Clinical assessment, neuroimaging and immunomarkers in Chagas disease study (CLINICS): rationale, study design and preliminary findings

Oliveira-Filho, Jamary; Dias, Jesângeli de S.; Jesus, Pedro A.P.; J.S.B. Neto, Nestor; Aras, Roque; Reis, Francisco J.F.B.; Furie, Karen L.

doi:10.1590/S1980-57642012DN06030012

ABSTRACT

Chagas disease (CD) is an important cause of cardiomyopathy and stroke in Brazil. Brain infarcts and atrophy seem to occur independently of cardiomyopathy severity and cognitive impairment is understudied.

Objective:

Compare the prevalence of brain magnetic resonance imaging abnormalities between patients with or without CD; determine if inflammatory biomarkers are increased in CD; and determine the efficacy of aspirin in reducing the rate of microembolization in these patients.

Methods:

500 consecutive patients with heart failure will undergo a structured cognitive evaluation, biomarker collection and search for microembolic signals on transcranial Doppler. The first 90 patients are described, evaluated with cognitive tests and brain magnetic resonance imaging to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (MI) and creatine (Cr).

Results:

Mean age was 55±11 years, 51% female, 38 (42%) with CD. Mean NAA/Cr ratio was lower in patients with CD as compared to other cardiomyopathies. Long-term memory and clock-drawing test were also significantly worse in CD patients. In the multivariable analysis correcting for ejection fraction, age, sex and educational level, reduced NAA/Cr (p=0.006) and cognitive dysfunction (long-term memory, p=0.023; clock-drawing test, p=0.015) remained associated with CD.

Conclusion:

In this preliminary sample, CD was associated with cognitive impairment and decreased NAA/Cr independently of cardiac function or educational level.

Key words:
Chagas disease; stroke; cognitive impairment; brain atrophy; biomarkers

RESUMO

A doença de Chagas (DC) é causa importante de cardiomiopatia e acidente vascular cerebral no Brasil. Os infartos e atrofia cerebral na DC parecem ocorrer independente da gravidade da cardiomiopatia, sendo o comprometimento cognitivo pouco estudado.

Objetivo:

Determinar a prevalência de alterações na ressonância magnética entre chagásicos e não chagásicos; determinar se os níveis de marcadores inflamatórios estão aumentados na DC e determinar a eficácia da aspirina em reduzir a taxa de microembolização nestes pacientes.

Métodos:

Quinhentos pacientes consecutivos com diagnóstico de insuficiência cardíaca serão submetidos a uma avaliação cognitiva estruturada, coleta de biomarcadores e pesquisa de sinais de microembolia por Doppler transcraniano. Os primeiros 90 pacientes são descritos, avaliados por testes cognitivos e ressonância magnética cerebral, com medida de N-acetil aspartato (NAA), colina (Cho), mioinositol (MI) e creatina (Cr).

Resultados:

A idade média foi de 55±11 anos, 51% eram do sexo feminino, 38 (42%) tinha DC. A média da relação NAA/Cr foi mais baixa em pacientes com DC quando comparada com outras miocardiopatias. O desempenho nos testes de memória de longo prazo e desenho do relógio foi significativamente pior nos portadores de DC. Na análise multivariada, corrigindo para fração de ejeção, idade, gênero e nível educacional, redução da relação NAA/Cr (p=0.006) e disfunção cognitiva (memória de longo prazo, p=0.023; teste do desenho do relógio, p=0.015) permaneceram associados a DC.

Conclusão:

Nesta amostra preliminar, a doença de Chagas esteve associada a disfunção cognitiva e redução dos níveis de NAA/Cr, independente da função cardíaca e nível educacional.

Palavras-chave:
doença de Chagas; acidente vascular cerebral; comprometimento cognitivo; atrofia cerebral; biomarcadores

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REFERENCES

Chagas C. Nova entidade mórbida do homem. Rezumo geral de estudos etiolojicos e clinicos. Mem Inst Osw Cruz 1911;3:219-275.
World Health Organization - Media Center: Chagas disease (American Trypansomiasis. Available at: Available at: http://www.who.int/mediacentre/factsheets/fs340/en/index.html Accessed 27 may 2012.
» http://www.who.int/mediacentre/factsheets/fs340/en/index.html
Reesink HW. European strategies against the parasite transfusion risk. Transfus Clin Biol 2005;12:1-4.
Frank M, Hegenscheid B, Janitschke K, Weinke T. Prevalence and epidemiological significance of Tripanossoma cruzi infection among Latin American immigrants in Berlin, Germany. Infection 1997;25:355-358.
Moncayo A. Chagas' disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Shouthern Cone countries. Mem Inst Oswaldo Cruz 2003;98:577-591.
Nussenzveig I, Spina-França-Neto A, Wajchemberg BL, Macruz R, Timoner J, Serro Azul LG. Acidentes vasculares cerebrais embolicos na cardiopatia cronica chagasica. Arq Neuropsiquiatr 1953;11:386-402.
Andrade Z, Sadigurski M. Tromboembolismo em chagasicos sem insuficiencia cardiaca. Gazeta Med 1971;71:59-64.
Queiroz AC, Ramos EA. Anatomo-patholological study of the brain in idiopathic cardiomegaly. Arq Neuropsiquiatr 1979;37:405-411.
Pitella JE. Ischemic cerebral changes in the chronic chagasic cardiopathy. Arq Neuropsiquiatr 1984;42:105-115.
Carod-Artal FJ, Vargas AP, Melo M, Horan TA. American trypanosomiasis (Chagas' disease): an unrecognized cause of stroke. J Neurol Neurosurg Psychiatry 2003;74:516-518.
Leon-Sarmiento FE, Mendonza E, Torres-Hillera M, et al. Trypanossoma cruzi- associated cerebro-vascular disease: a case-control study in Eastern Colombia. J Neurol Sci 2004;217:61-64.
Oliveira-Filho J, Viana LC, Vieira-de-Melo RM, et al. Chagas disease is an independent risk factor for stroke. Baseline characteristics of a Chagas disease cohort. Stroke 2005;36:2015-2017.
Nunes MC, Barbosa MM, Rocha MO. Peculiar aspects of cardiogenic embolism in patients with Chagas' cardiomiopathy: a transthoracic and transesophageal echocardiographic study. J Am Soc Echocard 2005;18:761-767.
Nunes MC, Barbosa MM, Ribeiro AL, Barbosa FB, Rocha MO. Ischemic cerebrovascular events in patients with Chagas cardiomyopathy: a prospective follow-up study. J Neurol Sci 2009;278:96-101.
Aras R, da Matta JA, Mota G, Gomes I, Mota G, Melo A. Cerebral infarction in autopsies of chagasic patients with heart failure. Arq Bras Cardiol 2003;81:414-416.
Lopes ER, Marquez JO, da Costa Neto B, Menezes AA, Chapadeiro ME. Association of encephalic vascular accidents and Chagas disease. Rev Soc Bras Med Trop 1991;24:101-104.
Oliveira JSM, Araújo RRC, Navarro MA, Muccillo G. Cardiac thrombosis and thromboembolism in chronic chagas' heart disease. Am J Cardiol 1983;52:147-151.
Carod-Artal FJ, Vargas AP, Falcao T. Stroke in asymptomatic Trypanosoma cruzi-infected patients. Cerebrovasc Dis 2011;31:24-28.
Jesus PA, Neville I, Cincurá C, et al. Stroke history and Chagas disease are independent predictors of silent cerebral microembolism in patients with congestive heart failure. Cerebrovasc Dis 2011;31:19-23.
Herrera RN S-YR, Rodrigues E, Bianchi I, et al. The Prothrombotic State in Early Stages of Chronic Chagas' disease. Rev Esp Cardiol 2003;56: 377-382.
Mangone CA, Sica REP, Pereyra S, et al. Cognitive impairment in human chronic Chagas' disease. Arq Neuropsiquiatr 1994;52:200-203.
Dias JS, Lacerda AM, Vieira-de-Melo RM, et al. Cognitive dysfunction in chronic Chagas disease cardiomyopathy. Dement Neuropsychol 2009; 3:27-33.
Smid J, Nitrini R, Bahia VS, Caramelli P. Clinical characteization of vascular dementia: retrospective evaluation of an outpatient sample. Arq Neuropsiquiatr 2001;59:390-393.
Lima-Costa MF, Castro-Costa E, Uchôa E, Firmo J, Ribeiro AL, Ferri CP, Prince M. A population-based study of the association between Trypanosoma cruzi infection and cognitive impairment in old age (the Bambuí Study). Neuroepidemiology 2009;32:122-128.
Py M, Pedrosa R, Silveira J, Medeiros A, Andre C. Neurological Manifestations in Chagas' disease without cardiac dysfunction: correlation between dysfunction of the parasympathetic nervous system and white matter lesions in the brain. J Neuroimaging 2009;19:332-336.
Wackermann PV, Fernandes RM, Elias JJr, Dos Santos AC, Marques WJr, Barreira AA. Involvement of the central nervous system in the chronic form of Chagas' disease. J Neurol Sci 2008;269:152-157.
O'Brien JT, Erkinjuntti T, Reisberg B, et al. Vascular cognitive impairment. Lancet Neurol 2003;2:89-98.
Trojano L, Incalzi RA, Acanfora D, et al. Cognitive impairment: a key feature of congestive heart failure in elderly. J Neurol 2003;250:1456-1463.
Zuccala G, Marzetti E, Cesari M, et al. Correlate of cognitive impairment among patients with heart failure: Results of a multicenter survey. Am J Med 2005;118:496-502.
Oliveira-Filho J, Vieira-de-Melo RM, Reis PS, et al. Chagas disease is independently associated with brain atrophy. J Neurol 2009;256:1363-1365.
Bernick C, Kuller L, Dulberg C, et al. Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001;57:1222-1229.
LongstrethJr WT, Arnold AM, Beauchamp Jr NJ, et al. Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2005;36:56-61.
Hachinski VC, Potter P, Merskey H. Leuko-araiosis: an ancient term for a new problem. Can J Neurol Sci 1986;13:533-534.
Jefferson AL, Massaro JM, Wolf PA, et al. Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study. Neurology 2007;68:1032-1038.
Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 1982;57:769-774.
Russell D, Brucher R. Online automatic discrimination between solid and gaseous cerebral microemboli with the first multifrequency transcranial Doppler. Stroke 2002;33:1975-1980.
Gucuyener D, Uzuner N, Ozkan S, Ozdemir O, Ozdemir G. Micro embolic signals in patients with cerebral ischaemic events. Neurol India 2001;49:225-230.
Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid artery stenosis. Stroke 1999;30:1440-1443.
Tong DC, Bolger A, Albers GW. Incidence of transcranial Doppler-detected cerebral microemboli in patients referred for echocardiography. Stroke 1994;25:2138-2141.
Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005;111:2233-2240.
Lind P, Engstrom G, Stavenow L, Janzon L, Lindgarde F, Hedblad B. Risk of myocardial infarction and stroke in smokers is related to plasma levels of inflammation-sensitive proteins. Arterioscler Thromb Vasc Biol 2004;24:577-582.
Petty GW, Brown RDJr, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Ischemic stroke subtypes : a population-based study of functional outcome, survival, and recurrence. Stroke 2000;31:1062-1068.
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Publication Dates

Publication in this collection
Jul-Sep 2012

History

Received
20 Mar 2012
Accepted
20 May 2012

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

[1] Chagas C. Nova entidade mórbida do homem. Rezumo geral de estudos etiolojicos e clinicos. Mem Inst Osw Cruz 1911;3:219-275.

[2] World Health Organization - Media Center: Chagas disease (American Trypansomiasis. Available at: Available at: http://www.who.int/mediacentre/factsheets/fs340/en/index.html Accessed 27 may 2012.
» http://www.who.int/mediacentre/factsheets/fs340/en/index.html

[3] Reesink HW. European strategies against the parasite transfusion risk. Transfus Clin Biol 2005;12:1-4.

[4] Frank M, Hegenscheid B, Janitschke K, Weinke T. Prevalence and epidemiological significance of Tripanossoma cruzi infection among Latin American immigrants in Berlin, Germany. Infection 1997;25:355-358.

[5] Moncayo A. Chagas' disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Shouthern Cone countries. Mem Inst Oswaldo Cruz 2003;98:577-591.

[6] Nussenzveig I, Spina-França-Neto A, Wajchemberg BL, Macruz R, Timoner J, Serro Azul LG. Acidentes vasculares cerebrais embolicos na cardiopatia cronica chagasica. Arq Neuropsiquiatr 1953;11:386-402.

[7] Andrade Z, Sadigurski M. Tromboembolismo em chagasicos sem insuficiencia cardiaca. Gazeta Med 1971;71:59-64.

[8] Queiroz AC, Ramos EA. Anatomo-patholological study of the brain in idiopathic cardiomegaly. Arq Neuropsiquiatr 1979;37:405-411.

[9] Pitella JE. Ischemic cerebral changes in the chronic chagasic cardiopathy. Arq Neuropsiquiatr 1984;42:105-115.

[10] Carod-Artal FJ, Vargas AP, Melo M, Horan TA. American trypanosomiasis (Chagas' disease): an unrecognized cause of stroke. J Neurol Neurosurg Psychiatry 2003;74:516-518.

[11] Leon-Sarmiento FE, Mendonza E, Torres-Hillera M, et al. Trypanossoma cruzi- associated cerebro-vascular disease: a case-control study in Eastern Colombia. J Neurol Sci 2004;217:61-64.

[12] Oliveira-Filho J, Viana LC, Vieira-de-Melo RM, et al. Chagas disease is an independent risk factor for stroke. Baseline characteristics of a Chagas disease cohort. Stroke 2005;36:2015-2017.

[13] Nunes MC, Barbosa MM, Rocha MO. Peculiar aspects of cardiogenic embolism in patients with Chagas' cardiomiopathy: a transthoracic and transesophageal echocardiographic study. J Am Soc Echocard 2005;18:761-767.

[14] Nunes MC, Barbosa MM, Ribeiro AL, Barbosa FB, Rocha MO. Ischemic cerebrovascular events in patients with Chagas cardiomyopathy: a prospective follow-up study. J Neurol Sci 2009;278:96-101.

[15] Aras R, da Matta JA, Mota G, Gomes I, Mota G, Melo A. Cerebral infarction in autopsies of chagasic patients with heart failure. Arq Bras Cardiol 2003;81:414-416.

[16] Lopes ER, Marquez JO, da Costa Neto B, Menezes AA, Chapadeiro ME. Association of encephalic vascular accidents and Chagas disease. Rev Soc Bras Med Trop 1991;24:101-104.

[17] Oliveira JSM, Araújo RRC, Navarro MA, Muccillo G. Cardiac thrombosis and thromboembolism in chronic chagas' heart disease. Am J Cardiol 1983;52:147-151.

[18] Carod-Artal FJ, Vargas AP, Falcao T. Stroke in asymptomatic Trypanosoma cruzi-infected patients. Cerebrovasc Dis 2011;31:24-28.

[19] Jesus PA, Neville I, Cincurá C, et al. Stroke history and Chagas disease are independent predictors of silent cerebral microembolism in patients with congestive heart failure. Cerebrovasc Dis 2011;31:19-23.

[20] Herrera RN S-YR, Rodrigues E, Bianchi I, et al. The Prothrombotic State in Early Stages of Chronic Chagas' disease. Rev Esp Cardiol 2003;56: 377-382.

[21] Mangone CA, Sica REP, Pereyra S, et al. Cognitive impairment in human chronic Chagas' disease. Arq Neuropsiquiatr 1994;52:200-203.

[22] Dias JS, Lacerda AM, Vieira-de-Melo RM, et al. Cognitive dysfunction in chronic Chagas disease cardiomyopathy. Dement Neuropsychol 2009; 3:27-33.

[23] Smid J, Nitrini R, Bahia VS, Caramelli P. Clinical characteization of vascular dementia: retrospective evaluation of an outpatient sample. Arq Neuropsiquiatr 2001;59:390-393.

[24] Lima-Costa MF, Castro-Costa E, Uchôa E, Firmo J, Ribeiro AL, Ferri CP, Prince M. A population-based study of the association between Trypanosoma cruzi infection and cognitive impairment in old age (the Bambuí Study). Neuroepidemiology 2009;32:122-128.

[25] Py M, Pedrosa R, Silveira J, Medeiros A, Andre C. Neurological Manifestations in Chagas' disease without cardiac dysfunction: correlation between dysfunction of the parasympathetic nervous system and white matter lesions in the brain. J Neuroimaging 2009;19:332-336.

[26] Wackermann PV, Fernandes RM, Elias JJr, Dos Santos AC, Marques WJr, Barreira AA. Involvement of the central nervous system in the chronic form of Chagas' disease. J Neurol Sci 2008;269:152-157.

[27] O'Brien JT, Erkinjuntti T, Reisberg B, et al. Vascular cognitive impairment. Lancet Neurol 2003;2:89-98.

[28] Trojano L, Incalzi RA, Acanfora D, et al. Cognitive impairment: a key feature of congestive heart failure in elderly. J Neurol 2003;250:1456-1463.

[29] Zuccala G, Marzetti E, Cesari M, et al. Correlate of cognitive impairment among patients with heart failure: Results of a multicenter survey. Am J Med 2005;118:496-502.

[30] Oliveira-Filho J, Vieira-de-Melo RM, Reis PS, et al. Chagas disease is independently associated with brain atrophy. J Neurol 2009;256:1363-1365.

[31] Bernick C, Kuller L, Dulberg C, et al. Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001;57:1222-1229.

[32] LongstrethJr WT, Arnold AM, Beauchamp Jr NJ, et al. Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2005;36:56-61.

[33] Hachinski VC, Potter P, Merskey H. Leuko-araiosis: an ancient term for a new problem. Can J Neurol Sci 1986;13:533-534.

[34] Jefferson AL, Massaro JM, Wolf PA, et al. Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study. Neurology 2007;68:1032-1038.

[35] Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 1982;57:769-774.

[36] Russell D, Brucher R. Online automatic discrimination between solid and gaseous cerebral microemboli with the first multifrequency transcranial Doppler. Stroke 2002;33:1975-1980.

[37] Gucuyener D, Uzuner N, Ozkan S, Ozdemir O, Ozdemir G. Micro embolic signals in patients with cerebral ischaemic events. Neurol India 2001;49:225-230.

[38] Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid artery stenosis. Stroke 1999;30:1440-1443.

[39] Tong DC, Bolger A, Albers GW. Incidence of transcranial Doppler-detected cerebral microemboli in patients referred for echocardiography. Stroke 1994;25:2138-2141.

[40] Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005;111:2233-2240.

[41] Lind P, Engstrom G, Stavenow L, Janzon L, Lindgarde F, Hedblad B. Risk of myocardial infarction and stroke in smokers is related to plasma levels of inflammation-sensitive proteins. Arterioscler Thromb Vasc Biol 2004;24:577-582.

[42] Petty GW, Brown RDJr, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Ischemic stroke subtypes : a population-based study of functional outcome, survival, and recurrence. Stroke 2000;31:1062-1068.

[43] Grossetete M, Rosenberg GA. Matrix metalloproteinase inhibition facilitates cell death in intracerebral hemorrhage in mouse. J Cereb Blood Flow Metab 2008;28:752-763.

[44] Lee CZ, Xue Z, Zhu Y, Yang GY, Young WL. Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracerebral hemorrhage. Stroke 2007;38:2563-2568.

[45] Smith CJ, Emsley HC, Gavin CM, et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004;4:2.

[46] Engstrom G, Lind P, Hedblad B, Stavenow L, Janzon L, Lindgarde F. Effects of cholesterol and inflammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men. Circulation 2002;105:2632-2637.

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