Post-mortem assessment in vascular dementia: advances and aspirations

McAleese et al. BMC Medicine (2016) 14:129 DOI 10.1186/s12916-016-0676-5 Vascular Dementia OPINION Open Access Post-mortem assessment in vascular dementia: advances and aspirations Kirsty E. McAleese1, Irina Alafuzoff2, Andreas Charidimou3, Jacques De Reuck4, Lea T. Grinberg5,6, Atticus H. Hainsworth7, Tibor Hortobagyi8, Paul Ince9, Kurt Jellinger10, Jing Gao11, Raj N. Kalaria1, Gabor G. Kovacs12, Enikö Kövari13, Seth Love14, Mara Popovic15, Olivia Skrobot14, Ricardo Taipa16, Dietmar R. Thal17, David Werring18, Stephen B. Wharton9 and Johannes Attems1* Abstract Background: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. Discussion: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer’s disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer’s disease, vascular dementia and mixed Alzheimer’s disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. Conclusion: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses. Keywords: Vascular dementia, Vascular cognitive impairment, Cerebrovascular disease, Cerebrovascular lesions, Neuropathology, Magnetic resonance imaging, Post-mortem MRI, Mixed dementia Abbreviations: AD, Alzheimer’s disease; ARWMC, Age-Related White Matter Change score; AS, Atherosclerosis; Aβ, Amyloid-beta; BBB, Blood–brain barrier; CAA, Cerebral amyloid angiopathy; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; CMI, Cortical microinfarcts; CSF, Cerebrospinal fluid; CVD, Cerebrovascular disease; CVL, Cerebrovascular lesion; DLB, Dementia with Lewy bodies; DSM-V, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; EDN1, Endothelin 1; FTLD, Frontotemporal lobar degeneration; HPτ, Hyperphosphorylated tau; MAG, Myelin-associated glycoprotein; MRI, Magnetic resonance imaging; NFT, Neurofibrillary tangle; NIA– AA, National Institute on Aging–Alzheimer’s Association; PLP1, Proteolipid protein 1; SVD, Cerebral small vessel disease; SVD-AS, Small vessel disease atherosclerosis; SWI, Susceptibility-weighted imaging; VaD, Vascular dementia; VCI, Vascular cognitive impairment; VCING, Vascular Cognitive Impairment Neuropathological Guidelines; VEGF, Vascular endothelial growth factor; VWF, Von Willebrand factor; WMH, White matter hyperintensity; WML, White matter lesion * Correspondence: 1 Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. McAleese et al. BMC Medicine (2016) 14:129 Background Cerebrovascular disease (CVD) is highly prevalent in brains of the elderly. However, its impact on cognition is less clear and while prevalence rates of vascular dementia (VaD) are high in clinical studies CVD is rarely found to be the neuropathological correlate of clinical dementia in post-mortem studies. In this review we highlight some of the current problems in the diagnosis of CVD and present novel approaches that may prove helpful to elucidate the impact of CVD on cognitive performance. Methods This article was conceived at the 9th International Congress of Vascular Dementia by participants of the Neuropathology symposium following a discussion on current problems regarding the clinical and pathological diagnosis of VaD and CVD. Neuropathology of cerebrovascular disease Degenerative cerebral vessel pathology Three diseases of cerebral blood vessels mainly contribute to vascular cognitive impairment (VCI) and/or VaD: (1) atherosclerosis (AS), (2) small vessel disease (SVD) and (3) cerebral amyloid angiopathy (CAA). AS is a degenerative vessel disorder affecting large to medium sized cerebral arteries, most commonly the basilar artery and the circle of Willis [1], and results in the formation of atherosclerotic plaques due to accumulation of cholesterol-laden macrophages. Mature atherosclerotic plaques calcify, which may lead to narrowing of the artery lumen, and they are prone to rupture, resulting in subsequent thrombosis and potential thromboembolism [2]. SVD encompasses three degenerative alterations of the vessel walls of smaller cerebral arteries and arterioles. The first, SVD-AS, has a similar pathogenesis to large vessel AS but affects small intracerebral and leptomeningeal arteries (200–800 μm in diameter), which develop microatheromas. The second, lipohyalinosis, affects smaller arteries and arterioles (40–300 μm in diameter) and is characterised by asymmetric fibrosis/hyalinosis associated with cholesterol-laden macrophage infiltration that can occur with or without plasma protein leakage as a result of blood–brain barrier (BBB) breakdown. The third, arteriolosclerosis, presents as concentric hyaline thickening of small arterioles (40–150 μm) that may lead to stenosis of the blood vessel [3]. SVD initially manifests as lipohyalinosis and arteriolosclerosis in vessels of the basal ganglia, that is, the putamen and globus pallidus, and then in leptomeningeal arteries. By contrast, SVD-AS develops in the leptomeningeal arteries, and affects brain stem arterioles only in the end stages of SVD. Cortical vessels on the other hand remain relatively free of SVD pathology [4]. Page 2 of 16 CAA is characterised by the deposition of amyloidbeta (Aβ) (predominately Aβ-40) in the vessel walls of leptomeningeal and cortical arteries, arterioles, capillaries and, rar (...truncated)