Review Article Behavioral and Psychological Symptoms in ...

Review ArticleBehavioral and Psychological Symptoms in Alzheimerrsquos Disease

Xiao-Ling Li1 Nan Hu1 Meng-Shan Tan2 Jin-Tai Yu1 and Lan Tan12

1 Department of Neurology Qingdao Municipal Hospital School of Medicine Qingdao UniversityNo 5 Donghai Middle Road Qingdao 266071 China

2Department of Neurology Qingdao Municipal Hospital College of Medicine and PharmaceuticsOcean University of China Qingdao 266003 China

Correspondence should be addressed to Jin-Tai Yu yu-jintai163com and Lan Tan drtanlan163com

Received 8 February 2014 Revised 23 June 2014 Accepted 29 June 2014 Published 15 July 2014

Academic Editor Hanna Rosenmann

Copyright copy 2014 Xiao-Ling Li et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Neuropsychiatric symptoms (NPS) such as depression apathy aggression and psychosis are now recognized as core features ofAlzheimerrsquos disease (AD) and there is a general consensus that greater symptom severity is predictive of faster cognitive declineloss of independence and even shorter survival Whether these symptoms result from the same pathogenic processes responsiblefor cognitive decline or have unique etiologies independent of AD-associated neurodegeneration is unclear Many structural andmetabolic features of the AD brain are associated with individual neuropsychiatric symptoms or symptom clusters In additionmany genes have been identified and confirmed that are associated with symptom risk in a few cases However there are no singlegenes strongly predictive of individual neuropsychiatric syndromes while functional and structural brain changes unique to specificsymptoms may reflect variability in progression of the same pathological processes Unfortunately treatment success for thesepsychiatric symptomsmay be lowerwhen comorbidwithAD underscoring the importance of future research on their pathobiologyand treatment This review summarizes some of the most salient aspects of NPS pathogenesis

1 Introduction

The recent establishment of a professional interest area (PIA)within the International Society to Advance AlzheimerrsquosResearch and Treatment (ISTAART) devoted to the neu-ropsychiatric symptoms (NPS) of Alzheimerrsquos is a sign of theemerging consensus among researchers and clinicians alikethat these symptoms are major components of Alzheimerrsquosdisease (AD) and significant influences on both patient andcaregiver quality of life (QOL) [1] Indeed neuropsychiatricsymptoms such as apathy depression aggression agitationsleep disruption and psychosis are now recognized as coresymptoms of AD that are expressed to varying degreesthroughout the course of the illness [2] In addition to pro-viding insight into AD pathology specific neuropsychiatricand behavioral anomalies during the early prodromal phaseof mild cognitive impairment (MCI) may have prognosticvalues For example late-life depression increases AD riskby 2-fold [3] In this review the major neuropsychiatric andbehavioral symptoms of AD are reviewed with emphasis onhow these symptoms may illuminate disease pathogenesis or

provide prognostic information Alzheimerrsquos dementia is theend result of multiple pathogenic processes including aber-rant amyloid processing [4 5] changes in lipid metabolismdue to apolipoprotein E (APOE) risk alleles [6 7] tau hyper-phosphorylation [8] protein misfolding and endoplasmicreticulum (ER) stress [9] vascular dysfunction [10] oxidativestress and mitochondrial dysfunction [11 12] neurotrophicfactor dysregulation [13] disrupted leptin signaling [14]fibrin clots [15] and processes mediated by a myriad of otherAD-associated gene [16] and the pathogenic processes alsooccurred in major neuropsychiatric symptoms (Figure 1) Itis likely that these processes target nonoverlapping neuralnetworks accounting for difference in disease progressionand the variability in neuropsychiatric symptoms

The neuropsychiatric symptoms and behavioral anoma-lies of AD have a significant impact on patient QOL andare thought to be predictive of eventual (or more severe)dementia [17 18] more extensive neurodegeneration [19]loss of functional independence and institutionalization [20]and early death [21] Thus there is general agreement thatthese neuropsychiatric symptoms and behavioral anomalies

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 927804 9 pageshttpdxdoiorg1011552014927804

2 BioMed Research International

ADDepression

Apathy

Agitation

Psychosis

5-HT system

Inflammation

Hypoperfusion

Hypoperfusion

5-HT system

5-HT system

Hypoperfusion

Dopamine oxidasm A geneMuscarinic receptor

Dopamine receptor Tau

Serum GABA

Hypoperfusion

A120573 metabolism and APOE 4


A120573 metabolism

A120573 and APOE 4

3998400UTR prion

Figure 1 Possible mechanism linking the neuropsychiatric symptoms (NPS) with AD NPS such as depression apathy aggression andpsychosis shared some pathogenic processes (in red color) with AD while they also have their unique pathogenic processes

are predictive of poor outcome although symptom incidenceprogression and prognostic significance are highly variableacross studies possibly due to the different neuropsychiatricinstruments used or clinical definitions Moreover despiterecent identification of noninvasive biomarkers related to AD[22] and advances in imagingAD-associated plaques [23 24]AD is still a diagnosis that can only be confirmed at autopsyso most such studies relate neuropsychiatric symptoms toldquopresumed ADrdquo Another uncertainty is whether these neu-ropsychiatric and behavioral abnormalities such as depres-sion and psychosis are etiologically similar in patients withand without AD or constitute clinical entities unique to AD

2 Depression

Depression is a common comorbidity in AD with preva-lence estimates ranging from 25 to 749 in a groupof recent studies [23ndash28] This variability is likely due tothe multitude of instruments used for diagnosis includingthe DSM Neuropsychiatric Inventory Depression subscale(NPI-D) and Geriatric Depression scale (GDS) Indeed onestudy reported rates in the same cohort of 105 usingthe NPI-D (significant) 564 based on the NPI-D (any)30 based on the Geriatric Depression scale (GDS) and16 based on antidepressant usage [24] A French Networkon AD (REALFR) study following several hundred ADpatients without depression or antidepressant use over 4 yearsreported an incidence of 1745year [27] Thus about 40of AD patients are expected to show symptoms of clinicaldepression within 5 years Moreover voluminous evidenceindicates that AD with depression results in worse clinicaloutcome [20]

Based on studies in depressed non-AD populations earlystudies on the pathophysiology of depression in AD focusedon serotonergic transmission One of the earliest studiesreported an association between major depression in AD atbaseline and 5-HT (2A) and 5-HT (2C) receptor polymor-phisms with CC carriers of the 5-HT (2A) C102 allele fivetimesmore likely than heterozygotes and 5-HT (2C) Ser allelecarriers 12 times more likely than 5-HT (2C) Cys allele carri-ers to develop depression [29] Moreover reduced 5-HT (1A)receptor expression was specifically correlated with depres-sive symptoms [30] In contrast Pritchard and colleaguesfound no significant association between depression in ADand either the C alleleCC genotype of the T102C variantof 5HT (2A) or the cys23ser variant of 5HT (2C) receptoralthough these alleles were associated with psychosis andaberrant motor behavior [31] Moreover no association wasfound between depression in AD and alleles of the serotonintransporter (SERT) [32] Similarly although SERT expressionwas reduced in the frontal cortex of AD patients there was nodifference in expression in patients with or without comorbiddepression [33] It is possible that serotonergic dysfunctionmay be heterogeneous among brain regions across patientsaccounting for these differences in association In addition to5-HT signaling elderly subjects destined to exhibit signs ofmajor depressionweremore likely to harbor theGGgenotypeof the tumor necrosis factor (TNF)-alpha 308 (GA) SNPvariant implicating inflammation in late-onset MD [34]

Early studies also examined the relationship betweendepression and molecules implicated in general AD pathol-ogy particularly A120573 and APOE 4 the strongest risk allelefor AD Early onset depression was associated with a higherserumA12057340A12057342 ratio [19] suggesting that depressionmay

BioMed Research International 3

be associated with AD pathogenesis One early small samplestudy found no association between APOE genotype anddepression in AD [35] although subsequent studies havedemonstrated that APOE genotype can modify the effects ofother genes associated with the neuropsychiatric symptomsof AD (see below) A higher serum concentration of A120573at baseline predicted both depression and AD over 5 yearssuggesting shared etiology [36] Plasma GABAwas positivelycorrelated with depression and apathy scores on the NPI inAD patients [37]

In addition to gene association studies the pathogenesisof AD has also been examined by various neuroimag-ing modalities which have revealed morphological andmetabolic signs of neurodegeneration in the AD brain specif-ically associated with depression Compared to nondepressedAD patients those with depression exhibited hypoperfusionin the left frontal lobe on single-photon emission com-puted tomography (SPECT) images [38] and reduced glucosemetabolism in the dorsolateral prefrontal regions as revealedby (18)F-fluorodeoxyglucose PET [39] Correlation analysisof brain SPECT and NPI score revealed a region in theleft middle frontal gyrus (Brodmann area 9) specificallyassociated with depressive symptoms [40] Depression inAD has also been associated with specific neurochemicalchanges GDS scores but not agitation scores were correlatedwith cholinecreatine ratio in left dorsolateral prefrontalcortex [41] Cortical atrophy associated with depressionwas observed in wide regions of the prefrontal cortex andtemporal cortex [42] and decreased graymatter volume in theleft inferior temporal gyrus was confirmed in an independentstudy [43] Depressed AD patients also exhibited greaterwhite matter atrophy in frontal temporal and parietal lobesthan AD patients without depressive symptoms [44] Onestudy also reported lesions in the caudate nucleus andlentiform nucleus of AD patients with late-onset depression[45] Expansion of the lateral ventricles was also correlatedwith depression general cognitive decline and poor outcome[46] Thus depression is associated with both gray andwhite matter atrophy particularly in specific regions of theprefrontal cortex

However it remains unclear if depression results fromAD or conversely if geriatric depression is a risk factor forAD In the first case depression may be a psychologicalresponse to AD or result from the same pathogenic processesthat lead to the other symptoms of AD (eg aberrantamyloid A120573 processing tau hyperphosphorylation etc) [47]Depression in AD is associated with accelerated corticalregression and white matter atrophy particularly in frontaland temporal areas It has been proposed that AD-associateddegeneration may eventually damage regions involved inregulation of mood a finding consistent with the high ratesof depression in severe AD Nonetheless several genetic riskfactors for major depression appear to increase the risk ofdepression in AD but not AD without depression so theemergence of depression may not be entirely dependent onAD pathogenesis For example the tryptophan hydroxylase-1 (TPH1) A218C allele monoamine oxidase A (MAOA) vari-able number tandem repeat (VNTR) and BDNF Val66Metallele were associated with depression in females with AD

with significantly increased likelihood of comorbid AD anddepression in homozygous TPH1 A-allele andMAOAVNTRcarriers [48] In this same study there was also a significantassociation between the chaperone FK506 binding protein 5(FKBP5) rs1360780 SNP and depression in all AD patientsIn addition homozygous carriers of the rs10410544T alleleof the SIRT2 gene (encoding an NAD-dependent deacetylasepossibly involved in cell cycle regulation) may have reduceddepression risk in AD [49] Aside from the Val66Met alleleof BDNF the C allele of the SNP G11757C and the A alleleof G196A were also more common in AD patients withdepression [50] One of the strongest associations with late-onset AD and depression is that with the transforminggrowth factor 1 (TGF-1) gene the CC genotype of the +10 TCSNP was associated with AD and conferred a 5-fold increasein depression in AD as well as an increase in depressionseverity [51] Finally the presence of the APOE 4 alleleincreased depression in women with AD by 4-fold [52] Incontrast another study reported that APOE 4 was associatedwith anxiety but not depression [53] while others havefound no association between APOE 4 and neuropsychiatricsymptoms [35]

Whether depression increases AD risk in premorbid orMCI patients is still a matter of debate In an Italian studynewly diagnosed AD patients with persistent depressionexhibited a greater cognitive decline over one year andpatients with incident depression demonstrated the greatestdrop in cognitive function while cognitive decline in caseswith resolved depression was not different from nonde-pressedADpatients [54] Late-onset depression does increasethe risk of progression to MCI but chronic depressionwas associated with only a modest increase in the risk ofMCI-to-AD transition Another Italian study reported thatapathy but not depression was associated with MCI to ADtransition [55] In contrast the Honolulu-Asia Aging Studyusing the Center for Epidemiological Studies depression scale(CES-D) reported that depression was an independent riskfactor for cognitive decline in AD Moreover the effect wasindependent of pathological progression such as increasesin the numberdensity of neurofibrillary tangles (NTs) Lewybodies or ischemic lesions [56] These differences in thereported prognostic value of depressionmay depend on diag-nostic criteria for example the Vienna Transdanube Agingstudy did report an association with AD emergence over a5-year period in 75-year-old individuals with no history ofdepression but only 1 of 9 depression subsyndromes ldquoloss ofinterestrdquo was associated with AD risk [57] Another reportconcluded that depression does appear to increase the risk oftransition fromMCI to dementia but this effect was strongerfor all-cause dementia and vascular dementia than AD [3] orexclusive to vascular dementia [58]

Regardless of this etiological relationship it is clearthat AD-associated depression markedly reduces cognitivecapacity QOL and activities of daily function (ADF) Thustreatment of depressive symptoms is expected to benefit ADpatients However there have been relatively few controlledclinical trials on antidepressant therapy for depression inAD and clinical response is generally poor to modest [59ndash64] The uncertain relationship between AD and depression


undoubtedly arises in part from diagnostic uncertainty Asmentioned AD is only confirmed at autopsy while estimatesof depression vary marked depending on the instrumentsused Furthermore only certain depressive symptomsmay beassociated with AD [57] In sum depressionmay be amodestrisk factor in premorbid patients [59ndash64] for additionalreviews but when present it markedly reduces cognitionQOL and ADL in AD patients

3 Apathy

Apathy is defined by a cluster of motivational deficits suchas loss of goal-directed cognition action and emotion [65]Like other neuropsychiatric symptoms associated with ADpersistent apathy is predictive of more rapid cognitive declinecompared to AD without apathy Apathy and depression areoften comorbid In one relatively large cohort (255 patients)479 of the study group had depression 416 apathyand 324 both with smaller prevalence of depression andapathy alone (154 and 94 resp) [23] A similar patternhas been reported in other studies (eg 23 depressiononly 23 depression + apathy and 20 apathy only) [6667] This frequent comorbidity suggests shared etiologyIndeed like depression apathy is generally associated withhypofrontality as well as serum GABA [37] However apa-thy was specifically correlated with hypometabolism in leftorbitofrontal areas while depression was associated withhypometabolism in left dorsolateral prefrontal regions [39]Scores on the frontal assessment battery (FAB) for execu-tive function are decreased by both apathy and depressionalone but the largest decrease was observed in comorbidpatients [68] This hypofrontality has been correlated withAD-associated pathogenesis [68] Retention of the (11C)Pittsburgh compound-B (PIB) under PET to reveal A120573plaques was higher in the bilateral frontal cortex of patientswith apathy as determined by the NPI apathy subscale thanin AD patients without apathy and apathy scores werepositively correlated with PIB signal in bilateral frontal andright anterior cingulate cortices No correlations were foundbetween PIB and any other NPI subscale including depres-sion [68] This same study found no correlation betweenapathy and morphometric changes by MRI A larger scalestudy of the Alzheimer Disease Neuroimaging Initiativedatabase found that cortical thinning in temporal cortex wasassociated with more severe apathy over time after correctingfor multiple covariates such as sex age APOE genotypepremorbid intelligence memory performance processingspeed antidepressant use and AD duration [69] Studies ofwhite matter atrophy in AD patients with apathy [70] havereported significantly reduced fractional anisotropy (FA) val-ues in the genu of the corpus callosum negative correlationsbetween apathy scores and FA values in the left anterior andposterior cingulum right superior longitudinal fasciculussplenium body and genuof the corpus callosum andbilateraluncinate fasciculus [69] or right anterior cingulate cortexright thalamus and bilateral parietal cortex

Possible genetic associations specific for apathy havenot be investigated as extensively as possible depression-associated genes In AD patients T allele carriers of

the 31015840UTR prion-like protein were more likely to exhibitapathy although scores were increased for many other NPIsubscales [71] While apathy is often comorbid with depres-sion apathy and depression may have different prognosticsignificance Apathy but not depression was strongly associ-ated with the transition from MCI to AD MCI patients withamnestic-MCI and apathy were seven times more likely toprogress to AD compared to amnestic-MCI patients withoutapathy after adjusting for covariates including depressionwhile depression alone did not increase risk of transition [72]Also distinct from depression depression tends to stabilizeduring AD progression while apathy tends to increase [73]

4 Agitation and Aggression

Agitation and aggression are significant dangers both topatients and caregivers Like other behavioral and neu-ropsychiatric abnormalities rates of agitation and aggressioncorrelate with cognitive decline loss of independence andother metrics of poor outcome [74] Aggression and agitationare more common in male patients [75] Among nursinghome residences the severity of cognitive declinedementiawas correlated with physical agitation and verbal aggressionas measured by the Cohen-Mansfield Agitation Inventory(CMAI) The intensity of dementia disorders is associatedmost strongly with physical agitation and verbal aggres-sion Aggression- and (or) agitation-specific changes inneurochemistry and neuropathology have been observedBased on the well-established correlation between frontallobe serotonergic dysfunction and aggression many stud-ies have investigated the correlations between aggressionpresenceseverity and 5-HT signaling molecules Among thefirst such studies reported a significant association betweenaggression in AD and the more highly expressed serotonintransporter long variant (5-HTTPRL) [76] Male AD patientswith a history of agitationaggression were also more likely toharbor the C allele of the 5-HT synthetic enzyme tryptophanhydroxylase A218C intronic polymorphism [77] Aggressivepatients also exhibited an altered 5-HT6 receptor to cholineacetyltransferase (ChAT) ratio in frontal and temporal cor-tices [78] and reduced 5-HT1A binding in temporal cortexafter controlling for dementia severity [79] However othershave found a much more complex interaction among genderdementia severity aggression and serotonergic function [80]Serotonin transporter polymorphisms have also been linkedto a combined aggressivepsychotic phenotype [81] Poly-morphisms of dopamine receptor alleles also confer complexassociations among psychotic symptoms and aggressivenessPsychosis and aggression were more frequent in DRD1 B2B2allele carriers [82] In a subsequent study carriers of theD1 B2allele were more prone to aggression and (or) to experiencehallucinations while carriers of the DRD3 1 allele were morelikely to experience delusions [83] In fact there is a strongcorrelation between psychosis and aggression Delusions areamong the strongest predictors of aggression [84] possiblybecause aggression is driven by specific delusions of persecu-tion [85 86]

The CMAI scores but not GDS scores were negativelycorrelated with the N-acetylaspartate (NAA) to creatine ratio


in the left posterior cingulate gyrus [41] indicating neuro-chemical changes specific to the aggressive AD phenotypeMoreover only agitationirritability scores were correlatedwith A12057342 accumulation [87] and only Behavioral Pathologyin Alzheimerrsquos Disease (Behave-AD) aggressiveness subscalescores correlated with serum BDNF [70] in AD and MCIpatients One study demonstrated a correlation betweenaggressive symptoms and the magnitude of locus coeruleusdamage suggesting a role for reduced norepinephrine orcompensatory changes in adrenergic receptors in aggression[88] In fact a test of 120573

2receptor function the growth

hormone (GH) response to clonidine was blunted in aggres-sive patients compared to nonaggressive AD patients [89]Higher NPI Agitation and Aggression subscale scores wereassociated with greater atrophy in a large number of regionsof interest in the frontal and cingulated cortices as well as theinsula amygdala and hippocampus [90] The phospho-tauto tau ratio was also higher postmortem in the frontal lobe ofAD patients with aggression compared to those without [91]Similarly hippocampal NTs and hypoperfusion in the mesialtemporal lobe [92] were associated with aggressive symptomsinADThe frequency of the APOE 4 allele was also associatedwith aggression [93]

Neuroleptics and other antipsychotics may be modestlyeffective in treating aggression and agitation but longer-termtreatment is associated with a significant increase in adverseevents [94]

5 Psychosis

Psychotic symptoms including delusions and hallucinationsare obviously the most salient and serious neuropsychiatricsymptoms associated with AD also generally the least fre-quent symptoms during the early stages of AD [80] Likedepression the emergence of psychotic symptoms predictsgreater or more rapid cognitive decline [44 95] Halluci-nations are among those noncognitive AD symptoms alsoincluding cognitive impairment level physical aggressionand depressive symptoms strongly predictive of institution-alization [96] A longitudinal study found that psychosisin AD (observed in 78 of patients) was associated withgreater initial cognitive dysfunction more accelerated cog-nitive decline and greater mortality [97] Like aggression towhich it is strongly correlated psychosis is associated withdifference in the 5-HT system such as a higher frequency ofthe C allele and CC genotype of the T102C variant of 5HT(2A) receptors in patients with hallucinations and delusions[31] There may also be an association between the SERTlong form and psychosis in AD [96] Moreover psychosis isassociated with CSF tau suggesting more severe tauopathyin psychotic patients [98] and with greater intracellularaccumulation of hyperphosphorylated tau [99] The APOE4 allele also increases psychosis risk [100] In general AD-associated psychosis follows the severity of AD-associatedneurodegeneration and cognitive dysfunction [101] 18F-Fluorodeoxyglucose positron emission tomography revealedreduced metabolic activity in the right lateral frontal cortexorbitofrontal cortex and bilateral temporal cortex in patientswith delusions overlapping with areas associated with loss

of memory and insight [102] Atrophy of the supramarginalcortex of the parietal lobe was predictive of increasinghallucinations over time Active psychosis is associated withhypofrontality particularly in orbitofrontal regions [102]and thus is strongly correlated with disruption in executivefunction particularly working memory [103] Another studyfound lateral frontal lateral parietal and anterior cingulateatrophy in AD patients with psychosis with the lateralfrontal region most severely degenerated [104] Individualdelusions may be associated with specific abnormalities inneural processing as evidence by PET imaging [105] withdelusions of persecution associatedwith hypoperfusion in theprecuneus and hyperperfusion in the insula and thalamusOther delusional forms are associated with distinct changesin perfusion metabolism receptor binding and structuralalternations [106] Persecutory delusions occur early duringthe progression of AD and associate with disruption offrontostriatal circuits [107] One study found delusions in274 of AD patients with paranoid delusions being themostcommon (603) followed by misidentification delusions(190) and then mixed delusions (175) the latter appear-ing later and associated with greater cognitive impairment[108] Psychotic patients show greater A1205731-42 at autopsy[109] A recent genome wide association study identifiedan intergenic region on chromosome 4 (rs753129) SNPsupstream of SLC2A9 (rs6834555) and within the neuronalCa2+-sensor (NCS) proteins VSNL1 (rs4038131) as promisingregions for specific associations with psychosis [110] Notehowever that VSNLs are associated with A120573 and tau andso may reflect the overall severity of AD neurodegenerationrather than psychosis per se Other possible associationsspecific to AD-associated psychosis include that with thedopamine oxidase A (DOA) gene and muscarinic receptorsin orbital frontal cortex [110]

6 Conclusion

The neuropsychiatric symptoms in the early stages of AD arepredictive of more rapid deterioration of cognitive functionThese symptoms may simply reflect more rapid and exten-sive neuronal death caused by the myriad of primary andsecondary degenerative processes associated with AD In thiscase the appearance of different neuropsychiatric symptomsreflects variability in the progression of neurodegenerationacross neural systems There are genes associated with spe-cific symptoms or symptom clusters but none appear toexert strong and specific effects Moreover many of theseassociation studies have not been followed up suggestingsome publication bias for positive results Regardless of thedependence of these symptoms on AD pathogenesis andcognitive decline the deleterious effect of these symptomson both patient and caregiver quality of life warrant furtherstudies on more effective treatments

Conflict of Interests

We declare that we have no conflicts of interest


Acknowledgments

This work was supported by Grants from the NationalNatural Science Foundation of China (81000544 81171209and 81371406) and Shandong Provincial Natural ScienceFoundation China (ZR2010HQ004 and ZR2011HZ001)

References

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[2] C G Lyketsos M C Carrillo J M Ryan et al ldquoNeu-ropsychiatric symptoms in Alzheimerrsquos diseaserdquo Alzheimerrsquos ampDementia vol 7 no 5 pp 532ndash539 2011

[3] D E Barnes K Yaffe A L Byers M McCormick C Schaeferand R A Whitmer ldquoMidlife vs late-life depressive symptomsand risk of dementia differential effects for Alzheimer diseaseand vascular dementiardquo Archives of General Psychiatry vol 69no 5 pp 493ndash498 2012

[4] B J Gilbert ldquoThe role of amyloid 120573 in the pathogenesis ofAlzheimerrsquos diseaserdquo Journal of Clinical Pathology vol 66 no5 pp 362ndash366 2013

[5] N N Nalivaeva and A J Turner ldquoThe amyloid precursor pro-tein a biochemical enigma in brain development function anddiseaserdquo FEBS Letters vol 587 no 13 pp 2046ndash2054 2013

[6] C Liu T Kanekiyo H Xu and G Bu ldquoApolipoprotein e andAlzheimer disease risk mechanisms and therapyrdquo NatureReviews Neurology vol 9 no 2 pp 106ndash118 2013

[7] C Reitz ldquoDyslipidemia and the risk of Alzheimerrsquos diseaserdquoCurrent Atherosclerosis Reports vol 15 no 3 p 307 2013

[8] Y Duan S Dong F Gu Y Hu and Z Zhao ldquoAdvances in thepathogenesis of Alzheimerrsquos disease focusing on tau-mediatedneurodegenerationrdquoTranslational Neurodegeneration vol 1 no1 p 24 2012

[9] V H Cornejo and C Hetz ldquoThe unfolded protein response inAlzheimerrsquos diseaserdquo Seminars in Immunopathology vol 35 no3 pp 277ndash292 2013

[10] R J Kelleher and R L Soiza ldquoEvidence of endothelial dysfunc-tion in the development of Alzheimerrsquos disease is Alzheimerrsquosa vascular disorderrdquo The American Journal of CardiovascularDisease vol 3 no 4 pp 197ndash226 2013

[11] G L Caldeira I L Ferreira and A C Rego ldquoImpairedtranscription in Alzheimerrsquos disease key role in mitochondrialdysfunction and oxidative stressrdquo Journal of Alzheimerrsquos Diseasevol 34 no 1 pp 115ndash131 2013

[12] A M Swomley S Forster J T Keeney et al ldquoAbeta oxidativestress in Alzheimer disease evidence based on proteomicsstudiesrdquoBiochimica et BiophysicaActa vol 1842 no 8 pp 1248ndash1257 2013

[13] K Sopova K Gatsiou K Stellos and C Laske ldquoDysregu-lation of neurotrophic and haematopoietic growth factors inAlzheimerrsquos disease from pathophysiology to novel treatmentstrategiesrdquo Current Alzheimer Research vol 11 no 1 pp 27ndash392014

[14] G Marwarha and O Ghribi ldquoLeptin signaling and Alzheimerrsquosdiseaserdquo The American Journal of Neurodegenerative Diseasevol 1 no 3 pp 245ndash265 2012

[15] B Lipinski and E Pretorius ldquoThe role of iron-induced fibrin inthe pathogenesis of Alzheimerrsquos disease and the protective role

of magnesiumrdquo Frontiers in Human Neuroscience vol 7 article735 2013

[16] V K Ramanan and A J Saykin ldquoPathways to neurodegenera-tion mechanistic insights from GWAS in Alzheimerrsquos diseaseParkinsonrsquos disease and related disordersrdquo The American Jour-nal of Neurodegenerative Disease vol 2 no 3 pp 145ndash175 2013

[17] M E Peters P B Rosenberg M Steinberg et al ldquoNeuropsy-chiatric symptoms as risk factors for progression from CINDto dementia the cache county studyrdquo The American Journal ofGeriatric Psychiatry vol 21 no 11 pp 1116ndash1124 2013

[18] B S Diniz M A Butters S M Albert M A Dew and C FReynolds III ldquoLate-life depression and risk of vascular dementiaand Alzheimerrsquos disease systematic review and meta-analysisof community-based cohort studiesrdquo The British Journal ofPsychiatry vol 202 no 5 pp 329ndash335 2013

[19] Y Namekawa H Baba H Maeshima et al ldquoHeterogeneity ofelderly depression Increased risk of Alzheimerrsquos disease andA120573protein metabolismrdquo Progress in Neuro-Psychopharmacologyand Biological Psychiatry vol 43 pp 203ndash208 2013

[20] L B Zahodne K Ornstein S Cosentino D P Devanandand Y Stern ldquoLongitudinal relationships between Alzheimerdisease progression and psychosis depressed mood and agita-tionaggressionrdquo The American Journal of Geriatric Psychiatry2013

[21] J Vilalta-Franch S Lopez-Pousa L Calvo-Perxas and J Garre-Olmo ldquoPsychosis of Alzheimer disease prevalence incidencepersistence risk factors and mortalityrdquo The American Journalof Geriatric Psychiatry vol 21 no 11 pp 1135ndash1143 2013

[22] C Rosen O Hansson K Blennow and H Zetterberg ldquoFluidbiomarkers in Alzheimerrsquos diseasemdashcurrent conceptsrdquoMolecu-lar Neurodegeneration vol 8 no 1 article 20 2013

[23] M Benoit G Berrut J Doussaint et al ldquoApathy and depressionin mild Alzheimerrsquos disease a cross-sectional study usingdiagnostic criteriardquo Journal of Alzheimerrsquos Disease vol 31 no2 pp 325ndash334 2012

[24] Y T Kwak Y Yang S J Pyo and M S Koo ldquoClinical char-acteristics according to depression screening tools in patientswithAlzheimerrsquos disease view from self caregiver-reported anddrug-intervention patternrdquo Geriatrics amp Gerontology Interna-tional 2013

[25] B Borroni S Archetti C Costanzi et al ldquoRole of BDNFVal66Met functional polymorphism in Alzheimerrsquos disease-related depressionrdquo Neurobiology of Aging vol 30 no 9 pp1406ndash1412 2009

[26] S Usman H R Chaudhary A Asif and M I Yahya ldquoSeverityand risk factors of depression in Alzheimerrsquos diseaserdquo Journal ofthe College of Physicians and Surgeons Pakistan vol 20 no 5pp 327ndash330 2010

[27] C Arbus V Gardette C E Cantet et al ldquoIncidence and predic-tive factors of depressive symptoms in Alzheimerrsquos disease theREALFR studyrdquo Journal of Nutrition Health and Aging vol 15no 8 pp 609ndash617 2011

[28] S Van derMussele K Bekelaar N Le Bastard et al ldquoPrevalenceand associated behavioral symptoms of depression in mildcognitive impairment anddementia due toAlzheimerrsquos diseaserdquoInternational Journal of Geriatric Psychiatry vol 28 no 9 pp947ndash958 2013

[29] C Holmes M Arranz D Collier J Powell and S LovestoneldquoDepression in Alzheimerrsquos disease The effect of serotoninreceptor gene variationrdquo The American Journal of MedicalGeneticsmdashNeuropsychiatric Genetics vol 119 no 1 pp 40ndash432003


[30] M K P Lai S W Tsang M M Esiri P T Francis P T Wongand C P Chen ldquoDifferential involvement of hippocampalserotonin1A receptors and re-uptake sites in non-cognitivebehaviors of Alzheimerrsquos diseaserdquo Psychopharmacology vol 213no 2-3 pp 431ndash439 2011

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and 5HT2119862

polymorphisms in behavioural and psychologicalsymptoms of Alzheimerrsquos diseaserdquo Neurobiology of Aging vol29 no 3 pp 341ndash347 2008

[32] A L Pritchard C W Pritchard P Bentham and C LLendon ldquoRole of serotonin transporter polymorphisms in thebehavioural and psychological symptoms in probable Alzheim-er disease patientsrdquoDementia andGeriatric Cognitive Disordersvol 24 no 3 pp 201ndash206 2007

[33] A J Thomas M Hendriksen M Piggott et al ldquoA study ofthe serotonin transporter in the prefrontal cortex in late-lifedepression and Alzheimerrsquos disease with and without depres-sionrdquo Neuropathology and Applied Neurobiology vol 32 no 3pp 296ndash303 2006

[34] A P Cerri B Arosio C Viazzoli R Confalonieri F Teruzziand G Annoni ldquo-308(GA) TNF-alpha gene polymorphismand risk of depression late in the liferdquo Archives of Gerontologyand Geriatrics vol 49 supplement 1 pp 29ndash34 2009

[35] C Y Liu C J Hong T Y Liu et al ldquoLack of association betweenthe apolipoprotein E genotype and depression in Alzheimerrsquosdiseaserdquo Journal of Geriatric Psychiatry and Neurology vol 15no 1 pp 20ndash23 2002

[36] I Blasko G Kemmler S Jungwirth et al ldquoPlasma amyloidbeta-42 independently predicts both late-onset depression andAlzheimer diseaserdquo The American Journal of Geriatric Psychia-try vol 18 no 11 pp 973ndash982 2010

[37] K L Lanctot N Herrmann L Rothenburg and G EryavecldquoBehavioral correlates of GABAergic disruption in Alzheimerrsquosdiseaserdquo International Psychogeriatrics vol 19 no 1 pp 151ndash1582007

[38] K Kataoka H Hashimoto J Kawabe et al ldquoFrontal hypoper-fusion in depressed patients with dementia of Alzheimer typedemonstrated on 3DSRTrdquoPsychiatry andClinical Neurosciencesvol 64 no 3 pp 293ndash298 2010

[39] V A Holthoff B Beuthien-Baumann E Kalbe et al ldquoRegionalcerebral metabolism in early Alzheimerrsquos disease with clinicallysignificant apathy or depressionrdquo Biological Psychiatry vol 57no 4 pp 412ndash421 2005

[40] S Terada E Oshima S Sato et al ldquoDepressive symptoms andregional cerebral blood flow in Alzheimerrsquos diseaserdquo PsychiatryResearch vol 221 no 1 pp 86ndash91 2014

[41] C F Tsai C W Hung J F Lirng S J Wang and J LFuh ldquoDifferences in brainmetabolism associated with agitationand depression in Alzheimerrsquos diseaserdquo East Asian Archives ofPsychiatry vol 23 no 3 pp 86ndash90 2013

[42] AV LebedevMK Beyer F Fritze EWestman C Ballard andD Aarsland ldquoCortical changes associated with depression andantidepressant use in Alzheimer and Lewy body dementia anMRI surface-basedmorphometric studyrdquoTheAmerican Journalof Geriatric Psychiatry vol 22 no 1 pp 4ndash13 2014

[43] J H Son D H Han K J Min and B S Kee ldquoCorrela-tion between gray matter volume in the temporal lobe anddepressive symptoms in patients with Alzheimerrsquos diseaserdquoNeuroscience Letters vol 548 pp 15ndash20 2013

[44] G J Lee P H Lu X Hua et al ldquoDepressive symptoms in mildcognitive impairment predict greater atrophy in alzheimerrsquos

disease-related regionsrdquo Biological Psychiatry vol 71 no 9 pp814ndash821 2012

[45] J A Brommelhoff B M Spann J L Go W J MacK and MGatz ldquoStriatal hypodensities not whitematter hypodensities onCT Are Associated with Late-Onset Depression in AlzheimerrsquosDiseaserdquo Journal of Aging Research vol 2011 Article ID 18721911 pages 2011

[46] Y-Y Chou N Lepore P Saharan et al ldquoVentricular mapsin 804 ADNI subjects correlations with CSF biomarkers andclinical declinerdquo Neurobiology of Aging vol 31 no 8 pp 1386ndash1400 2010

[47] J Mintzer and C OrsquoNeill ldquoDepression in Alzheimerrsquos diseaseconsequence or contributing factorrdquo Expert Review of Neu-rotherapeutics vol 11 no 11 pp 1501ndash1503 2011

[48] S Arlt C Demiralay B Tharun et al ldquoGenetic risk factors fordepression in Alzheimerlsquos disease patientsrdquo Current AlzheimerResearch vol 10 no 1 pp 72ndash81 2013

[49] S Porcelli R Salfi A Politis et al ldquoAssociation between Sirtuin2 gene rs10410544 polymorphismanddepression inAlzheimerrsquosdisease in two independent European samplesrdquo Journal ofNeural Transmission vol 120 no 12 pp 1709ndash1715 2013

[50] L Zhang Y Fang Z Zeng et al ldquoBDNF gene polymorphismsare associated with Alzheimerrsquos disease-related depression andantidepressant responserdquo Journal of Alzheimerrsquos Disease vol 26no 3 pp 523ndash530 2011

[51] F Caraci P Bosco M Signorelli et al ldquoThe CC genotypeof transforming growth factor-1205731 increases the risk of late-onset Alzheimerrsquos disease and is associated with AD-relateddepressionrdquo European Neuropsychopharmacology vol 22 no 4pp 281ndash289 2012

[52] L Delano-Wood W S Houston J A Emond et al ldquoAPOEgenotype predicts depression in women with Alzheimerrsquos dis-ease a retrospective studyrdquo International Journal of GeriatricPsychiatry vol 23 no 6 pp 632ndash636 2008

[53] A Michels M Multhammer M Zintl M C Mendoza andH Klunemann ldquoAssociation of apolipoprotein E 1205764 (ApoE 1205764)homozygosity with psychiatric behavioral symptomsrdquo Journalof Alzheimerrsquos Disease vol 28 no 1 pp 25ndash32 2012

[54] G Spalletta C Caltagirone P Girardi W Gianni A RCasini and K Palmer ldquoThe role of persistent and incidentmajor depression on rate of cognitive deterioration in newlydiagnosed Alzheimerrsquos disease patientsrdquo Psychiatry Researchvol 198 no 2 pp 263ndash268 2012

[55] K Palmer F Di Iulio A E Varsi et al ldquoNeuropsychiatric pre-dictors of progression from amnesticmdashMild cognitive impair-ment to Alzheimerrsquos disease the role of depression and apathyrdquoJournal of Alzheimerrsquos Disease vol 20 no 1 pp 175ndash183 2010

[56] D R Royall and R F Palmer ldquoAlzheimerrsquos disease pathologydoes not mediate the association between depressive symptomsand subsequent cognitive declinerdquo Alzheimerrsquos and Dementiavol 9 no 3 pp 318ndash325 2013

[57] N Mossaheb S Zehetmayer S Jungwirth et al ldquoAre specificsymptoms of depression predictive of Alzheimerrsquos dementiardquoJournal of Clinical Psychiatry vol 73 no 7 pp 1009ndash1015 2012

[58] H Lenoir C Dufouil S Auriacombe et al ldquoDepression historydepressive symptoms and incident dementia the 3C studyrdquoJournal of Alzheimerrsquos Disease vol 26 no 1 pp 27ndash38 2011

[59] C Even and D Weintraub ldquoCase for and against specificityof depression in Alzheimerrsquos diseaserdquo Psychiatry and ClinicalNeurosciences vol 64 no 4 pp 358ndash366 2010


[60] S Aznar and G M Knudsen ldquoDepression and alzheimerrsquosdisease is stress the initiating factor in a common neuropatho-logical cascaderdquo Journal of Alzheimerrsquos Disease vol 23 no 2pp 177ndash193 2011

[61] F Caraci A Copani F Nicoletti and F Drago ldquoDepressionand Alzheimerrsquos disease neurobiological links and commonpharmacological targetsrdquo European Journal of Pharmacologyvol 626 no 1 pp 64ndash71 2010

[62] P J Modrego ldquoDepression in Alzheimerrsquos disease Pathophysi-ology diagnosis and treatmentrdquo Journal of Alzheimerrsquos Diseasevol 21 no 4 pp 1077ndash1087 2010

[63] A S Sierksma D L van den Hove H W Steinbusch andJ Prickaerts ldquoMajor depression cognitive dysfunction andAlzheimerrsquos disease is there a linkrdquo European Journal ofPharmacology vol 626 no 1 pp 72ndash82 2010

[64] S Wuwongse R C Chang and A C K Law ldquoThe putativeneurodegenerative links between depression and Alzheimerrsquosdiseaserdquo Progress in Neurobiology vol 91 no 4 pp 362ndash3752010

[65] MOta N Sato YNakata K Arima andMUno ldquoRelationshipbetween apathy and diffusion tensor imaging metrics of thebrain in Alzheimers diseaserdquo International Journal of GeriatricPsychiatry vol 27 no 7 pp 722ndash726 2012

[66] D Grossi G Santangelo A M Barbarulo et al ldquoApathyand related executive syndromes in dementia associated withParkinsonrsquos disease and in Alzheimerrsquos diseaserdquo BehaviouralNeurology vol 27 no 4 pp 515ndash522 2013

[67] S Nakaaki Y Murata J Sato et al ldquoAssociation betweenapathydepression and executive function in patients withAlzheimerrsquos diseaserdquo International Psychogeriatrics vol 20 no5 pp 964ndash975 2008

[68] T Mori H Shimada H Shinotoh et al ldquoApathy correlateswith prefrontal amyloid beta deposition in Alzheimerrsquos diseaserdquoJournal of Neurology Neurosurgery amp Psychiatry vol 85 no 4pp 449ndash455 2014

[69] C Hahn H Lim W Y Won K J Ahn W Jung and C ULee ldquoApathy and white matter integrity in Alzheimerrsquos Diseasea whole brain analysis with tract-based spatial statisticsrdquo PLoSONE vol 8 no 1 Article ID e53493 2013

[70] N J Donovan L P Wadsworth N Lorius et al ldquoRegionalcortical thinning predicts worsening apathy and hallucinationsacross the Alzheimer disease spectrumrdquo American Journal ofGeriatric Psychiatry 2013

[71] M Flirski M Sieruta E Golanska I Kłoszewska P P Liberskiand T Sobow ldquoPRND 31015840UTR polymorphismmay be associatedwith behavioral disturbances in Alzheimer diseaserdquo Prion vol6 no 1 pp 73ndash80 2012

[72] E Richard B Schmand P Eikelenboom et al ldquoSymptoms ofapathy are associated with progression from mild cognitiveimpairment to Alzheimerrsquos disease in non-depressed subjectsfor the Alzheimerrsquos disease neuroimaging initiativerdquo Dementiaand Geriatric Cognitive Disorders vol 33 no 2-3 pp 204ndash2092012

[73] S Gonfrier S Andrieu D Renaud B Vellas and P RobertldquoCourse of neuropsychiatric symptoms during a 4-year followup in the REAL-FR cohortrdquo Journal of Nutrition Health andAging vol 16 no 2 pp 134ndash137 2012

[74] L Bidzan M Bidzan and M Pachalska ldquoAggressive andimpulsive behavior in Alzheimerrsquos disease and progression ofdementiardquo Medical Science Monitor vol 18 no 3 pp CR182ndashCR189 2012

[75] T Kitamura M Kitamura S Hino N Tanaka and K KurataldquoGender differences in clinical manifestations and outcomesamong hospitalized patients with behavioral and psychologicalsymptoms of dementiardquo Journal of Clinical Psychiatry vol 73no 12 pp 1548ndash1554 2012

[76] D L Sukonick B G Pollock R A Sweet et al ldquoThe5-HTTPRlowastSlowastL polymorphism and aggressive behavior inAlzheimer diseaserdquo Archives of Neurology vol 58 no 9 pp1425ndash1428 2001

[77] D Craig D J Hart R Carson S PMcIlroy andA P PassmoreldquoAllelic variation at the A218C tryptophan hydroxylase poly-morphism influences agitation and aggression in AlzheimerrsquosdiseaserdquoNeuroscience Letters vol 363 no 3 pp 199ndash202 2004

[78] M Garcia-Alloza W D Hirst C P L Chen B Lasheras PT Francis and M J Ramırez ldquoDifferential involvement of 5-HT(1B1D) and 5-HT6 receptors in cognitive and non-cognitivesymptoms in Alzheimerrsquos diseaserdquo Neuropsychopharmacologyvol 29 no 2 pp 410ndash416 2004

[79] M K P Lai S W Y Tsang P T Francis et al ldquoReducedserotonin 5-HT1A receptor binding in the temporal cortexcorrelates with aggressive behavior in Alzheimer diseaserdquo BrainResearch vol 974 no 1-2 pp 82ndash87 2003

[80] K L Lanctot N Herrmann G Eryavec R van ReekumK Reed and C A Naranjo ldquoCentral serotonergic activityis related to the aggressive behaviors of Alzheimerrsquos diseaserdquoNeuropsychopharmacology vol 27 no 4 pp 646ndash654 2002

[81] R A Sweet B G Pollock D L Sukonick et al ldquoThe 5-HTTPRpolymorphism confers liability to a combined phenotype ofpsychotic and aggressive behavior in Alzheimer diseaserdquo Inter-national Psychogeriatrics vol 13 no 4 pp 401ndash409 2001

[82] R A Sweet V L Nimgaonkar M L Kamboh O L LopezF Zhang and S T Dekosky ldquoDopamine receptor geneticvariation psychosis and aggression in Alzheimer diseaserdquoArchives of Neurology vol 55 no 10 pp 1335ndash1340 1998

[83] C Holmes H Smith R Ganderton et al ldquoPsychosis andaggression in Alzheimerrsquos disease the effect of dopaminereceptor gene variationrdquo Journal of Neurology Neurosurgery andPsychiatry vol 71 no 6 pp 777ndash779 2001

[84] N Gormley M R Rizwan and S Lovestone ldquoClinical predic-tors of aggressive behaviour in Alzheimerrsquos diseaserdquo Interna-tional Journal of Geriatric Psychiatry vol 13 no 2 pp 109ndash1151998

[85] D W Gilley R S Wilson L A Beckett and D A EvansldquoPsychotic symptoms and physically aggressive behavior inAlzheimerrsquos diseaserdquo Journal of the American Geriatrics Societyvol 45 no 9 pp 1074ndash1079 1997

[86] A Eustace N Kidd E Greene et al ldquoVerbal aggression inAlzheimerrsquos disease Clinical functional and neuropsychologi-cal correlatesrdquo International Journal of Geriatric Psychiatry vol16 no 9 pp 858ndash861 2001

[87] T Nagata N Kobayashi S Shinagawa H Yamada K Kondoand K Nakayama ldquoPlasma BDNF levels are correlated withaggressiveness in patients with amnestic mild cognitive impair-ment or Alzheimer diseaserdquo Journal of Neural Transmission vol121 no 4 pp 433ndash441 2013

[88] K LMatthews C P L ChenMM Esiri J Keene S LMingerand P T Francis ldquoNoradrenergic changes aggressive behaviorand cognition in patients with dementiardquo Biological Psychiatryvol 51 no 5 pp 407ndash416 2002

[89] N Herrmann K L Lanctot G Eryavec R van Reekum andL R Khan ldquoGrowth hormone response to clonidine predicts


aggression in Alzheimerrsquos diseaserdquo Psychoneuroendocrinologyvol 29 no 9 pp 1192ndash1197 2004

[90] P T Trzepacz P Yu P K Bhamidipati et al ldquoFrontolimbicatrophy is associated with agitation and aggression in mildcognitive impairment and Alzheimerrsquos diseaserdquoAlzheimerrsquos andDementia vol 9 no 5 Supplement pp S95e1ndashS104e1 2013

[91] S Guadagna M M Esiri R J Williams and P T Francis ldquoTauphosphorylation in human brain relationship to behavioraldisturbance in dementiardquo Neurobiology of Aging vol 33 no 12pp 2798ndash2806 2012

[92] K L Lanctot N Herrmann N K Nadkarni F S LeibovitchC B Caldwell and S E Black ldquoMedial temporal hypoperfusionand aggression inAlzheimer diseaserdquoArchives of Neurology vol61 no 11 pp 1731ndash1737 2004

[93] D Craig D J Hart K McCool S P McIlroy and A PPassmore ldquoApolipoprotein E e4 allele influences aggressivebehaviour in Alzheimerrsquos diseaserdquo Journal of Neurology Neuro-surgery and Psychiatry vol 75 no 9 pp 1327ndash1330 2004

[94] C Ballard and A Corbett ldquoAgitation and aggression in peoplewithAlzheimerrsquos diseaserdquoCurrentOpinion in Psychiatry vol 26no 3 pp 252ndash259 2013

[95] P A Wilkosz H J Seltman B Devlin et al ldquoTrajectoriesof cognitive decline in Alzheimerrsquos diseaserdquo International Psy-chogeriatrics vol 22 no 2 pp 281ndash290 2010

[96] B Creese C Ballard and E Jones ldquoCognitive impairment instudies of 5HTTLPR and psychosis in alzheimerrsquos disease asystematic reviewrdquoDementia and Geriatric Cognitive Disordersvol 35 no 3-4 pp 155ndash164 2013

[97] DW Gilley J L Bienias R SWilson D A Bennett T L Beckand D A Evans ldquoInfluence of behavioral symptoms on ratesof institutionalization for persons with Alzheimerrsquos diseaserdquoPsychological Medicine vol 34 no 6 pp 1129ndash1135 2004

[98] J Koppel S Sunday J Buthorn T Goldberg P Davies and BGreenwald ldquoElevated CSF Tau is associated with psychosis inAlzheimerrsquos diseaserdquo The American Journal of Psychiatry vol170 no 10 pp 1212ndash1213 2013

[99] P S Murray C M Kirkwood M C Gray et al ldquoHyper-phosphorylated Tau is elevated in Alzheimerrsquos disease withpsychosisrdquo Journal of Alzheimerrsquos Disease vol 39 no 4 pp 759ndash773 2014

[100] K F Zdanys T G KleimanM GMacAvoy et al ldquoApolipopro-tein E

1205764 allele increases risk for psychotic symptoms in

Alzheimerrsquos diseaserdquo Neuropsychopharmacology vol 32 no 1pp 171ndash179 2007

[101] D L Sultzer L P Leskin R J Melrose et al ldquoNeurobiologyof delusions memory and insight in alzheimer diseaserdquo TheAmerican Journal of Geriatric Psychiatry 2013

[102] J Koppel S Sunday T E Goldberg P Davies E Christen andB S Greenwald ldquoPsychosis in Alzheimerrsquos disease is associatedwith frontal metabolic impairment and accelerated declinein working memory findings from the Alzheimerrsquos diseaseneuroimaging initiativerdquo The American Journal of GeriatricPsychiatry vol 22 no 7 pp 698ndash707 2013

[103] J Koppel T E Goldberg M L Gordon et al ldquoRelation-ships between behavioral syndromes and cognitive domainsin alzheimer disease the impact of mood and psychosisrdquo TheAmerican Journal of Geriatric Psychiatry vol 20 no 11 pp 994ndash1000 2012

[104] M S Rafii C S Taylor H T Kim et al ldquoNeuropsychiatricsymptoms and regional neocortical atrophy in mild cognitiveimpairment and Alzheimerrsquos diseaserdquo American Journal of

Alzheimerrsquos Disease amp Other Dementias vol 29 no 2 pp 159ndash165 2014

[105] K Nomura H Kazui TWada et al ldquoClassification of delusionsin Alzheimerrsquos disease and their neural correlatesrdquo Psychogeri-atrics vol 12 no 3 pp 200ndash210 2012

[106] Z Ismail M Nguyen C E Fischer T A Schweizer and B HMulsant ldquoNeuroimaging of delusions in Alzheimerrsquos diseaserdquoPsychiatry ResearchmdashNeuroimaging vol 202 no 2 pp 89ndash952012

[107] S J Reeves R L Gould J F Powell and R J HowardldquoOrigins of delusions in Alzheimerrsquos diseaserdquo Neuroscience ampBiobehavioral Reviews vol 36 no 10 pp 2274ndash2287 2012

[108] Y T Kwak Y Yang S Kwak andM Koo ldquoDelusions of Koreanpatients with Alzheimerrsquos disease Study of drug-naıve patientsrdquoGeriatrics and Gerontology International vol 13 no 2 pp 307ndash313 2013

[109] P S Murray C M Kirkwood M C Gray et al ldquo120573-Amyloid4240 ratio and kalirin expression in Alzheimer disease withpsychosisrdquoNeurobiology of Aging vol 33 no 12 pp 2807ndash28162012

[110] E Di Maria C Bonvicini C Bonomini A Alberici OZanetti andM Gennarelli ldquoGenetic variation in the G720G30gene locus (DAOA) influences the occurrence of psychoticsymptoms in patients with Alzheimerrsquos diseaserdquo Journal ofAlzheimerrsquos Disease vol 18 no 4 pp 953ndash960 2009

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


ADDepression

Apathy

Agitation

Psychosis

5-HT system

Inflammation

Hypoperfusion

Hypoperfusion

5-HT system

5-HT system

Hypoperfusion

Dopamine oxidasm A geneMuscarinic receptor

Dopamine receptor Tau

Serum GABA

Hypoperfusion



A120573 metabolism

A120573 and APOE 4

3998400UTR prion

Figure 1 Possible mechanism linking the neuropsychiatric symptoms (NPS) with AD NPS such as depression apathy aggression andpsychosis shared some pathogenic processes (in red color) with AD while they also have their unique pathogenic processes

are predictive of poor outcome although symptom incidenceprogression and prognostic significance are highly variableacross studies possibly due to the different neuropsychiatricinstruments used or clinical definitions Moreover despiterecent identification of noninvasive biomarkers related to AD[22] and advances in imagingAD-associated plaques [23 24]AD is still a diagnosis that can only be confirmed at autopsyso most such studies relate neuropsychiatric symptoms toldquopresumed ADrdquo Another uncertainty is whether these neu-ropsychiatric and behavioral abnormalities such as depres-sion and psychosis are etiologically similar in patients withand without AD or constitute clinical entities unique to AD

2 Depression

Depression is a common comorbidity in AD with preva-lence estimates ranging from 25 to 749 in a groupof recent studies [23ndash28] This variability is likely due tothe multitude of instruments used for diagnosis includingthe DSM Neuropsychiatric Inventory Depression subscale(NPI-D) and Geriatric Depression scale (GDS) Indeed onestudy reported rates in the same cohort of 105 usingthe NPI-D (significant) 564 based on the NPI-D (any)30 based on the Geriatric Depression scale (GDS) and16 based on antidepressant usage [24] A French Networkon AD (REALFR) study following several hundred ADpatients without depression or antidepressant use over 4 yearsreported an incidence of 1745year [27] Thus about 40of AD patients are expected to show symptoms of clinicaldepression within 5 years Moreover voluminous evidenceindicates that AD with depression results in worse clinicaloutcome [20]

Based on studies in depressed non-AD populations earlystudies on the pathophysiology of depression in AD focusedon serotonergic transmission One of the earliest studiesreported an association between major depression in AD atbaseline and 5-HT (2A) and 5-HT (2C) receptor polymor-phisms with CC carriers of the 5-HT (2A) C102 allele fivetimesmore likely than heterozygotes and 5-HT (2C) Ser allelecarriers 12 times more likely than 5-HT (2C) Cys allele carri-ers to develop depression [29] Moreover reduced 5-HT (1A)receptor expression was specifically correlated with depres-sive symptoms [30] In contrast Pritchard and colleaguesfound no significant association between depression in ADand either the C alleleCC genotype of the T102C variantof 5HT (2A) or the cys23ser variant of 5HT (2C) receptoralthough these alleles were associated with psychosis andaberrant motor behavior [31] Moreover no association wasfound between depression in AD and alleles of the serotonintransporter (SERT) [32] Similarly although SERT expressionwas reduced in the frontal cortex of AD patients there was nodifference in expression in patients with or without comorbiddepression [33] It is possible that serotonergic dysfunctionmay be heterogeneous among brain regions across patientsaccounting for these differences in association In addition to5-HT signaling elderly subjects destined to exhibit signs ofmajor depressionweremore likely to harbor theGGgenotypeof the tumor necrosis factor (TNF)-alpha 308 (GA) SNPvariant implicating inflammation in late-onset MD [34]

Early studies also examined the relationship betweendepression and molecules implicated in general AD pathol-ogy particularly A120573 and APOE 4 the strongest risk allelefor AD Early onset depression was associated with a higherserumA12057340A12057342 ratio [19] suggesting that depressionmay










3 Apathy












5 Psychosis



6 Conclusion





Acknowledgments


References


































and 5HT2119862





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























3 Apathy












5 Psychosis



6 Conclusion





Acknowledgments


References


































and 5HT2119862





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















5 Psychosis



6 Conclusion





Acknowledgments


References


































and 5HT2119862





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Acknowledgments


References


































and 5HT2119862





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















and 5HT2119862





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Behavioral and Psychological Symptoms in ...

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Transcript of Review Article Behavioral and Psychological Symptoms in ...