Advertisement

Pre-clinical models of human cerebral small vessel disease: Utility for clinical application

      Abstract

      Small vessel disease (SVD) is a frequent cause of vascular cognitive impairment (VCI), encompassing vascular dementia. SVD is characterised by vasculopathy in deep penetrating arteries, diffuse white matter lesions (seen radiologically as leukoaraiosis) and focal, lacunar infarcts. Risk factors are age and hypertension but the pathogenic mechanism is unknown. Recent systematic reviews assessed experimental models of SVD or VCI. Chronically hypertensive animals (e.g. stroke-prone spontaneously hypertensive rats) display some features of SVD vasculopathy, such as vessel wall thickening. White matter lesions are seen in chronic hypoperfusion states (e.g. carotid occlusion/stenosis models). Small focal infarcts are induced by targeted ischemic challenge (surgical occlusion of a small artery, or stereotaxic endothelin-1 injection). Some degree of cognitive impairment is detectable in most cerebrovascular models, probably reflecting the broad neuroanatomical mapping of cognitive function. Important confounds to be considered in animal models of VCI are somatosensory impairment and hippocampal damage. Advances in clinical understanding will come from targeting specific questions on some aspect of SVD (e.g. vasculopathy, white matter damage) to the appropriate model in vivo. In vivo models of SVD are likely to benefit experimental studies of pathological processes, interactions with other brain disease states (such as Alzheimer disease), and therapeutic strategies.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Dozono K.
        • Ishii N.
        • Nishihara Y.
        • Horie A.
        An autopsy study of the incidence of lacunes in relation to age, hypertension, and arteriosclerosis.
        Stroke. 1991; 22: 993-996
        • Fisher C.M.
        The arterial lesions underlying lacunes.
        Acta Neuropathol. 1968; 12: 1-15
        • Rossi R.
        • Joachim C.
        • Geroldi C.
        • Combrinck M.
        • Esiri M.M.
        • Smith A.D.
        • et al.
        Association between subcortical vascular disease on CT and neuropathological findings.
        Int J Geriatr Psychiatry. 2004; 19: 690-695
        • Fernando M.S.
        • Simpson J.E.
        • Matthews F.
        • Brayne C.
        • Lewis C.E.
        • Barber R.
        • et al.
        White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury.
        Stroke. 2006; 37: 1391-1398
        • Schmidt R.
        • Schmidt H.
        • Haybaeck J.
        • Loitfelder M.
        • Weis S.
        • Cavalieri M.
        • et al.
        Heterogeneity in age-related white matter changes.
        Acta Neuropathol. 2011; 122: 171-185
        • Tomimoto H.
        Subcortical vascular dementia.
        Neurosci Res. 2011; 71: 193-199
        • Esiri M.M.
        • Wilcock G.K.
        • Morris J.H.
        Neuropathological assessment of the lesions of significance in vascular dementia.
        J Neurol Neurosurg Psychiatry. 1997; 63: 749-753
        • Kalaria R.N.
        • Erkinjuntti T.
        Small-vessel diseases of the brain.
        in: Wahlund L.O. Erkinjuntti T. Gauthier S. Vascular Cognitive Impairment in Clinical Practice. 1st ed. Cambridge University Press, 2009: 118-134
        • O'Brien J.T.
        • Erkinjuntti T.
        • Reisberg B.
        • Roman G.
        • Sawada T.
        • Pantoni L.
        • et al.
        Vascular cognitive impairment.
        Lancet Neurol. 2003; 2: 89-98
        • MRC-CFAS
        Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS).
        Lancet. 2001; 357: 169-175
        • Savva G.M.
        • Wharton S.B.
        • Ince P.G.
        • Forster G.
        • Matthews F.E.
        • Brayne C.
        Age, neuropathology, and dementia.
        N Engl J Med. 2009; 360: 2302-2309
        • Hainsworth A.H.
        • Markus H.S.
        Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review.
        J Cereb Blood Flow Metab. 2008; 28: 1877-1891
        • Bailey E.L.
        • McCulloch J.
        • Sudlow C.
        • Wardlaw J.M.
        Potential animal models of lacunar stroke: a systematic review.
        Stroke. 2009; 40: e451-e458
        • Bailey E.L.
        • Wardlaw J.M.
        • Graham D.
        • Dominiczak A.F.
        • Sudlow C.L.
        • Smith C.
        Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats.
        Neuropathol Appl Neurobiol. 2011; 37: 711-726
        • Jiwa N.S.
        • Garrard P.
        • Hainsworth A.H.
        Experimental models of vascular dementia and vascular cognitive impairment. A systematic review.
        J Neurochem. 2010; 115: 814-828
        • Joutel A.
        • Monet-Lepretre M.
        • Gosele C.
        • Baron-Menguy C.
        • Hammes A.
        • Schmidt S.
        • et al.
        Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease.
        J Clin Invest. 2010; 120: 433-445
        • Moss M.B.
        • Jonak E.
        Cerebrovascular disease and dementia: a primate model of hypertension and cognition.
        Alzheimers Dement. 2007; 3: S6-S15
        • Zhang K.
        • Sejnowski T.J.
        A universal scaling law between gray matter and white matter of cerebral cortex.
        Proc Natl Acad Sci U S A. 2000; 97: 5621-5626
        • Ndung'u M
        • Hartig W
        • Wegner F
        • Mwenda JM
        • Low RW
        • Akinyemi RO
        • et al.
        Cerebral Abeta(42) deposits and microvascular pathology in ageing baboons.
        Neuropathol Appl Neurobiol. 2012; 38: 487-499
        • Rhyu I.J.
        • Bytheway J.A.
        • Kohler S.J.
        • Lange H.
        • Lee K.J.
        • Boklewski J.
        • et al.
        Effects of aerobic exercise training on cognitive function and cortical vascularity in monkeys.
        Neuroscience. 2010; 167: 1239-1248
        • Kemper T.
        • Moss M.B.
        • Hollander W.
        • Prusty S.
        Microinfarction as a result of hypertension in a primate model of cerebrovascular disease.
        Acta Neuropathol (Berl). 1999; 98: 295-303
        • Kemper T.L.
        • Blatt G.J.
        • Killiany R.J.
        • Moss M.B.
        Neuropathology of progressive cognitive decline in chronically hypertensive rhesus monkeys.
        Acta Neuropathol (Berl). 2001; 101: 145-153
        • Fisher C.M.
        Lacunes: small, deep cerebral infarcts.
        Neurology. 1965; 15: 774-784
        • Sarti C.
        • Pantoni L.
        • Bartolini L.
        • Inzitari D.
        Cognitive impairment and chronic cerebral hypoperfusion: what can be learned from experimental models.
        J Neurol Sci. 2002; 203–204: 263-266
        • Yamori Y.
        • Horie R.
        • Handa H.
        • Sato M.
        • Fukase M.
        Pathogenetic similarity of strokes in stroke-prone spontaneously hypertensive rats and humans.
        Stroke. 1976; 7: 46-53
        • Yamori Y.
        • Horie R.
        Developmental course of hypertension and regional cerebral blood flow in stroke-prone spontaneously hypertensive rats.
        Stroke. 1977; 8: 456-461
        • Baumbach G.L.
        • Walmsley J.G.
        • Hart M.N.
        Composition and mechanics of cerebral arterioles in hypertensive rats.
        Am J Pathol. 1988; 133: 464-471
        • Nordborg C.
        • Fredriksson K.
        • Johansson B.B.
        The morphometry of consecutive segments in cerebral arteries of normotensive and spontaneously hypertensive rats.
        Stroke. 1985; 16: 313-320
        • Tagami M.
        • Nara Y.
        • Kubota A.
        • Sunaga T.
        • Maezawa H.
        • Fujino H.
        • et al.
        Ultrastructural characteristics of occluded perforating arteries in stroke-prone spontaneously hypertensive rats.
        Stroke. 1987; 18: 733-740
        • Lin J.X.
        • Tomimoto H.
        • Akiguchi I.
        • Wakita H.
        • Shibasaki H.
        • Horie R.
        White matter lesions and alteration of vascular cell composition in the brain of spontaneously hypertensive rats.
        Neuroreport. 2001; 12: 1835-1839
        • Maguire S.
        • Strittmatter R.
        • Chandra S.
        • Barone F.C.
        Stroke-prone rats exhibit prolonged behavioral deficits without increased brain injury: an indication of disrupted post-stroke brain recovery of function.
        Neurosci Lett. 2004; 354: 229-233
        • Schreiber S.
        • Bueche C.Z.
        • Garz C.
        • Kropf S.
        • Angenstein F.
        • Goldschmidt J.
        • et al.
        The pathologic cascade of cerebrovascular lesions in SHRSP: is erythrocyte accumulation an early phase?.
        J Cereb Blood Flow Metab. 2012; 32: 278-290
        • Lee J.M.
        • Zhai G.
        • Liu Q.
        • Gonzales E.R.
        • Yin K.
        • Yan P.
        • et al.
        Vascular permeability precedes spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats.
        Stroke. 2007; 38: 3289-3291
        • Ohta H.
        • Nishikawa H.
        • Kimura H.
        • Anayama H.
        • Miyamoto M.
        Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats.
        Neuroscience. 1997; 79: 1039-1050
        • Shibata M.
        • Yamasaki N.
        • Miyakawa T.
        • Kalaria R.N.
        • Fujita Y.
        • Ohtani R.
        • et al.
        Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion.
        Stroke. 2007; 38: 2826-2832
        • Nishio K.
        • Ihara M.
        • Yamasaki N.
        • Kalaria R.N.
        • Maki T.
        • Fujita Y.
        • et al.
        A mouse model characterizing features of vascular dementia with hippocampal atrophy.
        Stroke. 2010; 41: 1278-1284
        • Yoshizaki K.
        • Adachi K.
        • Kataoka S.
        • Watanabe A.
        • Tabira T.
        • Takahashi K.
        • et al.
        Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice.
        Exp Neurol. 2008; 210: 585-591
        • Kitamura A.
        • Fujita Y.
        • Oishi N.
        • Kalaria R.N.
        • Washida K.
        • Maki T.
        • et al.
        Selective white matter abnormalities in a novel rat model of vascular dementia 3.
        Neurobiol Aging. 2012; 33: 1012-1035
        • Chabriat H.
        • Joutel A.
        • Dichgans M.
        • Tournier-Lasserve E.
        • Bousser M.G.
        Cadasil.
        Lancet Neurol. 2009; 8: 643-653
        • Joutel A.
        Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature.
        Bioessays. 2011; 33: 73-80
        • Ayata C.
        CADASIL: experimental insights from animal models 15.
        Stroke. 2010; 41: S129-S134
        • Bailey E.L.
        • Smith C.
        • Sudlow C.L.
        • Wardlaw J.M.
        Is the spontaneously hypertensive stroke prone rat a pertinent model of sub cortical ischemic stroke? A systematic review.
        Int J Stroke. 2011; 6: 434-444
        • Lammie G.A.
        • Brannan F.
        • Slattery J.
        • Warlow C.
        Nonhypertensive cerebral small-vessel disease. An autopsy study.
        Stroke. 1997; 28: 2222-2229
        • Lammie G.A.
        Pathology of small vessel stroke.
        Br Med Bull. 2000; 56: 296-306
        • Pantoni L.
        Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges.
        Lancet Neurol. 2010; 9: 689-701
        • Giwa M.O.
        • Williams J.
        • Elderfield K.
        • Jiwa N.S.
        • Bridges L.R.
        • Kalaria R.N.
        • et al.
        Neuropathologic evidence of endothelial changes in cerebral small vessel disease.
        Neurology. 2012; 78: 167-174
        • Hachinski V.
        • Iadecola C.
        • Petersen R.C.
        • Breteler M.M.
        • Nyenhuis D.L.
        • Black S.E.
        • et al.
        National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards.
        Stroke. 2006; 37: 2220-2241
        • Tayebati S.K.
        Animal models of cognitive dysfunction.
        Mech Ageing Dev. 2006; 127: 100-108
        • Takeda S.
        • Sato N.
        • Uchio-Yamada K.
        • Sawada K.
        • Kunieda T.
        • Takeuchi D.
        • et al.
        Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes.
        Proc Natl Acad Sci U S A. 2010; 107: 7036-7041
        • Farkas E.
        • De Jong G.I.
        • Apro E.
        • Keuker J.I.
        • Luiten P.G.
        Calcium antagonists decrease capillary wall damage in aging hypertensive rat brain.
        Neurobiol Aging. 2001; 22: 299-309
        • Fujita Y.
        • Lin J.X.
        • Takahashi R.
        • Tomimoto H.
        Cilostazol alleviates cerebral small-vessel pathology and white-matter lesions in stroke-prone spontaneously hypertensive rats.
        Brain Res. 2008; 1203: 170-176
        • Hart M.N.
        • Heistad D.D.
        • Brody M.J.
        Effect of chronic hypertension and sympathetic denervation on wall/lumen ratio of cerebral vessels.
        Hypertension. 1980; 2: 419-423
        • Kitamura N.
        • Araya R.
        • Kudoh M.
        • Kishida H.
        • Kimura T.
        • Murayama M.
        • et al.
        Beneficial effects of estrogen in a mouse model of cerebrovascular insufficiency.
        PLoS One. 2009; 4: e5159
        • Henning E.C.
        • Warach S.
        • Spatz M.
        Hypertension-induced vascular remodeling contributes to reduced cerebral perfusion and the development of spontaneous stroke in aged SHRSP rats.
        J Cereb Blood Flow Metab. 2010; 30: 827-836
        • Holland P.R.
        • Bastin M.E.
        • Jansen M.A.
        • Merrifield G.D.
        • Coltman R.B.
        • Scott F.
        • et al.
        MRI is a sensitive marker of subtle white matter pathology in hypoperfused mice 3.
        Neurobiol Aging. 2011; 32: 2325-2326
        • Jalal F.Y.
        • Yang Y.
        • Thompson J.
        • Lopez A.C.
        • Rosenberg G.A.
        Myelin Loss Associated With Neuroinflammation in Hypertensive Rats.
        Stroke. 2012; 43: 1115-1122
        • Borras D.
        • Ferrer I.
        • Pumarola M.
        Age-related changes in the brain of the dog.
        Vet Pathol. 1999; 36: 202-211
        • Kilkenny C.
        • Browne W.J.
        • Cuthill I.C.
        • Emerson M.
        • Altman D.G.
        Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research.
        PLoS Biol. 2010; 8: e1000412
        • Lecrux C.
        • McCabe C.
        • Weir C.J.
        • Gallagher L.
        • Mullin J.
        • Touzani O.
        • et al.
        Effects of magnesium treatment in a model of internal capsule lesion in spontaneously hypertensive rats.
        Stroke. 2008; 39: 448-454
        • Tsukuda K.
        • Mogi M.
        • Li J.M.
        • Iwanami J.
        • Min L.J.
        • Sakata A.
        • et al.
        Amelioration of cognitive impairment in the type-2 diabetic mouse by the angiotensin II type-1 receptor blocker candesartan.
        Hypertension. 2007; 50: 1099-1105
        • Dong Y.F.
        • Kataoka K.
        • Toyama K.
        • Sueta D.
        • Koibuchi N.
        • Yamamoto E.
        • et al.
        Attenuation of brain damage and cognitive impairment by direct renin inhibition in mice with chronic cerebral hypoperfusion 3.
        Hypertension. 2011; 58: 635-642
        • Yang C.
        • Devisser A.
        • Martinez J.A.
        • Poliakov I.
        • Rosales-Hernandez A.
        • Ayer A.
        • et al.
        Differential impact of diabetes and hypertension in the brain: adverse effects in white matter 2.
        Neurobiol Dis. 2011; 42: 446-458
        • Arboleda-Velasquez J.F.
        • Manent J.
        • Lee J.H.
        • Tikka S.
        • Ospina C.
        • Vanderburg C.R.
        • et al.
        Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease 8.
        Proc Natl Acad Sci U S A. 2011; 108: E128-E135
        • Tang Y.
        • Nyengaard J.R.
        • Pakkenberg B.
        • Gundersen H.J.
        Age-induced white matter changes in the human brain: a stereological investigation.
        Neurobiol Aging. 1997; 18: 609-615
        • Duvernoy H.M.
        • Delon S.
        • Vannson J.L.
        Cortical blood vessels of the human brain.
        Brain Res Bull. 1981; 7: 519-579
        • Umansky F.
        • Juarez S.M.
        • Dujovny M.
        • Ausman J.I.
        • Diaz F.G.
        • Gomes F.
        • et al.
        Microsurgical anatomy of the proximal segments of the middle cerebral artery.
        J Neurosurg. 1984; 61: 458-467
        • Umansky F.
        • Gomes F.B.
        • Dujovny M.
        • Diaz F.G.
        • Ausman J.I.
        • Mirchandani H.G.
        • et al.
        The perforating branches of the middle cerebral artery. A microanatomical study.
        J Neurosurg. 1985; 62: 261-268
        • Linz W.
        • Jessen T.
        • Becker R.H.
        • Scholkens B.A.
        • Wiemer G.
        Long-term ACE inhibition doubles lifespan of hypertensive rats.
        Circulation. 1997; 96: 3164-3172