Review Article
Neuroimaging correlates of neuropsychiatric symptoms in Alzheimer's disease: a review of 20 years of research
N. Boublay,
A. M. Schott,
P. Krolak-Salmon,
Corresponding Author
N. Boublay
Memory Clinical and Research Center of Lyon, Hospital of Charpennes, University Hospital of Lyon, Lyon, France
University of Lyon, Lyon, France
Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Lyon, France
INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, Lyon, France
These authors have contributed equally to the paper.Correspondence: N. Boublay, Hôpital des Charpennes, 27 rue Gabriel Péri, 69100 Villeurbanne, France (tel.: +33 427 856 302; fax: +33 427 859 267; e-mail: [email protected]).Search for more papers by this authorA. M. Schott
Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Lyon, France
University Lyon 1, Lyon, France
Search for more papers by this authorP. Krolak-Salmon
Memory Clinical and Research Center of Lyon, Hospital of Charpennes, University Hospital of Lyon, Lyon, France
University of Lyon, Lyon, France
Clinical Research Centre CRC – VCF (Vieillissement – Cerveau – Fragilité), Hospital of Charpennes, University Hospital of Lyon, Lyon, France
INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, Lyon, France
These authors have contributed equally to the paper.Search for more papers by this authorN. Boublay,
A. M. Schott,
P. Krolak-Salmon,
Corresponding Author
N. Boublay
Memory Clinical and Research Center of Lyon, Hospital of Charpennes, University Hospital of Lyon, Lyon, France
University of Lyon, Lyon, France
Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Lyon, France
INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, Lyon, France
These authors have contributed equally to the paper.Correspondence: N. Boublay, Hôpital des Charpennes, 27 rue Gabriel Péri, 69100 Villeurbanne, France (tel.: +33 427 856 302; fax: +33 427 859 267; e-mail: [email protected]).Search for more papers by this authorA. M. Schott
Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Lyon, France
University Lyon 1, Lyon, France
Search for more papers by this authorP. Krolak-Salmon
Memory Clinical and Research Center of Lyon, Hospital of Charpennes, University Hospital of Lyon, Lyon, France
University of Lyon, Lyon, France
Clinical Research Centre CRC – VCF (Vieillissement – Cerveau – Fragilité), Hospital of Charpennes, University Hospital of Lyon, Lyon, France
INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, Lyon, France
These authors have contributed equally to the paper.Search for more papers by this authorAbstract
Assessing morphological, perfusion and metabolic brain changes preceding or associated with neuropsychiatric symptoms (NPSs) will help in the understanding of pathophysiological underlying processes in Alzheimer's disease (AD). This review aimed to highlight the main findings on significant associations between neuroimaging and NPSs, the pathophysiology to elucidate possible underlying mechanisms, and methodological issues to aid future research. Research papers published from January 1990 to October 2015 were identified in the databases PsycInfo, Embase, PubMed and Medline, using key words related to NPSs and imaging techniques. In addition to a semi-systematic search in the databases, we also performed hand searches based on reported citations identified to be of interest. Delusions, apathy and depression symptoms were particularly associated with brain changes in AD. The majority of studies disclosed an association between frontal lobe structural and/or metabolic changes and NPSs, implicating, interestingly, for all 12 NPSs studied, the anterior cingulate cortex although temporal, subcortical and parietal regions, and insula were also involved. Given the high degree of connectivity of these brain areas, frontal change correlates of NPSs may help in the understanding of neural network participation. This review also highlights crucial methodological issues that may reduce the heterogeneity of results to enable progress on the pathophysiological mechanisms and aid research on NPS treatments in AD. Based on a broad review of the current literature, a global brain pattern to support the huge heterogeneity of neuroimaging correlates of NPSs in AD and methodological strategies are suggested to help direct future research.
Supporting Information
| Filename | Description |
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| ene13076-sup-0001-TableS1.docWord document, 209.2 KB | Table S1. Detailed brain change correlates of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Cummings JL. Alzheimer's disease. N Engl J Med 2004; 351: 56–67.
- 2Tekin 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.
- 3Germain S, Adam S, Olivier C, et al. Does cognitive impairment influence burden in caregivers of patients with Alzheimer's disease? J Alzheimers Dis 2009; 17: 105–114.
- 4Voisin T, Andrieu S, Cantet C, Vellas B, REAL.FR Group. Predictive factors of hospitalizations in Alzheimer's disease: a two-year prospective study in 686 patients of the REAL.FR study. J Nutr Health Aging 2010; 14: 288–291.
- 5Rocca P, Leotta D, Liffredo C, et al. Neuropsychiatric symptoms underlying caregiver stress and insight in Alzheimer's disease. Dement Geriatr Cogn Disord 2010; 30: 57–63.
- 6Missotten P, Squelard G, Ylieff M, et al. Relationship between quality of life and cognitive decline in dementia. Dement Geriatr Cogn Disord 2008; 25: 564–572.
- 7M F-M, Molano A, Castro J, Zarranz JJ. Prevalence of neuropsychiatric symptoms in mild cognitive impairment and Alzheimer's disease, and its relationship with cognitive impairment. Curr Alzheimer Res 2010; 7: 517.
- 8Casanova MF, Starkstein SE, Jellinger KA. Clinicopathological correlates of behavioral and psychological symptoms of dementia. Acta Neuropathol 2011; 122: 117.
- 9Guimarães HC, Levy R, Teixeira AL, Beato RG, Caramelli P. Neurobiology of apathy in Alzheimer's disease. Arq Neuropsiquiatr 2008; 66: 436–443.
- 10Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res 2002; 53: 647–654.
- 11Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry 2000; 157: 708–714.
- 12Lee DY, Choo IH, Kim KW, et al. White matter changes associated with psychotic symptoms in Alzheimer's disease patients. J Neuropsychiatry Clin Neurosci 2006; 18: 191–198.
- 13Shinno H, Inagaki T, Miyaoka T, et al. A decrease in N-acetylaspartate and an increase in myoinositol in the anterior cingulate gyrus are associated with behavioral and psychological symptoms in Alzheimer's disease. J Neurol Sci 2007; 260: 132–138.
- 14Stern Y, Mayeux R, Sano M, Hauser WA, Bush T. Predictors of disease course in patients with probable Alzheimer's disease. Neurology 1987; 37: 1649–1653.
- 15Staff RT, Shanks MF, Macintosh L, Pestell SJ, Gemmell HG, Venneri A. Delusions in Alzheimer's disease: spet evidence of right hemispheric dysfunction. Cortex 1999; 35: 549.
- 16Mentis MJ, Weinstein EA, Horwitz B, et al. Abnormal brain glucose metabolism in the delusional misidentification syndromes: a positron emission tomography study in Alzheimer disease. Biol Psychiatry 1995; 38: 438–449.
- 17Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 2002; 288: 1475–1483.
- 18Rosen HJ, Allison SC, Schauer GF, Gorno-Tempini ML, Weiner MW, Miller BL. Neuroanatomical correlates of behavioural disorders in dementia. Brain 2005; 128: 2612–2625.
- 19Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL. Neuropathologic correlates of apathy in Alzheimer's disease. Dement Geriatr Cogn Disord 2006; 21: 144–147.
- 20Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995; 118(Pt 1): 279–306.
- 21Kile SJ, Ellis WG, Olichney JM, Farias S, DeCarli C. Alzheimer abnormalities of the amygdala with Klüver-Bucy syndrome symptoms: an amygdaloid variant of Alzheimer disease. Arch Neurol 2009; 66: 125–129.
- 22Förstl H, Burns A, Levy R, Cairns N, Luthert P, Lantos P. Neuropathological correlates of behavioural disturbance in confirmed Alzheimer's disease. Br J Psychiatry 1993; 163: 364–368.
- 23Garre-Olmo J, López-Pousa S, Vilalta-Franch J, de Gracia Blanco M, Vilarrasa AB. Grouping and trajectories of the neuropsychiatric symptoms in patients with Alzheimer's disease, part I: symptom clusters. J Alzheimers Dis 2010; 22: 1157.
- 24Stern Y. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol 2012; 11: 1006–1012.
- 25Raskind MA. Diagnosis and treatment of depression comorbid with neurologic disorders. Am J Med 2008; 121: S28–S37.
- 26Jicha GA, Carr SA. Conceptual evolution in Alzheimer's disease: implications for understanding the clinical phenotype of progressive neurodegenerative disease. J Alzheimers Dis 2010; 19: 253–272.
- 27Rapp MA, Schnaider-Beeri M, Wysocki M, et al. Cognitive decline in patients with dementia as a function of depression. Am J Geriatr Psychiatry 2011; 19: 357–363.
- 28Bell-McGinty S, Butters MA, Meltzer CC, Greer PJ, Reynolds CF, Becker JT. Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration. Am J Psychiatry 2002; 159: 1424–1427.
- 29Baxter LR, Schwartz JM, Phelps ME, et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 1989; 46: 243–250.
- 30Arikuni T, Sako H, Murata A. Ipsilateral connections of the anterior cingulate cortex with the frontal and medial temporal cortices in the macaque monkey. Neurosci Res 1994; 21: 19–39.
- 31Ismail Z, Nguyen M-Q, Fischer CE, Schweizer TA, Mulsant BH. Neuroimaging of delusions in Alzheimer's disease. Psychiatry Res 2012; 202: 89–95.
- 32Minnix JA, Kline JP, Blackhart GC, Pettit JW, Perez M, Joiner TE. Relative left-frontal activity is associated with increased depression in high reassurance-seekers. Biol Psychol 2004; 67: 145–155.
- 33Hirono N, Mori E, Ishii K, et al. Frontal lobe hypometabolism and depression in Alzheimer's disease. Neurology 1998; 50: 380–383.
- 34Levy-Cooperman N, Burhan AM, Rafi-Tari S, et al. Frontal lobe hypoperfusion and depressive symptoms in Alzheimer disease. J Psychiatry Neurosci 2008; 33: 218–226.
- 35Shanks MF, Venneri A. Thinking through delusions in Alzheimer's disease. Br J Psychiatry 2004; 184: 193–194.
- 36Davidson RJ, Irwin W. The functional neuroanatomy of emotion and affective style. Trends Cogn Sci 1999; 3: 11.
- 37Serra L, Perri R, Cercignani M, et al. Are the behavioral symptoms of Alzheimer's disease directly associated with neurodegeneration? J Alzheimers Dis 2010; 21: 627–639.
- 38Vogt BA, Finch DM, Olson CR. Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. Cereb Cortex 1992; 2: 435–443.
- 39Ring HA, Bench CJ, Trimble MR, Brooks DJ, Frackowiak RS, Dolan RJ. Depression in Parkinson's disease. A positron emission study. Br J Psychiatry 1994; 165: 333.
- 40Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002; 125: 391–403.
- 41Gur RE, Keshavan MS, Lawrie SM. Deconstructing psychosis with human brain imaging. Schizophr Bull 2007; 33: 921–931.
- 42Ballmaier M, Toga AW, Blanton RE, et al. Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly depressed patients: an MRI-based parcellation of the prefrontal cortex. Am J Psychiatry 2004; 161: 99–108.
- 43Mega MS, Cummings JL. The cingulate and cingulate syndromes. In: MR Trimble, JL Cummings, eds. Contemp. Behav. Neurol. Woburn: Butterworth-Heinemann, 1997: 189–222.
- 44Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci USA 2001; 98: 676–682.
- 45Zhou J, Greicius MD, Gennatas ED, et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease. Brain 2010; 133: 1352–1367.
- 46Seeley WW, Menon V, Schatzberg AF, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 2007; 27: 2349–2356.
- 47Peng H, Zheng H, Li L, et al. High-frequency rTMS treatment increases white matter FA in the left middle frontal gyrus in young patients with treatment-resistant depression. J Affect Disord 2012; 136: 249–257.
- 48MacDonald AW, Cohen JD, Stenger VA, Carter CS. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science 2000; 288: 1835–1838.
- 49Paus T. Primate anterior cingulate cortex: where motor control, drive and cognition interface. Nat Rev Neurosci 2001; 2: 417–424.
- 50Zhou J, Seeley WW. Network dysfunction in Alzheimer's disease and frontotemporal dementia: implications for psychiatry. Biol Psychiatry 2014; 75: 565–573.
- 51Zatorre RJ, Jones-Gotman M, Evans AC, Meyer E. Functional localization and lateralization of human olfactory cortex. Nature 1992; 360: 339–340.
- 52Critchley HD, Mathias CJ, Dolan RJ. Fear conditioning in humans: the influence of awareness and autonomic arousal on functional neuroanatomy. Neuron 2002; 33: 653–663.
- 53Mori T, Shimada H, Shinotoh H, et al. Apathy correlates with prefrontal amyloid β deposition in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2014; 85: 449–455.
- 54Trzepacz PT, Yu P, Bhamidipati PK, et al. Frontolimbic atrophy is associated with agitation and aggression in mild cognitive impairment and Alzheimer's disease. Alzheimers Dement 2013; 9: S95.e1
- 55Wallis JD. Orbitofrontal cortex and its contribution to decision-making. Annu Rev Neurosci 2007; 30: 31–56.
- 56Minger SL, Esiri MM, McDonald B, et al. Cholinergic deficits contribute to behavioral disturbance in patients with dementia. Neurology 2000; 55: 1460–1467.
- 57O'Doherty JP, Deichmann R, Critchley HD, Dolan RJ. Neural responses during anticipation of a primary taste reward. Neuron 2002; 33: 815–826.
- 58Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 2006; 442: 1042–1045.
- 59Volkow ND, Logan J, Fowler JS, et al. Association between age-related decline in brain dopamine activity and impairment in frontal and cingulate metabolism. Am J Psychiatry 2000; 157: 75–80.
- 60Kim JS, Choi-Kwon S. Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 2000; 54: 1805–1810.
- 61Hricak H, Choi BI, Scott AM, et al. Global trends in hybrid imaging. Radiology 2010; 257: 498–506.
- 62Burhan AM, Marlatt NM, Palaniyappan L, Anazodo UC, Prato FS. Role of hybrid brain imaging in neuropsychiatric disorders. Diagnostics (Basel) 2015; 5: 577–614.
- 63Palmqvist S, Sarwari A, Wattmo C, et al. Association between subcortical lesions and behavioral and psychological symptoms in patients with Alzheimer's disease. Dement Geriatr Cogn Disord 2011; 32: 417–423.
- 64Adams KB. Depressive symptoms, depletion, or developmental change? Withdrawal, apathy, and lack of vigor in the Geriatric Depression Scale. The Gerontologist 2001; 41: 768–777.
- 65Migneco O, Benoit M, Koulibaly PM, et al. Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer's disease and nondemented patients. NeuroImage 2001; 13: 896–902.
- 66Naarding P, Janzing JGE, Eling P, van der Werf S, Kremer B. Apathy is not depression in Huntington's disease. J Neuropsychiatry Clin Neurosci 2009; 21: 266–270.
- 67Kirsch-Darrow L, Fernandez HH, Fernandez HF, Marsiske M, Okun MS, Bowers D. Dissociating apathy and depression in Parkinson disease. Neurology 2006; 67: 33–38.
- 68Simpson JR, Drevets WC, Snyder AZ, Gusnard DA, Raichle ME. Emotion-induced changes in human medial prefrontal cortex: II. During anticipatory anxiety. Proc Natl Acad Sci USA 2001; 98: 688–693.
- 69Moran M, Lynch CA, Walsh C, Coen R, Coakley D, Lawlor BA. Sleep disturbance in mild to moderate Alzheimer's disease. Sleep Med 2005; 6: 347–352.
- 70Berlow 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.
- 71Yoshita M, Fletcher E, Harvey D, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology 2006; 67: 2192–2198.
- 72Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010; 341: c3666.
- 73Aharon-Peretz J, Masiah A, Pillar T, Epstein R, Tzischinsky O, Lavie P. Sleep-wake cycles in multi-infarct dementia and dementia of the Alzheimer type. Neurology 1991; 41: 1616–1619.
- 74Treiber KA, Lyketsos CG, Corcoran C, et al. Vascular factors and risk for neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study. Int Psychogeriatr 2008; 20: 538–553.
- 75Robinson RG, Kubos KL, Starr LB, Rao K, Price TR. Mood disorders in stroke patients. Importance of location of lesion. Brain 1984; 107(Pt 1): 81–93.
- 76Förstl H, Burns A, Jacoby R, Levy R. Neuroanatomical correlates of clinical misidentification and misperception in senile dementia of the Alzheimer type. J Clin Psychiatry 1991; 52: 268–271.
- 77Hirono N, Mori E, Ishii K, et al. Alteration of regional cerebral glucose utilization with delusions in Alzheimer's disease. J Neuropsychiatry Clin Neurosci 1998; 10: 433–439.
- 78Cook SE, Miyahara S, Bacanu S-A, et al. Psychotic symptoms in Alzheimer disease: evidence for subtypes. Am J Geriatr Psychiatry 2003; 11: 406–413.
- 79Nakano S, Yamashita F, Matsuda H, Kodama C, Yamada T. Relationship between delusions and regional cerebral blood flow in Alzheimer's disease. Dement Geriatr Cogn Disord 2006; 21: 16–21.
- 80Fountoulakis KN, Iacovides A, Gerasimou G, et al. The relationship of regional cerebral blood flow with subtypes of major depression. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 537–546.
- 81Honda H, Terada S, Sato S, et al. Subjective depressive mood and regional cerebral blood flow in mild Alzheimer's disease. Int Psychogeriatr 2014; 26: 817–823.
- 82Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer's disease. Neurology 1996; 46: 130–135.
- 83Ropacki SA, Jeste DV. Epidemiology of and risk factors for psychosis of Alzheimer's disease: a review of 55 studies published from 1990 to 2003. Am J Psychiatry 2005; 162: 2022–2030.
- 84Gonfrier S, Andrieu S, Renaud D, Vellas B, Robert PH. Course of neuropsychiatric symptoms during a 4-year follow up in the REAL-FR cohort. J Nutr Health Aging 2012; 16: 134–137.
- 85Palmer K, Berger AK, Monastero R, Winblad B, Bäckman L, Fratiglioni L. Predictors of progression from mild cognitive impairment to Alzheimer disease. Neurology 2007; 68: 1596–1602.
- 86Devanand DP, Marder K, Michaels KS, et al. A randomized, placebo-controlled dose-comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer's disease. Am J Psychiatry 1998; 155: 1512–1520.
- 87Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry 2000; 57: 968–976.
- 88Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med 2012; 366: 893–903.
- 89Meguro K, Meguro M, Tanaka Y, Akanuma K, Yamaguchi K, Itoh M. Risperidone is effective for wandering and disturbed sleep/wake patterns in Alzheimer's disease. J Geriatr Psychiatry Neurol 2004; 17: 61–67.
- 90Tanaka M, Namiki C, Thuy DHD, et al. Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer's disease. J Neurol Sci 2004; 225: 135–141.
- 91Mega MS, Dinov ID, Lee L, et al. Orbital and dorsolateral frontal perfusion defect associated with behavioral response to cholinesterase inhibitor therapy in Alzheimer's disease. J Neuropsychiatry Clin Neurosci 2000; 12: 209–218.
