Invited Review
Post-stroke cognitive decline: an update and perspectives for clinical research
M. Brainin,
J. Tuomilehto,
W.-D. Heiss,
N. M. Bornstein,
P. M. W. Bath,
Y. Teuschl,
E. Richard,
A. Guekht,
T. Quinn,
for
the Post Stroke Cognition Study Group,
Corresponding Author
M. Brainin
Department for Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria
Correspondence: M. Brainin, Department for Clinical Neurosciences and Preventive Medicine, Danube University Krems, Dr.-Karl-Dorrek-Str. 30, A-3500 Krems, Austria (tel.: +43 2732893 2814; fax: +43 2732893 4810; e-mail: [email protected]).Search for more papers by this authorJ. Tuomilehto
Center for Vascular Prevention, Danube University Krems, Krems, Austria
Search for more papers by this authorW.-D. Heiss
Max Planck Institute for Neurological Research, Cologne, Germany
Search for more papers by this authorN. M. Bornstein
Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Search for more papers by this authorP. M. W. Bath
Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
Search for more papers by this authorY. Teuschl
Department for Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria
Search for more papers by this authorE. Richard
Department of Neurology, University of Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorA. Guekht
Moscow Research and Clinical Center for Neuropsychiatry, Moscow, Russia
Search for more papers by this authorT. Quinn
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
Search for more papers by this authorthe Post Stroke Cognition Study Group
See the Acknowledgements.
Search for more papers by this authorM. Brainin,
J. Tuomilehto,
W.-D. Heiss,
N. M. Bornstein,
P. M. W. Bath,
Y. Teuschl,
E. Richard,
A. Guekht,
T. Quinn,
for
the Post Stroke Cognition Study Group,
Corresponding Author
M. Brainin
Department for Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria
Correspondence: M. Brainin, Department for Clinical Neurosciences and Preventive Medicine, Danube University Krems, Dr.-Karl-Dorrek-Str. 30, A-3500 Krems, Austria (tel.: +43 2732893 2814; fax: +43 2732893 4810; e-mail: [email protected]).Search for more papers by this authorJ. Tuomilehto
Center for Vascular Prevention, Danube University Krems, Krems, Austria
Search for more papers by this authorW.-D. Heiss
Max Planck Institute for Neurological Research, Cologne, Germany
Search for more papers by this authorN. M. Bornstein
Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Search for more papers by this authorP. M. W. Bath
Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
Search for more papers by this authorY. Teuschl
Department for Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria
Search for more papers by this authorE. Richard
Department of Neurology, University of Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorA. Guekht
Moscow Research and Clinical Center for Neuropsychiatry, Moscow, Russia
Search for more papers by this authorT. Quinn
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
Search for more papers by this authorthe Post Stroke Cognition Study Group
See the Acknowledgements.
Search for more papers by this authorAbstract
The close relationship between stroke and dementia is an important health issue. Ischaemic stroke can facilitate the onset of vascular dementia as well as aggravate pre-existing cognitive decline. The onset of cognitive decline may become manifest immediately following the onset of ischaemic stroke, but often there is a delay in the development of cognitive decline after a stroke. This delay can be seen as a therapeutic time window allowing interventions to be applied to preserve cognition following stroke. Both neurodegenerative and vascular mechanisms are activated and probably result in overlapping processes within the neurovascular unit. This review focuses on the incidence and prevalence of cognitive decline following stroke, predisposing stroke aetiologies, pre-stroke decline, imaging factors and biomarkers. Outcomes are discussed in relation to timing of assessment and neuropsychological tests used for evaluation of cognitive decline in ischaemic stroke patients. Including such tests in routine evaluations of stroke patients after some weeks or months is recommended. Finally, an outlook on ongoing and planned intervention trials is added and some recommendations for future research are proposed.
References
- 1Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet 2014; 383: 245–254.
- 2Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol 2009; 8: 1006–1018.
- 3Olesen J, Gustavsson A, Svensson M, et al. The economic cost of brain disorders in Europe. Eur J Neurol 2012; 19: 155–162.
- 4Kalaria RN. Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathological studies in humans. Stroke 2012; 43: 2526–2534.
- 5Hénon H, Pasquier F, Leys D. Poststroke dementia. Cerebrovasc Dis 2006; 22: 61–70.
- 6Kokmen E, Whisnant JP, O'Fallon WM, Chu CP, Beard CM. Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960–1984). Neurology 1996; 46: 154–159.
- 7Ballard C, Rowan E, Stephens S, Kalaria R, Kenny RA. Prospective follow-up study between 3 and 15 months after stroke: improvements and decline in cognitive function among dementia-free stroke survivors >75 years of age. Stroke 2003; 34: 2440–2444.
- 8Popović IM, Serić V, Demarin V. Mild cognitive impairment in symptomatic and asymptomatic cerebrovascular disease. J Neurol Sci 2007; 257: 185–193.
- 9Gottesman RF, Hillis AE. Predictors and assessment of cognitive dysfunction resulting from ischaemic stroke. Lancet Neurol 2010; 9: 895–905.
- 10Schaapsmeerders P, Maaijwee NAM, van Dijk EJ, et al. Long-term cognitive impairment after first-ever ischemic stroke in young adults. Stroke 2013; 44: 1621–1628.
- 11Appelros P, Andersson AG. Changes in Mini Mental State Examination score after stroke: lacunar infarction predicts cognitive decline. Eur J Neurol 2006; 13: 491–495.
- 12Makin SDJ, Turpin S, Dennis MS, Wardlaw JM. Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence and comparison with other stroke subtypes. J Neurol Neurosurg Psychiatry 2013; 84: 893–900.
- 13Rostamian S, Mahinrad S, Stijnen T, Sabayan B, de Craen AJM. Cognitive impairment and risk of stroke: a systematic review and meta-analysis of prospective cohort studies. Stroke 2014; 45: 1342–1348.
- 14Wang Q, Capistrant BD, Ehntholt A, Glymour MM. Long-term rate of change in memory functioning before and after stroke onset. Stroke 2012; 43: 2561–2566.
- 15Koistinaho M, Koistinaho J. Interactions between Alzheimer's disease and cerebral ischemia – focus on inflammation. Brain Res Brain Res Rev 2005; 48: 240–250.
- 16Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS. Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology 2005; 64: 834–841.
- 17Del Ser T, Hachinski V, Merskey H, Munoz DG. Alzheimer's disease with and without cerebral infarcts. J Neurol Sci 2005; 231: 3–11.
- 18Huang K-L, Lin K-J, Ho M-Y, et al. Amyloid deposition after cerebral hypoperfusion: evidenced on [(18)F]AV-45 positron emission tomography. J Neurol Sci 2012; 319: 124–129.
- 19Lee MJ, Seo SW, Na DL, et al. Synergistic effects of ischemia and β-amyloid burden on cognitive decline in patients with subcortical vascular mild cognitive impairment. JAMA Psychiatry 2014; 71: 412–422.
- 20Whitehead SN, Cheng G, Hachinski VC, Cechetto DF. Progressive increase in infarct size, neuroinflammation, and cognitive deficits in the presence of high levels of amyloid. Stroke 2007; 38: 3245–3250.
- 21Gerhard A, Schwarz J, Myers R, Wise R, Banati RB. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. NeuroImage 2005; 24: 591–595.
- 22Thiel A, Heiss W-D. Imaging of microglia activation in stroke. Stroke 2011; 42: 507–512.
- 23Hughes JL, Beech JS, Jones PS, Wang D, Menon DK, Baron JC. Mapping selective neuronal loss and microglial activation in the salvaged neocortical penumbra in the rat. NeuroImage 2010; 49: 19–31.
- 24Okello A, Edison P, Archer HA, et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology 2009; 72: 56–62.
- 25Mok V, Leung EYL, Chu W, et al. Pittsburgh compound B binding in poststroke dementia. J Neurol Sci 2010; 290: 135–137.
- 26Thiel A, Cechetto DF, Heiss W-D, Hachinski V, Whitehead SN. Amyloid burden, neuroinflammation, and links to cognitive decline after ischemic stroke. Stroke 2014; 45: 2825–2829.
- 27DeKosky ST, Marek K. Looking backward to move forward: early detection of neurodegenerative disorders. Science 2003; 302: 830–834.
- 28Pakkenberg B, Pelvig D, Marner L, et al. Aging and the human neocortex. Exp Gerontol 2003; 38: 95–99.
- 29Pannese E. Morphological changes in nerve cells during normal aging. Brain Struct Funct 2011; 216: 85–89.
- 30Leys D, Hénon H, Mackowiak-Cordoliani M-A, Pasquier F. Poststroke dementia. Lancet Neurol 2005; 4: 752–759.
- 31Potter G, Doubal F, Jackson C, Sudlow C, Dennis M, Wardlaw J. Associations of clinical stroke misclassification (‘clinical-imaging dissociation’) in acute ischemic stroke. Cerebrovasc Dis 2010; 29: 395–402.
- 32Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013; 12: 822–838.
- 33Schmidt R, Ropele S, Ferro J, et al. Diffusion-weighted imaging and cognition in the leukoariosis and disability in the elderly study. Stroke 2010; 41: e402–e408.
- 34Yang J, Wong A, Wang Z, et al. Risk factors for incident dementia after stroke and transient ischemic attack. Alzheimers Dement 2014; pii: S1552-5260(14)00004-1. doi: 10.1016/j.jalz.2014.01.003 [Epub ahead of print].
- 35Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997; 277: 813–817.
- 36Breier JI, Hasan KM, Zhang W, Men D, Papanicolaou AC. Language dysfunction after stroke and damage to white matter tracts evaluated using diffusion tensor imaging. AJNR Am J Neuroradiol 2008; 29: 483–487.
- 37Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia. A cause of mental deterioration in the elderly. Lancet 1974; 2: 207–210.
- 38Heiss W-D, Zimmermann-Meinzingen S. PET imaging in the differential diagnosis of vascular dementia. J Neurol Sci 2012; 322: 268–273.
- 39Bu G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 2009; 10: 333–344.
- 40Davidson Y, Gibbons L, Purandare N, et al. Apolipoprotein E epsilon4 allele frequency in vascular dementia. Dement Geriatr Cogn Disord 2006; 22: 15–19.
- 41Hsiung G-YR, Sadovnick AD, Feldman H. Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging. CMAJ 2004; 171: 863–867.
- 42Mortimer JA, Snowdon DA, Markesbery WR. The effect of APOE-epsilon4 on dementia is mediated by Alzheimer neuropathology. Alzheimer Dis Assoc Disord 2009; 23: 152–157.
- 43Rippon GA, Tang MX, Lee JH, Lantigua R, Medrano M, Mayeux R. Familial Alzheimer disease in Latinos: interaction between APOE, stroke, and estrogen replacement. Neurology 2006; 66: 35–40.
- 44Jin YP, Østbye T, Feightner JW, Di Legge S, Hachinski V. Joint effect of stroke and APOE 4 on dementia risk: the Canadian Study of Health and Aging. Neurology 2008; 70: 9–16.
- 45Qian L, Ding L, Cheng L, et al. Early biomarkers for post-stroke cognitive impairment. J Neurol 2012; 259: 2111–2118.
- 46Kölsch H, Jessen F, Freymann N, et al. ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia. Neurosci Lett 2005; 377: 37–39.
- 47Miners JS, Ashby E, Van Helmond Z, et al. Angiotensin-converting enzyme (ACE) levels and activity in Alzheimer's disease, and relationship of perivascular ACE-1 to cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 2008; 34: 181–193.
- 48Hassan A, Lansbury A, Catto AJ, et al. Angiotensin converting enzyme insertion/deletion genotype is associated with leukoaraiosis in lacunar syndromes. J Neurol Neurosurg Psychiatry 2002; 72: 343–346.
- 49Szolnoki Z, Maasz A, Magyari L, et al. Coexistence of angiotensin II type-1 receptor A1166C and angiotensin-converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke. Neuromolecular Med 2006; 8: 353–360.
- 50Bartrés-Faz D, Junqué C, Clemente IC, et al. Angiotensin I converting enzyme polymorphism in humans with age-associated memory impairment: relationship with cognitive performance. Neurosci Lett 2000; 290: 177–180.
- 51Richard F, Berr C, Amant C, Helbecque N, Amouyel P, Alpérovitch A. Effect of the angiotensin I-converting enzyme I/D polymorphism on cognitive decline. The EVA Study Group. Neurobiol Aging 2000; 21: 75–80.
- 52Bour AMJJ, Rasquin SMC, Baars L, et al. The effect of the APOE-epsilon4 allele and ACE-I/D polymorphism on cognition during a two-year follow-up in first-ever stroke patients. Dement Geriatr Cogn Disord 2010; 29: 534–542.
- 53Baum L, Chen X, Cheung WS, et al. Polymorphisms and vascular cognitive impairment after ischemic stroke. J Geriatr Psychiatry Neurol 2007; 20: 93–99.
- 54Arpa A, del Ser T, Goda G, Barba R, Bornstein B. Apolipoprotein E, angiotensin-converting enzyme and alpha-1-antichymotrypsin genotypes are not associated with post-stroke dementia. J Neurol Sci 2003; 210: 77–82.
- 55Slooter AJ, Tang MX, van Duijn CM, et al. Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation. JAMA 1997; 277: 818–821.
- 56Khedr EM, Hamed SA, El-Shereef HK, et al. Cognitive impairment after cerebrovascular stroke: relationship to vascular risk factors. Neuropsychiatr Dis Treat 2009; 5: 103–116.
- 57Hankey GJ, Ford AH, Yi Q, et al. Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis. Stroke 2013; 44: 2232–2239.
- 58Karlsson H, Ahlborg B, Dalman C, Hemmingsson T. Association between erythrocyte sedimentation rate and IQ in Swedish males aged 18–20. Brain Behav Immun 2010; 24: 868–873.
- 59Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 2009; 66: 300–305.
- 60Eikelenboom P, van Exel E, Hoozemans JJM, et al. Neuroinflammation – an early event in both the history and pathogenesis of Alzheimer's disease. Neurodegener Dis 2010; 7: 38–41.
- 61Schram MT, Euser SM, de Craen AJM, et al. Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc 2007; 55: 708–716.
- 62Hoth KF, Haley AP, Gunstad J, et al. Elevated C-reactive protein is related to cognitive decline in older adults with cardiovascular disease. J Am Geriatr Soc 2008; 56: 1898–1903.
- 63Kliper E, Bashat DB, Bornstein NM, et al. Cognitive decline after stroke: relation to inflammatory biomarkers and hippocampal volume. Stroke 2013; 44: 1433–1435.
- 64Rothenburg LS, Herrmann N, Swardfager W, et al. The relationship between inflammatory markers and post stroke cognitive impairment. J Geriatr Psychiatry Neurol 2010; 23: 199–205.
- 65Gold AB, Herrmann N, Swardfager W, et al. The relationship between indoleamine 2,3-dioxygenase activity and post-stroke cognitive impairment. J Neuroinflammation 2011; 8: 17.
- 66Quinn TJ, Dawson J, Walters MR, Lees KR. Functional outcome measures in contemporary stroke trials. Int J Stroke 2009; 4: 200–205.
- 67Hennerici MG. What are the mechanisms for post-stroke dementia? Lancet Neurol 2009; 8: 973–975.
- 68Oldenbeuving AW, de Kort PLM, Jansen BPW, Algra A, Kappelle LJ, Roks G. Delirium in the acute phase after stroke: incidence, risk factors, and outcome. Neurology 2011; 76: 993–999.
- 69Dong Y, Slavin MJ, Chan BP-L, et al. Cognitive screening improves the predictive value of stroke severity scores for functional outcome 3–6 months after mild stroke and transient ischaemic attack: an observational study. BMJ Open 2013; 3: e003105.
- 70Patel M, Coshall C, Rudd AG, Wolfe CDA. Natural history of cognitive impairment after stroke and factors associated with its recovery. Clin Rehabil 2003; 17: 158–166.
- 71Hénon H, Pasquier F, Durieu I, et al. Preexisting dementia in stroke patients. Baseline frequency, associated factors, and outcome. Stroke 1997; 28: 2429–2436.
- 72Quinn TJ, Fearon P, Noel-Storr AH, Young C, McShane R, Stott DJ. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the diagnosis of dementia within community dwelling populations. Cochrane Database Syst Rev 2014; 4: CD010079.
- 73Godefroy O, Fickl A, Roussel M, et al. Is the Montreal Cognitive Assessment superior to the Mini-Mental State Examination to detect poststroke cognitive impairment? A study with neuropsychological evaluation. Stroke 2011; 42: 1712–1716.
- 74Lees R, Corbet S, Johnston C, Moffitt E, Shaw G, Quinn TJ. Test accuracy of short screening tests for diagnosis of delirium or cognitive impairment in an acute stroke unit setting. Stroke 2013; 44: 3078–3083.
- 75McArthur KS, Johnson PCD, Quinn TJ, et al. Improving the efficiency of stroke trials: feasibility and efficacy of group adjudication of functional end points. Stroke 2013; 44: 3422–3428.
- 76Noel-Storr AH, McCleery JM, Richard E, et al. Reporting standards for studies of diagnostic test accuracy in dementia: the STARDdem Initiative. Neurology 2014; 83: 364–373.
- 77Pollock A, St George B, Fenton M, Firkins L. Top ten research priorities relating to life after stroke. Lancet Neurol 2012; 11: 209.
- 78Ali M, Bath P, Brady M, et al. Development, expansion, and use of a stroke clinical trials resource for novel exploratory analyses. Int J Stroke 2012; 7: 133–138.
- 79Pendlebury ST, Mariz J, Bull L, Mehta Z, Rothwell PM. MoCA, ACE-R, and MMSE versus the National Institute of Neurological Disorders and Stroke−Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Neuropsychological Battery after TIA and stroke. Stroke 2012; 43: 464–469.
- 80Ankolekar S, Geeganage C, Anderton P, Hogg C, Bath PMW. Clinical trials for preventing post stroke cognitive impairment. J Neurol Sci 2010; 299: 168–174.
- 81Dichgans M, Zietemann V. Prevention of vascular cognitive impairment. Stroke 2012; 43: 3137–3146.
- 82Teuschl Y, Matz K, Brainin M. Prevention of post-stroke cognitive decline: a review focusing on lifestyle interventions. Eur J Neurol 2013; 20: 35–49.
- 83Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke−Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006; 37: 2220–2241.
- 84Maruta C, Guerreiro M, de Mendonça A, Hort J, Scheltens P. The use of neuropsychological tests across Europe: the need for a consensus in the use of assessment tools for dementia. Eur J Neurol 2011; 18: 279–285.
- 85Wagle J, Farner L, Flekkøy K, et al. Cognitive impairment and the role of the ApoE epsilon4-allele after stroke – a 13 months follow-up study. Int J Geriatr Psychiatry 2010; 25: 833–842.
- 86Sachdev PS, Brodaty H, Valenzuela MJ, Lorentz LM, Koschera A. Progression of cognitive impairment in stroke patients. Neurology 2004; 63: 1618–1623.
- 87Ihle-Hansen H, Thommessen B, Fagerland MW, et al. Multifactorial vascular risk factor intervention to prevent cognitive impairment after stroke and TIA: a 12-month randomized controlled trial. Int J Stroke 2014; 9: 932–938.
- 88Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003; 163: 1069–1075.
- 89Hochstenbach JB, den Otter R, Mulder TW. Cognitive recovery after stroke: a 2-year follow-up. Arch Phys Med Rehabil 2003; 84: 1499–1504.
- 90Rasquin SMC, Verhey FRJ, Lousberg R, Winkens I, Lodder J. Vascular cognitive disorders: memory, mental speed and cognitive flexibility after stroke. J Neurol Sci 2002; 203–204: 115–119.
- 91 The Montreal Cognitive Assessment. http://www.mocatest.org/ (accessed 14/10/2014).
- 92Brainin M, Matz K, Nemec M, et al. Prevention of poststroke cognitive decline: ASPIS – a multicenter, randomized, observer-blind, parallel group clinical trial to evaluate multiple lifestyle interventions – study design and baseline characteristics. Int J Stroke 2013; doi: 10.1111/ijs.12188 [Epub ahead of print].
- 93Diener H-C, Sacco RL, Yusuf S, et al. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 2008; 7: 875–884.
- 94 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22.
- 95Collins R, Armitage J, Parish S, Sleight P, Peto R, Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363: 757–767.
- 96Amarenco P, Labreuche J, Lavallée P, Touboul P-J. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004; 35: 2902–2909.
- 97Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–559.
- 98Manktelow BN, Potter JF. Interventions in the management of serum lipids for preventing stroke recurrence. Cochrane Database Syst Rev 2009; 3: CD002091.
- 99Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360: 1623–1630.
- 100Bath PM, Willmot M, Leonardi-Bee J, Bath FJ. Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke. Cochrane Database Syst Rev 2002; 4: CD000398.
- 101Ankolekar S, Fuller M, Cross I, et al. Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824). Stroke 2013; 44: 3120–3128.
- 102Kamal AK, Naqvi I, Husain MR, Khealani BA. Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin. Cochrane Database Syst Rev 2011; 1: CD008076.
- 103Dinicolantonio JJ, Lavie CJ, Fares H, et al. Meta-analysis of cilostazol versus aspirin for the secondary prevention of stroke. Am J Cardiol 2013; 112: 1230–1234.
- 104Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010; 9: 959–968.
- 105Bath PMW, Bath-Hextall FJ. Pentoxifylline, propentofylline and pentifylline for acute ischaemic stroke. Cochrane Database Syst Rev 2004; 3: CD000162.
- 106Bath PMW. Theophylline, aminophylline, caffeine and analogues for acute ischaemic stroke. Cochrane Database Syst Rev 2004; 3: CD000211.
- 107Frampton M, Harvey RJ, Kirchner V. Propentofylline for dementia. Cochrane Database Syst Rev 2003; 2: CD002853.
- 108Costa J, Ferro JM, Matias-Guiu J, Alvarez-Sabin J, Torres F. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev 2005; 3: CD004296.
- 109Leonardi-Bee J, Bath PMW, Bousser M-G, et al. Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials. Stroke 2005; 36: 162–168.
- 110Halkes PHA, Gray LJ, Bath PMW, et al. Dipyridamole plus aspirin versus aspirin alone in secondary prevention after TIA or stroke: a meta-analysis by risk. J Neurol Neurosurg Psychiatry 2008; 79: 1218–1223.
- 111Cassidy A, Rimm EB, O'Reilly EJ, et al. Dietary flavonoids and risk of stroke in women. Stroke 2012; 43: 946–951.
- 112Dehghan M, Mente A, Teo KK, et al. Relationship between healthy diet and risk of cardiovascular disease among patients on drug therapies for secondary prevention: a prospective cohort study of 31 546 high-risk individuals from 40 countries. Circulation 2012; 126: 2705–2712.
- 113Lawrence M, Kerr S, McVey C, Godwin J. The effectiveness of secondary prevention lifestyle interventions designed to change lifestyle behavior following stroke: summary of a systematic review. Int J Stroke 2012; 7: 243–247.
- 114Ihle-Hansen H, Thommessen B, Fagerland MW, et al. Effect on anxiety and depression of a multifactorial risk factor intervention program after stroke and TIA: a randomized controlled trial. Aging Ment Health 2014; 18: 540–546.
- 115Kivipelto M, Solomon A, Ahtiluoto S, et al. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): study design and progress. Alzheimers Dement 2013; 9: 657–665.
- 116Carrié I, van Kan GA, Gillette-Guyonnet S, et al. Recruitment strategies for preventive trials. The MAPT study (MultiDomain Alzheimer Preventive Trial). J Nutr Health Aging 2012; 16: 355–359.
- 117Richard E, Van den Heuvel E, Moll van Charante EP, et al. Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress. Alzheimer Dis Assoc Disord 2009; 23: 198–204.
- 118Richard E, Andrieu S, Solomon A, et al. Methodological challenges in designing dementia prevention trials – the European Dementia Prevention Initiative (EDPI). J Neurol Sci 2012; 322: 64–70.
- 119Calabrò RS, Gervasi G, Bramanti P. Does L-arginine supplementation play a role in cerebral small vessels disease? Implication in the treatment of leukoaraiosis. Med Hypotheses 2011; 77: 671–673.
- 120Calabro RS, Gervasi G, Baglieri A, Furnari A, Marino S, Bramanti P. Is high oral dose L-arginine intake effective in leukoaraiosis? Preliminary data, study protocol and expert's opinion. Curr Aging Sci 2013; 6: 170–177.
- 121Chen CLH, Ikram K, Anqi Q, et al. The NeuroAiD II (MLC901) in vascular cognitive impairment study (NEURITES). Cerebrovasc Dis 2013; 35: S23–S29.
