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Vascular dementia: why pathology is still important

Published online by Cambridge University Press:  24 October 2011

JW Neal
JW Neal*
Affiliation:
Department of Histopathology, School of Medicine, Cardiff University, UK
*
Address for correspondence: Dr JW Neal, Department of Histopathology, University of Cardiff Medical School, University Hospital of Wales, Cardiff CF14 4XN. Email: [email protected]
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Summary

Cerebral infarction, as the result of atheroma in large blood vessels, was one of the first explanations for dementia in older people. However, this was a relatively uncommon finding in those presenting with dementia and it was soon realized that subcortical infarctions due to non-atheromatous changes in small blood vessel walls were more important factors in cognitive decline. Furthermore, small vessel disease (SVD) producing lacunar infarcts (LI) and white matter changes increased dementia severity in individuals with only moderate Alzheimer's disease (AD) pathology. Magnetic resonance imaging (MRI) found subcortical (lacunar) ‘silent infarcts’ and white matter changes were surrogate markers for SVD and increased significantly the likelihood of developing dementia. Detailed histopathological studies of SVD showed it was in fact a range of pathologies, but the aetiology of the most common type (arteriosclerosis/lipohyalinosis) is difficult to explain. Theories to explain SVD include effects of hypertension, a leaky blood–brain barrier (BBB), amyloid accumulation, microbleeds, venous changes and endothelial inflammation. Endothelial expressed inflammatory molecules could represent potential biomarkers of SVD. Many of the risk factors associated with SVD are also present in AD, such as diabetes, systemic hypertension and ageing; all of these can target the endothelium with the potential to initiate SVD, resulting in ischaemic changes and neurodegeneration, including AD pathology.

Keywords

dementiacerebral ischaemiasmall vessellacunar infarctleukoaraiosis
Type
Neuropsychiatry of old age
Information
Reviews in Clinical Gerontology , Volume 22 , Issue 1 , February 2012 , pp. 35 - 51
Copyright
Copyright © Cambridge University Press 2011

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References

1Lobo, A, Launer, LJ, Fratiglioni, L. Neurological disease of the elderly research group. Prevalence of dementia and major subtypes in Europe: a collaborative study of population based cohorts. Neurology 2000; 54: S4–49.Google Scholar
2Roman, GC. Stroke, cognitive decline and vascular dementia: the silent epidemic of the 21st century. Stroke 2003; 22: 161–64.Google ScholarPubMed
3Roman, GC. Vascular dementia may be the most common form of dementia in the elderly. J Neurol Sci 2002; 15: 203–4.Google Scholar
4Jellinger, KA. The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropath 2007; 113: 349–88.CrossRefGoogle ScholarPubMed
5Snowdon, DA, Greiner, LH, Mortimer, JA. Brain infarction and the clinical expression of Alzheimer's disease. The Nun study. JAMA 1997; 277: 813–17.CrossRefGoogle ScholarPubMed
6Ross, GW, Petrovitch, H, White, LR. Characterization of risk factors for vascular dementia: the Honolulu-Asia Aging study. Neurology 1999; 53: 337–43.CrossRefGoogle ScholarPubMed
7Neuropathology Group Medical Research Council for Cognitive Function and Ageing study. Pathological correlates of late onset dementia in a multicentre, community base population in England and Wales. Neuropathology Group Medical Research Council for Cognitive Function and Ageing study (MRC CFAS). Lancet 2002; 359: 624–25.Google Scholar
8White, LR, Petrovich, H, Hardmann, J et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging study participants. Ann NY Acad Sci 2002; 977: 9–23.CrossRefGoogle ScholarPubMed
9Langa, KM, Foster, NL, Blarson, E. Mixed dementia: emerging concepts and therapeutic implications. JAMA 2004; 292: 2901–8.CrossRefGoogle ScholarPubMed
10Jellinger, KA, Attems, J. Neuropathological evaluation of mixed dementia. J Neurol Sci 2007; 257: 80–87.CrossRefGoogle ScholarPubMed
11Schneider, JA, Arvanitakis, Z, Bang, W, Bennet, DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007; 69: 2197–204.CrossRefGoogle ScholarPubMed
12Savva, GM, Wharton, SB, Ince, PG, Forster, G, Matthews, FE, Brayne, C; Medical Research Council Cognitive Function and Ageing Study. Age, neuropathology, and dementia. NEJM 2009; 360: 2302–9.CrossRefGoogle ScholarPubMed
13Brayne, C, Richardson, K, Matthews, FE, Fleming, J, Hunter, S, Xuereb, JH, Paykel, E, Mukaetova-Ladinska, EB, Huppert, FA, O'Sullivan, A, Dening, T; Cambridge City Over-75s Cohort Cc75c Study Neuropathology Collaboration. Neuropathological correlates of dementia in over 80 year-old brain donors from population-based Cambridge city over-75s cohort (CC75C). J Alzheimer's Dis 2009; 18: 645–58.CrossRefGoogle ScholarPubMed
14Jellinger, KA, Attems, J. Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropath 2010; 119: 421–33.CrossRefGoogle ScholarPubMed
15Erkinjuntti, T, Halatia, M, Palo, J, Sulkava, R, Paetau, A. Accuracy of the clinical diagnosis of vascular dementia: a prospective clinical and post mortem neuropathological study. J Neurol Neurosurg Psych 1988; 51: 1037–44.CrossRefGoogle ScholarPubMed
16Esiri, MM, Wilcock, GK, Morris, JH. Neuropathological assessment of the lesions of significance in vascular dementia. JNNP 1997; 63: 749–53.Google ScholarPubMed
17Markus, H. Small vessel versus large vessel vascular dementia. Risk factors and MRI findings. J Neurol 2008; 255: 1813–14.CrossRefGoogle Scholar
18Dolan, H, Crain, B, Troncoso, J, Resnick, SM, Zonderman, AB, O'Brien, RJ. Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging Cohort. Ann Neurol 2010; 68: 231–40.CrossRefGoogle ScholarPubMed
19Pantoni, L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9: 689–701.CrossRefGoogle ScholarPubMed
20Hachinski, VC, Lassen, NA, Marshall, J. Multi-infarct dementia: A cause of mental deterioration in the elderly. Lancet 1974; 27: 207–9.CrossRefGoogle Scholar
21Roher, AE, Esh, C, Kokjohn, TA, Kalback, W, Luehrs, DC, Seward, JD, Sue, LI, Beach, TG. Circle of Willis atherosclerosis is a risk factor for sporadic Alzheimer's disease. Arteriosclerosis Thromb Vasc Biol 2003; 23: 2055–62.CrossRefGoogle ScholarPubMed
22Beach, TG, Wilson, JR, Sue, LI. Circle of Willis atherosclerosis: association with Alzheimer's disease, neuritic plaques and neurofibrillary tangles. Acta Neuropath 2007; 113: 13–21.CrossRefGoogle ScholarPubMed
23Troncosco, JC, Zonderman, AB, Resnick, SM, Crain, B, Pletnikova, O, O'Brien, RJ. Effects of infarcts on dementia in the Baltimore Longitudinal Study of Aging. Ann Neurol 2008; 64: 168–76.CrossRefGoogle Scholar
24Luoto, TM, Haikonen, S, Haapasalo, H, Goebeler, S, Huhtala, H, Erkinjuntti, T, Karhunen, PJ. Large vessel cerebral atherosclerosis is not in direct association with neuropathological lesions of Alzheimer's disease. Eur Neurol 2009; 62: 93–98.CrossRefGoogle Scholar
25Esiri, MM, Nagy, Z, Smith, MZ, Barnetson, L, Smith, AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 1999; 345: 919–20.CrossRefGoogle Scholar
26Petrovitch, H, Ross, GW, Steinhorn, SC, Abbott, RD, Markesbery, W, Davis, D, Nelson, J, Hardman, J, Masaki, K, Vogt, MR, Launer, L, White, LR. AD lesions and infarcts in demented and non demented Japanese-American men. Ann Neurol 2005; 57: 98–103.CrossRefGoogle ScholarPubMed
27Fazekas, F, Kleinert, R, Offenbacher, H, Schmidt, R, Kleinert, G, Payer, F, Radner, H, Lechner, H. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993; 43: 1683–89.CrossRefGoogle ScholarPubMed
28Breteler, MM, van Swieten, JC, Bots, ML et al. Cerebral white matter lesions, vascular risk factors and cognitive function in population based study: the Rotterdam Study. Neurology 1994; 44: 1246–52.CrossRefGoogle ScholarPubMed
29Pantoni, L, Garcia, JH. The significance of cerebral white matter abnormalities 100 years after Binswangers report. Stroke 1995; 26: 1293–1301.CrossRefGoogle Scholar
30Prins, ND, van Dijk, EJ, den Heijer, T, Vermeer, SE, Koudstaal, PJ, Oudkerk, M, Hofman, A, Breteler, MM. Cerebral white matter lesions and the risk of dementia. Arch Neurol 2004; 61: 1531–34.CrossRefGoogle ScholarPubMed
31Vermeer, SE, Longstreth, WT Jr, Koudstaal, PJ. Silent brain infarcts: a systemic review. Lancet Neurology 2007; 6: 611–19.CrossRefGoogle Scholar
32Patel, B, Markus, HS. Magnetic resonance imaging in cerebral small vessel disease and its use as a surrogate disease marker. Int J Stroke 2011; 6: 47–59.CrossRefGoogle ScholarPubMed
33Gold, G, Giannakopoulos, Herrmann, FR, Bouras, C, Kovari, E. Identification of Alzheimer and vascular lesion thresholds for mixed dementia. Brain 2007; 130: 2830–36.CrossRefGoogle ScholarPubMed
34Wiederkehr, S, Simard, M, Fortin, C, van Reekum, R. Validity of the clinical diagnostic criteria for vascular dementia: a critical review. Part II. J Neuropsychiatry Clin Neurosci 2008; 20: 162–77.CrossRefGoogle ScholarPubMed
35Bronge, L, Wahlund, LO. White matter changes in dementia: does radiology matter? Br J Radiol 2007; 80: S115–20.CrossRefGoogle ScholarPubMed
36Pantoni, L, Gorelick, P. Advances in vascular cognitive Impairment. Stroke 2011; 42: 291–93.CrossRefGoogle ScholarPubMed
37Hassan, A, Hunt, BJ, O'Sullivan, M, Parmar, K, Bamford, JM, Briley, D, Brown, MM, Thomas, DJ, Markus, HS. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain 2003; 126: 424–32.CrossRefGoogle ScholarPubMed
38Zlokovic, BV. New therapeutic targets in neurovascular pathway in Alzheimer's disease. Neurotherapeutics 2008; 5: 409–14.CrossRefGoogle ScholarPubMed
39Grammas, P. Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease. J Neuroinflammation 2011; 8: 26.CrossRefGoogle ScholarPubMed
40Marchesi, VT. Alzheimer's disease begins as a disease of small blood vessels, damaged by oxidative induced inflammation and dysregulation of amyloid metabolism: implications for early detection and therapy. FASEB J 2011; 25: 5–13.CrossRefGoogle Scholar
41Tomlinson, BE, Blessed, G, Roth, M. Observations on the brains of non-demented old people. J Neurol Sci 1968; 7: 331–56.CrossRefGoogle ScholarPubMed
42Tomlinson, BE, Blessed, G, Roth, M. Observations on the brains of demented old people. J Neurol Sci 1970; 11: 205–42.CrossRefGoogle ScholarPubMed
43Hachinski, VC. Binswanger's disease. Neither Binswanger's or a disease. J Neurol Sci 1991; 103: 1.CrossRefGoogle ScholarPubMed
44Hachinski, VC. Preventable senility: a call for action against the vascular dementias. Lancet 1992; 430: 645–48.CrossRefGoogle Scholar
45Mirra, SS, Heyman, A, McKeel, D. The consortium to establish a registry of Alzheimer's disease (CERAD). Part II. Standardization of the neuropathological assessment of Alzheimer's disease. Neurology 1991; 41: 479–86.CrossRefGoogle Scholar
46Chui, H. Subcortical ischaemic vascular dementia. Neurol Clin 2007; 25: 717–30.CrossRefGoogle Scholar
47Khachaturian, Z. Diagnosis of Alzheimer disease. Arch Neurol 1985; 42: 1097–105.CrossRefGoogle Scholar
48Schneider, JA, Boyle, PA, Arvanitakis, Z, Bienias, JL, Bennet, DA. Subcortical infarcts, Alzheimer's disease pathology and memory function in older persons. Ann Neurol 2007; 62: 59–66.CrossRefGoogle ScholarPubMed
49Lopez, OL, Jagust, WJ, Dulberg, C, Becker, JT, DeKosky, ST, Fitzpatrick, A, Breitner, J, Lyketsos, C, Jones, B, Kawas, C, Carlson, M, Kuller, LH. Risk factors for mild cognitive impairment in the Cardiovascular Health Study. Cognition study 2. Arch Neurol 2003; 60: 1394–99.CrossRefGoogle Scholar
50Braak, H, Braak, E. Neuropathological staging of Alzheimer related changes. Acta Neuropath 1991; 82: 239–59.CrossRefGoogle ScholarPubMed
51Honig, LS, Kukull, W, Mayeux, R. Atherosclerosis and AD: analysis of data from US National Alzheimer's Coordinating Centre. Neurology 2005; 64: 494–500.CrossRefGoogle Scholar
52Hofman, A, Ott, A, Breteler, MM, Bots, ML, Slooter, AJ, van Harskamp, F, van Duijn, CN, Van Broeckhoven, C, Grobbee, DE. Atherosclerosis, apoprotein E and prevalence of dementia and Alzheimer's disease. Lancet 1997; 349: 151–54.CrossRefGoogle ScholarPubMed
53van Oijen, M, de Jong, FJ, Witteman, JC, Hofman, A, Koudstaal, PJ, Breteler, MM. Atherosclerosis and risk for dementia. Ann Neurol 2007; 61: 403–10.CrossRefGoogle ScholarPubMed
54Vermeer, SE, Prins, ND, den Heijer, T, Hofman, A, Koudstaal, PJ, Breteler, MM. Silent brain infarcts and the risk of dementia. NEJM 2003; 348: 1215–22.CrossRefGoogle ScholarPubMed
55Zhu, YC, Dufoil, C, Tzourio, C, Chabriat, H. Silent brain infarcts. A review of MRI diagnostic criteria. Stroke 2011; 42: 1140–45.CrossRefGoogle ScholarPubMed
56Wuerfel, J, Haertle, M, Waiczies, H, Tysiak, E, Bechmann, I, Wernecke, KD, Zipp, F, Paul, F. Perivascular spaces – MRI marker of inflammatory activity in the brain? Brain 2008; 131: 2332–40.CrossRefGoogle ScholarPubMed
57Van Djik, EJ, Prins, ND, Vrooman, HA. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences; Rotterdam scan study. Stroke 2008; 39: 2712–19.CrossRefGoogle Scholar
58Kobayashi, S, Okada, K, Koide, H, Bokura, H, Yamaguchi, S. Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke 1997; 28: 1932–39.CrossRefGoogle ScholarPubMed
59Prins, ND, van Dijk, EJ, den Heijer, T, Vermeer, SE, Jolles, J, Koudstaal, PJ, Hofman, A, Breteler, MM. Cerebral small vessel disease and decline in information processing speed, executive function and memory. Brain 2005; 128: 2034–41.CrossRefGoogle ScholarPubMed
60Gold, G, Kövari, E, Herrmann, FR, Canuto, A, Hof, PR, Michel, JP, Bouras, C, Giannakopoulos, P. Cognitive consequences of thalamic, basal ganglia and deep white matter lacunes in brain ageing and dementia. Stroke 2005; 36: 1184–88.CrossRefGoogle Scholar
61Tatemichi, TK, Steinke, W, Duncan, C, Bello, JA, Odel, JG, Behrens, MM, Hilal, SK, Mohr, JP. Paramedian thalamo peduncular infarction: clinical syndromes and magnetic resonance imaging. Ann Neurol 1992; 32: 162–71.CrossRefGoogle Scholar
62Benisty, S, Gouw, AA, Porcher, R, Madureira, S, Hernandez, K, Poggesi, A, van der Flier, WM, Van Straaten, EC, Verdelho, A, Ferro, J, Pantoni, L, Inzitari, D, Barkhof, F, Fazekas, F, Chabriat, H; LADIS Study group. Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white matter changes: the LADIS study. JNNP 2009; 80: 478–83.Google Scholar
63O'Sullivan, M. Leukoaraiosis. Pract Neurol 2008; 8: 26–38.CrossRefGoogle ScholarPubMed
64Pantoni, L. Leukoaraiosis: from an ancient term to an actual marker of poor prognosis. Stroke 2008; 39: 1401–3.CrossRefGoogle Scholar
65van der Flier, WM, van Straaten, EC, Barkhof, F, Verdelho, A, Madureira, S, Pantoni, L, Inzitari, D, Erkinjuntti, T, Crisby, M, Waldemar, G, Schmidt, R, Fazekas, F, Scheltens, P. Small vessel disease and general cognitive function in non-disabled elderly: the LADIS study. Stroke 2005; 36: 2116–20.CrossRefGoogle Scholar
66Pantoni, L, Basile, AM, Pracucci, G, Asplund, K, Bogousslavsky, J, Chabriat, H, Erkinjuntti, T, Fazekas, F, Ferro, JM, Hennerici, M, O'Brien, J, Scheltens, P, Visser, MC, Wahlund, LO, Waldemar, G, Wallin, A, Inzitari, D. Impact of age-related cerebral white matter changes on the transition to disability. The LADIS (Leukoaraiosis And Disability in Elderly) study: rationale, design methodology. Neuroepidemiology 2005; 24: 51–62.CrossRefGoogle Scholar
67Basile, AM, Pantoni, L, Pracucci, G, Asplund, K, Chabriat, H, Erkinjuntti, T, Fazekas, F, Ferro, JM, Hennerici, M, O'Brien, J, Scheltens, P, Visser, MC, Wahlund, LO, Waldemar, G, Wallin, A, Inzitari, D; LADIS Study Group. Age, hypertension and lacunar stroke are the major determinants of severity of age-related white matter changes. The LADIS (Leukoaraiosis and Disability in the Elderly) Study. Cerebrovascular Dis 2006; 21: 315–22.CrossRefGoogle Scholar
68Debette, S, Markus, HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systemic review and meta-analysis. BMJ 2010; 341: c3666.CrossRefGoogle Scholar
69Frisioni, GB, Gallizzi, S, Pantoni, L, Filippi, M. The effect on cognition of white matter lesions in the elderly; small but detectable. Nat Clin Pract Neurol 2007; 3: 620–27.CrossRefGoogle Scholar
70O'Sullivan, M, Lythgoe, DJ, Pereria, AC et al. Patterns of cerebral blood flow reduction in patients with ischaemic leukoarariosis. Neurology 2002; 59: 321–26.CrossRefGoogle Scholar
71Fernando, MS, Simpson, JE, Matthews, F, Brayne, C, Lewis, CE, Barber, R, Kalaria, RN, Forster, G, Esteves, F, Wharton, SB, Shaw, PJ, O'Brien, JT, Ince, PG; MRC Cognitive Function and Ageing Neuropathology Study Group. White matter lesions in an unselected cohort of elderly: molecular pathology suggests origin from chronic perfusion injury. Stroke 2006; 7: 1391–98.CrossRefGoogle Scholar
72Schmidt, R, Petrovic, HK, Ropele, S, Enzinger, C, Fazekas, F. Progression of leukoaraiosis and cognition. Stroke 2007; 38: 2619–25.CrossRefGoogle ScholarPubMed
73van Swieten, JC, van den Hout, JH, van Ketel, BA, Hijdra, A, Wokke, JH, van Gijn, J. Periventricular lesions in white matter on magnetic resonance imaging in the elderly. A morphometeric correlation with arteriosclerosis and dilated peri- vascular spaces. Brain 1991; 114: 761–74.CrossRefGoogle Scholar
74Kovari, E, Gold, G, Herrmann, FR. Cortical microinfarcts and demyelination significantly affect cognition in brain ageing. Stroke 2004; 35: 410–14.CrossRefGoogle Scholar
75Gold, G, Kövari, E, Herrmann, FR, Canuto, A, Hof, PR, Michel, JP, Bouras, C, Giannakopoulos, P. Cognitive consequences of thalamic, basal ganglia and deep white matter lacunes in brain ageing and dementia. Stroke 2005; 36: 1184–88.CrossRefGoogle Scholar
76Polvikoski, TM, van Straaten, EC, Barkhof, F, Sulkava, R, Aronen, HJ, Niinistö, L, Oinas, M, Scheltens, P, Erkinjuntti, T, Kalaria, RN. Frontal lobe white matter hyperintensities and neurofibrillary pathology in the oldest old. Neurology 2010; 75: 2071–78.CrossRefGoogle ScholarPubMed
77Brown, WR, Thorne, CR. Cerebral microvascular pathology in ageing and neurodegeneration. Neuropath Appl Neuro Biol 2001; 37: 56–74.CrossRefGoogle Scholar
78Riddle, DR, Sonntag, WE, Lichtenwalner, RJ. Microvascular plasticity in aging. Ageing Res Review 2003; 2: 149–68.CrossRefGoogle ScholarPubMed
79Black, JE, Polinsky, M, Greenough, WT. Progressive failure of cerebral angiogenesis supporting neural plasticity in aging rats. Neurobiol Aging 1989; 10: 353–58.CrossRefGoogle ScholarPubMed
80Rivard, A, Fabre, JE, Silver, M, Chen, D, Murohara, T, Kearney, M, Magner, M, Asahara, T, Isner, JM. Age dependent impairment of angiogenesis. Circulation 1999; 99: 111–20.CrossRefGoogle ScholarPubMed
81Frenkle–Denkberg, G, Gershon, D, Levy, AP. The function of hypoxia-inducible factor (HIF-1) is impaired in senescent mice. FEBS Lett 1999; 462: 341–44.CrossRefGoogle Scholar
82Van Beek, AH, Claasen, JA, Rikkert, MG, Jansen, RW. Cerebral autoregulation: an overview of current concepts and methodology with special focus on the elderly. J Cereb Blood Flow Metab 2008; 28: 1071–85.CrossRefGoogle ScholarPubMed
83Weller, RO, Subash, M, Preston, SD, Mazanti, I, Carare, RO. Perivascular drainage of amyloid beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol 2008; 8: 253–66.CrossRefGoogle Scholar
84Ince, P. Acquired forms of vascular dementia. In Kalimo, H (ed), Cerebrovascular Disease (Pathology and Genetics). Basel, ISN Neuropath Press; 2005.Google Scholar
85Ogata, J, Yamanishi, H, Ishibashi-Ueda, H. Role of cerebral vessels in ischaemic injury of the brain. Neuropath Appl Neuro Biol 2011; 37: 40–55.CrossRefGoogle ScholarPubMed
86Lammie, GA. Small vessel disease. In Kalimo, H (ed), Cerebrovascular Disease (Pathology and Genetics). Basel, ISN Neuropath Press; 2005.Google Scholar
87Grinberg, LT, Thal, DR. Vascular pathology in the aged human brain. Acta Neuropath 2010; 119: 277–90.CrossRefGoogle ScholarPubMed
88Jackson, C, Sudlow, C. Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and non-lacunar infarcts. Stroke 2005; 36: 891–904.CrossRefGoogle Scholar
89Jackson, CA, Hutchison, A, Dennis, MS, Wardlaw, JM, Lewis, SC, Sudlow, CL. Differences between ischaemic stroke subtypes in vascular outcomes support a distinct lacunar ischaemic stroke arteriopathy. A prospective hospital based study. Stroke 2009; 40: 3679–84.CrossRefGoogle ScholarPubMed
90Fisher, CM. Lacunes: small deep cerebral infarcts. Neurology 1964; 15: 774–84.CrossRefGoogle Scholar
91Lammie, GA, Brannan, F, Slatery, J, Wardlaw, C. Non-hypertensive small vessel disease. An autopsy study. Stroke 1997; 28: 2222–29.CrossRefGoogle Scholar
92Wardlaw, JM, Sandercock, P, Dennis, MS, Starr, J. Is breakdown of the blood brain barrier responsible for lacunar stroke, leukoaraiosis and dementia? Stroke 2003; 43: 806–12.CrossRefGoogle Scholar
93Wardlaw, JM. What causes lacunar strokes? JNNP 2005; 76: 617–19.Google Scholar
94Bogousslavsky, J. The plurality of subcortical infarction. Stroke 1992; 23: 629–31.CrossRefGoogle ScholarPubMed
95Bailey, EL, McCulloch, J, Sudlow, C, Wardlaw, JM. Potential animal models of lacunar stroke: a systematic review. Stroke 2009; 40: e451–58.CrossRefGoogle ScholarPubMed
96Jiwa, NS, Garrad, P, Hainsworth, AH. Experimental models of vascular dementia and vascular cognitive impairment: a systematic review. J Neurochem 2010; 115: 814–28.CrossRefGoogle ScholarPubMed
97Thompson, CS, Hakim, AM. Living beyond our physiological means: small vessel disease of the brain is an expression of a systematic failure of arteriolar function; a unifying hypothesis. Stroke 2009; 40: e322–30.CrossRefGoogle Scholar
98Black, S, Gao, FQ, Bilbao, J. Understanding white matter disease imaging. Pathological correlations in vascular cognitive impairment. Stroke 2009; 40 (suppl 1): S48–52.CrossRefGoogle ScholarPubMed
99Rosenberg, GA, Sullivan, N, Esiri, MM. White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke 2001; 32: 1162–68.CrossRefGoogle ScholarPubMed
100Rosenberg, GA. Inflammation and white matter damage in vascular cognitive impairment. Stroke 2009; 40: S20–23.CrossRefGoogle ScholarPubMed
101Fisher, M, Rench, S, Ji, P, Kim, RC. Cerebral microbleeds in the elderly. Stroke 2010; 41: 2782–85.CrossRefGoogle ScholarPubMed
102Viswanathan, A, Guichard, JP, Gschwendtner, A, Buffon, F, Cumurcuic, R, Boutron, C, Vicaut, E, Holtmannspötter, M, Pachai, C, Bousser, MG, Dichgans, M, Chabriat, H. Blood pressure and haemoglobin 1Ac are associated with micro haemorrhage in CADASIL: two centre cohort. Brain 2006; 129: 2375–83.CrossRefGoogle Scholar
103Xi, G, Greiser, RF, Keep, FR. The role of thrombin and thrombin receptors in ischaemic, haemorrhagic and traumatic brain injury: deleterious or protective. J Neurochem 2003; 84: 3–9.CrossRefGoogle ScholarPubMed
104Gingrich, MB, Traynelis, SF. Serine proteases and brain damage – is there a link? Trends Neurosci 2000; 23: 399–407.CrossRefGoogle ScholarPubMed
105Striggow, F, Riek, M, Breder, J, Henrich-Noack, P, Reymann, KG, Reiser, G. The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations. Proc Natl Acad Sci 2000; 97: 2264–69.CrossRefGoogle ScholarPubMed
106Huang, C, Ma, R, Sun, S, Wei, G, Fang, Y, Liu, R, Liu, G. JAK2-STAT3 signalling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro. J Neuroimmunol 2008; 204: 118–25.CrossRefGoogle ScholarPubMed
107Craft, S. The role of metabolic disorders in Alzheimer disease and vascular dementia. Arch Neurol 2009; 66: 300–5.CrossRefGoogle ScholarPubMed
108Panza, F, Frisardi, V, Capurso, C, Imbimbo, BP, Vendemiale, G, Santamato, A, D'Onofrio, G, Seripa, D, Sancarlo, D, Pilotto, A, Solfrizzi, V. Metabolic syndrome and cognitive impairment: current epidemiology and possible underlying mechanisms. J Alzheimer Dis 2010; 21: 691–724.CrossRefGoogle ScholarPubMed
109Nunomura, A, Castellani, RJ, Zhu, X. Involvement of oxidative stress in Alzheimer disease. J Neuropath Exp Neurol 2006; 65: 631–41.CrossRefGoogle ScholarPubMed
110Ciallela, JR, Figueiredo, H, Smith-Swintosky, V, McGillis, JP. Thrombin induces surface and intercellular secretion of amyloid precursor protein from human endothelial cells. Thromb Haemost 1999; 81: 630–37.Google Scholar
111Markus, HS, Hunt, B, Palmer, K, Enzinger, C, Schmidt, H, Schmidt, R. Markers of endothelial and haemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of Austrian stroke prevention study. Stroke 2005; 36: 1410–14.CrossRefGoogle ScholarPubMed
112Schmidt, R, Schmidt, H, Curb, JD, Masaki, K, White, LR, Launer, LJ. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging study. Ann Neurol 2002; 52: 168–74.CrossRefGoogle ScholarPubMed
113Knottnerus, IL, Govers-Riemslag, JW, Hamulyak, K, Rouhl, RP, Staals, J, Spronk, HM, van Oerle, R, van Raak, EP, Lodder, J, ten Cate, H, van Oostenbrugge, RJ. Endothelial activation in lacunar stroke subtypes. Stroke 2010; 41: 1617–22.CrossRefGoogle ScholarPubMed
114Benchenane, K, Berezowski, V, Ali, C, Fernández-Monreal, M, López-Atalaya, JP, Brillault, J, Chuquet, J, Nouvelot, A, MacKenzie, ET, Bu, G, Cecchelli, R, Touzani, O, Vivien, D. Tissue type-plasminogen activator crosses the intact blood brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation 2005; 111: 2241–49.CrossRefGoogle ScholarPubMed
115Fornage, M, Chiang, YA, O'Meara, ES, Psaty, BM, Reiner, AP, Siscovick, DS, Tracy, RP, Longstreth, WT Jr. Biomarkers of inflammation and MRI-defined small vessel disease of the brain. The Cardiovascular Health Study. Stroke 2008; 39: 1952–59.CrossRefGoogle Scholar
116Hoshi, T, Kitagawa, K, Yamagami, H, Furukado, S, Hougaku, H, Hori, M. Relation between interleukin-6 level and subclinical intracranial large artery atherosclerosis. Atherosclerosis 2008; 197: 326–32.CrossRefGoogle ScholarPubMed