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Neuroscience and Biobehavioral Reviews 36 (2012) 2274–2287

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

journa l h o me pa g e: www.elsev ier .com/ locate /neubiorev

eview

rigins of delusions in Alzheimer’s disease

uzanne J. Reevesa,∗, Rebecca L. Goulda, John F. Powellb, Robert J. Howarda

Department of Old Age Psychiatry, Institute of Psychiatry, Kings College London, De Crespigny Park, Camberwell, London SE58AF, UKDepartment of Neuroscience, Institute of Psychiatry, Kings College London, De Crespigny Park, Camberwell, London SE58AF, UK

r t i c l e i n f o

rticle history:eceived 20 March 2012eceived in revised form 19 July 2012ccepted 3 August 2012

eywords:elusionslzheimer’s

a b s t r a c t

Research over the past two decades supports a shared aetiology for delusions in Alzheimer’s disease (AD)and schizophrenia. Functional networks involved in salience attribution and belief evaluation have beenimplicated in the two conditions, and striatal D2/3 receptors are increased to a comparable extent. Exec-utive/frontal deficits are common to both disorders and predict emergent symptoms. Putative risk genesfor schizophrenia, which may modify the AD process, have been more strongly implicated in delusionsthan those directly linked with late-onset AD. Phenotypic correlates of delusions in AD may be dependentupon delusional subtype. Persecutory delusions occur early in the disease and are associated with neuro-

orticostriatalopamineeuropsychologyeuroimagingeneticseurochemistry

chemical and neuropathological changes in frontostriatal circuits. In contrast, misidentification delusionsare associated with greater global cognitive deficits and advanced limbic pathology. It is unclear whetherthe two subtypes are phenomenologically and biologically distinct or are part of a continuum, in whichmisidentification delusions manifest increasingly as the pathological process extends. This has treatmentimplications, particularly if they are found to have discrete chemical and/or pathological markers.

© 2012 Elsevier Ltd. All rights reserved.
europathology
ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22752. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22753. Phenomenology, prevalence and persistence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2275

3.1. Phenomenology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22753.2. Prevalence and persistence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2276

4. Neuropathological changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22764.1. Accelerated AD pathology is restricted to the misidentification subtype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22764.2. In vivo markers of neuronal integrity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2276

5. Disruption of the cholinergic/dopaminergic axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22765.1. Early neurochemical theories and contemporary models of delusions formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22765.2. Excessive striatal dopamine D2/3 receptor availability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22765.3. Muscarinic receptor dysfunction in the orbitofrontal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2277

6. Structural and functional neuroimaging correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22776.1. Structural imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22776.2. Functional (metabolism and perfusion) imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2277

7. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22797.1. Disease modifier and heterogeneity models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22797.2. Association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2279
7.3. Genome-wide studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Neuropsychological correlates of delusions in AD . . . . . . . . . . . . . . . . . . . . . . . . .8.1. Cognitive deficits may be subtype dependent . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +44 20 7848 0548; fax: +44 20 7848 0632.E-mail addresses: [email protected] (S.J. Reeves), [email protected] (R.

[email protected] (R.J. Howard).

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L. Gould), [email protected] (J.F. Powell),

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S.J. Reeves et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 2274–2287 2275

8.2. Cognitive markers of delusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22808.2.1. Cross-sectional studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22808.2.2. Longitudinal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2280

9. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2280Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2284Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2284

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Cook et al. (Cook et al., 2003) have argued for a separation betweenparanoid (persecutory delusions) and misidentification (misiden-tification phenomena and/or hallucinations) subtypes, based onthe application of factor and cluster analysis to psychosis items

Table 1Phenomenology of delusions in Alzheimer’s disease (AD).

Persecutory delusions‘Theft’ – others are stealing from him/her‘Harm’ – others are trying to hurt or harm‘Morbid jealousy’ – spouse is having an affair‘Abandonment; – family/spouse/carer (s) are planning to abandon

Misidentification phenomena‘Phantom boarder’ – real or imagined people are staying in the house‘Mirror sign’ – inability to recognize oneself in the mirror‘TV sign’ – inability to differentiate between the TV and reality‘Picture sign’ – inability to differentiate between a picture/photograph and reality

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Since the first description of Auguste D (Alzheimer, 1906),elusions have been amongst the most commonly recognised neu-opsychiatric symptoms of Alzheimer’s disease (AD). It was notntil the 1980s that research was directed towards describinghenomenology and exploring pathophysiological mechanisms,riven by an increasing awareness that delusions contributed sig-ificantly to carer stress (Greene et al., 1982; Rabins et al., 1982).iewed initially as a ‘logical attempt to understand the environ-ent’ within the context of cognitive deficits (Rabins et al., 1982),

eurobiological theories regarding the aetiology of delusion for-ation (Cummings and Victoroff, 1990) quickly gained ascendancy.

errios (Berrios, 1989) suggested that disinhibition of cortical func-ions may result in ‘release symptomatology’, whereas Malloy andichardson (Malloy and Richardson, 1994) proposed that memoryetrieval deficits, combined with a ‘lack of corrective judgements’rom the right frontal lobe, were crucial factors in the developmentf content-specific delusions including misidentification. The mostnfluential theory was proposed by Cummings (Cummings, 1992),

ho suggested a shared aetiology for delusions in organic brainisease. This model, which overlaps with contemporary theoriesKapur, 2003), suggested that dysfunction within limbic neuro-ircuitry, and of the cholinergic/dopaminergic axis, may interfereith the assessment of environmental threat, resulting in paranoia

nd delusions (Cummings, 1992; Cummings and Back, 1998). Thebservation of an apparently faster trajectory of cognitive declinen delusional patients (Cummings and Victoroff, 1990) supportedhe subsequent hypothesis that delusions may represent a moreggressive phenotype of AD, perhaps characterised by an exagger-ted limbic pathology (Zubenko et al., 1991).

The past two decades have seen an abundance of research in thisrea and there is now clear evidence that the psychosis syndromedelusions and/or hallucinations) (Jeste and Finkel, 2000) repre-ents a distinct behavioural phenotype of AD, with a heritabilityf around 60% (DeMichele-Sweet and Sweet, 2010; Sweet et al.,003). However some researchers have argued against a ‘global’pproach to psychotic symptoms, as delusions and hallucinationsave been found to have discrete clinical and neurobiologicalorrelates (Ballard et al., 1995; Bassiony and Lyketsos, 2003;assiony et al., 2000; Casanova et al., 2011; Cassimjee, 2008). Oth-rs have suggested that ‘paranoid’ (persecutory delusions) and

misidentification’ (misidentification delusions and/or hallucina-ions) symptoms (Cook et al., 2003) may represent two distinctubtypes, characterised by different pathological and cognitive tra-ectories (Ismail et al., 2011).

Given the modest efficacy and high incidence of adverse effectsssociated with antipsychotic prescribing in AD (Schneider et al.,006a, 2006b), there is an urgent need for research that aims toxplore the biological mechanisms underpinning psychotic symp-oms and identify target symptoms and/or pathology which maye more likely to respond to pharmacotherapy (Jeste et al., 2008).his review aims to summarise research into the neurobiological
nd neuropsychological correlates of delusions in AD over the pastwo decades, with an emphasis on contemporary models of delu-ion formation, (Coltheart, 2010; Corlett et al., 2010; Kapur, 2003)nd articulates emerging views regarding delusional subtypes.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2284

2. Methods

A computerised MEDLINE search was performed for English-language articles published between 1991 and 2011 that examined‘psychotic symptoms’ or ‘delusions’ within the context of‘Alzheimer’s disease’, in the areas of ‘genetics’, ‘neuroimag-ing’ (‘PET’, ‘SPECT’, ‘regional blood flow’, ‘structural’, ‘MRI’ ‘CT’),‘neuropathology’, ‘neurochemistry’, and ‘neuropsychology’ (‘cog-nitive’). Additional papers were identified from the bibliographiesof these articles. Publications prior to 1991 were included wherenecessary, to summarise historical and phenomenological aspects.Manuscripts which focused solely on hallucinations in AD, or ontreatment strategies, were excluded from the review.

3. Phenomenology, prevalence and persistence

3.1. Phenomenology

The phenomenological characteristics of delusions in AD werefirst explored in depth in the 1980s and two broad symptomcategories were typically described (summarised in Table 1):Persecutory delusions relating to ‘theft’, ‘harm’, ‘infidelity’, or ‘aban-donment’ (Burns et al., 1990a; Deutsch et al., 1991; Reisberget al., 1987; Rubin et al., 1988); and a variety of misidentifica-tion phenomena (Burns et al., 1990b; Deutsch et al., 1991; Merriamet al., 1988; Reisberg et al., 1987; Rubin et al., 1988) which were ini-tially described as perceptual abnormalities (Burns et al., 1990b),but are now generally classified as delusions. Subsequent stud-ies largely support this classification (Gormley and Rizwan, 1998;Hwang et al., 2003), with the addition of content-specific auto-biographical delusions, most commonly involving the belief thata dead family member is alive. Viewed by some as an additionaldelusional subtype (Staff et al., 2000; Venneri et al., 2000), they aregenerally grouped within the misidentification domain. Diagnos-tic criteria for psychotic symptoms in AD (Jeste and Finkel, 2000)make no distinction between delusions or hallucinations. However

‘Capgras’ – carer has been replaced by an imposter‘House is not one’s home’ – inability to recognise one’s home environment‘Dead person is alive’ – calls out, looks for dead spouse or family membera

aContent-specific autobiographical delusions.

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rom the CERAD (Tariot et al., 1995). Although their findings haveot generalised to other rating scales (Mizrahi et al., 2006), thislassification has been adopted by several studies which havexamined the neurobiological and neuropsychological correlatesf psychotic symptoms (Borroni et al., 2006; Perez-Madrinan et al.,004; Wilkosz et al., 2006).

.2. Prevalence and persistence

A wide range of prevalence estimates have been reported forelusions, largely reflecting ongoing difficulties in their classifica-ion, sampling differences and, prior to 1990, unreliable diagnosticriteria for AD. In a recent review of 55 studies published between990 and 2003, Ropacki and Jeste (Ropacki and Jeste, 2005)eported a median prevalence of 36% (9.3–63%) for delusions,he content most often involving theft; and a median prevalencef 25.6% (3.6–38.9%) for ‘other’ unclassified symptoms whichere most frequently described as ‘misidentification phenomena’.

ubsequent studies have supported these findings (Harciarek andertesz, 2008; Savva et al., 2009; Steinberg et al., 2008; Sweett al., 2010).

The prevalence of delusions typically increases through mildmedian 23.5%) to moderate (median 46%) disease (Ropacki andeste, 2005). However the trajectory appears to be dependent uponelusional subtype, as misidentification phenomena increase inrevalence as the disease progresses (Devanand et al., 1997; Savvat al., 2009). Once present, delusions show a moderate degreef persistence (Ropacki and Jeste, 2005), which appears to beimilar across delusional subtypes (Devanand et al., 1997; Savvat al., 2009). The degree of transition between persecutory andisidentification delusions within the same individual has not

een explored, but it is clear that the two subtypes co-occur in proportion of cases (12–38%) (Cook et al., 2003; Perez-Madrinant al., 2004).

. Neuropathological changes

.1. Accelerated AD pathology is restricted to theisidentification subtype

The suggestion that psychotic symptoms might characterise anccelerated form of AD was based partly on early post-mortemndings of increased senile plaque density in the hippocampusnd neurofibrillary tangles (NFT) in the middle frontal cortex inatients with a history of psychotic symptoms (Zubenko et al.,991). Subsequent studies which have focussed specifically onelusions have tended to separate groups on the basis of delusionalontent, and have found more marked pathology in the hippocam-us (CA1 region) and its projection zones (parahippocampal gyrus,ransentorhinal cortex), but only in patients with misidentifica-ion delusions (Forstl et al., 1994; Mukaetova-Ladinska et al., 1993;weet et al., 2000). The absence of additional pathology in patientsith persecutory delusions (Forstl et al., 1994; Sweet et al., 2000)ay simply reflect their tendency to occur earlier in the dis-

ase course, making it more difficult to identify state markersost-mortem. Alternatively, these findings may represent true dif-erences in the underlying neurobiology of the two subtypes.

.2. In vivo markers of neuronal integrity

In recent years, increasing interest in shared theories regarding
elusion formation (White and Cummings, 1996) has shifted theocus of research towards markers of neuronal integrity that haveeen implicated in schizophrenia. Data on delusions are limitedo a single study which used 1H magnetic resonance spectroscopy
vioral Reviews 36 (2012) 2274–2287

(MRS) in vivo to measure NAA/creatinine ratio (a marker of neu-ronal density that is decreased in AD) and myoinositol/creatinineratio (a glial marker raised in early AD) in patients with mild tomoderate AD (Shinno et al., 2007). Their finding of an exagger-ated pattern of change in the anterior cingulate gyrus in delusionalpatients who presented with no other behavioural symptoms(including hallucinations) is important for several reasons. Firstly,this provides evidence of a direct association between early mark-ers of pathological change and delusions, in a sample wherepersecutory delusions are likely to have predominated. Secondly,the region identified is part of a functional network that assignssalience to environmental stimuli and has been implicated in delu-sion formation in young adults (Corlett et al., 2010). Thirdly, the factthat disease severity was associated with changes in these mark-ers in the posterior but not anterior cingulate gyrus, suggests thatthe AD process may be modified rather than simply accelerated indelusional patients.

5. Disruption of the cholinergic/dopaminergic axis

5.1. Early neurochemical theories and contemporary models ofdelusions formation

The importance of maintaining a dynamic balance betweencholinergic and dopaminergic influences has long been recog-nised (McGeer et al., 1977) and disruption of the choliner-gic/dopaminergic axis is believed to play an integral part in thedevelopment of delusions in AD. Cummings (Cummings, 1992)suggested that the relative preservation of dopaminergic func-tion, within the context of profound cholinergic loss, may leadto a relative hyperdopaminergia and an increased propensity tomisinterpret the environment (Cummings, 1992; Cummings andBack, 1998; Cummings and Kaufer, 1996). This model overlapswith contemporary theories which view the aberrant signalling ofsalience by sensitised dopaminergic neurones as a final commonpathway to delusion formation (Kapur, 2003; Laruelle et al., 1999;Seeman et al., 2005). In schizophrenia the sensitization processhas been linked with deficits in cortical development, which leavedopaminergic neurones more responsive to dopamine-releasingstimuli, including psychostimulants (Laruelle, 2000). Pre-clinicalstudies suggest that a similar process of sensitisation may beoccurring in AD, as cholinergic denervation of rodents increasesstriatal dopamine release in response to amphetamine challengeand is accompanied by psychotic-like behaviour (Mattsson et al.,2007, 2004). The mechanisms underpinning this sensitizationprocess have not been clearly established, but disruption of pre-frontal cortical (glutaminergic and GABAergic) control over striataldopaminergic neurones (Carr and Sesack, 2000; Gao et al., 2007;Rossner et al., 1995), and of muscarinic (M1/M4) receptor controlover striatal dopamine release (Gerber et al., 2001; Ichikawa et al.,2002; Tzavara et al., 2004) are possible explanations.

5.2. Excessive striatal dopamine D2/3 receptor availability

Research in the AD population is surprisingly sparse. Early post-mortem work, which examined monoamines and their metabolitesalongside neuropathological data, found differences in serotonin(reduced in the hippocampus) and noradrenaline (increased in thesubstantia nigra) in psychotic patients, but not in dopamine or itsmetabolites (Zubenko et al., 1991). A decade later, a single post-mortem study reported a 70% increase in D3 receptor availability in
the ventral striatum of psychotropic-naïve patients with delusionsand/or hallucinations (Sweet et al., 2001). These findings, whichwere independent of Lewy Body pathology, are comparable withpost-mortem data on schizophrenia (Gurevich et al., 1997). More

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ecently, using [11C] raclopride PET, we have investigated striatalopamine D2/3 receptor correlates of neuropsychiatric symptoms

n vivo in psychotropic-naïve patients with mild to moderate ADReeves et al., 2009). Our finding of a 14% increase in tracer bind-ng in the striatum of delusional patients is comparable with datan young adults with schizophrenia (Kestler et al., 2001; Laruelle,998; Zakzanis and Hansen, 1998), and a single study which hasirectly compared psychotic and non-psychotic patients with bipo-

ar illness (Pearlson et al., 1995). Combined with post-mortem data,ur findings are supportive of a shared aetiology for delusions andarrant further exploration. The fact that delusional patients from

ur sample exhibited mild, transient persecutory beliefs, which didot require pharmacological intervention, suggests that elevatedopamine D2/D3 receptor availability may be an early marker ofelusion proneness in AD. From imaging data alone, the contri-ution of D3 receptors to this increase is unclear, as ligands thatarget the D2 receptor bind with equal affinity to D3 receptor sites.owever post-mortem findings (Gurevich et al., 1997; Sweet et al.,001) suggest that at least a proportion of the increase involves D3eceptors.

.3. Muscarinic receptor dysfunction in the orbitofrontal cortex

Only two studies have examined the role of muscarinic recep-ors in the development of psychotic symptoms in AD (Lai et al.,001; Tsang et al., 2008), both of which were post-mortem,estricted their investigation to limbic regions, and controlled forhe potential confounding effects of disease severity and psy-hotropic medication. Lai et al. (Lai et al., 2001) found increasedinding of the M2/M4 tracer AF-DX384 in the orbitofrontal cor-ex (OFC) of patients with a history of persecutory delusions, buto difference in binding of the M1/M4 tracer pirenzipine. Givenhe predominance of M2 over M4 autoreceptors in this region, andhe binding properties of the two tracers, these findings probablyeflect a compensatory increase in M2 autoreceptors on surviv-ng cholinergic neurones. The fact that delusional symptoms hadot been reported for at least 3 years prior to post-mortem sug-ests that regional increases in M2 receptor density may be a traitather than a state marker for delusions, or more specifically forersecutory delusions. More recently, lower binding of the non-2 receptor tracer 4H-DAMP has been found in the OFC of AD

atients with a history of psychotic symptoms (Tsang et al., 2008).lthough poor tracer specificity means that it is not possible toetermine which receptor subtype(s) is responsible for this change,hese findings are likely to represent a reduction in post-synapticignalling.

. Structural and functional neuroimaging correlates

.1. Structural imaging

Alongside neurochemical and neuropathological studies,dvances in imaging technologies have helped to more clearlydentify key regions and functional networks that are involvedn delusion formation in AD. Although the main focus has beenpon functional imaging, structural imaging (CT or MRI) studiesave reported asymmetric volume loss in AD patients with per-ecutory delusions, including a greater right:left temporal hornatio (Geroldi et al., 2000) and increased atrophy in left-sideduperior temporal cortex and medial OFC (Whitehead et al., 2012).n contrast, misidentification delusions are associated with more

arked changes (volume loss and/or white matter hypertensities)n right frontal (Forstl et al., 1991), or bilateral frontoparietal (Bruent al., 2008; Lee et al., 2006) regions. Studies which have groupedelusions as a single domain have reported inconsistent findings,

vioral Reviews 36 (2012) 2274–2287 2277

including no differences in cortical atrophy or ventricular brainratio (Howanitz et al., 1995), and a decrease in grey matter volumein the right hippocampus (Serra et al., 2010) of delusional patients.These findings show some overlap with data on young adultswith schizophrenia, as two recently published meta-analyses haveshown that frontal and temporolimbic structural abnormalitiespredominate in schizophrenia (Shepherd et al., 2012), and are alsoevident in individuals with an at-risk mental state (Chan et al.,2011).

6.2. Functional (metabolism and perfusion) imaging

The majority of studies have used functional imaging of regionalcerebral glucose metabolism (FDG-PET) or perfusion (Tc HMPOA-SPECT) to investigate delusions and/or hallucinations in AD. Thereis considerable heterogeneity in study design, including the crite-ria used to classify delusions, sample selection, disease stageand clinical/medication status. In addition, differences in theapproach to image analysis (region-of-interest versus voxel-basedapproaches; number of regions investigated; absolute differenceversus asymmetry index) mean that direct comparison of thesedata is problematic. Despite these caveats, several broad themeshave emerged (summarised in Table 2). Typically, frontal hypoper-fusion or hypometabolism (dorsolateral PFC, medial PFC, superiorfrontal gyrus, OFC) has been shown in psychotic (Mega et al., 2000;Moran et al., 2008; Sultzer et al., 1995) and delusional patients(Kotrla et al., 1995; Lee et al., 2009; Nakano et al., 2006; Staff et al.,1999; Sultzer et al., 2003). However there is no consensus regardinglaterality, as bilateral (Lee et al., 2009; Sultzer et al., 1995), right-sided (Nakano et al., 2006; Staff et al., 1999; Sultzer et al., 2003)left-sided (Kotrla et al., 1995) and mixed findings (Mega et al., 2000)have all been reported. A single study, which found no absolute dif-ferences between delusional and non-psychotic groups, reported anegative correlation between delusions scores and hypoperfusionin the right anterior insula (Matsuoka et al., 2010), a region whichhas functional connections with the anterior cingulate (Cauda et al.,2011). Although many studies have restricted their investigationto cortical areas, altered perfusion has also been shown within left(Mega et al., 2000) and right (Moran et al., 2008) striatal regions.

These findings overlap considerably with neuroimaging datafrom young adults with schizophrenia (Blackwood et al., 2001) andare consistent with the involvement of corticostriatal dopaminer-gic networks in delusions in AD. Connections between prefrontal(OFC and anterior cingulate) cortex and the ventral striatum, whichform part of the limbic corticostriatal loop (Kunishio and Haber,1994), have received most attention because of their crucial role inassigning subjective value to incoming dopaminergic signals fromthe midbrain (Corlett et al., 2010; Rushworth and Behrens, 2008;Takahashi et al., 2009). However, the associative corticostriatalloop, which projects from the dorsolateral PFC to the dorsal cau-date/putamen (Selemon and Goldman-Rakic, 1985) may be equallyimportant because of its role in cognitive control and belief evalu-ation (Coltheart, 2010; Corlett et al., 2010).

In addition to corticostriatal networks, several studies haveshown altered perfusion and/or metabolism in temporal regions(inferior and/or superior temporal gyrus) (Hirono et al., 1998;Nakano et al., 2006; Ponton et al., 1995; Starkstein et al., 1994)in delusional patients. These regions have also been implicatedin young adults and are believed to form part of a mentalisingnetwork, activated in conjunction with the medial PFC and tem-poroparietal junction during tasks that require inferences to bemade about the intentions of others (Amodio and Frith, 2006;
Blackwood et al., 2001). A minority of studies have focussed specif-ically on delusional subtypes (Fukuhara et al., 2001; Mentis et al.,1995; Nakano et al., 2006; Staff et al., 2000). Their findings showsome overlap with the studies described above, as they have

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Table 2Functional (metabolism and perfusion) imaging correlates of delusions in Alzheimer’s disease.

Author, Year Symptom(s)/ratingscale

Sample characteristics Confounding factors Imaging modality/ROIvs voxel-based

Findings in the presenceof symptoms

Starkstein et al., 1994 Delusions: PSE (DSMIIIR)

Delusional (n = 16; 7M)MMSE = 19.1 ± 5.6Non-delusional (n = 29;6 M)MMSE =18.5 ± 4.7

Hallucinations notspecifiedMedication not specified

99MTc-HMPAO SPECTROI/using patient’s CTto guide

↓ inferior and superiortemporal cortex

Sultzer et al., 1995 Psychosis: NRS(delusions,hallucinations,suspiciousness)

n = 21 (20 M)MMSE = 18.6 ± 6.6

Medication free for atleast 3 weeks prior toimagingDid not examineassociation betweenpsychosis scores andMMSE

[18F]FDG-PETROI/MRI andatlas-guided

↓ frontal cortex(meanweightedhypometabolism index)

Ponton et al., 1995 Delusions: No ratingscale specified

n = 15 (5 M);MMSE = 19.4 ± 3.9All non-psychotic atbaseline; 6 developeddelusions over 1 yr

No group differences inMMSEHallucinations notspecifiedMedication not specified

99MTc-HMPAO SPECTROI analysis/bonferronicorrection

↑ superior temporal gyrusand R inferior temporalgyrus at baseline in‘delusional ‘group; nodifferences at 1 yearfollow up

Kotrla et al., 1995 Psychosis: BEHAVE-AD(DMS-IIIR)Secondary analysisdelusions

Delusional (n = 29; 9with hallucinations);MMSE = 15.3 ± 6.4Never psychotic;MMSE = 15.5 ± 6.6

Medication not specified 99MTc-HMPAO SPECTROI analysis- atlasguided

Delusions: No absolutegroup differences, butasymmetry found: ↓ Llateral frontal

Mentis et al., 1995 Delusions: Misidentifi-cation/CSAD, rated bypsychiatrist

Misidentification(n = 9; 6 M; 7 CSAD);MMSE = 14.6 ± 9.9No misidentification(n = 15; 10 M);MMSE = 19.6 ± 6.8

*did not control fordifferences in MMSEOther psychoticsymptoms not specifiedMedication not specified

18F-FDG-PETManual ROI placement

↓ orbitofrontal, anteriorcingulate, L medialtemporalcortex ↑ sensoryassociation cortex(superior temporal,inferior parietal)

Hirono et al., 1998 Delusions:BEHAVE-AD/NPI(DSM-IV)

Delusional (n = 26; 4 M;7 hallucinations);MMSE = 18.5 ± 4.2No delusions (n = 39;13 M; 1hallucinations); MMSE=19.5 ± 4.0

Medication not specified FDG-PETROI/co-registrationwith MRI

↓ L medial occipitalcortex, ↑ L inferiortemporal cortex

Staff et al., 1999 Delusions: DSM-IV Delusions(n = 18; 4 M);MMSE = 19.1 ± 6.4No delusions (15; 5 M);MMSE =20.6 ± 4.9

Hallucinations notspecified

99MTc-HMPAO SPECTROI and voxel-basedapproaches

No differences in absoluteuptake, but asymmetryfound: ↓ R sided-uptakein frontal, parietal and‘limbic’ regions (limbic notdefined)

Mega et al., 2000 Psychosis: NPI (delu-sions/hallucinations)

Psychotic (n = 10; all F)MMSE = 14.3 ± 2.3Non psychotic (n = 19;1 M)MMSE = 17.4 ± 2.1

*did not control fordifferences in diseaseseverityMedication not specified

99MTc-HMPAO SPECTROI guided byprobabilistic atlas

↓ DLPFC, L anteriorcingulate, L ventralstriatum, L pulvinar, Ldorsolateral parietal

Staff et al., 2000 Delusions: CSADDMSIV

CSAD (n = 10; 2 M)Mixed paranoid andmisidentification(n = 15; 7 M)No delusions(n = 20; M)

No group differences inMMSEHallucinations notspecifiedMedication not specified

99MTc-HMPAO SPECTROI and voxel-basedapproach

↓ R frontal(B 9 medial PFC, B10superior frontal gyrus)

Fukuhara et al., 2001 Delusions: TheftNPI (delusions, scoringonly on ‘theft’)

Delusions (n = 9;hallucinations=0.1 ± 0.3); MMSE = 20.0+-2.9No delusions (n = 9; nohallucinations);MMSE = 20.9 ± 4.2

Medication not specified 99MTc-HMPAO SPECTVoxel-based approach

↓ R medial posteriorparietal

Sultzer et al., 2003 Delusions: NRS(delusion item)

n = 25 (24 M);MMSE = 16.5 ± 6;delusion scores 0–6

Controlled for cognitivedeficits in delusionalgroupNo psychotropicmedication for 3 weeksbefore the study; none oncholinesterase inhibitorsHallucinations notspecified

FDG-PETROI/guided by MRI andprobabilistic atlas)

↓ R superior dorsolateralfrontal (B8, middle frontalgyrus)↓ R inferior frontal pole(B10, superior frontalgyrus)↓ R lateral orbitofrontalcortex (B47)

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Table 2 (Continued)

Author, Year Symptom(s)/ratingscale

Sample characteristics Confounding factors Imaging modality/ROIvs voxel-based

Findings in the presenceof symptoms

Nakano et al., 2006 Delusions: NPI(delusions)

Delusions (n = 25; allM)MMSE = 16.8 ± 5.9No delusions (n = 39;all M)MMSE = 19.5 ± 4.7

No group differences inMMSENever treated withantipsychotic medicationor cholinesteraseinhibitors

99MTc-ECDVoxel-based approach

Delusions (all) ↓ R frontal,R inferior-middletemporal, R parietalcortexSecondary analysis:‘theft’ ↓ anterior cingulate‘house not my own’ ↓ Llingual and R occipital

Moran et al., 2008 Psychosis/secondaryanalysis delusions:BEHAVE-AD

n = 103; 35 M; 51psychotic; matched forage, MMSE

Medication not specified 99MTc-HMPAO SPECTVoxel-based analysis

Delusions:F: ↓ R inferolateral PFCM: nil

Lee et al., 2009 Delusions: BEHAVE-AD n = 22; 13 delusions(subsample of a largegroup that examinedconfabulation anddelusions)

No group differences inMMSEHallucinations notspecified

99MTc-HMPAOVoxel-based approach

↓ PFC (including B9medial PFC)

Matsuoka et al., 2010 Delusions: NPI(delusions)

Delusions (n = 14; 2 M;hallucina-tions = 0.2 ± 0.8)MMSE = 20.8 ± 3.8Non-delusional (n = 21;3 M; hallucinations = 0)

Matched for illnessdurationNewly diagnosed, not onpsychotropic or othermedication

[123I] –iodoamphetamineSPECTVoxel-based approach

No difference betweendelusional andnon-delusional groupsbut negative correlationbetween delusions scoreand r CBF in R anterior

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MMSE = 20.7 ± 3.5

ll diagnosed using NINCDS-ADRDA criteria.bbreviations: BEHAVE AD, behavioural pathology in AD rating scale; CSAD, conten

mplicated prefrontal (anterior cingulate, OFC) regions in delusionsf theft (Nakano et al., 2006) and misidentification (Mentis et al.,995). They have however provided some additional insights. Delu-ions of misidentification (including the belief that a dead persons alive) are associated with altered perfusion and/or metabolismn regions which have a key role in the retrieval of autobiograph-cal memories (medial hippocampus, lingual gyrus, medial PFC)Mentis et al., 1995; Staff et al., 2000); and a single study has shownn association between delusions of theft and perfusional deficitsn the right medial posterior parietal cortex (PPC), a region whichs involved in directing attention, but also contributes to episodic

emory retrieval (Cabeza et al., 2008).

. Genetics

.1. Disease modifier and heterogeneity models

Research over the past decade has provided clear evidence of genetic contribution to psychotic symptoms in AD, in termsf familial aggregation, heritability and linkage (DeMichele-Sweetnd Sweet, 2010). It has however proved more difficult to establishhe possible pathway(s) by which genetic variation might result insychotic symptoms, a phenotype typically described as ‘AD + P’.wo models have been proposed: a heterogeneity model, in whichenes directly associated with late-onset AD increase the liabilityo develop AD pathology and psychotic symptoms; and a disease

odifier model, in which genes modify the neurodegenerative pro-ess to increase the risk of psychotic symptoms (DeMichele-Sweetnd Sweet, 2010; Hollingworth et al., 2011; Sweet et al., 2003).

.2. Association studies

Association studies which have investigated these pathwaysocus predominantly on AD + P, but some have reported specif-cally on delusions and hallucinations, with the aim of more
learly establishing genotype–phenotype relationships. Numer-us studies have targeted the APOE gene because of its wellstablished link with late-onset AD, but there is little evidenceo support a heterogeneity model either for AD + P or delusions
insula

ific autobiographical delusion; DL-PFC, dorsolateral prefrontal cortex.

(Demichele-Sweet et al., 2011; DeMichele-Sweet and Sweet, 2010).Negative findings have also been reported in relation to genesinvolved in the generation of soluble A�, and downstream effectorsof synaptic loss, (APP, MAPT, SORL1, BACE1) (De-Michele-Sweetet al., 2011). There is more evidence to support the involvementof potential disease modifying genes. A single nucleotide poly-morphism (SNP) in the catechol-O-methyltransferase (COMT) gene(rs4860 locus) has been a particular focus of interest, as it has beenidentified as a risk factor for schizophrenia. Sweet et al. (Sweet et al.,2005) were the first to find an association between the rs4860polymorphism and psychotic symptoms in AD, but the associa-tion was specific to women, and to the misidentification subtype.Subsequent studies which have not stratified for gender have repli-cated the association with psychotic symptoms (Borroni et al., 2006,2007) and with hallucinations but not delusions (Borroni et al.,2006). Association studies of other genes involved in monoamin-ergic neurotransmission have been inconclusive in relation toserotonin (5-HT 2A/2C) and dopamine (D1-4) receptor sites andboth dopamine and 5HT transporters (DeMichele-Sweet and Sweet,2010). Data on other putative risk genes for schizophrenia are morelimited. Two studies have examined neuregulin (NRG1), but resultshave been conflicting (Go et al., 2005; Middle et al., 2010). Othershave reported associations specifically with delusions, including apolymorphism of the interleukin-1beta-gene promoter (Craig et al.,2004), the alpha-7-nicotinic receptor gene CHRNA 7, (Carson et al.,2008); and the G27/DAOA gene, which has a key role in the glu-tamate pathway (Di Maria et al., 2009). This area of research canbe a difficult one to interpret, particularly when sample sizes aresmall, as false positive and false negative findings are more likely.In addition, population stratification (unidentified differences ingenetic ancestry) may lead to spurious associations that can onlybe detected and accounted for in studies that type multiple SNPs,rather than a single SNP within a gene of interest.

7.3. Genome-wide studies

Studies which investigate the whole genome are one wayof addressing this issue, and also have the potential to identifynovel gene loci. A recently published study, which carried out

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combined analysis of three large, multi-centre, genome-widessociation studies, evaluated gene loci that might contribute to

heterogeneity’ and ‘disease modifier’ models (Hollingworth et al.,011). Consistent with earlier studies, the findings did not supporthe involvement of APOE, but did find some sub-threshold associ-tions with candidate loci for genes that have been implicated inther psychotic disorders; including the SLC2A gene which has aole in glucose homeostasis; and VSLN1 which may be involved inntracellular signalling.

. Neuropsychological correlates of delusions in AD

.1. Cognitive deficits may be subtype dependent

Since the early findings of an accelerated decline in delusionalatients with AD (Cummings and Victoroff, 1990), this area haseen a major focus of research interest. Studies have consistentlyound more marked deficits in global functioning in AD patientsith psychotic symptoms (Ropacki and Jeste, 2005), and there is

lso evidence that these deficits predict the onset of psychoticymptoms (Emanuel et al., 2011; Paulsen et al., 2000b; Weamert al., 2009). However, the relationship is a complex one and may beependent upon delusional subtype; lower MMSE scores have beeneported in patients with misidentification (Burns et al., 1990b;evanand et al., 1992; Harwood et al., 1999; Perez-Madrinan et al.,004) but not persecutory delusions (Burns et al., 1990a; Ikeda et al.,003; Perez-Madrinan et al., 2004); and longitudinal data suggesthat lower MMSE scores may only predict emergent misidentifica-ion symptoms (Devanand et al., 1997; Wilkosz et al., 2006).

These findings, combined with post-mortem data, have ledo the suggestion that paranoid and misidentification subtypes

ay be phenomenologically and biologically distinct (Ismail et al.,011). However it is also possible that the two subtypes are part of

continuum; persecutory delusions occurring early in the diseaseourse when differences between delusional and non-psychoticroups are more subtle; and misidentification delusions emerg-ng as the pathological and cognitive trajectory diverges more

arkedly from that seen in non-psychotic patients. There is robustvidence that psychotic symptoms (Wilkosz et al., 2010; Wilsont al., 2000, 2006), and more specifically delusions (Scarmeas et al.,005), predict a faster speed of cognitive decline. However, cogni-ive trajectories have not been explored in relation to delusionalubtypes.

.2. Cognitive markers of delusions

.2.1. Cross-sectional studiesOther researchers have approached this area with the aim of

ore clearly localising cognitive deficits (summarised in Table 3),ased on the early finding of executive dysfunction in AD patientsith delusions and/or hallucinations (Jeste et al., 1992). Many

nconsistencies have been reported in the literature, in relationo executive and other aspects of neuropsychological test perfor-

ance (Bylsma et al., 1994; Chen et al., 1998; Heinik et al., 2001;opez et al., 1991; Mentis et al., 1995; Migliorelli et al., 1995;izrahi et al., 2006; Murayama et al., 2009; Staff et al., 1999;

tarkstein et al., 1994), which may be partly explained by vari-ble sample size, the lack of a standardised approach to potentialonfounding variables (MMSE, educational level, medication statusnd depressive symptoms) and moderate floor effects (Chen et al.,998).

More convincing evidence of executive/frontal dysfunction haseen found in studies which have focussed specifically on confabu-

ation. Although no group differences were found using a globaleasure of confabulation (Migliorelli et al., 1995), an increased

vioral Reviews 36 (2012) 2274–2287

tendency to confabulate about personal/autobiographical events(responses to questions such as ‘What did you do for your lastbirthday?’) has been reported in patients with delusions and/oraggression (Lee et al., 2007a) and in those with delusions alone(Lee et al., 2009, 2007b). Greater deficits on scales which have beendesigned to measure ‘frontal’ impairment have also been found inpatients with delusions (Paulsen et al., 2000a), including those whopresent solely with persecutory delusions (Nagata et al., 2009).Other data on delusional subtypes is limited. Two studies havereported paradoxical findings of improved performance on testsof attention (Bylsma et al., 1994) and social cognition (Murayamaet al., 2009) in patients with persecutory delusions. However, theirfindings are difficult to interpret because of the absence of infor-mation on educational level (Bylsma et al., 1994) or on psychoticsymptoms other than ‘theft’ in the two groups (Murayama et al.,2009). A single study reported no differences on a range of cogni-tive domain in patients with misidentification phenomena (Mentiset al., 1995), but the sample size was small and the study wasprimarily designed to image the metabolic correlates of delusions.

8.2.2. Longitudinal studiesAlongside cross-sectional data, prospective studies have con-

sistently shown that executive dysfunction predicts emergentpsychotic symptoms (Paulsen et al., 2000b; Swanberg et al., 2004),and a greater increase in psychotic symptoms (Tsai et al., 2010)and delusions (Aalten et al., 2007) over time. These findings overlapconsiderably with the literature on young adults with schizophre-nia, which suggests that deficits in executive (prefrontal) controlare not only present in affected individuals, but may be a cognitivemarker of an at-risk mental state (Lesh et al., 2011).

9. Future perspectives

The past two decades have seen considerable advances in thisarea of research and have provided evidence to support sharedtheories regarding delusion formation in AD and schizophrenia.Functional imaging studies in AD overlap considerably with datafrom young adults with schizophrenia, as they have implicatedregions and/or functional networks that are involved in salienceattribution, belief evaluation and mentalising. In addition, regionsthat have a key role in the retrieval of autobiographical memoriesappear to be more compromised in patients with misidentificationdelusions.

Consistent with Cummings’ original theory (Cummings, 1992;Cummings and Back, 1998) there is evidence of a greater disruptionof the cholinergic/dopaminergic axis in delusional patients, partic-ularly those with persecutory delusions. Although neurochemicaldata are relatively sparse, the findings of post-mortem and imagingstudies of dopamine D2/3 receptor function in AD are directly com-parable with data on young psychotic adults and supportive of ashared aetiology for delusions. However it is unclear whether a rel-ative excess of striatal dopamine D2/3 receptors is a trait marker fordelusions, or more specifically for persecutory symptoms and thiswill need to be explored in future studies. The investigation shouldalso be extended to include other indices of striatal dopaminer-gic function, such as pre-synaptic dopamine synthesis capacity,which is increased in schizophrenia and appears to be a more robustmarker of psychosis-proneness in young adults than D2/3 receptoravailability (Howes and Kapur, 2009).

Assuming that increased dopaminergic activity represents a‘final common pathway’ to delusion formation (Kapur, 2003),
future research should focus primarily on neurotransmitters whichmay be involved in the sensitization process, if novel therapeu-tic targets are to be identified. Muscarinic receptors are a primecandidate, as post-mortem data suggest there may be reciprocal

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Table 3Neuropsychological correlates of delusions in Alzheimer’s disease.

Author, Year Symptoms/rating scale Sample characteristics Confounding factors Neuropsychological test domain

Executive‘frontal’ Language Memory Visuoperceptual/visuospatial/praxis

Lopez et al., 1991 Psychosis DSM-III-R Psychosis (n = 17); 12delusional, 13hallucinations, 7 bothNon-psychotic (n = 17)

Medication statusprovided but notdirectly comparedDid not exclude 5patients who metcriteria for depressiveillness

Letter cancellationTMT-A

Receptive ↓ ***(composite score ofToken Test, auditorycomprehension,reading)Boston Naming

Verbal memoryFace memoryPaired associatelearningImmediate recall of afigureShort story

Visual formdiscrimination,Figure copyBlock design

Jeste et al., 1992 DelusionsDIS/DSM-III-R

Delusional (n = 37;16 M); 18hallucinations;MMSE = 13.9 ± 7.2Non-psychotic (n = 70;35 M); MMSE =18.5 ±6.3

Did not control fordifferences in MMSE

Category fluency ↓ *DRS:conceptualisation↓ **DRS: attentionDigit spanLetter fluency

Boston namingNumber information

DRS: Memory ↓ * Block designClock drawingDRS-construction

Bylsma et al., 1994 DelusionsCUSPAD

Delusional (n = 45;20 M)(no misidentification,no hallucinations)Non-psychotic(n = 135; 58 M)

Educational level nsMean MMSE notspecified

mMMSE:attention ↑ ** mMMSE:naming ↓*

Starkstein et al.,1994

Delusions: PSE (DSMIIIR)

Delusional (n = 16;7 M);MMSE = 19.1 ± 5.6Non-delusional (n = 29;6 M); MMSE =18.5 ± 4.7

Hallucinations notspecifiedMedication not specified

Digit spanWCSTTMTLetter fluency (COWA)

Boston namingToken test

Buschke selectiveremindingBenton visual retention

Block designIdeomotor apraxiaRaven’s progressivematrices

Mentis et al., 1995 Delusions(misidentification)rated by a psychiatrist

Misidentification(n = 9;6 M; 7 CSAD)MMSE = 14.6 ± 9.9No misidentification(n = 15;10 M);MMSE = 19.6 ± 6.8

Did not control fordifferences in MMSEHallucinations notspecifiedMedication not specified

Porteus mazeBlock tappingStroopTMTLetter fluency

Boston NamingReadingAuditorycomprehension

WMS:logical memoryvisual memorySelective Reminding

Raven’s progressivematricesBenton FacialRecognitionExtended RangeDrawingHiskey-Nebraska BlockPatterns

Migliorelli et al.,1995

Delusions PSE(DMS-III-R)DPS

Delusional (n = 21;7 M);MMSE = 19.2 ± 6.5Non-delusional (n = 82;20 M);MMSE = 17.1 ± 6.6

Medication provided butnot directly compared

CQDigit SpanWCSTTMT

Token TestBoston Naming

Buschke SelectiveRemindingBenton VisualRetention

Ideomotor apraxiaBlock DesignRaven’s progressivematrices

Chen et al., 1998 Psychosis factorNRS score

n = 31 (M); mean MMSE17.6; no SD given

Partialled out MMSE inthe analysis, but notother confoundersNo psychotropics 3weeks prior toassessment

Letter fluency ↓**WCST ↓*DRS:conceptualisation/initiationStroopTMT- BWCST

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Staff et al., 1999 Delusions: DSM-IV Delusions(n = 18; 4 M);MMSE = 19.1 ± 6.4No delusions (15; 5 M);MMSE =20.6 ± 4.9

Educational level notspecifiedHallucinationsnotspecified

Digit cancellationLetter and categoryfluencyDigit span

Token testConfrontation naming

Paired associateslearning

Raven’s progressivematricesVisuoconstructiveapraxia

Paulsen et al.,2000a

PsychosisDIS/DMS-III-R

Psychosis (n = 20; 94%delusions; 35%hallucinations);MMSE = 11.7 ± 7.8Non-psychotic (n = 21);MMSE = 13.0 ± 6.5

Medication not specified FLOPs: total ↑ *executive dysfunctiondisinhibition ↑ *apathy

Heinik et al., 2001 DelusionsBEHAVE-ADAD diagnosed usingDSM-IV

Delusional (n = 21)Mean MMSE = 16.0, SDnsNon-delusional(n = 29); MeanMMSE = 17.9, SD ns

Medication not specifiedHallucinations notspecified

Clock Drawing ↓*

Perez-Madrinanet al., 2004

Psychotic symptomsCBRS

Paranoid (n = 24; 9 M)MMSE = 16.9 ± 4.9Misidentification+-Hallucinations(n = 32; 8 M)MMSE = 13.4 ± 5.4Both (n = 14; 5 M);MMSE = 15.8 ± 4.7Non-psychotic (n = 49;20 M)MMSE = 18.7 ± 5.0

Medication not specified Category Fluency ↓**Digit span

Rey-Osterrieth ↓**ADAS-cog: word recalland word recognition

Benton VisualDiscrimination test

Mizrahi et al., 2006 Delusions andhallucinationsDPS/DSM-IV

Delusions only(n = 204);MMSE = 20.6 ± 6.3Hallucinations only(n = 13); MMSE=21.2 ± 4.2Delusions+Hallucinations(n = 43);MMSE = 17.1 ± 6.3No psychoticsymptoms(n = 511);MMSE = 22.7 ± 6.0

No past or currenttreatment withantipsychoticmedicationDid not exclude patientswith depressivesymptoms whencomparing testperformance

Digit spanLetter fluency (COWA)

Boston Naming Semantic memoryverbal learning andmemoryBuschke Selectivereminding task

Block Design

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Table 3 (Continued)

Author, Year Symptoms/rating scale Sample characteristics Confounding factors Neuropsychological test domain

Executive‘frontal’ Language Memory Visuoperceptual/visuospatial/praxis

Lee et al., 2007b DelusionsBEHAVE-AD-FW

Delusions (n = 21, 3 M);MMSE = 15.7 ± 5.0; hal-lucinations = 0.8 ± 2.6Non-delusional (n = 29,4 M);MMSE = 15.5 ± 5.2; hal-lucinations = 0.1 ± 0.7

MCB: personalepisodic ↑ ***MCB: personalsemanticCASI: attention,category fluency,concentration/mentalmanipulation,abstraction, judgement

CASI: language CASI:STM/LTM CASI: visualconstruction

Lee et al., 2007a Delusions/AggressionBEHAVE-AD-FW

Delusional/aggressive(n = 15; 3 M);MMSE = 14.5 ± 5.3; hal-lucinations = 0.3 ± 0.7Non-delusional/non-aggressive (n = 17;2 M);MMSE = 16.8 ± 5.3; hal-lucinations = 0.2 ± 0.2

Medication notcompared

Confabulation test:personal episodic(past and future) ↑*

CASI: language CASI:STM/LTM CASI: visualconstruction

Murayama et al.,2009

Delusions (theft)BEHAVE-AD

Delusions of theft(n = 14; 1 M);MMSE = 20.6 ± 3.0No delusions of theft(n = 42; 16 M);MMSE = 19.8 ± 2.2

Medication not specifiedPresence of otherpsychotic symptoms notspecified

COGNISTAT: socialcognition ↑* attentionsimilarities judgement

COGNISTAT: namingrepetitioncomprehension

COGNISTAT: memory COGNISTAT:constructional ability

Nagata et al., 2009 Delusions BEHAVE-AD Persecutory delusions(n = 19; 8 M);MMSE = 22.0 ± 2.7Non-delusional (n = 29;12 M);MMSE = 23.3 ± 2.2

Excluded if prescribedcholinesteraseinhibitors, but othermedication not specifiedHallucinations notspecified

FAB: total **Similarities ↓ *motor series ↓*conflictinginstructions ↓*Letter fluencygo-no goprehension behaviour

Lee et al., 2009 DelusionsBEHAVE-AD-FW

n = 41(MMSE = 15.7 ± 4.6); 17delusions

Hallucinations notspecified

MCB: personalepisodic ↑***MCB: personalsemantic

All diagnosed using NINCDS/ARDRA criteria unless other specified.Level of significance is indicated by *p < 0.05, **p < 0.01, ***p < 0.001.Findings which achieved significance are shown in bold. Arrows indicate whether scores were higher (↑) or lower (↓) in patients with delusions.Findings which did not remain significant after controlling for potential confounding variables are shown in italics.� – participants in the ‘low’ performance group at baseline were found to have a greater increase in delusions scores over a 2 year period.All references are detailed in the manuscript.Abbreviations: BEHAVE-AD, behavioural pathology in AD rating scale; BEHAVE-AD-FW, behavioural pathology in AD rating scale (frequency weighted); CASI, cognitive abilities screening instrument; CBRS, CERAD behaviouralrating scale; COGNISTAT, neurobehavioural cognitive status examination; COWA, controlled oral word association test; CQ, confabulation questionnaire; CUSPAD, Columbia University scale for psychopathology in AD; DIS/DSM-III-R, diagnostic interview schedule for DSM-III-R; DPS, Dementia Psychosis Scale; DRS, Dementia Rating Scale; FAB, frontal assessment battery; FLOPs, Frontal Lobe Personality Scales; LTM, long term memory; MCB, modifiedconfabulation battery; mMMSE, modified MMSE; NPI, neuropsychiatric inventory; PSE, present state examination; STM, short term memory; WMS, Wechsler Memory Scale.

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hanges in M2 and non-M2 receptor subtypes in the OFC ofelusional patients, including those who present solely with per-ecutory symptoms. In order to explore this further, PET tracersith a greater specificity for individual receptor subtypes will need

o be developed for clinical use, to allow the interplay betweenre- and post synaptic mechanisms to be investigated in striatals well as cortical regions. Future studies should also aim to tar-et other neurotransmitters which modulate striatal dopamineelease, including glutamate and GABA.

The mechanisms underpinning the genetic contribution to psy-hotic symptoms in AD have not been clearly established, buthere is more evidence to support the involvement of putativeisk genes for schizophrenia than those which are directly linkedith late-onset AD. Although the COMT gene has been consistently

mplicated in AD + P, it is unclear to what extent the grouping ofisidentification phenomena with hallucinations is responsible

or the observed association with the misidentification subtype.ther potential disease modifying genes, including those involved

n immune modulation, cholinergic (nicotinic receptor) and glu-amatergic function are promising targets for future research. Itill however be important to collect data from sample sizes large

nough to meaningfully investigate subphenotypes (delusions, hal-ucinations and delusional subtypes) and to explore multiple as

ell as single SNPs.The suggestion that delusional patients have a more accelerated

orm of AD has only been supported in relation to patients withisidentification delusions, who have an exaggerated AD pathol-

gy in hippocampal region and projection zones, and more markedeficits in global cognitive function. Whilst it has proved more dif-cult to identify key regions of pathological change in relation toersecutory delusions, techniques such as MRS, which are able toetect neuronal dysfunction in vivo, suggest that early changesay be occurring in the anterior cingulate cortex. Combined with

eurochemical data, this suggests that there may be an earliernvolvement of frontostriatal neurocircuitry. Use of neuropsychol-gical test measures which are more intimately linked with striatal2/3 receptor function (Reeves et al., 2010) or have been strongly

mplicated in schizophrenia (Lesh et al., 2011), could prove infor-ative in this respect, as they may be more sensitive cognitivearkers of persecutory delusions.It is unclear whether persecutory and misidentification delu-

ions represent discrete subtypes, or are part of the sameontinuum, manifesting at different time points. This could havemplications for treatment, particularly if they are found to haveistinct neurochemical and/or neuropathological targets. Longi-udinal studies which more clearly elaborate upon the degree ofransition between delusional subtypes and their cognitive trajec-ories could help to resolve this issue, particularly if combined withiological markers.

onflict of interest

Dr. Reeves, Dr. Gould, Dr. Powell and Professor Howard reporto biomedical financial interests or potential conflicts of interest.

cknowledgements

The authors acknowledge support from the NIHR Biomedical
esearch Centre for Mental Health at the South London and Maud-ley NHS Foundation Trust (SLaM) and Institute of Psychiatry, King’sollege London, Alzheimer’s Research UK, and the 7th frameworkrogramme of the European Union (HEALTH-F4-2009-242257).
vioral Reviews 36 (2012) 2274–2287

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origins of delusions in alzheimer's disease

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