Translational models for vascular cognitive impairment: a review including larger species

Hainsworth et al. BMC Medicine (2017) 15:16 DOI 10.1186/s12916-017-0793-9 Vascular Dementia MINIREVIEW Open Access Translational models for vascular cognitive impairment: a review including larger species Atticus H. Hainsworth1,2*, Stuart M. Allan3, Johannes Boltze4,5, Catriona Cunningham3, Chad Farris6,7, Elizabeth Head8, Masafumi Ihara9, Jeremy D. Isaacs1,2, Raj N. Kalaria10, Saskia A. M. J. Lesnik Oberstein11, Mark B. Moss6,7, Björn Nitzsche12,13,14, Gary A. Rosenberg15, Julie W. Rutten11,18, Melita Salkovic-Petrisic16 and Aron M. Troen17 Abstract Background: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. Methods: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). Conclusions: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required. Keywords: Vascular dementia, Vascular cognitive impairment, VCID, Experimental models, In vivo models, Translational models Introduction Vascular cognitive impairment (VCI) is a spectrum of clinical disease states [1–4] that range from poststroke mild cognitive impairment or dementia following a large artery stroke, through ‘sporadic’ small vessel disease (SVD), to pure genetic small vessel arteriopathy (CADASIL, CARASIL, COL4A1/4A2 mutations) [1, 5, 6]. The most common pathology underlying VCI is cerebral SVD, which leads to focal lacunar ischaemic infarcts, diffuse white matter lesions, and small haemorrhages in deep brain areas [3, 4]. These disease states manifest in a * Correspondence: 1 Clinical Neurosciences (J-0B) Molecular and Clinical Sciences Research Institute, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK 2 Department of Neurology, St George’s University Hospitals NHS Foundation Trust, London, UK Full list of author information is available at the end of the article spectrum of cognitive impairments. Further complexity arises as most clinical dementia in older persons is likely to be ‘mixed’ as a result of Alzheimer’s disease (AD) combined with vascular pathology [7, 8]. While characterisation of the neuropathological and radiological features of human VCI has improved over the last two decades (see adjoining articles) the molecular changes that underpin these characteristics remain elusive [6]. VCI currently lacks symptomatic treatment (comparable to donepezil for AD) and molecular targets (comparable to tau, amyloid precursor protein (APP) and β-amyloid (Aβ)). Because VCI arises from a spectrum of diseases, no single model will reproduce all pathological and cognitive features of SVD or VCI [6, 9–12] (Table 1). Furthermore, as with any animal model for dementia, the behavioural-cognitive phenotype of any given model can never fully represent human cognitive deficits. We define a ‘translational’ model as © The Author(s). 2017 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. NR NR Chronic hypoperfusion Baboons CAA in some models Diffuse WML; micro-Hge; Impaired BBB; microglial activation; NA HT (SHRSP) No motor deficits reported for BCAS NA Diffuse WML; microglial activation; Impaired BBB NA NA motor deficits NR on rotarod (GCAS mice). Working memory and reference memory deficits Chronic hypoperfusion Rats, mice Chronic HT: monkeys Diffuse WML in animals with UCCAo BBB changes, neuroinflammation. Ischaemic lesions and He; variable extent, location HT, dietary risk factors (high fat, high salt); hypo-perfusion Increased tortuosity Focal microinfarcts; No diffuse WML NA HT Sensori-motor NA deficits. Severity depends on lesion type, location, size Spatial memory Reduced impaired executive function, attention, short-term memory Chronic HT: SHRSP CAA, microBBB vascular dysfunction rarefaction; (some studies) BBB dysfunction in some models Micro-Hge in some models NA Co-morbidities e.g., mutant APP HHCy NA Impaired spatial learning, working memory HHCy Rats, mice CADASIL mice CAA. BBB dysfunction (on MRI) Aβ plaques, hippocampal neuronal loss, gliosis, micro-Hge Ventricles enlarged; brain atrophy; spontaneous lesions Age (obesity?) NR GOM deposits, impaired CVR; BBB dysfunction (some studies) WML vacuolisation; focal lesions in some aged animals NR Notch3 mutation Motor deficits in some aged animals Executive function, spatial NR learning and memory; visuo-spatial function, simple associative learning; open field activity, anxiety, dis-orientation; restlessness Aged dogs Clinical and pathological aspects of VCI are summarised in the first column. How selected animal models relate to these is summarised in the succeeding columns Abbreviations: BBB blood–brain-barrier, CVR cerebrovascular reactivity, GOM granular osmiophilic material, Hge haemorrhage, HHCy hyperhomocysteinemia, HT hypertension, NA not applicable, NR not reported, SHRSP stroke-prone spontaneously hypertensive rats, UCCAo unilateral common carotid artery occlusion WML white matter lesions Small vessel changes: NA Arteriolosclerosis, BBB dysfunction, CAA acute cell death in core; inflammatory response; lepto-meningeal and vascular re-organisation; delayed neuroinflammatory response in remote areas Focal ischaemic lesion; Focal ischaemic lesion; cortical and striatal atrophy and pseudo-cyst in chronic stage Brain gross pathology: atrophy, large infarcts.. Rapid cell death in ischaemic core. Leukocyte infiltration, neuro-inflammatory changes. Delayed damage in remote areas. some studies: age, HT, NR obesity Risk factors: age, hypertension, DM, obesity Brain neurop (...truncated)