Serum levels of soluble TNF-α receptors but not BDNF are associated with apathy symptoms in mild Alzheimer's disease and amnestic mild cognitive impairment

Guimarães, Henrique Cerqueira; Caramelli, Paulo; Fialho, Patricia Paes Araujo; França, Elisa de Paula; Afonso, Marcelo Pelizzaro Dias; Teixeira, Antonio Lucio

doi:10.1590/S1980-57642013DN70300011

ABSTRACT

Apathy is intimately associated with dementia. Unfortunately, its pathophysiology remains poorly understood. The motivational impairment that characterizes this disorder might share the same inflammatory mechanisms, as suggested by the sickness behavior theory.

Objective:

The primary aim of this study was to investigate the association between apathy symptoms and serum levels of tumor necrosis factor alpha (TNF-α) and its soluble receptors. Brain-derived neurotrophic factor (BDNF) levels were also analyzed since these have been associated with depression, a condition which shares abulic features with apathy.

Methods:

The sample consisted of 27 subjects with mild Alzheimer's disease or amnestic mild cognitive impairment, who were submitted to specific apathy evaluation using the Apathy Scale (AS) and provided blood samples for biomarker analysis. Participants were categorized into two groups according to median AS scores (17 points).

Results:

Subjects with higher apathy symptoms (n=13) displayed higher levels of TNF-α soluble receptors (type 1: p=0.03; type 2: p=0.04). No other difference was found between groups.

Conclusion:

These findings point to the involvement of inflammatory mediators in the genesis of apathy symptoms, as suggested by the sickness behavior theory.

Key words:
apathy; dementia; Alzheimer's disease; mild cognitive impairment; TNF-α; sTNFR1; sTNFR2; BDNF.

RESUMO

Apatia está intimamente associada à demência. Lamentavelmente, sua fisiopatologia ainda é pouco compreendida. O comprometimento motivacional que caracteriza este transtorno poderia compartilhar mecanismos inflamatórios como sugere a teoria do comportamento associado à doença.

Objetivo:

O principal objetivo deste estudo foi investigar a associação entre apatia e os níveis séricos do fator de necrose tumoral alfa (TNF-α) e de seus receptores solúveis. Os níveis de fator neurotrófico derivado do cérebro também foram analisados já que estes foram associados à depressão, que compartilha aspectos abúlicos com a apatia.

Métodos:

A amostra consistiu de 27 indivíduos com doença de Alzheimer leve ou com comprometimento cognitivo leve amnéstico, que foram submetidos à avaliação de apatia pela Escala de Apatia (EA), e proveram amostra de sangue para análise de biomarcadores. De acordo com a mediana de escores na EA (17 pontos), a amostra foi divida em dois grupos.

Resultados:

O grupo com mais sintomas de apatia apresentou maiores níveis séricos de receptores solúveis de TNF-α (tipo 1: p=0,03 ; tipo 2: p=0,04). Nenhuma outra diferença foi encontrada entre os grupos.

Conclusão:

Estes achados sugerem o envolvimento de mediadores inflamatórios na gênese de sintomas de apatia, assim como sugere a teoria do comportamento associado à doença.

Palavras-chave:
apatia; demência; doença de Alzheimer; comprometimento cognitivo leve; TNF-α; sTNFR1; sTNFR2,BDNF.

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REFERENCES

van Reekun R, Stuss DT, Ostrander L. Apathy: why care? J Neuropsychiatry Clin Neursoci 2005;17:7-19.
Guimaraes HC, Levy R, Teixeira AL, Beato RG, Caramelli P. Neurobiology of apathy in Alzheimer's disease. Arq Neuropsiquiatr 2008;66: 436-443.
Robert P, Onyike CU, Leentjens AF, et al. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry 2009;24:98-104.
Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP. A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease. Am J Geriatr Psychiatry 2005;13:460-468.
Starkstein SE, Petraca G, Chemerinski E, Kremer J. Syndromic validity of apathy in Alzheimer's disease. Am J Psychiatry 2001;158:872-877.
Starkstein SE, Jorge R, Mizrahi R, et al. A prospective longitudinal study of apathy in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2006;77:8-11.
Robert PH, Berr C, Volteau M, et al. Neuropsychological performance in mild cognitive impairment with and without apathy. Dement Geriatr Cogn Disord 2006;21:192-197.
Geda YE, Roberts RO, Knopman DS, et al. Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: a population-based study. Arch Gen Psychiatr 2008;65:1193-1198.
Robert PH, Berr C, Volteau M, et al. Apathy in patients with mild cognitive impairment and the risk of developing dementia of Alzheimer's disease: a one-year follow-up study. Clin Neurol Neurosurg 2006;108:733-736.
Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991;3:243-254.
Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci 2001;933:22-34.
Palin K, Bluthe RM, McCusker RH, et al. The type 1 TNF receptor and its associated adapter, FAN, are required to TNF-α induced sickness behavior. Psychopharmcaology 2009;201:549-56.
Bermejo P, Martín-Aragón S, Benedí J, et al. Differences in peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease. Immunol Lett 2008;117:198-202.
Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology 2010;129:154-169.
Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ 2003;10:46-65.
Diniz BS, Teixeira AL, Talib LL, Mendonça VA, Gattaz WF, Forlenza OV. Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression.World J Biol Psychiatry 2010;11:550-555.
Hubbard RE, O'Mahony MS, Sawa GM, Calver BL, Woodhouse KW. Inflammation and frailty measures in older people. J Cell Mol Med 2009;13:3103-3109.
Coelho FM, Narciso FM, Oliveira DM, et al. sTNFR-1 is an early inflammatory marker in community versus institutionalized elderly women. Inflamm Res 2010;59:129-134.
Caramelli P, Barbosa MT, Sakurai E, et al. The Pietà Study: epidemiological investigation in successful brain aging in Caeté(MG), Brazil. Methods and baseline cohort characteristics. Arq Neuropsiquatr 2011;69:579-584.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical Diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology 1984;34: 939-944.
Reisberg B. Functional assessment staging (FAST). Psychopharmacol Bull 1988;24:653-659.
Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology1993;43:250-260.
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183-194.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM). 4th ed. Washington, DC: American Psychiatric Association, 1994.
Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. Reliability, validity and clinical correlate of apathy in Parkinsons's disease. J Neuropsychiatry Cli Neurosci 1992;4;134-139
Funkiewiez A, Bertoux M, de Souza LC, Levy R, Dubois B. The SEA (Social Cognition and Emotional Assessment): A clinical neuropsychological tool for early diagnosis of frontal variant frontotemporal lobar degeneration. Neuropsychology 2012;26:81-90.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessments of psychopathology in dementia. Neurology1994;44: 2308-2313.
Hall JR, Vo HT, Johnson LA, Winter S, Barber RC, O'Bryant SE. Biomarkers and depressive symptoms in a sample of cognitively intact and Alzheimer's disease elderly males. Neuroscience Med 2011;2:306-312.
Maas DW, van der Mast RC, de Craen AJ. Increased C-reactive protein is not associated with apathy: the Leiden 85-Plus Study. Int J Geriatr Psychiatry 2009;24:1177-1184.
Chaudhry IB, Hallak J, Husain N, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 2012;26:1185-93.
Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammation 2012;9:62.
Boyle PA, Malloy PF, Salloway S, Cahn-Weiner DA, Cohen R, Cummings JL. Executive dysfunction and apathy predict functional impairment in Alzheimer disease.. Am J Geriatr Psychiatry 2003;11:214-221.
Petersen RC, Aisen P, Boeve BF, et al. Criteria for mild cognitive impairment due to alzheimer's disease in the community. Ann Neurol. 2013 [Epub ahead of print].

Publication Dates

Publication in this collection
Jul-Sep 2013

History

Received
05 June 2013
Accepted
18 Aug 2013

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

[1] van Reekun R, Stuss DT, Ostrander L. Apathy: why care? J Neuropsychiatry Clin Neursoci 2005;17:7-19.

[2] Guimaraes HC, Levy R, Teixeira AL, Beato RG, Caramelli P. Neurobiology of apathy in Alzheimer's disease. Arq Neuropsiquiatr 2008;66: 436-443.

[3] Robert P, Onyike CU, Leentjens AF, et al. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry 2009;24:98-104.

[4] Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP. A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease. Am J Geriatr Psychiatry 2005;13:460-468.

[5] Starkstein SE, Petraca G, Chemerinski E, Kremer J. Syndromic validity of apathy in Alzheimer's disease. Am J Psychiatry 2001;158:872-877.

[6] Starkstein SE, Jorge R, Mizrahi R, et al. A prospective longitudinal study of apathy in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2006;77:8-11.

[7] Robert PH, Berr C, Volteau M, et al. Neuropsychological performance in mild cognitive impairment with and without apathy. Dement Geriatr Cogn Disord 2006;21:192-197.

[8] Geda YE, Roberts RO, Knopman DS, et al. Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: a population-based study. Arch Gen Psychiatr 2008;65:1193-1198.

[9] Robert PH, Berr C, Volteau M, et al. Apathy in patients with mild cognitive impairment and the risk of developing dementia of Alzheimer's disease: a one-year follow-up study. Clin Neurol Neurosurg 2006;108:733-736.

[10] Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991;3:243-254.

[11] Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci 2001;933:22-34.

[12] Palin K, Bluthe RM, McCusker RH, et al. The type 1 TNF receptor and its associated adapter, FAN, are required to TNF-α induced sickness behavior. Psychopharmcaology 2009;201:549-56.

[13] Bermejo P, Martín-Aragón S, Benedí J, et al. Differences in peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease. Immunol Lett 2008;117:198-202.

[14] Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology 2010;129:154-169.

[15] Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ 2003;10:46-65.

[16] Diniz BS, Teixeira AL, Talib LL, Mendonça VA, Gattaz WF, Forlenza OV. Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression.World J Biol Psychiatry 2010;11:550-555.

[17] Hubbard RE, O'Mahony MS, Sawa GM, Calver BL, Woodhouse KW. Inflammation and frailty measures in older people. J Cell Mol Med 2009;13:3103-3109.

[18] Coelho FM, Narciso FM, Oliveira DM, et al. sTNFR-1 is an early inflammatory marker in community versus institutionalized elderly women. Inflamm Res 2010;59:129-134.

[19] Caramelli P, Barbosa MT, Sakurai E, et al. The Pietà Study: epidemiological investigation in successful brain aging in Caeté(MG), Brazil. Methods and baseline cohort characteristics. Arq Neuropsiquatr 2011;69:579-584.

[20] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical Diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology 1984;34: 939-944.

[21] Reisberg B. Functional assessment staging (FAST). Psychopharmacol Bull 1988;24:653-659.

[22] Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology1993;43:250-260.

[23] Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183-194.

[24] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM). 4th ed. Washington, DC: American Psychiatric Association, 1994.

[25] Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. Reliability, validity and clinical correlate of apathy in Parkinsons's disease. J Neuropsychiatry Cli Neurosci 1992;4;134-139

[26] Funkiewiez A, Bertoux M, de Souza LC, Levy R, Dubois B. The SEA (Social Cognition and Emotional Assessment): A clinical neuropsychological tool for early diagnosis of frontal variant frontotemporal lobar degeneration. Neuropsychology 2012;26:81-90.

[27] Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessments of psychopathology in dementia. Neurology1994;44: 2308-2313.

[28] Hall JR, Vo HT, Johnson LA, Winter S, Barber RC, O'Bryant SE. Biomarkers and depressive symptoms in a sample of cognitively intact and Alzheimer's disease elderly males. Neuroscience Med 2011;2:306-312.

[29] Maas DW, van der Mast RC, de Craen AJ. Increased C-reactive protein is not associated with apathy: the Leiden 85-Plus Study. Int J Geriatr Psychiatry 2009;24:1177-1184.

[30] Chaudhry IB, Hallak J, Husain N, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 2012;26:1185-93.

[31] Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammation 2012;9:62.

[32] Boyle PA, Malloy PF, Salloway S, Cahn-Weiner DA, Cohen R, Cummings JL. Executive dysfunction and apathy predict functional impairment in Alzheimer disease.. Am J Geriatr Psychiatry 2003;11:214-221.

[33] Petersen RC, Aisen P, Boeve BF, et al. Criteria for mild cognitive impairment due to alzheimer's disease in the community. Ann Neurol. 2013 [Epub ahead of print].

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