Vascular cognitive impairment (VCI): Progress towards knowledge and treatment

Di Legge, Silvia; Hachinski, Vladimir

doi:10.1590/S1980-57642010DN40100002

Abstract

Until recently, the study of cognitive impairment as a manifestation of cerebrovascular disease (CVD) has been hampered by the lack of common standards for assessment. The term vascular cognitive impairment (VCI) encompasses all levels of cognitive decline associated with CVD from mild deficits in one or more cognitive domains to crude dementia syndrome. VCI incorporates the complex interactions among classic vascular risk factors (i.e. arterial hypertension, high cholesterol, and diabetes), CVD subtypes, and Alzheimer's Disease (AD) pathology. VCI may be the earliest, commonest, and subtlest manifestation of CVD and can be regarded as a highly prevalent and preventable syndrome. However, cognition is not a standardized outcome measure in clinical trials assessing functional ability after stroke. Furthermore, with the exception of anti-hypertensive medications, the impact of either preventive or acute stroke treatments on cognitive outcome is not known. Although clinical, epidemiological, neuroimaging, and experimental data support the VCI concept, there is a lack of integrated knowledge on the role played by the most relevant pathophysiological mechanisms involved in several neurological conditions including stroke and cognitive impairment such as excitotoxicity, apoptosis, mitochondrial DNA damage, oxidative stress, disturbed neurotransmitter release, and inflammation. For this reason, in 2006 the National Institute of Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) defined a set of data elements to be collected in future studies aimed at defining VCI etiology, clinical manifestations, predictive factors, and treatment. These recommendations represent the first step toward developing diagnostic criteria for VCI based on sound knowledge rather than on hypotheses. The second step will be to integrate all studies using the agreed methodologies. This is likely to accelerate the search for answers.

Key words:
cerebrovascular disease; dementia; vascular cognitive impairment; diagnostic criteria

Resumo

Até recentemente, o estudo do comprometimento cognitivo como manifestação de doença cerebrovascular (DCV) tem sido comprometido pela falta de métodos de abordagem. O termo comprometimento cognitivo vascular (CCV) inclui todos os níveis de declínio cognitivo associados à DCV, de déficites discretos em um ou mais domínios cognitivos a uma síndrome demencial inequívoca. CCV incorpora interações complexas entre fatores de risco vasculares clássicos (i.e. hipertensão arterial, colesterol elevado e diabetes), subtipos de DCV e patologia de Doença de Alzheimer (DA). CCV pode ser a mais precoce, comum e sutil manifestação de DCV e pode ser encarada como uma demência altamente prevalente e prevenível. Todavia, a cognição não é uma medida de desfecho em ensaios clínicos que avaliam habilidades funcionais após acidente vascular cerebral (AVC). Além disso, com exceção de medicações anti-hipertensivas, o impacto tanto de medidas preventivas quanto tratamento agudo de AVC em desfecho cognitivo não é conhecido. A despeito de que dados clínicos, epidemiológicos, de neuroimagem e experimentais suportam o conceito de CCV, há falta de conhecimento integrado no papel desempenhado pelos mecanismos patofisiológicos mais relevantes envolvidos em muitas condições neurológicas incluindo AVC e comprometimento cognitivo, como excitotoxicidade, apoptose, dano ao DNA mitocondrial, stress oxidativo, distúrbios na liberação de neurotransmissores e inflamação. Por esta razão, em 2006 o National Institute of Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) definiram um conjunto de dados a serem coletados em estudos futures auxiliando na definição da etiologia, manifestações clínicas, fatores preditivos e tratamento. Estas recomendações representam o primeiro degrau para o desenvolvimento dos critérios diagnósticos para CCV baseados em conhecimentos mais do que em hipóteses. O segundo degrau seria integrar todos os estudos usando metodologias aceitas, o que aceleraria a busca por respostas.

Palavras-chave:
doença cerebrovascular; demência; comprometimento cognitivo vascular; critérios diagnósticos

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

References

¹
Seshadri S, Beiser A, Kelly-Hayes M, et al. The lifetime risk of stroke: estimates from the Framingham Study. Stroke 2006;37: 345-350.
²
Tatemichi TK, Desmond DW, Mayeux R, et al. Dementia after stroke: baseline frequency, risks, and clinical features in a hospitalized color. Neurology 1992;42:1185-1193.
³
Pohjasvaara T, Erkinjuntti T, Vataja R, Kaste M. Dementia three months after stroke. Baseline frequency and effect of different definitions of dementia in the Helsinki Stroke Aging Memory Study (SAM) cohort. Stroke 1997;28:785-792.
⁴
Barba R, Martínez-Espinosa S, Rodríguez-García E, Pondal M, Vivancos J, Del Ser T. Poststroke dementia: clinical features and risk factors. Stroke 2000;31:1494-1501
⁵
Jin YP, Di Legge S, Ostbye T, Feightner JW, Hachinski V. The Reciprocal risks of stroke and cognitive impairment in an elderly population. Alzheimers Dement 2006;2:171-178.
⁶
Hénon H, Durieu I, Guerouaou D, Lebert F, Pasquier F, Leys D. Poststroke dementia: incidence and relationship to prestroke cognitive decline. Neurology 2001;57:1216-1222.
⁷
Neuropathology Group. Medical Research Council Cognitive Function and Aging Study. 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(9251):169-175.
⁸
White L, Petrovitch H, Hardman J, et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci 2002;977:9-23.
⁹
Barker WW, Luis CA, Kashuba A, et al. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 2002;16:203-212.
¹⁰
Knopman DS, Parisi JE, Boeve BF, et al. Vascular dementia in a population-based autopsy study. Arch Neurol 2003;60:569-575.
¹¹
Snowdon 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.
¹²
Petrovitch H, Ross GW, Steinhorn SC, et.al. AD lesions and infarcts in demented and non-demented Japanese-American men. Ann Neurol 2005;57:98-103.
¹³
Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA. Subcortical infarcts, Alzheimer's disease pathology, and memory function in older patients. Ann Neurol 2007;62:59-66.
¹⁴
Smith EE, Greenberg SM. b-amyloid, blood vessels, and brain function. Stroke 2009;40:2601-2606.
¹⁵
Bowler JV, Hachinski V. Vascular cognitive impairment: a new approach to vascular dementia. Baillieres Clin Neurol 1995; 4:357-376.
¹⁶
Bowler JV, Steenhuis R, Hachinski V. Conceptual background to vascular cognitive impairment. Alzheimer Dis Assoc Disord 1999;13(S3):S30-S37.
¹⁷
Bowler JV, Hachinski V. Vascular cognitive impairment. Preventable dementia. Oxford University Press, 2003.
¹⁸
Hachinski 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.
¹⁹
Longstreth WT, Bernick C, Manolio TA, Bryan N, Jungreis CA, Price TR. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people. Arch Neurol 1998;55:1217-1225.
²⁰
Mirra SS, Hart MN, Terry RD. Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists Arch Pathol Lab Med 1993;117:132-144.
²¹
Oksala N, Jokinen H, Melkas S, et al. Cognitive impairment predicts poststroke death in long-term follow up. J Neurol Neurosurg Psychiatry 2009;80:1230-1235.
²²
Troncoso 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: 64:168-176.
²³
Saczynski JS, Sigurdsson S, Jonsdottir MK, et al. Cerebral infarcts and cognitive performance: importance of location and number of infarcts. Stroke . 2009;40:667-682.
²⁴
Silbert LC, Howieson DB, Dodge H, Kaye JA. Cognitive impairment risk: white matter hyperintensity progression matters. Neurology. 2009;73:120-125.
²⁵
Black S, Gao F, Bilbao J. Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment. Stroke 2009;40(suppl 1):S48-S52.
²⁶
Griffith HR, Stewart CC, den Hollander JA. Proton magnetic resonance spectroscopy in dementias and mild cognitive impairment. Int Rev Neurobiol. 2009;84:105-131.
²⁷
Rosenberg GA. Inflammation and white matter damage in vascular cognitive impairment. Stroke . 2009;40(3 Suppl):S20-23.
²⁸
Wiederkehr S, Laurin D, Simard M, Verrault R, Lindsay J. Vascular risk factors and cognitive functions in nondemented elderly. J Geriatr Psychiatry Neurol 2009:22:196-206.
²⁹
Knecht S, Wersching H, Lohmann H, Berger K, Ringelstein EB. How much does hypertension affect cognition?: explained variance in cross-sectional analysis of non-demented community-dwelling individuals in the SEARCH study. J Neurol Sci 2009;283:149-152.
³⁰
Xu W, Qiu C, Gatz M, Pederesen NL, Johansson B, Fratiglioni L. Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes 2009;58:71-77.
³¹
Alonso A, Mosley TH, Gottesman RF, Catellier D, Sharrett AR, Coresh J. Risk of dementia hospitalization with cardiovascular risk factors in midlife and older age: the atherosclerotic risk in communities (ARIC) study. J Neurol Neurosurg Psychiatry 2009;80:1194-201.
³²
Saczynski JS, Jonsdottir MK, Garcia ME, et al. Cognitive impairment: an increasingly important complication of type 2 diabetes: the age, gene/environment susceptibility-Reykjavik study. Am J Epidemiol 2008;168:1132-1139.
³³
Peila R, Rodriguez BL, launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes 2002; 51:1256-1262.
³⁴
Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA. Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later. Dement Geriatr Cogn Disord. 2009;28:75-80.
³⁵
Liem MK, Lesnik Oberstein SA, Haan J, et al. MRI correlates of cognitive decline in CADASIL: a 7-year follow-up study. Neurology 2009;72:143-148.
³⁶
Dichgans M. Cognition in CADASIL. Stroke . 2009;40(3 Suppl):S45-47.
³⁷
Chalmers K, Wilcock GK, Love S. APOEe4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of Ab protein. Neuropat and Appl Neurobiol 2003;29:231-238.
³⁸
Jin 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.
³⁹
Knopman DS, Mosley TH, Catellier DJ, Coker LH. Atherosclerosis risk in communities study brain MRI study: fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: the ARIC MRI Study. Alzheimers Dement 2009;5:207-214.
⁴⁰
Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998;352(9137): 1347-1351.
⁴¹
Forette F, Seux ML, Staessen JA, et al. Systolic Hypertension in Europe Investigators. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med 2002;162(18):2046-2052.
⁴²
Tzourio C, Anderson C, Chapman N, et al. The PROGRESS Collaborative Group. 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.
⁴³
Murray MD, Lane KA, Gao S, et al. Preservation of cognitive function with antihypertensive medications: a longitudinal analysis of a community-based sample of African Americans. Arch Intern Med 2002;162:2090-2096.
⁴⁴
Lithell H, Hansson L, Skoog I, et al. For the SCOPE Study Group The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21:875-886.
⁴⁵
Yasar S, Zhou J, Varadhan R, Carlson MC. The use of angiotensin-converting enzyme inhibitors and diuretics is associated with a reduced incidence of impairment on cognition in elderly women. Clin Pharmacol Ther 2008;84:119-126.
⁴⁶
Stewart R, Xue QL, Masaki K, et al. Change in blood pressure and incident dementia: a 32-year prospective study. Hypertension. 2009;54:233-240.
⁴⁷
Verghese J, Cuiling Wang, Katz MJ, Sanders A, Lipton RB. Leisure activities and risk of vascular cognitive impairment in older adults. 2009;22:110-118.
⁴⁸
Ferri CP, Prince M, Brayne C, et al. Alzheimer's disease international. Lancet. 2005;366(9503):2112-2117.
⁴⁹
Centro Latinoamericano y Caribeño de Demografia (CELADE). Los Adultos Mayores en America Latina y el Caribe - Datos y Indicadores. Santiago de Chile: CELADE, División de Población; 2002.
⁵⁰
Nitrini R, Bottino CM, Albala C, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts. Int Psychogeriatr 2009;21:622-630.
⁵¹
Iadecola C, Park L, Capone C. Threats to the mind: aging, amyloid and hypertension. Stroke 2009;40(suppl 1):S40-S44.
⁵²
Pikula A, Böger RH, Beiser AS, et al. Association of plasma ADMA levels with MRI markers of vascular brain injury. Framingham Offspring Study. Stroke 2009;40:2959-2964.
⁵³
Gunstad J, Benitez A, Hoth KF, et al. P-Selectin 1087G/A polymorphism is associated with neuropsychological test performance in older adults with cardiovascular disease. Stroke . 2009;40:2969-2972.
⁵⁴
Ravid R. Biobanks for biomarkers in neurological disorders: the Da Vinci bridge for optimal clinico-pathological connection. J Neurol Sci 2009;283:119-126.
⁵⁵
Launer LJ. Diabetes: vascular or neurodegenerative: an epidemiologic perspective. Stroke 2009;40 (suppl 1):S53-S55.

Publication Dates

Publication in this collection
Jan-Mar 2010

History

Received
15 Sept 2009
Accepted
17 Dec 2009

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹
Seshadri S, Beiser A, Kelly-Hayes M, et al. The lifetime risk of stroke: estimates from the Framingham Study. Stroke 2006;37: 345-350.

[2] ²
Tatemichi TK, Desmond DW, Mayeux R, et al. Dementia after stroke: baseline frequency, risks, and clinical features in a hospitalized color. Neurology 1992;42:1185-1193.

[3] ³
Pohjasvaara T, Erkinjuntti T, Vataja R, Kaste M. Dementia three months after stroke. Baseline frequency and effect of different definitions of dementia in the Helsinki Stroke Aging Memory Study (SAM) cohort. Stroke 1997;28:785-792.

[4] ⁴
Barba R, Martínez-Espinosa S, Rodríguez-García E, Pondal M, Vivancos J, Del Ser T. Poststroke dementia: clinical features and risk factors. Stroke 2000;31:1494-1501

[5] ⁵
Jin YP, Di Legge S, Ostbye T, Feightner JW, Hachinski V. The Reciprocal risks of stroke and cognitive impairment in an elderly population. Alzheimers Dement 2006;2:171-178.

[6] ⁶
Hénon H, Durieu I, Guerouaou D, Lebert F, Pasquier F, Leys D. Poststroke dementia: incidence and relationship to prestroke cognitive decline. Neurology 2001;57:1216-1222.

[7] ⁷
Neuropathology Group. Medical Research Council Cognitive Function and Aging Study. 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(9251):169-175.

[8] ⁸
White L, Petrovitch H, Hardman J, et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci 2002;977:9-23.

[9] ⁹
Barker WW, Luis CA, Kashuba A, et al. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 2002;16:203-212.

[10] ¹⁰
Knopman DS, Parisi JE, Boeve BF, et al. Vascular dementia in a population-based autopsy study. Arch Neurol 2003;60:569-575.

[11] ¹¹
Snowdon 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.

[12] ¹²
Petrovitch H, Ross GW, Steinhorn SC, et.al. AD lesions and infarcts in demented and non-demented Japanese-American men. Ann Neurol 2005;57:98-103.

[13] ¹³
Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA. Subcortical infarcts, Alzheimer's disease pathology, and memory function in older patients. Ann Neurol 2007;62:59-66.

[14] ¹⁴
Smith EE, Greenberg SM. b-amyloid, blood vessels, and brain function. Stroke 2009;40:2601-2606.

[15] ¹⁵
Bowler JV, Hachinski V. Vascular cognitive impairment: a new approach to vascular dementia. Baillieres Clin Neurol 1995; 4:357-376.

[16] ¹⁶
Bowler JV, Steenhuis R, Hachinski V. Conceptual background to vascular cognitive impairment. Alzheimer Dis Assoc Disord 1999;13(S3):S30-S37.

[17] ¹⁷
Bowler JV, Hachinski V. Vascular cognitive impairment. Preventable dementia. Oxford University Press, 2003.

[18] ¹⁸
Hachinski 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.

[19] ¹⁹
Longstreth WT, Bernick C, Manolio TA, Bryan N, Jungreis CA, Price TR. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people. Arch Neurol 1998;55:1217-1225.

[20] ²⁰
Mirra SS, Hart MN, Terry RD. Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists Arch Pathol Lab Med 1993;117:132-144.

[21] ²¹
Oksala N, Jokinen H, Melkas S, et al. Cognitive impairment predicts poststroke death in long-term follow up. J Neurol Neurosurg Psychiatry 2009;80:1230-1235.

[22] ²²
Troncoso 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: 64:168-176.

[23] ²³
Saczynski JS, Sigurdsson S, Jonsdottir MK, et al. Cerebral infarcts and cognitive performance: importance of location and number of infarcts. Stroke . 2009;40:667-682.

[24] ²⁴
Silbert LC, Howieson DB, Dodge H, Kaye JA. Cognitive impairment risk: white matter hyperintensity progression matters. Neurology. 2009;73:120-125.

[25] ²⁵
Black S, Gao F, Bilbao J. Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment. Stroke 2009;40(suppl 1):S48-S52.

[26] ²⁶
Griffith HR, Stewart CC, den Hollander JA. Proton magnetic resonance spectroscopy in dementias and mild cognitive impairment. Int Rev Neurobiol. 2009;84:105-131.

[27] ²⁷
Rosenberg GA. Inflammation and white matter damage in vascular cognitive impairment. Stroke . 2009;40(3 Suppl):S20-23.

[28] ²⁸
Wiederkehr S, Laurin D, Simard M, Verrault R, Lindsay J. Vascular risk factors and cognitive functions in nondemented elderly. J Geriatr Psychiatry Neurol 2009:22:196-206.

[29] ²⁹
Knecht S, Wersching H, Lohmann H, Berger K, Ringelstein EB. How much does hypertension affect cognition?: explained variance in cross-sectional analysis of non-demented community-dwelling individuals in the SEARCH study. J Neurol Sci 2009;283:149-152.

[30] ³⁰
Xu W, Qiu C, Gatz M, Pederesen NL, Johansson B, Fratiglioni L. Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes 2009;58:71-77.

[31] ³¹
Alonso A, Mosley TH, Gottesman RF, Catellier D, Sharrett AR, Coresh J. Risk of dementia hospitalization with cardiovascular risk factors in midlife and older age: the atherosclerotic risk in communities (ARIC) study. J Neurol Neurosurg Psychiatry 2009;80:1194-201.

[32] ³²
Saczynski JS, Jonsdottir MK, Garcia ME, et al. Cognitive impairment: an increasingly important complication of type 2 diabetes: the age, gene/environment susceptibility-Reykjavik study. Am J Epidemiol 2008;168:1132-1139.

[33] ³³
Peila R, Rodriguez BL, launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes 2002; 51:1256-1262.

[34] ³⁴
Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA. Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later. Dement Geriatr Cogn Disord. 2009;28:75-80.

[35] ³⁵
Liem MK, Lesnik Oberstein SA, Haan J, et al. MRI correlates of cognitive decline in CADASIL: a 7-year follow-up study. Neurology 2009;72:143-148.

[36] ³⁶
Dichgans M. Cognition in CADASIL. Stroke . 2009;40(3 Suppl):S45-47.

[37] ³⁷
Chalmers K, Wilcock GK, Love S. APOEe4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of Ab protein. Neuropat and Appl Neurobiol 2003;29:231-238.

[38] ³⁸
Jin 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.

[39] ³⁹
Knopman DS, Mosley TH, Catellier DJ, Coker LH. Atherosclerosis risk in communities study brain MRI study: fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: the ARIC MRI Study. Alzheimers Dement 2009;5:207-214.

[40] ⁴⁰
Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998;352(9137): 1347-1351.

[41] ⁴¹
Forette F, Seux ML, Staessen JA, et al. Systolic Hypertension in Europe Investigators. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med 2002;162(18):2046-2052.

[42] ⁴²
Tzourio C, Anderson C, Chapman N, et al. The PROGRESS Collaborative Group. 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.

[43] ⁴³
Murray MD, Lane KA, Gao S, et al. Preservation of cognitive function with antihypertensive medications: a longitudinal analysis of a community-based sample of African Americans. Arch Intern Med 2002;162:2090-2096.

[44] ⁴⁴
Lithell H, Hansson L, Skoog I, et al. For the SCOPE Study Group The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21:875-886.

[45] ⁴⁵
Yasar S, Zhou J, Varadhan R, Carlson MC. The use of angiotensin-converting enzyme inhibitors and diuretics is associated with a reduced incidence of impairment on cognition in elderly women. Clin Pharmacol Ther 2008;84:119-126.

[46] ⁴⁶
Stewart R, Xue QL, Masaki K, et al. Change in blood pressure and incident dementia: a 32-year prospective study. Hypertension. 2009;54:233-240.

[47] ⁴⁷
Verghese J, Cuiling Wang, Katz MJ, Sanders A, Lipton RB. Leisure activities and risk of vascular cognitive impairment in older adults. 2009;22:110-118.

[48] ⁴⁸
Ferri CP, Prince M, Brayne C, et al. Alzheimer's disease international. Lancet. 2005;366(9503):2112-2117.

[49] ⁴⁹
Centro Latinoamericano y Caribeño de Demografia (CELADE). Los Adultos Mayores en America Latina y el Caribe - Datos y Indicadores. Santiago de Chile: CELADE, División de Población; 2002.

[50] ⁵⁰
Nitrini R, Bottino CM, Albala C, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts. Int Psychogeriatr 2009;21:622-630.

[51] ⁵¹
Iadecola C, Park L, Capone C. Threats to the mind: aging, amyloid and hypertension. Stroke 2009;40(suppl 1):S40-S44.

[52] ⁵²
Pikula A, Böger RH, Beiser AS, et al. Association of plasma ADMA levels with MRI markers of vascular brain injury. Framingham Offspring Study. Stroke 2009;40:2959-2964.

[53] ⁵³
Gunstad J, Benitez A, Hoth KF, et al. P-Selectin 1087G/A polymorphism is associated with neuropsychological test performance in older adults with cardiovascular disease. Stroke . 2009;40:2969-2972.

[54] ⁵⁴
Ravid R. Biobanks for biomarkers in neurological disorders: the Da Vinci bridge for optimal clinico-pathological connection. J Neurol Sci 2009;283:119-126.

[55] ⁵⁵
Launer LJ. Diabetes: vascular or neurodegenerative: an epidemiologic perspective. Stroke 2009;40 (suppl 1):S53-S55.

Brasil