neurobiology of delusions, memory, and insight in alzheimer disease

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Neurobiology of Delusions, Memory, and Insight in Alzheimer Disease David L. Sultzer, M.D., Lorraine P. Leskin, Ph.D., Rebecca J. Melrose, Ph.D., Dylan G. Harwood, Ph.D., Theresa A. Narvaez, M.A., Timothy K. Ando, B.A., Mark A. Mandelkern, M.D., Ph.D. Objective: Delusional thoughts are common among patients with Alzheimer disease (AD) and may be conceptually linked to memory decits (cannot recall accurate information, which leads to inaccurate beliefs) and poor insight (unable to appre- ciate the illogic of beliefs). This studys goals were to examine the clinical associations among delusions, memory decits, and poor insight; explore neurobiologic correlates for these symptoms; and identify shared mechanisms. Methods: In a cross-sectional analysis, 88 outpatients with AD (mean Mini-Mental State Exam score: 19.3) were studied. Delusional thoughts were assessed with the Neuropsychiatric Inventory, level of inaccurate insight was assessed with the Neurobehavioral Rating Scale, and memory was assessed with the Mattis Dementia Rating Scale memory subscale. 18 F- uorodeoxyglucose positron emission tomography was used to measure regional cortical metabolism. Relationships between clinical ratings and regional cortical metabolic activity (voxel-based) were assessed using SPM2. Results: Patients with delusions had lower Dementia Rating Scale memory subscale scores. Neuro- behavioral Rating Scale inaccurate insight scores were no different in those with and without delusions. Cortical metabolic activity was lower in the right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions. Low cortical metabolic activity in the right lateral, inferior, and medial temporal cortex was associated with poorer memory. This region partially overlapped the region of hypometabolism associated with delusions. In contrast, low cortical meta- bolic activity in bilateral medial frontal cortex was associated with poor insight. Conclusion: Delusions in AD are associated with dysfunction in specic frontal and temporal cortical regions. Delusions are partially clinically and neurobiologically linked to memory decits but not to poor insight. (Am J Geriatr Psychiatry 2013; -:-e-) Key Words: Alzheimer disease, delusions, insight, memory, FDG-PET, cerebral metabolism Received November 26, 2012; revised June 14, 2013; accepted June 18, 2013. From the Brain, Behavior, and Aging Research Center (DLS, LPL, RJM, DGH, TAN, TKA) and Nuclear Medicine Service (MAM), VA Greater Los Angeles Healthcare System, Los Angeles, CA; Department of Psychiatry & Biobehavioral Sciences (DLS, RJM, DGH), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Physics (MAM), University of California, Irvine, Irvine, CA. Presented in part at the 25th annual meeting of the American Association for Geriatric Psychiatry, Washington, DC, March 16e19, 2012. Send correspondence and reprint requests to David L. Sultzer, M.D., Brain, Behavior, and Aging Research Center, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, 116AE, Los Angeles, CA 90073. e-mail: [email protected] Ó 2013 American Association for Geriatric Psychiatry http://dx.doi.org/10.1016/j.jagp.2013.06.005 Am J Geriatr Psychiatry -:-, - 2013 1

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Page 1: Neurobiology of Delusions, Memory, and Insight in Alzheimer Disease

Neurobiology of Delusions, Memory, andInsight in Alzheimer Disease

David L. Sultzer, M.D., Lorraine P. Leskin, Ph.D., Rebecca J. Melrose, Ph.D.,Dylan G. Harwood, Ph.D., Theresa A. Narvaez, M.A., Timothy K. Ando, B.A.,

Mark A. Mandelkern, M.D., Ph.D.

Received NovemRJM, DGH, TANPsychiatry & BioPhysics (MAM),Geriatric PsychiaBehavior, and Age-mail: dsultzer@

� 2013 Amehttp://dx.d

Am J Geriatr Ps

Objective: Delusional thoughts are common among patients with Alzheimer disease

(AD) and may be conceptually linked to memory deficits (cannot recall accurate

information, which leads to inaccurate beliefs) and poor insight (unable to appre-

ciate the illogic of beliefs). This study’s goals were to examine the clinical associations

among delusions, memory deficits, and poor insight; explore neurobiologic correlates

for these symptoms; and identify shared mechanisms. Methods: In a cross-sectional

analysis, 88 outpatients with AD (mean Mini-Mental State Exam score: 19.3) were

studied. Delusional thoughts were assessed with the Neuropsychiatric Inventory, level

of inaccurate insight was assessed with the Neurobehavioral Rating Scale, and

memory was assessed with the Mattis Dementia Rating Scale memory subscale.18F-

fluorodeoxyglucose positron emission tomography was used to measure regional

cortical metabolism. Relationships between clinical ratings and regional cortical

metabolic activity (voxel-based) were assessed using SPM2. Results: Patients with

delusions had lower Dementia Rating Scale memory subscale scores. Neuro-

behavioral Rating Scale inaccurate insight scores were no different in those with and

without delusions. Cortical metabolic activity was lower in the right lateral frontal

cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions.

Low cortical metabolic activity in the right lateral, inferior, and medial temporal

cortex was associated with poorer memory. This region partially overlapped the

region of hypometabolism associated with delusions. In contrast, low cortical meta-

bolic activity in bilateral medial frontal cortex was associated with poor insight.

Conclusion: Delusions in AD are associated with dysfunction in specific frontal and

temporal cortical regions. Delusions are partially clinically and neurobiologically

linked to memory deficits but not to poor insight. (Am J Geriatr Psychiatry 2013;-:-e-)

KeyWords: Alzheimer disease, delusions, insight, memory, FDG-PET, cerebral metabolism

ber 26, 2012; revised June 14, 2013; accepted June 18, 2013. From the Brain, Behavior, and Aging Research Center (DLS, LPL,, TKA) and Nuclear Medicine Service (MAM), VA Greater Los Angeles Healthcare System, Los Angeles, CA; Department ofbehavioral Sciences (DLS, RJM, DGH), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department ofUniversity of California, Irvine, Irvine, CA. Presented in part at the 25th annual meeting of the American Association fortry, Washington, DC, March 16e19, 2012. Send correspondence and reprint requests to David L. Sultzer, M.D., Brain,ing Research Center, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, 116AE, Los Angeles, CA 90073.ucla.edurican Association for Geriatric Psychiatryoi.org/10.1016/j.jagp.2013.06.005

ychiatry -:-, - 2013 1

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Delusions, Memory, and Insight in AD

INTRODUCTION

Delusional thoughts are common among patientswith Alzheimer disease (AD).1 These noncognitivesymptoms have important clinical implicationsbecause they contribute prominently to behavioraldisturbances, institutionalization, and caregiverburden.2,3 However, the etiologic factors underlyingdelusions in AD remain unclear. Conceptually,delusional thoughts may be associated with memorydeficits and poor insight. For example, the inability torecall accurate information may foster inaccuratebeliefs. Poor insight, defined as reduced awareness ofcognitive or functional deficits and impaired intuitiveunderstanding, may undermine the patient’s appre-ciation of the illogical nature of these beliefs.Although impaired memory and insight may belinked to delusional thoughts, the relationships arenot necessarily causal and the extent of relationshipsand the neuropathologic processes that mediate themare not known.

Studies of the clinical correlates of delusionalthoughts have typically evaluated relationships withglobal cognition. Most studies find that delusions aremore common among those AD patients withadvanced cognitive deficits.1,4,5 Few studies haveexamined the relationship between delusionalthoughts and memory deficits specifically6 or therelationship between delusional thoughts andimpaired insight. Two studies found a correlationbetween delusional thoughts and a lack of awarenessof cognitive deficits in AD.7,8 In addition, Kazui et al.9

found that both memory impairment and delusionswere significantly associated with lack of insight,suggesting that these three symptoms are clinicallyrelated.

Although the exact pathophysiologic mechanismsare unclear, neuroimaging studies indicate that delu-sional thoughts may be associatedwith dysfunction infrontal and temporal cortex in patients with AD.10e15

Previous research has also shown an associationbetween lack of insight in AD and right hemisphereand frontal lobe dysfunction that incompletely over-laps with regions of cortical dysfunction associatedwith delusions.16,17 Thus, delusions and poor insightmay have a shared relationship with right frontalcortex dysfunction. Further elucidation of the clinicaland neuropathologic associations among delusions,

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memory, and insight can help to identify criticalmechanisms underlying cognitive and neuropsychi-atric symptoms in AD and can help to inform clinicaltreatment.

The goals of this study were to examine the clinicalassociations among delusional thoughts, memorydeficits, and poor insight in mild to moderateAD and to explore the neurobiologic basis andpossible shared mechanisms for these symptomsusing fluorodeoxyglucose positron emission tomog-raphy (FDG-PET). We hypothesized that bothdelusions and poor insight would be associatedwith right lateral/inferior frontal cortex hypo-metabolism and that memory deficits would beassociated with inferior and medial temporal cortexhypometabolism.

METHODS

Participants

Eighty-eight participants with AD were recruitedfrom outpatient clinics that included the VA GreaterLos Angeles Healthcare System Memory Clinic andGeropsychiatry Clinic. Participants completed a clin-ical evaluation of neurologic, psychiatric, and cogni-tive functioning and a structural neuroimaging scan.Final diagnosis was based on the criteria for probableAD established by the National Institute of Neuro-logical and Communicative Disorders and Strokeand the Alzheimer’s Disease and Related DisordersAssociation and is consistent with National Instituteof Aging/Alzheimer’s Association criteria for prob-able AD.18 Exclusion criteria were history ofpsychotic disorder unrelated to dementia, history ofhead trauma with loss of consciousness, history orneuroimaging evidence of stroke or cerebrovasculardisease, seizure disorder, substance use disorder,severe aphasia, or systemic illness or other neurologicillness that could account for cognitive deficits.Thirty-two participants were on a stable dose (3months or more) of cholinesterase inhibitor medica-tion and 21 were on a stable dose of selectiveserotonin reuptake inhibitor antidepressant. Noparticipants were being treated with an antipsy-chotic, benzodiazepine, or other psychotropic medi-cation. The study was reviewed and approved by thelocal institutional review board.

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Clinical Assessment

Participants and their caregivers underwent a struc-tured clinical assessment that included the Neuro-psychiatric Inventory (NPI)19 and the NeurobehavioralRating Scale (NRS).20 The NPI is a caregiver-basedmeasure of 12 distinct psychiatric and behavioraldisturbances in dementia. Presence or absence ofdelusions was based on question A of the NPI. Forpatients with delusions, frequency (1e4 scale) andseverity (1e3 scale) of delusions were assessed. Delu-sionswere classified as either paranoid type (e.g., beliefthat others are stealing from him or her) or misidenti-fication type (e.g., belief that his or her house is not hisor her home).

The NRS consists of 28 items that measure theseverity of a broad range of neuropsychiatric symp-toms and behavioral disturbances based on informa-tion from the caregiver and a semistructured patientinterview. Each NRS item is scored from 0 (notpresent) to 6 (extremely severe). Level of insight wasmeasured with the inaccurate insight item of the NRS.The item score is based on a comparison of thepatient’s assessment of his or her cognitive skills,functional abilities, and other circumstances alongwith future goals and plans. The participant’s ideasand plans are contrasted with objective evidencederived from a clinical interview, cognitive testing,and caregiver report. The examiner’s overall assess-ment of the patient’s awareness and insight, using allinformation available, is captured on the item score.The NRS has been shown to have satisfactory inter-rater reliability21 and to be a valid measure ofpsychopathology in individuals with dementia.20

All participants completed a neuropsychologicaltest battery as part of a comprehensive evaluation.The Mattis Dementia Rating Scale (DRS)22 memorysubscalewas used to assessmemory. TheDRS has beenshown to have satisfactory reliability and validity.23,24

Memory subtest total scores range from 0 to 25, witha higher score indicating better performance. Thissubscalemeasures orientation, verbal recall, and verbalandvisual recognition.Gross cognitive functioningwasassessed using the Mini-Mental State Exam (MMSE).

FDG-PET Imaging

Patients completed PET imaging on the same dayas the clinical assessment. Three different positron

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emission tomographs with similar imaging charac-teristics were used over the course of this study(Siemens 953/31, Malvern, PA; GE Advance PET-CT,Piscataway, NJ; and Philips Gemini TF PET-CTscanners, Andover, MA). Each scanner had in-planeand axial resolution of approximately 5 mm at full-width half maximum. 18F-FDG was synthesized atthe VA Greater Los Angeles Healthcare System PETImaging Facility according to the technique ofHamacher et al.25 Patients received 5e10 mCi of FDGintravenously and rested with their eyes open duringthe 40-minute uptake phase. Participants were thenplaced in the scanner with the imaging plane parallelto the canthomeatal plane, and data were acquiredfor 30 minutes.

Voxel-Based PET Image Analyses

PET data were analyzed using SPM2 (WellcomeTrust Centre for Neuroimaging, London, UK) inMatlab 6.5 (MathWorks Inc., Natick, MA). Imageswere normalized to Montreal Neuroimaging Institute(MNI) space using trilinear interpolation and resam-pled to 2 � 2 � 2 mm voxels. Images were thensmoothed using a 6-mm full-width half maximumsmoothing kernel. The t test procedure in SPM2 wasused to assess differences in metabolism betweenparticipants with and without delusions.

To determine the contribution of insight andmemory, an analysis of covariance procedure wasused that included NRS inaccurate insight scores andDRS memory subscale scores as covariates in themodel. In addition, the simple correlation procedurewas used to assess the association between NRSinaccurate insight score and metabolic activity andthe association between DRS memory subscale scoreand metabolic activity. Images were normalizedusing proportional scaling, and threshold maskingwas used to remove signal from structures outside ofgray matter. The voxel-level statistical threshold wasset at p <0.01, and results were considered significantfor voxel clusters at the p <0.05 level, corrected forthe search volume in each analysis.

Clinical Assessment Score Analyses

Univariate analyses of variance were used to assessdifferences between those with delusions and thosewithout delusions for DRS total, DRS memorysubscale, MMSE, and NRS inaccurate insight scores.

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Delusions, Memory, and Insight in AD

RESULTS

Patient Characteristics

Eight-eight patients (71 men and 17 women)participated in the study. Mean age was 78 years(standard deviation [SD]: 8.0), mean education was14 years (SD: 3.6), and mean duration of dementiawas 3.2 years (SD: 2.4). Distribution of race/ethnicitywas 56 white, 24 African American, 3 Hispanic, and 5Asian/Pacific Islander.

Twenty-eight participants (32%) had recent delu-sional thoughts, and 60 participants (68%) did not.Among participants with delusions, the mean NPIdelusion frequency times severity score was 4.4 (SD:3.5), with a range of 1e12. Mean scores on the clin-ical measures are listed in Table 1. Participants withdelusions were more impaired on measures ofoverall cognition (MMSE and DRS total) and hadlower scores on the DRS memory subscale thanparticipants without delusions. In contrast, inaccu-rate insight scores on the NRS did not differ in thosewith and without delusions. Inaccurate insight scoresand DRS memory subscale scores showed a signifi-cant, albeit weak, negative correlation (r ¼ �0.24,p ¼ 0.03, N ¼ 83). The duration of dementia was notsignificantly different in the group with no delusions(mean: 3.1 years; SD: 2.0 years) versus those withdelusions (mean: 3.5 years; SD: 2.0 years; t(83) ¼ 0.75,p ¼ 0.45).

With regard to the content of delusional thoughts, 26participants presented with paranoid-type delusionsand 11 presented with misidentification-type delu-sions. All but two participants with misidentification

TABLE 1. Clinical Assessment Scores in the AD Sample

No Delusions(N [ 60)

Delusions(N [ 28) Fa p

MMSE 20.9 (5.2) 16.0 (5.0) 17.6 <0.001DRS total 110.5 (14.9) 90.1 (22.9) 23.9 <0.001DRS memory subscale 13.3 (4.1) 8.8 (3.5) 24.7 <0.001NRS inaccurate insight

item2.3 (1.8) 2.7 (1.7) 0.8 0.36

Notes: Values are means with SD in parentheses. Higher scoreson the MMSE, DRS total, and DRS memory subscale indicate betterperformance. Higher scores on NRS inaccurate insight itemindicate poorer insight.

aF statistic with df (1,86), (1,81), (1,82), and (1,85) for the MMSE,DRS total, DRS memory subscale, and NRS inaccurate insight itemscores, respectively. df varies due to occasional missing data.

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delusions also had paranoid delusions. Patients withboth misidentification and paranoid delusions (N¼ 9)had lower MMSE scores (mean: 12.0; SD: 5.4) thanthosewith only paranoid delusion (N¼ 17;mean: 17.9;SD: 3.9; t(24) ¼ 3.22, p ¼ 0.004).

Cortical Metabolism in Patients With VersusWithout Delusions

Cortical metabolic activity was lower in ADpatients with delusions compared with those withoutdelusions in three regions: right lateral frontal(middle and inferior frontal gyrus) and orbitofrontalcortex and bilateral temporal cortex (Fig. 1, Table 2).Regions of lower cortical metabolic activity in thetemporal cortex included most of the middle andinferior temporal gyri and the midportion of theparahippocampal gyrus, bilaterally. When DRS totalscore was included as a covariate in the analysis, thepattern of hypometabolism in those with delusionscompared with those without delusions wasunchanged, although only the difference in righttemporal cortex remained statistically significant atthe corrected cluster level. In a sensitivity analysis,participants with NPI delusion score ¼ 1 (infrequentand mild symptom) were switched from the delusiongroup to the no-delusion group, and the between-group analysis of cortical metabolism was repeated.Results were unchanged. Finally, a post-hoc analysiscompared cortical metabolism in patients with para-noid delusions only with those with both paranoidand misidentification delusions. Patients withcombined delusions had lower metabolic activitythan those with only paranoid delusions in the leftinferior parietal lobule (results not shown).

Relationship Between Cortical Metabolism andInsight and Memory

When NRS inaccurate insight scores and DRSmemory subscale scores were included as covariatesin the model assessing metabolic activity in thosewith versus those without delusions, the relationshipbetween delusions and right temporal corticalhypometabolism was unchanged. Relationships withlow metabolic activity in right lateral frontal and lefttemporal cortex persisted on SPM2 maps, althoughthey were not significant at the corrected cluster level.

Poor insight on the NRS inaccurate insight itemwas associated with lower metabolic activity in

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FIGURE 1. T-map of voxels where AD patients with delusions had lower metabolic activity than those without delusions. (top row)Rendering of the results of the SPM2 t test analysis, projected onto the left and right cortical surface. (middle row) SPM2maps showing coronal and axial views of bilateral temporal hypometabolism. (bottom row) SPM2 maps showingcoronal and axial views of right frontal hypometabolism. Images are displayed at p <0.01.

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bilateral medial frontal cortex (Fig. 2, Table 3). Therewas no qualitative overlap between the regions ofhypometabolism associated with delusions and thoseassociated with poor insight.

Lower scores (more impairment) on the DRSmemory subscale were associated with lower meta-bolic activity in the right temporal cortex, includingthe middle, inferior, fusiform, and parahippocampalgyri. This region overlapped qualitatively witha region of hypometabolism associated with delu-sions (Fig. 3, Table 4). Low cortical metabolic activityin the left temporal, bilateral posterior cingulate, andright inferior parietal regions was also associatedwith lower scores on the DRS memory subscale butwas not significant at the cluster level.

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DISCUSSION

The goals of this study were to examine the clinicalassociations among delusional thoughts, memorydeficits, and poor insight in AD and to assess thecortical metabolic activity associated with thesesymptoms. We observed that, clinically, delusionalthoughtswere linked to poormemory but not to lowerinsight. Neurobiologically, delusions were associatedwith relative hypometabolism in the right frontal andbilateral temporal cortex. Regions of hypometabolismassociated with delusions did not qualitatively over-lap with hypometabolic regions associated withpoor insight. However, hypometabolism in the right

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TABLE 2. Cortical Regions Where AD Patients with Delusions Had Lower Metabolic Activity Than Those Without Delusions

Region BA Side x, y, z k T Statistic (df), Peak Voxel p, Cluster Level

Frontal 11, 12, 47, 46, 8, 6 R 36, 46, �12 4,589 3.81 (86) <0.001Temporal 20, 21 R 52, �4, �30 4,847 5.49 (86) <0.001Temporal 20, 21 L �44, �32, �26 1,958 3.75 (86) 0.01

Notes: BA: approximate Brodmann’s area; x, y, z: coordinates of peak voxel in MNI space; R: right; L: left; k: number of voxels within thecluster. Voxel size is 2 mm � 2 mm � 2 mm. Cluster-level p values are corrected for the search volume.

Delusions, Memory, and Insight in AD

temporal cortex associated with memory impairmentdid overlap with a region of hypometabolism in ADpatients with delusions. These results suggest thatdelusions in AD are at least partly related to memorydeficits, both phenomenologically and neuro-biologically, but not to poor insight.

Several neurobiologic factors potentially contributeto psychosis in AD: genetic substrate,26 neurochemi-cal alterations,27 neurofibrillary tangle density,28 andamyloid burden.29 The research findings vary con-siderably, and study samples have generally beensmall. The in vivo neuroimaging literature has high-lighted a relationship between frontal cortexdysfunction and psychosis30,31 or delusions specifi-cally.10e12,32,33 Temporal dysfunction also has beenfound in AD patients with delusional thoughts,12e14,34

although with less consistency in terms of lateralityand subregions and with findings of both low andhigh metabolism or perfusion. Other regions found tobe associated with delusions/psychosis in ADinclude anterior cingulate12,35 and parietal11,12,35,36

FIGURE 2. T-map of voxels showing direct correlation between NRSInaccurate insight is correlated with low metabolic activiviews. Image displayed at p <0.01.

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and occipital regions.34 Heterogeneity of previousresults likely reflects small sample sizes, differentassessment tools, and different neuroimaging tech-niques. Our results, based on a larger sample, showedlower cortical metabolic activity in AD patients withdelusions in three regions, the right lateral frontal andorbitofrontal cortex and bilateral lateral and inferiortemporal cortex, suggesting a more prominent role ofthe temporal cortex in the neurobiology of delusionsin AD than had been highlighted in previous research.Global cognition scores were lower in the delusionsgroup than in the nondelusions group, and thusdelusions and cortical hypometabolism could bothreflect more advanced dementia. However, whenglobal cognition was included as a covariate in themodel, the pattern of results was unchanged, indi-cating that the relationship between delusions andregional hypometabolism is at least partly indepen-dent of global cognitive decline.

The content of delusional thoughts may be relatedto metabolic dysfunction in different cortical regions,

inaccurate insight item and cortical metabolism in AD patients.ty in bilateral medial frontal cortex in (A) coronal and (B) axial

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TABLE 3. Cortical Region with Significant Correlation Between NRS Inaccurate Insight Item Score and Metabolic Activity

Region BA Side x, y, z k T Statistic (df), Peak Voxel p, Cluster Level

Frontal 24, 32, 8, 9, 10 R 4, 54, 6 1,926 4.57 (85) 0.01

Notes: BA: approximate Brodmann’s area; x, y, z: coordinates of peak voxel in MNI space; R: right; k: number of voxels within the cluster.Voxel size is 2 mm � 2 mm � 2 mm. Cluster-level p values are corrected for the search volume.

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which may also explain different findings acrossstudies. We were not able to distinguish relationshipsbetween specific delusional thoughts and corticalmetabolic activity, because there were insufficientpatients with misidentification delusions only.However, when metabolic activity in those withparanoid delusions only was contrasted with that ofAD patients with both paranoid and misidentifica-tion delusions, there were no metabolic differences ineither frontal or temporal cortex, indicating that thefrontal and temporal relationships observed in theoverall group with delusions are not driven exclu-sively by the misidentification delusions. There waslower metabolic activity in the left inferior parietallobule in patients with combined delusions versusthose with only paranoid delusions. However, thisdifference may reflect the greater cognitive impair-ment in the combined delusions group rather thana link to the content of delusional thoughts specifi-cally, because prior studies have demonstratedgreater parietal hypometabolism associated withmore advanced cognitive deficits in AD.

The overlap of relationships between temporalhypometabolism and both poor memory and

FIGURE 3. T-map of voxels showing direct correlation between DRmemory is associated with hypometabolism in right mecoronal views. Image displayed at p <0.01.

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delusions suggests that an inability to recall infor-mation and delusional thoughts have shared func-tional underpinnings. Hypometabolism in the rightlateral frontal and orbitofrontal cortex was also seenin AD patients with delusions and was not associatedwith poor memory. Although speculative, thesefrontal areas have been shown to be involved inworking memory and executive functioning,37,38

suggesting that the inability to hold onto andsuccessfully manipulate information may play a rolein the failure to maintain and consider alternativepossibilities necessary to successfully reject incorrecttheories.

Many studies have found reduced medial temporallobe activity on memory tasks in patients withAD.39e41 This is consistent with the course of ADpathology in the medial temporal lobe, including theentorhinal cortex and hippocampus.42 Results fromthis study showed an association between lowcortical metabolic activity and poor memory in theright lateral, inferior, and medial temporal cortex,including the parahippocampal and entorhinalregions. Memory in this study was assessed with theDRS memory subscale, which includes orientation

S memory subscale score and lower metabolism in AD. Poordial and inferior lateral temporal cortex in (A) sagittal and (B)

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TABLE 4. Cortical Region with Significant Correlation Between DRS Memory Subscale Score and Metabolic Activity

Region BA Side x, y, z k T Statistic (df), Peak Voxel p, Cluster Level

Temporal 20, 21, 28, 37 R 56, �16, �34 3,408 4.74 (82) 0.001

Notes: BA: approximate Brodmann’s area; x, y, z: coordinates of peak voxel in MNI space; R: right; k: number of voxels within the cluster.Voxel size is 2 mm � 2 mm � 2 mm. Cluster-level p values are corrected for the search volume.

Delusions, Memory, and Insight in AD

and verbal recall items and tasks of verbal and visualrecognition. A quantitative meta-analysis of func-tional neuroimaging studies during encoding andretrieval phases of episodic memory tasks found thatpatients with AD failed to show significant engage-ment of medial temporal lobe areas duringretrieval.43 Recognition is associated with increasedactivity in hippocampal and parahippocampal areas,including the entorhinal cortex,44 in healthy individ-uals and reduced activation in those regions in indi-viduals with AD.43 Thus, our findings are consistentwith pathologic and neuroimaging studies ofmemory in AD. Moreover, qualitative overlapping ofright temporal hypometabolism related to bothdelusions and impaired memory suggests a neuro-biologic association that can help the individual tocontrast beliefs and mental imagery with memory forspecific events, which can aid reality checking.

Our findings indicate that level of insight does notdiffer between AD patients with and without delu-sional thoughts. These results are in accordance withLopez et al.45 and Harwood et al.,46 who did not finda relationship between poor insight and psychoticsymptoms in AD. However, other researchers founda relationship between lack of awareness and delu-sions,7,9,47 and our finding may have reflected insuf-ficient power to detect a small difference between thegroups. We observed an association between lowcortical metabolic activity and reduced insight in thebilateral medial frontal cortex. This finding isconsistent with one previous imaging study.48

However, these medial prefrontal relationships arenot entirely consistent with other studies that haveobserved an association between poor awareness inAD and right hemisphere dysfunction, particularlyinvolving frontal and temporal regions.16,17,49e52

There is no gold standard for assessment of insightin AD, and instruments may include clinician ratings,questionnaire-based methods, performance-basedmethods, phenomenologic methods, or a combina-tion of methods.53 Also, the domain of awarenessthat is measured varies substantially from study to

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study and has included insight related to memoryfunctioning, overall cognitive functioning, behavioralproblems, or activities of daily functioning.8 Thesedifferences may underlie inconsistencies in theresearch literature. Finally, insight encompassescomplex cognitive processes such as awareness,understanding, and intuition, which may be lesslocalizable to a discrete set of cortical regionscompared with more elemental cognitions such asmemory or language.

This study has several methodologic limitations.Three different position emission tomographs wereused, although multiple scanners have been usedsuccessfully previously,54 and the SPM2 normaliza-tion procedure results in ratio scaling for each partic-ipant that limits the impact of different scanners.55

Another potential limitation was inclusion of partici-pants taking cholinesterase inhibitor and antidepres-sant medications. However, this is not atypical for anoutpatient AD population, and no participants hadbeen treated with an antipsychotic or other psycho-tropic medication. Most participants weremen, whichlimits the generalizability of the findings. Finally, allbut two of our participants had paranoid delusions,which prohibited thorough comparisons by delusiontype. The negative valence and suspicious nature seenin paranoid delusions may be related to temporaldysfunction seen in other disorders with persecutorydelusions such as schizophrenia and temporal lobeepilepsy.56,57 It is possible that delusions of misiden-tification are more closely linked to insight.

AD is a neurodegenerative disorder withoutspecific focal lesions. Yet, our findings show thatdelusions and poor memory do overlap both clini-cally and neurobiologically. Although delusions arenot likely an exclusive product of memory deficits,the findings suggest that mechanisms may be partlyshared and the inability to recall accurate informationcould contribute to the development or mainten-ance of inaccurate beliefs. Right lateral and inferiorfrontal cortical dysfunction was also associated withdelusional thoughts but was not linked to either

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memory or insight, either clinically or neuro-biologically, suggesting an independent role of rightfrontal dysfunction in the clinical expression ofdelusional thoughts in AD. The findings here alsosuggest that FDG-PET provides a biologically basedmarker that may aid the development of treatmentsfor psychosis in AD by defining a more homoge-neous subgroup of patients with delusions who mayrespond more consistently to a particular interven-tion. Moreover, regional cortical metabolism canchange over the course of treatment,58,59 and FDG-PET imaging may shed light on critical metabolicchanges that occur with successful treatment.

Successful psychosis treatment in AD may alsobenefit executive skills and memory via effects onfrontal/temporal cortical dysfunction and thereby

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improve day-to-day living skills. Future studies canexplore such metabolic changes with treatment,identify causal brainebehavior relationships usinga longitudinal design, examine relationships withindividual delusional thoughts in larger samples, andexplore co-occurring neuropsychiatric symptoms thatmay influence the link between delusional thoughtsand cortical function in AD.

Supported in part by the Department of VeteransAffairs (Merit Review Award to DLS; Career Develop-ment Award to RJM) and the National Institute of MentalHealth (R01MH56031).

Dr. Sultzer has received research support from EliLilly and has served as a consultant to Otsuka Pharma-ceutical and Eli Lilly.

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