Neurobiology of neuropsychiatric symptoms in Alzheimer's disease: A critical review with a focus on neuroimaging

Tascone, Lyssandra dos Santos; Bottino, Cássio Machado de Campos

doi:10.1590/S1980-57642013DN70300002

ABSTRACT

The objective of this critical review of the literature was to reveal the neural circuits involved in the occurrence of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) patients through the association of these symptoms with neuroimaging findings. The search for articles was performed on PUBMED from January 2000 to May 2013, using the key words: Dementia AND BPSD; Dementia AND Neuropsychiatric Symptoms; and Dementia AND Psychosis, Delusions, Hallucinations, Agitation, Depression, Anxiety, Apathy, Euphoria, Disinhibition, Irritability, Aberrant Motor Behavior, Sleep or Eating Disorders. Forty-six articles were reviewed and important contributions, especially regarding the psychopathological concepts discussed, were also considered even if not included in this time period. The available evidence suggests the three most relevant neurobiological models for neuropsychiatric symptoms in Alzheimer's disease are the frontal-subcortical circuits, the cortico-cortical networks, and the monoaminergic system. We discussed the association of the individual symptoms or syndromes with these models.

Key words:
dementia; Alzheimer's disease; neuroimaging; neuropsychiatric symptoms; BPSD

RESUMO

O objetivo dessa revisão crítica da literatura é investigar os circuitos neurais envolvidos na ocorrência dos sintomas neuropsiquiátricos nos pacientes com doença de Alzheimer através da associação destes sintomas com achados de neuroimagem. A procura dos artigos foi feita no PUBMED de Janeiro de 2000 a Maio de 2013, usando as palavras-chave: Demência E BPSD; Demência E Sintomas Neuropsiquiátricos; e Demência E Psicose, Delírios, Alucinações, Agitação, Depressão, Anxiedade, Apatia, Euforia, Desinibição, Irritabilidade, Comportamento Motor Aberrante, Distúrbios do Sono ou Apetite. Quarenta e seis artigos foram revisados e contribuições importantes, especialmente considerando os conceitos psicopatológicos discutidos, foram também discutidos, mesmo se não incluídos neste periodo de tempo. As evidências disponíveis sugerem que os três modelos neurobiológicos mais relevantes para os sintomas neuropsiquiátricos na doença de Alzheimer são os circuitos frontal-subcorticais, as redes cortico-corticais, e o sistema monoaminérgico. Nós discutimos a associação dos sintomas individuais ou síndromes com esses modelos.

Palavras-chave:
demência; doença de alzheimer; neuroimagem; sintomas neuropsiquiátricos; BPSD

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REFERENCES

McIlroy S, Craig D. Neurobiology and Genetics of Behavioural Syndromes of Alzheimer's disease. Curr Alzheimer Res 2004;1:135-142.
Shinosaki K, Nishikawa T, Takeda M. Neurobiological basis of behavioral and psychological symptoms in dementia of the Alzheimer type. Psychiatry Clin Neurosci 2000;54:111-620.
Spalletta G, Baldinetti F, Buccione I, et al. Cognition and behaviour are independent and heterogeneous dimensions in Alzheimer's disease. J Neurol 2004;251:688-695.
Bruen PB, McGeown WJ, Sanks MF, Venneri, A. Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's Disease. Brain 2008;131:2455-2463.
Casanova MF, Starkstein SE, Jellinger KA. Clinicopathologic correlates of behavioral and psychological symptoms of dementia. Acta Neuropathol 2011;122:117-135.
Petersen RC, Jack CR Jr, Xu YC, et al. Memory and MRI-based hippocampal volumes in aging and AD. Neurology 2000;54:581-587.
Horinek D, Petrovicky P, Hort J, et al. Amygdalar volume and psychiatric symptoms in Alzheimer's disease: an MRI analysis. Acta Neurol Scand 2006;113:40-45.
Berlow YA, Wells WM, Ellison JM, Sung YH, Renshaw PF, Harper DG. Neuropsychiatric correlates of white matter hyperintensities in Alzheimer's disease. Int J Geriatr Psychiatry 2010; 25:780-788.
Shinno H, Inagaki T, Miyaoka T, et al. A decrease in N-acetylaspartate and an increase in the anterior cingulated gyrus are associated with behavioral and psychological symptoms in Alzheimer's disease. J Neurol Sci 2007;206:132-138.
Mesulam M. Principles of behavioral neurology. In: Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system, and hemispheric specializations. New York: Oxford University Press; 2000:1-120.
Ismail Z, Nguyen M-Q, Fischer CE, Schweizer TA, Mulsant BH, Mamo D. Neurobiology of Delusions in Alzheimer's Disease. Curr Psychiatry Rep 2011;13:211-218.
Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease. I: Disorders of thought content. Br J Psychiatry 1990;157: 72-76.
Nakatsuka M, Meguro K, Tsuboi H, Nakamura K, Akanuma K, Yamaguchi S. Content of delusional thoughts in Alzheimer's disease and assessment of content-specific brain dysfunctions with BEHAVE-AD-FW and SPECT. Int Psychogeriatr 2013;25:939-948.
Reeves SJ, Goulda RL, Powell JF, Howard RJ. Origins of delusions in Alzheimer's disease. Neurosci Biobehav Rev 2012;36:2274-2287.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology1994;44:2308- 2314.
Mega MS, Lee L, Dinov ID, Mishkin F, Toga AW, Cummings JL. Cerebral correlates of psychotic symptoms in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2000;69:167-171.
Lee E, Meguro K, Hashimoto R, et al. Confabulations in episodic memory are associated with delusions in Alzheimer's disease. J Geriatr Psychiatry Neurol 2007;20:34-40.
Palaniyappan L, Balain V, Liddle PF. The neuroanatomy of psychotic diathesis: A meta-analytic review. J Psychiatr Res 2012;46:1249-1256.
Palaniyappan L, Liddle PF. Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction. J Psychiatry Neurosci 2012;37:17-27.
Palaniyappan L, Mallikarjun P, Joseph V, Liddle PF. Appreciating symptoms and deficits in schizophrenia: Right posterior insula and poor insight. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:523-527.
Northoff G, Heinzel A, de Greck M, Bermpohl F. Self-referential processing in our brain. A meta-analysis of imaging studies on the self. NeuroImage 2006;31:440-457.
Ismail Z, Nguyen M-Q, Fischer CE, Schweizer TA, Mulsant BH. Neuroimaging of delusions in Alzheimer's disease. Psychiatry Res: Neuroimaging 2012;202:89-95.
Serra L, Perri R, Cercignani M, et al. Are the Behavioral Symptoms of Alzheimer's Disease Directly Associated with Neurodegeneration? J Alzeimers Dis 2010;21:627-639.
Whitehead D, Tunnard C, Hurt C, et al. Frontotemporal atrophy associated with paranoid delusions in women with Alzheimer's disease. Int Psychogeriatr 2012;24:99-107.
Blackwood NJ, Howard RJ, Bentall RP, Murray RM. Cognitive neuropsychiatric models of persecutory delusions. Am J Psychiatry 2001; 158:527-539.
Cohen-Mansfield J, Marx M, Rosenthal A. A description of agitation in a nursing home. J Gerontol 1989;44:M77-M84.
Pinto T, Lanctôt L, Herrmann N. Revisiting the cholinergic hypothesis of behavioral and psychological symptoms in dementia Alzheimer's type. Ageing Res Rev 2011:10;404-412
Lane SD, Kjome KL, Moeller FG. Neuropsychiatry of Aggression. Neurol Clin 2011;29:49-64.
Tekin S, Mega MS, Masterman DM, et al. Orbitofrontal and Anterior Cingulate Cortex Neurofibrillary Tangle Burden Is Associated with Agitation in Alzheimer Disease. Ann Neurol 2001;49:355-361.
Cummings J. Cognitive and behavioral heterogeneity in Alzheimer's disease: seeking the neurobiological basis. Neurobiol Aging 2000;21: 845-861.
Hirono N, Mori E, Ishii K, et al. Frontal lobe hypometabolism and depression in Alzheimer's disease. Neurology1998;50:380-383.
Levy ML, Cummings JL, Fairbanks LA, et al. Apathy is not depression. Neuropsychiatry Clin Neurosci 1998;10:314-319.
Drevets WC, Price JL, Furey ML. Brainstructural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. BrainStruct Funct 2008; 213:93-118.
Naismith SL, Norrie LM, Mowszowski L, Hickie IB. The neurobiology of depression in later-life: Clinical, neuropsychological, neuroimaging and pathophysiological features. Prog Neurobiol 2012;98:99-143.
Koenigs M, Grafman J. The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex. Behav BrainRes 2009;201:239-243.
Andreescu C, Butters MA, Begley A, et al. Gray Matter Changes in Late Life Depression - a Structural MRI Analysis. Neuropsychopharmacology 2008;33:2566-2572.
Van Tol MJ, van der Wee NJA, van den Heuvel OA, et al. Regional BrainVolume in Depression and anxiety disorders. Arch Gen Psychiatry 2010; 67:1002-1011.
Sprengelmeyer R, Steele D, Mwangi D, Kumar P. The insular cortex and the neuroanatomy of major depression. J Affect Disord 2011;133: 120-127.
Steffens DC, Byrum CE, McQuoid DR, et al. Hippocampal Volume in Geriatric Depression. Biol Psychiatry 2000;48:301-309.
Ballmaier M, Narr KL, Toga AW, et al. Hippocampal Morphology and Distinguishing Late-Onset From Early-Onset Elderly Depression. Am J Psychiatry2008;165:229-237.
Chang CC, Yu SC, McQuoid DR, et al. Reduction of dorsolateral prefrontal cortex gray matter in late-life depression. Psychiatry Res 2011; 193:1-6.
Ballmaier M, Sowell ER, Thompson PM, et al. Mapping BrainSize and Cortical Gray Matter Changes in Elderly Depression. Biol Psychiatry2004;55:382-389.
Lim HK, Jung WS, Ahn KJ, et al. Regional cortical thickness and subcortical volume changes are associated with cognitive impairments in the drug-naive patients with late-onset depression. Neuropsychopharmacology2012;37:838-849.
Lopez OL, Zivkovic S, Smith G, et al. Psychiatric symptoms associated with cortical-subcortical dysfunction in Alzheimer's disease. J Neuropsychiatry Clin Neurosci2001;13:56-60.
Hashimoto H, Monserratt L, Nguyen P, et al. Anxiety and regional cortical glucose metabolism in patients with Alzheimer's disease. J Neuropsychiatry Clin Neurosci2006;18:521-528.
Porter V, Buxton W, Fairbanks LA, et al. Frequency and Characteristics of Anxiety among patients with Alzheimer's disease and disorders related. J Neuropsychiatry Clin Neurosci2003;15:180-186.
Starkstein SE, Jorge R, Petracca G, Robinson R. The Construct of Generalized Anxiety Disorder in Alzheimer Disease. Am J Geriatr Psychiatry 2007;15:42-49.
Kühn S, Schubert F, Gallinat J. Structural correlates of trait anxiety: Reduced thickness in medial orbitofrontal cortex accompanied by volume increase in nucleus accumbens. J Affect Disord2011;134:315-319.
Marin RS. Differential diagnosis and classification of apathy. Am J Psychiatry1990;147:22-30.
Apostolova LG, Akopyan GG, Partiali N, et al. Structural Correlates of Apathy in Alzheimer's Disease. Dement Geriatr Cogn Disord 2007; 24:91-97.
Levy R, Dubois B. Apathy and the Functional Anatomy of the Prefrontal Cortex--Basal Ganglia Circuits. Cereb Cortex 2006;16:916-928.
Shackman AJ, Salomons TV, Slagter HA, Fox AS, Winter JJ, Davidson RJ. The integration of negative affect, pain and cognitive control in the cingulate cortex. Nat Rev Neurosci 2011;12:154-167.
Guimarães HC, Levy R, Teixeira AL, Beato RG, Caramelli P. Neurobiology of apathy in Alzheimer's disease. Arq Neuropsiquiatr 2008;66: 436-443.
Rosen HJ, Allison SC, Schauer GF, Gorno-Tempini ML, Weiner MW, Miller BL. Neuroanatomical correlates of behavioural disorders in dementia. Brain2005;128:2612-2625.
Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res 2002;53:647-654.
Hollingworth P, Hamshere ML, Moskvina V, et al. Four Components Describe Behavioral Symptoms in 1,120 Individuals with Late-Onset Alzheimer's Disease. J Am Geriatr Soc 2006; 54:1348-1354.
Aalten P, Verhey FRJ, Boziki M, et al. Neuropsychiatric syndromes in dementia Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord2007;24:457-463.
Lyketsos CG, Sheppard JME, Steinberg M, et al. Neuropsychiatric disturbances in Alzheimer's disease clusters into three groups: the cache county study. Int J Geriatr Psych 2001;16:1043-1053.
Schroeter ML, Vogt B, Frisch S, et al. Dissociating behavioral disorders in early dementia-An FDG-PET study. Psychiatry Res2011;194:235-244.
Nagata T, Shinagawa S, Ochiai Y, et al. Relationship of frontal lobe dysfunction and aberrant motor behaviors in patients with Alzheimer's disease. Int Psychogeriatr2010;22:463-469.
Robert PH, Verhey FRJ, Byrne EJ, et al. Grouping for behavioral and psychological symptoms in dementia: clinical and biological aspects. Consensus paper of the European Alzheimer disease consortium. Eur Psychiatry 2005;20:490-496.
Lyketsos CG, Kozauer N, Rabins PV. Psychiatric manifestations of neurologic disease: where are we headed? Dialogues Clin Neurosci 2007; 9:111-124.
Ikeda M, Brown J, Holland A J, Fukuhara R, Hodges JR. Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer's disease. J Neurol Neurosurg Psychiatry 2002;73: 371-376.
Hinton EC, Parkinson JA, Holland AJ, Arana FS, Roberts AC, Owen AM. Neural contributions to the motivational control of appetite in humans. Eur J Neurosci 2004;20:1411-1418.
Smith KL, Greenwood CE. Weight Loss and Nutritional Considerations in Alzheimer Disease. J Nutr Elder 2008;27:381-403.

Publication Dates

Publication in this collection
Jul-Sep 2013

History

Received
02 May 2013
Accepted
04 Aug 2013

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

[1] McIlroy S, Craig D. Neurobiology and Genetics of Behavioural Syndromes of Alzheimer's disease. Curr Alzheimer Res 2004;1:135-142.

[2] Shinosaki K, Nishikawa T, Takeda M. Neurobiological basis of behavioral and psychological symptoms in dementia of the Alzheimer type. Psychiatry Clin Neurosci 2000;54:111-620.

[3] Spalletta G, Baldinetti F, Buccione I, et al. Cognition and behaviour are independent and heterogeneous dimensions in Alzheimer's disease. J Neurol 2004;251:688-695.

[4] Bruen PB, McGeown WJ, Sanks MF, Venneri, A. Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's Disease. Brain 2008;131:2455-2463.

[5] Casanova MF, Starkstein SE, Jellinger KA. Clinicopathologic correlates of behavioral and psychological symptoms of dementia. Acta Neuropathol 2011;122:117-135.

[6] Petersen RC, Jack CR Jr, Xu YC, et al. Memory and MRI-based hippocampal volumes in aging and AD. Neurology 2000;54:581-587.

[7] Horinek D, Petrovicky P, Hort J, et al. Amygdalar volume and psychiatric symptoms in Alzheimer's disease: an MRI analysis. Acta Neurol Scand 2006;113:40-45.

[8] Berlow YA, Wells WM, Ellison JM, Sung YH, Renshaw PF, Harper DG. Neuropsychiatric correlates of white matter hyperintensities in Alzheimer's disease. Int J Geriatr Psychiatry 2010; 25:780-788.

[9] Shinno H, Inagaki T, Miyaoka T, et al. A decrease in N-acetylaspartate and an increase in the anterior cingulated gyrus are associated with behavioral and psychological symptoms in Alzheimer's disease. J Neurol Sci 2007;206:132-138.

[10] Mesulam M. Principles of behavioral neurology. In: Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system, and hemispheric specializations. New York: Oxford University Press; 2000:1-120.

[11] Ismail Z, Nguyen M-Q, Fischer CE, Schweizer TA, Mulsant BH, Mamo D. Neurobiology of Delusions in Alzheimer's Disease. Curr Psychiatry Rep 2011;13:211-218.

[12] Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease. I: Disorders of thought content. Br J Psychiatry 1990;157: 72-76.

[13] Nakatsuka M, Meguro K, Tsuboi H, Nakamura K, Akanuma K, Yamaguchi S. Content of delusional thoughts in Alzheimer's disease and assessment of content-specific brain dysfunctions with BEHAVE-AD-FW and SPECT. Int Psychogeriatr 2013;25:939-948.

[14] Reeves SJ, Goulda RL, Powell JF, Howard RJ. Origins of delusions in Alzheimer's disease. Neurosci Biobehav Rev 2012;36:2274-2287.

[15] Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology1994;44:2308- 2314.

[16] Mega MS, Lee L, Dinov ID, Mishkin F, Toga AW, Cummings JL. Cerebral correlates of psychotic symptoms in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2000;69:167-171.

[17] Lee E, Meguro K, Hashimoto R, et al. Confabulations in episodic memory are associated with delusions in Alzheimer's disease. J Geriatr Psychiatry Neurol 2007;20:34-40.

[18] Palaniyappan L, Balain V, Liddle PF. The neuroanatomy of psychotic diathesis: A meta-analytic review. J Psychiatr Res 2012;46:1249-1256.

[19] Palaniyappan L, Liddle PF. Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction. J Psychiatry Neurosci 2012;37:17-27.

[20] Palaniyappan L, Mallikarjun P, Joseph V, Liddle PF. Appreciating symptoms and deficits in schizophrenia: Right posterior insula and poor insight. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:523-527.

[21] Northoff G, Heinzel A, de Greck M, Bermpohl F. Self-referential processing in our brain. A meta-analysis of imaging studies on the self. NeuroImage 2006;31:440-457.

[22] Ismail Z, Nguyen M-Q, Fischer CE, Schweizer TA, Mulsant BH. Neuroimaging of delusions in Alzheimer's disease. Psychiatry Res: Neuroimaging 2012;202:89-95.

[23] Serra L, Perri R, Cercignani M, et al. Are the Behavioral Symptoms of Alzheimer's Disease Directly Associated with Neurodegeneration? J Alzeimers Dis 2010;21:627-639.

[24] Whitehead D, Tunnard C, Hurt C, et al. Frontotemporal atrophy associated with paranoid delusions in women with Alzheimer's disease. Int Psychogeriatr 2012;24:99-107.

[25] Blackwood NJ, Howard RJ, Bentall RP, Murray RM. Cognitive neuropsychiatric models of persecutory delusions. Am J Psychiatry 2001; 158:527-539.

[26] Cohen-Mansfield J, Marx M, Rosenthal A. A description of agitation in a nursing home. J Gerontol 1989;44:M77-M84.

[27] Pinto T, Lanctôt L, Herrmann N. Revisiting the cholinergic hypothesis of behavioral and psychological symptoms in dementia Alzheimer's type. Ageing Res Rev 2011:10;404-412

[28] Lane SD, Kjome KL, Moeller FG. Neuropsychiatry of Aggression. Neurol Clin 2011;29:49-64.

[29] Tekin S, Mega MS, Masterman DM, et al. Orbitofrontal and Anterior Cingulate Cortex Neurofibrillary Tangle Burden Is Associated with Agitation in Alzheimer Disease. Ann Neurol 2001;49:355-361.

[30] Cummings J. Cognitive and behavioral heterogeneity in Alzheimer's disease: seeking the neurobiological basis. Neurobiol Aging 2000;21: 845-861.

[31] Hirono N, Mori E, Ishii K, et al. Frontal lobe hypometabolism and depression in Alzheimer's disease. Neurology1998;50:380-383.

[32] Levy ML, Cummings JL, Fairbanks LA, et al. Apathy is not depression. Neuropsychiatry Clin Neurosci 1998;10:314-319.

[33] Drevets WC, Price JL, Furey ML. Brainstructural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. BrainStruct Funct 2008; 213:93-118.

[34] Naismith SL, Norrie LM, Mowszowski L, Hickie IB. The neurobiology of depression in later-life: Clinical, neuropsychological, neuroimaging and pathophysiological features. Prog Neurobiol 2012;98:99-143.

[35] Koenigs M, Grafman J. The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex. Behav BrainRes 2009;201:239-243.

[36] Andreescu C, Butters MA, Begley A, et al. Gray Matter Changes in Late Life Depression - a Structural MRI Analysis. Neuropsychopharmacology 2008;33:2566-2572.

[37] Van Tol MJ, van der Wee NJA, van den Heuvel OA, et al. Regional BrainVolume in Depression and anxiety disorders. Arch Gen Psychiatry 2010; 67:1002-1011.

[38] Sprengelmeyer R, Steele D, Mwangi D, Kumar P. The insular cortex and the neuroanatomy of major depression. J Affect Disord 2011;133: 120-127.

[39] Steffens DC, Byrum CE, McQuoid DR, et al. Hippocampal Volume in Geriatric Depression. Biol Psychiatry 2000;48:301-309.

[40] Ballmaier M, Narr KL, Toga AW, et al. Hippocampal Morphology and Distinguishing Late-Onset From Early-Onset Elderly Depression. Am J Psychiatry2008;165:229-237.

[41] Chang CC, Yu SC, McQuoid DR, et al. Reduction of dorsolateral prefrontal cortex gray matter in late-life depression. Psychiatry Res 2011; 193:1-6.

[42] Ballmaier M, Sowell ER, Thompson PM, et al. Mapping BrainSize and Cortical Gray Matter Changes in Elderly Depression. Biol Psychiatry2004;55:382-389.

[43] Lim HK, Jung WS, Ahn KJ, et al. Regional cortical thickness and subcortical volume changes are associated with cognitive impairments in the drug-naive patients with late-onset depression. Neuropsychopharmacology2012;37:838-849.

[44] Lopez OL, Zivkovic S, Smith G, et al. Psychiatric symptoms associated with cortical-subcortical dysfunction in Alzheimer's disease. J Neuropsychiatry Clin Neurosci2001;13:56-60.

[45] Hashimoto H, Monserratt L, Nguyen P, et al. Anxiety and regional cortical glucose metabolism in patients with Alzheimer's disease. J Neuropsychiatry Clin Neurosci2006;18:521-528.

[46] Porter V, Buxton W, Fairbanks LA, et al. Frequency and Characteristics of Anxiety among patients with Alzheimer's disease and disorders related. J Neuropsychiatry Clin Neurosci2003;15:180-186.

[47] Starkstein SE, Jorge R, Petracca G, Robinson R. The Construct of Generalized Anxiety Disorder in Alzheimer Disease. Am J Geriatr Psychiatry 2007;15:42-49.

[48] Kühn S, Schubert F, Gallinat J. Structural correlates of trait anxiety: Reduced thickness in medial orbitofrontal cortex accompanied by volume increase in nucleus accumbens. J Affect Disord2011;134:315-319.

[49] Marin RS. Differential diagnosis and classification of apathy. Am J Psychiatry1990;147:22-30.

[50] Apostolova LG, Akopyan GG, Partiali N, et al. Structural Correlates of Apathy in Alzheimer's Disease. Dement Geriatr Cogn Disord 2007; 24:91-97.

[51] Levy R, Dubois B. Apathy and the Functional Anatomy of the Prefrontal Cortex--Basal Ganglia Circuits. Cereb Cortex 2006;16:916-928.

[52] Shackman AJ, Salomons TV, Slagter HA, Fox AS, Winter JJ, Davidson RJ. The integration of negative affect, pain and cognitive control in the cingulate cortex. Nat Rev Neurosci 2011;12:154-167.

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

[54] Rosen HJ, Allison SC, Schauer GF, Gorno-Tempini ML, Weiner MW, Miller BL. Neuroanatomical correlates of behavioural disorders in dementia. Brain2005;128:2612-2625.

[55] Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res 2002;53:647-654.

[56] Hollingworth P, Hamshere ML, Moskvina V, et al. Four Components Describe Behavioral Symptoms in 1,120 Individuals with Late-Onset Alzheimer's Disease. J Am Geriatr Soc 2006; 54:1348-1354.

[57] Aalten P, Verhey FRJ, Boziki M, et al. Neuropsychiatric syndromes in dementia Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord2007;24:457-463.

[58] Lyketsos CG, Sheppard JME, Steinberg M, et al. Neuropsychiatric disturbances in Alzheimer's disease clusters into three groups: the cache county study. Int J Geriatr Psych 2001;16:1043-1053.

[59] Schroeter ML, Vogt B, Frisch S, et al. Dissociating behavioral disorders in early dementia-An FDG-PET study. Psychiatry Res2011;194:235-244.

[60] Nagata T, Shinagawa S, Ochiai Y, et al. Relationship of frontal lobe dysfunction and aberrant motor behaviors in patients with Alzheimer's disease. Int Psychogeriatr2010;22:463-469.

[61] Robert PH, Verhey FRJ, Byrne EJ, et al. Grouping for behavioral and psychological symptoms in dementia: clinical and biological aspects. Consensus paper of the European Alzheimer disease consortium. Eur Psychiatry 2005;20:490-496.

[62] Lyketsos CG, Kozauer N, Rabins PV. Psychiatric manifestations of neurologic disease: where are we headed? Dialogues Clin Neurosci 2007; 9:111-124.

[63] Ikeda M, Brown J, Holland A J, Fukuhara R, Hodges JR. Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer's disease. J Neurol Neurosurg Psychiatry 2002;73: 371-376.

[64] Hinton EC, Parkinson JA, Holland AJ, Arana FS, Roberts AC, Owen AM. Neural contributions to the motivational control of appetite in humans. Eur J Neurosci 2004;20:1411-1418.

[65] Smith KL, Greenwood CE. Weight Loss and Nutritional Considerations in Alzheimer Disease. J Nutr Elder 2008;27:381-403.

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