosclerosis in occipital white matter, and at least one large infarct (area under the receiver operating characteristic curve 77%). The presence of 0, 1, 2 or 3 of these features resulted in predicted probabilities of vascular cognitive impairment of 16%, 43%, 73% or 95%, respectively. We have developed VCING criteria that are reproducible and clinically predictive. Assuming our model can be validated in an independent dataset, we believe that this will be helpful for neuropathologists in reporting a low, intermediate or high likelihood that cerebrovascular disease contributed to cognitive impairment. 1 Dementia Research Group, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Learning and Research Level 1, Southmead Hospital, Bristol, BS10 5NB, UK 2 Institute of Neuroscience and Newcastle Institute for Ageing, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK 3 Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, OX3 9DU, UK 4 Department of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary Received May 8, 2016. Revised July 01, 2016. Accepted July 3, 2016. Advance Access publication September 2, 2016 ß The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: 2958 | BRAIN 2016: 139; 2957–2969 O. A. Skrobot et al. 5 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, SE5 8AF, UK 6 Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, Midlothian, EH4 2XU, UK 7 Department of Clinical Neuropathology, First floor, Academic Neuroscience Building, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK 8 Institute of Cancer and Genetics, Cardiff University School of Medicine, Institute of Medical Genetics Building, Heath Park, Cardiff, CF14 4XN, UK 9 Institute of Brain, Behaviour and Mental Health, Clinical and Cognitive Neuroscience Research Group, University of Manchester, A304 Clinical Sciences Building, Salford Royal Hospital, Stott Lane, Salford M6 8HD, UK 10 Institute of Infection and Immunity, Cardiff University School of Medicine, Henry Wellcome Building, Heath Park, Cardiff CF14 4N, UK 11 School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK Correspondence to: Seth Love, Dementia Research Group, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Learning and Research level 1, Southmead Hospital, Bristol BS10 5NB, UK E-mail: Keywords: vascular cognitive impairment; vascular dementia; cerebrovascular disease; neuropathology Abbreviations: CAA = cerebral amyloid angiopathy; MMSE = Mini-Mental State Examination; ROC = receiver operating characteristic; VCI = vascular cognitive impairment; VCING = vascular cognitive impairment neuropathology guidelines Introduction The spectrum of vascular cognitive impairment (VCI) encompasses mild cognitive deficits that do not necessarily progress to dementia, and includes post-stroke dementia, vascular dementia, subcortical ischaemic vascular dementia, multi-infarct dementia and mixed dementias (i.e. co-morbid neurodegenerative and vascular pathology) (O’Brien et al., 2003). VCI may be suspected if there is widespread disease of cerebral blood vessels (e.g. atherosclerosis, arteriolosclerosis or cerebral amyloid angiopathy (CAA), focal or diffuse ischaemic changes or foci of haemorrhage, particularly in the absence of an alternative pathological explanation for cognitive decline (Ferrer, 2010). However, these pathological abnormalities often occur, at least to some degree, without apparent cognitive impairment (Fernando et al., 2004; Grinberg and Thal, 2010; Thal et al., 2012) and become more prevalent with increased age (Jellinger and Attems, 2010). They are also very common in patients with Alzheimer’s disease and other neurodegenerative dementias, and probably lower the threshold for neurodegenerative dementia (Esiri et al., 1999; Schneider et al., 2004, 2009). Various protocols and definitions have been proposed to identify and categorize different types of cerebrovascular pathology in relation to dementia (Esiri et al., 1997; Chalmers et al., 2003; Kalaria et al., 2004; (...truncated)