British Journal of Psychiatry (1993), 163, 155—165

The overlap between depression and dementia in theelderlyisan areaof both clinicaland theoreticalimportance. Elderly patients with a depressive syndromehaveeasilymeasurablecognitivedysfunction.Although it is usually relatively minor, and comparable with that seen in younger patients with majordepression (Austin et al, 1992a), it may be severeenough to meet criteria for dementia (Folstein &McHugh, 1978). The more severe forms of cognitiveimpairmentaccompanyingdepressiveillnessintheelderlycommonlyattracttheimpreciseterm‘¿�pseudodementia' (Bulbena & Berrios, 1986), and in anunselected series of cognitively impaired elderlypatients,recoveryfrom a depressiveepisodewasaccompanied by incomplete recovery of cognitive performance (Abas et al, 1990).Even without the necessary prospective evidence, it appears probable that inelderlypatients,cognitiveimpairmentisanimportantriskfactorfordepression,andbecomingdepressedis likely, of itself, further to impair cognition. Suchimpairment implies disordered brain function. Hencethe anatomical pattern of brain disorder whichaccompaniesdepressionintheelderlyisrelevanttothe understanding of depressive illness in general.

With techniques for both structural and functionalbrain imaging, it is possible to investigate the biological basis for the close affinity between depressionand dementiain the elderly.In seminalstudies,Jacoby etal(Jacoby& Levy, 1980;Jacobyetal, 1983)showed that 9 of 41 elderly depressed patients had

enlarged ventricles on computerised tomography (CT)andareducedbrainsubstanceasdeterminedbytheattenuation of CT measures. Indeed, they proposedthat simply on the basis of radio-attenuation, thedepressed group more closely resembled a dementedgroup than normal controls of the same age.

Subsequent CT studies of elderly depressed patientshave confirmed that they tend to show indices ofstructural brain involvement like those of patientswith Alzheimer's disease, especially if onset of illnessis late (Alexopoulos et al, 1992). However, it is alsointhemostseverelycognitivelyimpairedpatientsthatpatterns of radio-attenuation become close to thoseof the Alzheimer group (Pearlson et al, 1989); sucheffects are also seen in areas containing mainly whitematter (Pearlson et al, 1991).

The link between structural change and impairmentof cognition was examined by Abas et al (1990),who showed that there was a correlation betweenventricle:brainratioon CT and impairmentoncognitivetestsperformedbothwhendepressedandafter recovery.

The reported similarity between Alzheimer-typedementiaand depressionhas not facilitatedeitherthe use of structural scanning in their differentialdiagnosis, or the identification of a particularhemisphere or brain region specifically associatedwith the risk of depression, although one study(Coffey et al, 1993) suggested a small reduction intotal frontal lobe volume in depressive illness.

155

A Single Photon Emission Computerised Tomography Study ofRegional Brain Function in Elderly Patients with Major Depression

and with Alzheimer-Type Dementia

S. M. CURRAN, C. M. MURRAY, M. VAN BECK, N. DOUGALL, R. E. O'CARROLL, M.-P. AUSTIN,K. P. EBMEIER and G. M. GOODWIN

The uptake, at rest, of s9mTc@exametazime into different brain regions was compared usingSPECT for 20 elderly subjects with major depressive disorder, 20 with Alzheimer-type dementia,and30 age-matchednormalvolunteers.Uptakewas referredtocalcarine-occipitalcortexasa reference sensory area. Cross-sectional differences between the three groups were highlystatistically significant, but reflected primarily the reductions in cortical uptake in the Alzheimergroup. A detailed comparison of depressed patients and controls identified decrements inanterior cingulate, temporal and frontal cortex and in caudate and thalamus in men only. Thesedecrements were correlated with impairment of performance on a trail-making task, but werealsoassociatedwithcontinuingtreatmentwithantidepressantsorbenzodiazepines.However,most depressedpatientshadquantitativelynormalscansforposteriorparietalassociationcortex, and this suggests that SPECTmay find a limited role in the differential diagnosis ofdepression and dementia. The reduced brain function in some depressed patients may parallelthe findings from studies of brain structure in elderly depressives; there was a weak associationbetween good outcome at 6—18 months and increased tracer uptake in subcortical areas.

156 CURRAN ET AL

Localisation of structural abnormality may requireboth the better resolution of magnetic resonanceimaging (MRI) and more detailed volumetric analysisthan has been attempted previously (e.g. Coffey etal, 1988;Churchill et al, 1991;Rabins et al, 1991).

The potential for extending the investigation ofbrain function with tomographic methods such aspositron emission tomography (PET) or single photonemission computerised tomography (SPECT) addsa further dimension to studies of depression anddementia. Under normal conditions, regional cerebralblood flow is tightly yoked to regional substratedemand. The lipophilic tracer 99mTc@labelledexametazime (@“Tc-hexamethy1propyleneamineoxime, or HMPAO) is taken up into brain inproportion to regional cerebral blood flow and isthen trapped, giving an estimate of regionalcerebral perfusion and, hence, regional brain function(Neirinckx et al, 1987). These properties make thetracer ideal for SPECT.

In Alzheimer-type dementia, such functionalimaging has shown reduced metabolism and brainblood flow in association cortex, and there is areasonably consistent association between thesechanges and the observed impairments of cognitivefunction (Burns et al, 1989; Hunter et al, 1989;Montaldi et a!, 1990). Furthermore, in individualpatients, reduced function may be quite regionallyspecific while structural scans show only globalchanges. This is most obvious in patients with decrements of parietal and temporal lobe function inAlzheimer's disease. It implies that functional investigation of the brain is more sensitive in detecting thetopography of brain/behaviour relationships than isstructural scanning. However, there have been fewsuch studies in elderly depressed patients. Upadhyayaet al (1990) observed that the uptake of @Tcexametazime in all cortical areas in elderly depressedsubjects was between that seen in demented patientsand normal controls. However, the spatial resolutionof this study was limited and the statistically significantcross-sectional differences appear largely to have arisenfrom the reduced uptake in Alzheimer-type dementia.

The present study compared elderly subjects witheither major depressive disorder or Alzheimer-typedementia with normal volunteers.We did notspecifically seek patients with a clinical diagnosis ofpseudodementia and we excluded those with a historysuggesting premorbid cognitive impairment.

Method

The studywasconductedat the RoyalEdinburghHospitalbetween August 1990 and February 1992, and was approvedby the Ethics of Medical Research Sub-Commitee for

Psychiatryand Psychologyof the Lothian Health Board,and the Administration of Radioactive Substances AdvisoryCommittee of the Department of Health (ARSAC). Allpatients and control subjects gave informed consent. Wherethere was doubt about a patient's understandingof whatthestudyentailed,theagreementofa closerelativewasobtained before the patient was included.

Twenty patients with unipolar depression aged 60 orover were entered in the study. All met DSM—III—Rcriteria (American Psychiatric Association, 1987) for majordepressiveepisode,withorwithoutmelancholicormoodcongruent psychotic features. Exactly half had an onset ofdepressionbefore the age of 60, half after. There was noconcurrent significant medical condition, no history ofneurologicaldisorder, alcohol abuse or other psychiatricdisorder, and no history suggestiveof dementia.

While we attempted to recruit drug-free patients, 11 whohad beenon a stabledoseof antidepressantmedicationfortwo weeksor morewereaccepted.Threeof thesewerealsotaking a benzodiazepine at a dose of 10mg diazepam dailyor less, or its equivalent. One patient not receivingantidepressanttherapywastakingnitrazepam(5mg daily).Theantidepressantsusedweredomipramine(2),lofepramine(2), amitriptyline (2), imipramine (2), fluvoxamine (1),trazodone (1), and doxepin (1). Nine patients receivednon-psychotropicdrugs.We excludedpatientsreceivingneurolepticmedicationand thosewhohad receivedelectroconvulsivetherapy within six months of recruitment.

Severity of depression was rated using the 17-itemHamilton Rating Scale for Depression (HRSD; Hamilton,1960) and the Geriatric Depression Scale (GDS; Yesavageci a!, 1983). The Newcastle Scale (Carney ci a!, 1965) wasalso used.

Twenty patients fulfilling NINCDS-ADRDA (McKhannci a!, 1984) criteria for probable Alzheimer's disease andDSM—III—Rcriteria for dementia were also recruited.Infective,metabolic, nutritional, and hormonal causesoforganic disorder had been excluded, as had functionalpsychiatric disorder. All patients resided at home and receivedpsychiatricsupport from a day hospitalor as out-patients.

Thirtyage-matchednormalcontrolsubjectswererecruitedfrom hospital staff and localvolunteergroups. They werefreeof symptomssuggestiveof physicalor mentaldisorderand none were prescribed psychotropic medication.

Scanning

Subjects were imaged with a single-slice, multidetector,dedicated head scanner (SME Multi-X 810 scanner,Strichman Medical Equipment Ltd) at the MRC BrainMetabolism Unit, Royal Edinburgh Hospital. This hasan intermediate 572-hole collimator, which gives amaximum in-slice resolution of 7.5 mm (at full-width,half-maximum)in slices15mm thick. The sensitivityof theinstrument was measured as 520 counts per second per1 kBq/ml (Ebmeier ci a!, 1991). An indwelling intravenous catheter was inserted into an arm vein 15—30minutes before the injection of 250—500mBq of @“¿�Tcexametazime. Subjects were required to stay silent and liestill on the imagingtable during, and for 5 minutesafter,the injection, with eyes covered with patches and ears

SPECT STUDY OF DEPRESSION IN THE ELDERLY AND DEMENTIA 157

unplugged. Eight of the female controls were injected whilea metronometickedinthebackground,as a controlcondition for another study (Ebmeier cia!, 1992).The slightdifference in environmental conditions had no discernibleeffecton theuptakeoftracer(datanotshown).

Brain images were acquired in slices 10mm apart, parallelto the orbito—meatal(OM)line.Twoslices,approximately4 cm and 6 cm above the OM line, were chosen for analysis(see Austin ei a!, 1992b).

Regionsof interest were drawn from a standard brainatlas (Talairach ei a!, 1988). The outer border of thetemplate was aligned by eye with the outer border of thecortex after the lowest 40% from the image's intensityspectrumhadbeenremoved.Thetemplatecouldbelinearlydeformed in the lateral and anterior/posterior planes, butthe resulting positions of the regions of interest wereautomatic and independent of any apparent landmarkswithin the image. The mean counts in each region of interestwere calculated automatically and used for statistical analysis.

The template for the lower slice identified anteriorcingulate, frontal, superior temporal, middle temporal andposterior cingulate cortex as well as caudate, putamen andthalamus on right and left sides of the brain. Regions ofinterest for the upper slice, drawn on a correspondingtemplate, were anterior cingulate, frontal, parietal andposterior cingulate areas on right and left sides. Eachtemplatealso includeda bilateralreferencearea comprisingoccipital and calcarine cortex.

Uptake of 99―Tc-exametazimeinto each individual regionof interest was expressed as a ratio of uptake in the occipitalarea within the relevant slice. The occipito-calcarine regionwas chosen because it includes the primary sensory areafor vision, input to which was occluded by the subjectswearing eye patches. It is also the area that provides theimmediatecontrast for qualitativeestimatesof decrementsof tracer uptake in posterior temporal or parietal areas usedclinically in the identification of Alzheimer-type dementia;it has been used quantitatively to discriminate patients withAlzheimer-type dementia from controls in other studies.There is no region that is ideal for the purpose ofnormalisation, and we could, for example, have chosen thecerebellum (Syed cia!, 1992).We did not because it is muchmore difficult to draw standard regions of interest forcerebellar sections in advance of fitting the template.Instead, the sections must be drawn individually and areperhaps excessively biased by the apparent anatomy.

Neuropsychological assessment

Neuropsychological assessment was completed within 72hours of scanning. Tests werechosen for their ability to detectevidence of organic impairment. Subjects were administeredthe Cambridge Cognitive Schedule (CAMCOG), whichprovidesa detailedassessmentof cognitivefunction(Rothcia!, 1986).The total CAMCOG score (CAMTOT) and theMini Mental State Examination (MMSE; Folstein ci a!,1975)were used as measures of global cognitive function.The digit symbol substitution test, a subtest from theWechsler Adult Intelligence Scale, Revised (WAIS-R;Wechsler,1981)was selected,sinceit is thought to be one

of the most sensitive of the WAIS-R subtests to organicimpairment (Lezak, 1983). Trail-making tests A and B(Army Individual Test Battery, 1944) were chosen tomeasure attention and psychomotor speed. Trails B, inaddition,teststheabilityto shiftcognitiveset.Somepatients(especiallywith Alzheimer-typedementia) had such difficultycompletingtrail-makingtestB,thatamaximumof5minuteswas allowed. The Wechsler Memory Scale, Revised (WMS-R;Wechsler, 1987),a reliable measure of attention, verbal andvisual memory, and delayed recall, was administered to 15of the 20 depressed patients. The National Adult ReadingTest (NART; Nelson & O'Connell, 1978) provided anestimate of premorbid IQ.

Eighteen of the depressed patients were reassessedat 6—18months —¿�either after full recovery as assessed by theirsupervisingclinician, or two years after the start of the study(a minimum of one-year follow-up), at which time abouthalf remained unwell. One patient had died and one refusedreassessment. CAMCOG, MMSE, digit symbol substitutionand trail-making tests were repeated. Clinical outcome wasassessed at interview, by completion of the HRSD, and byuse of information from the psychiatric case notes and thepatients' doctors. The classification into good outcome(recovered) or poor outcome (relapsed, continuously ill ordeceased) followed Murphy (1983).

Statistical analysis

Neuropsychological test results were analysed across the threecomparison groups using analysis of variance (ANOVA)or covariance (ANCOVA). To investigate the effect ofseverity of depression on cognitive impairment in thedepressed group, Speannan correlation coefficients betweenHRSD and cognitive test scores were calculated.

The scanning data for patients and control groups weresubjected to initial omnibus examination with multivariateanalysis of variance (MANOVA). Regions of interest andlaterality were treated as repeated measure factors. A maineffect was sought for differences between the three groupsand for further interactions of this effect by side, by regionof interest, and by side by region of interest. Groupcomparisons for tracer uptake in each region of interestwere then made with one-way ANOVA and conservativepost-hoc comparisons were made with the Scheffe test. Ourhypothesis was that the Alzheimer group would account formost of the between-group variance for most cortical areas.

The depressed group and controls were subjected tofurther exploratory comparison with MANOVA, in whichthe effect of sex and drug treatment was also examined.A detailed comparison of uptake into individual regionsof interest for depressed patients and controls was madeon unadjusted means with two-tailed i-tests.

Within the depressed sample, the simple main effects ofoutcome and age at onset were also examined and Spearmancorrelation coefficients between uptake ratios in each brainregion and cognitive scores were also calculated. Most ofthese comparisons were planned, but the results reflect theoutcome of many analyses on a finite data set and may havebeen influenced by factors such as drug treatment.Accordingly, the largest effects generate rather than confirmhypotheses. This is the case with most imaging studies

DepressedpatientsPatients

withAlzheimer-typeControlsdementiaSex(M:F)12:88:1210:20Mean

(s.d.) age: years70 (6.3)73.5 (11.6)67.1(6.2)range60-8154-8857-80Mean

(s.d.)years of10.3 (2.3)9.4 (1.0)13.2(3.2)educationMean

(s.d.) socialclass3.2 (1.2)3.4 (1.6)2.5 (0.9)

158 CURRAN ET AL

involving multiple comparisons and represents a necessarycompromise in relatively small studies which demand muchof both resources and patient cooperation.

Results

Table 1 shows the clinical characteristics of the 70 subjects.More controls had higher-status occupations and longereducational experience. This probably reflects the biaspresent in many studies recruiting controls as volunteers.It also has implications for general intelligence.

The sex ratio in the control population was recruited toreflect our expected excess of women in both the depressedand Alzheimer groups. In fact, women were underrepresented in the depressed group and this may have beena source of bias. In our experience, older patients with acutedepressive illness are commonly less able to tolerate therigours of an imaging protocol than are younger subjects.It is our further impression that this is more true for womenthan for men. Therefore, the 20 recruited subjects weremoderately depressed (mean HRSD score = 23.5) but forevery subject who was successfully recruited into the study,at least two others declined or were unable to tolerate theprocedure. An excess of patients were endogenous on thebasis of the Newcastle Scale (14 of 20 had a score of 6 ormore) (mean (s.d.) score was 6.5 (2.6) ). A correlation wasfound between the HRSD and Newcastle scores (Spearmanrho=0.75, P=0.00); the GDS (mean (s.d.) score=22.6(5.6))was not found to correlate with either of the other scalesand will not be used in subsequent analysis.

Table 2 summarises the cognitive function of patientswhen first seen. In view of the differences in age betweenthe groups, and particularly the difference in premorbidintelligence, these variables were entered as covariates ina cross-sectional comparison of cognitive performance onthe MMSE, the CAMCOG, the digit symbol substitutiontest, and trails A and B. Table 2 illustrates that afterallowing for the effects of age and premorbid IQ, there werestill gross differences between the Alzheimer group and thecontrol group. Differences between the depressed group andcontrols were confined to performance on digit symbolsubstitution and part B of the trails test. However, threedepressed subjects scored less than 24 on the MMSE, theconventional cut-off used in dementia screening; none hada clinical history suggestive of progressive dementia.

Table 1Clinical characteristics of subjects

A detailed assessment of memory performance wascompleted in 15 of the depressed patients only. Whencompared with WMS-R population norms (mean index foreach subscale = 100, standard deviation = 15), depressedsubjects were impaired on all indices except visual memory.Mean indices were as follows: verbal memory 89.7; visualmemory 102.3; general memory 93.5; attention and concentration 92.8; delayed recall 94.2.

Scores on the HRSD and cognitive tests were correlatedusing Spearman correlation coefficients. Severity ofdepression was associated with impaired performance onWechsler visual memory (rho = —¿�0.55,P<0.05), Wechslerdelayed recall (rho = —¿�0.59,P<0.05) and the digit symbolsubstitution test (rho = 0.63, P<0.Ol). A weaker associationwas found between HRSD and trail-making test A(rho = 0.36, P= 0.07) and Wechsler general memory(rho = —¿�0.41,P= 0.08). The trail-making test B wasuncorrelated with HRSD score (rho = 0.04).

Uptake of exametazime

The uptake ratios for individual regions of interest,averaged for the three groups, are shown in Table 3. Therewere extensive reductions in uptake in Alzheimer-typedementia compared with both controls and depressedpatients. Conservative contrasts calculated using the Scheffetest highlight that the main differences were confined tothe uptake in the Alzheimer group. The reductions that wereseen for cortical areas in the depressed group were greatestin anterior cingulate areas of the upper slice, and superiortemporal cortex in the lower slice; there were also apparentreductions in the caudate and thalamus. There was noevidence for laterality.

The tracer uptake, in the upper slice for posteriorcingulate, parietal and anterior cingulate regions of the leftbrain, is illustrated patient by patient in ascending orderof magnitude in Fig. 1. The left posterior cingulate appearsto be uniformly affected in Alzheimer-type dementia andunaffected in depressive illness. The left parietal cortex isuniformly affected in dementia but a single depressed casealso falls into the range between the two groups. This wasan 80-year-old woman with a score on the MMSE of 23.However, for the anterior cingulate region, more depressedpatients fall out of the control range and into an intermediateand more nearly Alzheimer-like range (Fig. 1).

A more detailed multivariate comparison of uptake inthe depressed and control groups was made. This showeda trend to differences between patients and controlsaveraged across regions of interest (F= 3.65, d.f. = 1,46,P=0.06) that was markedly present only in men (interactionof main effect by sex, P= 0.003). Unfortunately drugtreatment may also have contributed to the differencesbetween patients and controls, at least in some brainregions. Within the sample of depressed patients there wasa weak average effect of treatment with antidepressants orbenzodiazepines (F= 3.09, d.f. = 1,18, P= 0.096) but therewas a prominent interaction with region of interest(F=2.98, d.f.=l,l1, P=0.001).

For the sake of comparison with other studies, the patternof significant decrements in the unadjusted mean uptakes

1. Socio-economic class was scored according to RegistrarGeneral's classification into social classes 1 to 5.

TestDepressedpatients (D)Patients

withAlzheimer-type

dementia (A)Controls

(C)ANCFOVA' PUnivariate

ANA v. CCOVA:

PD v.CNART

lQ98.4 (13.6)97.1(11.4)115(8.8)18.620.0002MMSE26.6(2.8)16.5(5.1)28.6(1.3)32.00.0000.000NSCAMTOT90

(12.2)58(15.5)100(3.0)32.30.0000.000NSDigitsymbol

Trails A: s8.0(2.8)

83 (54)4.5(2.6)

127 (67)@11.9 38(2.3)(11)9.6 3.580.000 0.0400.003 0.0050.03NSTrailsB: s207 (76)275 (56)@84(37)10.450.0000.0000.001

BrainregionDepressed patients(D)Patients

withAlzheimer-typedementia(A)Controls

(C)FPScheffetestLower

sliceRightanteriorcingulate0.96 (0.12)0.82 (0.16)0.96 (0.09)10.010.000A<C,DLeft

anterior cingulate0.94(0.11)0.79 (0.15)0.95 (0.09)14.20.000A<C,DRightfrontal0.92 (0.08)0.87 (0.09)0.93(0.06)3.920.03A<CLeft

frontal0.91 (0.10)0.85 (0.10)0.94(0.07)6.640.002A<CRightsuperior temporal0.95 (0.09)0.90 (0.10)1.00(0.08)7.830.001A<CLeft

superiortemporal0.93 (0.10)0.86 (0.07)0.97 (0.07)12.560.000A<C,DRightmid-temporal1.03 (0.06)0.94 (0.09)1.02 (0.05)10.590.000A<C,DLeft

mid-temporal1.00 (0.07)0.90 (0.09)1.00 (0.06)13.690.000A<C,DRightposterior cingulate0.82 (0.12)0.86 (0.15)0.81(0.14)0.75NSLeft

posteriorcingulate0.78 (0.10)0.79 (0.11)0.78(0.10)0.17NSUpper

sliceRightanteriorcingulate0.98 (0.12)0.86 (0.15)1.03 (0.08)13.730.000A<C,DLeftantenorcingulate0.95

(0.12)0.85 (0.16)1.02(0.08)12.50.000A<C,DRightfrontal0.91 (0.07)0.87 (0.08)0.94(0.06)8.360.001A<CLeftfrontal0.93 (0.05)0.86 (0.08)0.94(0.05)7.470.001A<CRight

parietal0.95 (0.06)0.90 (0.07)0.97 (0.05)9.800.000A<C,DLeftparietal0.94 (0.07)0.87 (0.07)0.95 (0.05)11.670.000A<C,DRight

posterior cingulate1.15 (0.10)1.07 (0.08)1.15 (0.07)8.210.001A'rzC,DLeftposterior cingulate1.16 (0.06)1.04 (0.08)1.17 (0.06)23.370.000A<C,DSubcortica/Right

caudate0.78 (0.12)0.69 (0.16)0.90 (0.11)17.200.000A,D<CLeftcaudate0.82 (0.17)0.73 (0.14)0.88(0.13)6.440.003A<CRight

putamen1.00 (0.06)0.98 (0.09)1.01(0.09)1.05NSLeftputamen1.03 (0.07)1.00 (0.10)1.02(0.09)0.75NSRightthalamus0.90 (0.11)0.85 (0.14)0.98 (0.09)8.740.000A,D<CLeft

thalamus0.92 (0.09)0.89 (0.11)0.98 (0.09)6.210.003A<C

SPECT STUDY OF DEPRESSION IN THE ELDERLY AND DEMENTIA 159

Table 2Means (s.d.) of scores on cognitive tests

Lower scores indicate poorer performance for all tests except trail-making tests A and B, where the opposite applies.1. Entering age and premorbid IQ as covariates.2. ANOVA results for NARTIQ.3. Mean (s.d.) for the nine patients who completed the test. Most patients could not adequately perform it at all.

for men is shown in Fig. 2. There were no corresponding The outcome of patients in the depressed samplereductions among depressed women. Figure 2 also shows

At follow-up, nine depressed patients had made a completethe pattern of significant correlations between tracer uptake clinical recovery and were unequivocally classed as showingand trails B performance among the men. The two patterns

a good outcome. One had died, two had remained depressedlargely overlap.

Table 3Mean (s.d.) 9emTc@exametazimeuptake for each region of interest in lower and upper slices and subcortical regions

Groups compared for each region of interest using the one-way ANOVA with post-hoc Scheffe comparisons.

160 CURRAN ET AL

L.ftR@d

Correlation with traits B

Parietalcortex

A6

A@_____

0 Posteriorcingulate

Fig. 2 The relationship between decrements in the uptake ofw@0@Tc@exametazimein depressed male patients and male controls(upper) and correlations between tracer uptake and trail-makingtest B (lower) in same male patients. Uptake was expressed relativeto posterior visual sensory areas (shown filled). Decrements and correlations (allnegative)areshown byshadingand stipplingrespectivelyof regions of interest in which reductions were individually statistically significant (P<0.05). The brain regions are reproduced asthey appear in the templates fitted to scan data. The relationshiptoastandardbrainatlasisshowninFig.1ofAustinciaI(1992b).

20 on the MMSE when ill and 23, 27 and 24 at follow-up.Thus, none of the three showed clinical evidence of globalcognitive decline.

The effects of age at onset of depressive illness

There were no differences between patients with onset offirst illness under 60 years (mean (s.d.) 43(11)) and those withonset over 60 years (mean (s.d.) 68(7))in current age, sexratio, NART IQ, or scores on the HRSD, Newcastle scale,CAMCOG, or MMSE. The late-onset patients had slightlyimpaired performance on the digit symbol substitution test(6.6(2.1) v. 9.2(2.9); P=0.05) and trails A (54s(23) v.108 s(62); P= 0.03) but not significantly on trails B (188(69)v. 225(82); P=0.30).

There was no significant omnibus effect for age at onsetdetected upon tracer uptake ratios (F= 0.19, d.f. = 1,16,P= 0.67). Differences for individual regions were thereforenot sought.

Discussion

Fig. I The ratio between uptake of @“¿�Tc-exametazimeinto threebrain areas (shown filled) and the occipito-calcarine region(reference sensory area) (shown hatched) with respective scatter diagrams for the controls ( 0 ), depressed patients (•)and Alzheimerpatients with Alzheimer-type dementia (@ ). The data for eachgroup are plotted by ascending magnitude across the sample.

virtually from the time of the original study, and eightcontinued to describe symptoms of anxiety or depression,but did not meet criteria for a major depressive episode.One subject at follow-up was mildly hypomanic and hadhad recurrent but brief episodes of depression since theoriginal episode. Poor outcome was thus defined bypersisting affective symptoms. At original presentation,there were no important differences between depressedpatients with a good outcome and those with a pooroutcome, although the former had slightly higher HRSDscores and were slightly more endogenous (Table 4). Thisdid not reach statistical significance and they were notsignificantly different on any of the measures of cognitivefunction. At follow-up, patients with a good outcome hadimproved on the DSST, trails A and trails B, while thepatients who remained depressed had not.

Good outcome was weakly associated with increaseduptake in a number of brain areas. Multivariate comparisonsuggested an interaction by side (F=6.7, d.f. = 1,18,P= 0.02). This corresponded to statistically significantdifferences shown by unpaired i-tests in the thalamus(bilaterally), in the right posterior cingulate cortex in bothslices, the right parietal cortex in the upper slice, and rightcaudate (all greater in patients with a good outcome).

All three patients who scored less than 24 on the MMSEwhen first seen had a good outcome. Scores were 23,23 and

Much the most impressive differences were betweenthe patients with Alzheimer-type dementia and the

S... @AA

1.1

0

@ 0.9a

0.7

Anterior cingutate

10

0

@ 0.9a,

0.8

+4cm +6cm

1.3

1.2.9Co

@ 1.1to

D 10

Goodoutcome(n=9)Poor outcome (n=11)Initial

assessmentFollow-upPInitialassessmentFollow-upPAge:

yearsHRSDscoreNewcastlescoreMMSEscoreCAMTOTDigitsymbolscoreTrailsATrailsB68

287

2691

6.986

219(6.7)

(7.3)(2.5)(2.4)(9.3)(1.6)

(61)(63)-

0.5 (0.5)-

27 (2.2)92 (4.2)8.9 (1.7)

57 (44)158 (65)—

-

-

NSNS

0.0040.050.00171

(5.9)20 (6.8)

6 (2.6)

27 (3.1)90 (15)

9 (3.4)80 (51)

199 (86)-

9.7 (10)

-

27 (2.7)92 (8.0)8.9 (1.8)

59 (16)194 (85)-

-

-

NSNSNSNSNS

SPECT STUDY OF DEPRESSION IN THE ELDERLY AND DEMENTIA 161

Table 4Mean (s.d.) results at follow-up of the 20 depressed patients

control and depressed groups. Therefore, in contrast with some findings from structural scanning,depressed patients were more like controls thanpatients with Alzheimer-type dementia in theirpattern of uptake of the blood-flow marker @°“Tcexametazime. Normal tracer uptake in depressedpatients was most striking in posterior cortical areassuch as parietal association cortex (except for onepatient), which appear especially vulnerable to theeffects of Alzheimer-type dementia. In contrast,other areas, particularly anterior cingulate, frontaland temporal regions, uptake in a significant numberof depressed patients appeared to be between thatin the Alzheimer and control groups. The finding offrontal decrements echoes the findings of most ofthe published deoxyglucose PET studies in youngerpatients (Buchsbaum et a!, 1986; Post et a!, 1987;Baxter et a!, 1989). The results are also virtuallyidentical to a 1502 PET study of relatively old,predominantly male, and notably cognitively impaireddepressed patients described by Bench et a! (1992)(and again by Dolan et a!, 1992). Reduced frontalcerebral function may therefore form an importantcomponent of depression in the elderly, directlyreflected in reduced performance on the trail-makingtest (Fig. 2). However, this conclusion can only bedrawn with qualifications in relation to the effectsof current drug treatment, the apparent effects ofgender, the relationship with structural cerebralchange, and the extent to which the effect is areversible state marker of depression.

The problem of drug treatment may be critical inthe elderly or cognitively impaired, and we cannotexclude a contribution from this source in our data.The effect could have arisen by chance or becausepatients more likely to show anterior brain deficitsare also more likely to be already on drug treatment.However, in the worst case, it may explain the wholeeffect in patients compared with drug-free controls.A number of previous findings are against the latterinterpretation. Drug effects did not appear to explain

the magnitude of cortical decrements in a youngerdepressed group studied identically (Austin et a!,1992b) or in an older depressed group with comparable frontal changes (Bench et a!, 1992). Thesestudies appear to exclude an important contributionfrom antidepressants, but a further particular concernis the use of benzodiazepines; at present, the evidencein young controls and in patients with generalisedanxiety does not explain the effects described here(Mathew eta!, 1985; Wu eta!, 1991). However, drugtreatment or its recent withdrawal will continue topose problems for this sort of work.

The only previous SPECT study in the elderly(Upadhyaya eta!, 1990)used a different normalisationprocedure (to cerebellum) and, although depressedpatients were not statistically distinguishable fromnormal controls, there appeared to be modestreductions in tracer uptake in all cortical areas,including the occipito-calcarine. Such differences arelikely to reflect cortical atrophy and will be lesslocalising to individual cortical regions. Interpretationof the ratio of tracer uptake in cortical structuresrelative to cerebellum is ambiguous if, as somestudies suggest (e.g. Gemmell et a!, 1990), cerebellarperfusion is independently variable between subjectsrather than a physiological constant.

It is notable that the largest effects we saw wereconfined to men. Selection may have played a partin preventing detection of decrements in the women,since those who were included were likely to have beenless ill than those who could not be. On the otherhand, the marked impairments in men may reflect areal difference between the sexes, since a CT study ofdepressed patients reported ventricular enlargementto be most likely in men over 40 (Dolan eta!, 1985).

The relationship between depression and cognitiveimpairment

Elderly patients with depression are likely to showimpairment of cognition due to both the depression

162 CURRAN ET AL

and any pre-existing decline in intellectual performance. Our subjects showed significant impairment in performing digit symbol substitution, thetrail-making tests, and a memory battery. However,they did not show statistically discernible differencesfrom controls on either the MMSE or the CAMCOG.The latter are less sensitive tests of cognitive function,but they are more robust indications of dementia.Thus, depressive illness appears likely to have beenthe major determinant of the impairments in ourpatients. Indeed, a study in a younger group ofdepressed patients (Austin et a!, 1992a) showedeffects on memory and psychomotor speed similarto those seen in the present study. As in the youngerpatients, impairment on memory tests and the digitsymbol substitution test was correlated with theseverity of depression in our depressed group. Thiswould not be expected if cognitive function hadbeen largely determined by premorbid, persistingcognitive impairment.

However, the gradient of pre-existing cognitivedecline is likely to be variable across any sample ofelderly depressed patients. Deliberate selection ofpatients with ‘¿�pseudodementia'is likely to magnifythe apparent contribution from organic factors (e.g.Pearlson et a!, 1989; Dolan et a!, 1992; Bench et a!,1992); excluding patients with evidence of premorbiddecline as we have done will enhance the contributionfrom changes related to the state of depression butwill not eliminate a contribution from premorbidimpairment. Such subclinical impairment is still likely

to be present in some patients if it contributes to therisk of depression in the first place, and mustdetermine the performance of some patients whendepressed (see below).

The relationship with structural scanning in elderlydepressed patients

The association of reduced frontal function withdepression in our elderly male patients appears toconfirm studies of the psychiatric consequences ofboth cerebrovascular lesions and tumours in the samearea (Ross & Rush, 1981). It may also be related toreports of abnormal cortical structure in depression.Although these have not been confined to frontalareas (see Introduction), a more precise volumetricstudy has suggested a selective reduction of frontallobe volume in depression (Coffey et a!, 1993).However, the pathology that most commonly underlies the structural changes in the elderly is notestablished. Indeed, it may be far from homogeneousand could be variously a consequence of that seenin Alzheimer-type dementia, vascular disease, or dueto poorly understood subcortical changes. Reports of

subcortical structural abnormalities in depression areproliferating from MRI studies, in which both illdefined lesions and gross atrophy are described inbasal nuclei, the cerebellum and even the brain stem(Coffey et a!, 1988; Dupont et a!, 1990; Shah et a!,1992; Coffey et a!, 1993). Functional decrementsmay therefore be due to effective deafferentationfollowing the interruption of loops to and fromsubcortical structures. Indeed, we observed reductionsin the caudate nuclei and thalamus in men, althoughthe caudate in particular is likely to have been subjectto errors due to ventricular enlargement (see below).Finally, a more specific temporal lobe involvementhas been implicated by preliminary MRI and PETstudies in younger bipolar patients (Post eta!, 1987;Altshuler et a!, 1991) and the reductions in menshown here may prove significant.

There are advantages and disadvantages in usinga standard anatomical template for quantifying aregional distribution of tracer. The main disadvantageis the misfit to subcortical structures likely in thepresence of ventricular enlargement. In particular,widening of the intercaudate distance will havecontributed to the differences in caudate uptake seenin both the Alzheimer and the depressed groups. Itmay also be objected that cerebral atrophy, byreducing brain volume, may account for reductionsin tracer uptake (Herscovitch et a!, 1986). Thisimplies that the appropriate denominator for meantracer density is a CT or MRI determination of brainvolume. However, the choice of denominator willdepend upon the question being asked. The meanuptake of @‘¿�@Tc-exametazimeinto an expected regionof interest can reflect either structural or functionallesions, and at this stage in the development of ourunderstanding both are of interest. In Alzheimer-typedementia, both neuropsychological function and,one may propose, brain perfusion are likely to bemost closely related to the density of intact synapticterminals (Terry et a!, 1991).

The relationship between uptake of tracer andcognitive function in depressed patients

Within the male patient group, but not in femalepatients or controls, there was a pattern of associations between the reduced uptake of tracer in frontalregions and lengthening of time taken to completethe trails B test. This is comparable with the findingsof Bench et a! (1992), who also studied predominantlymen and included a subgroup of patients withclinically defined pseudodementia. In principle, thiswithin-group pattern helps to validate the pattern ofdifferences seen between patients and controls;however, the contribution to the effect from drug

SPECT STUDYOF DEPRESSIONIN THE ELDERLY AND DEMENTIA 163

treatment is a concern. It is possible that elderlydepressed patients are unusually sensitive to the corticalactionsofbenzodiazepinesand antidepressants,but thiswillrequirefurtherwork to establish.

The absence of an association between the severityof depression and performance on the trails B testin our group may imply that this cognitive deficitwas heavily influenced by premorbid impairment.The worsening of trails B performance in youngerpatients was not associated with anterior corticaldecrements (Austin et a!, l992b). This implies thatthe relationship between tracer uptake and mentalstate may well be dominated by premorbid cognitivedecline, which may necessarily imply premorbidorganic change. This is most likely to be the case ifthe patient sample deliberately includes an excess ofpatients with severe cognitive impairment (clinicalpseudodementia). That it also may apply within aclinically undemented sample underlines the fact thatorganic impairment may be a relatively common subclinical accompaniment of depression in the elderly.

The relationship between @mTc@exametazimeuptake and depressive symptoms has already beenshown to be a complicated one (Austin eta!, 1992b).In younger patients, PET studies using 1502haveactually shown increases in left frontal uptake indepressed patients compared with controls (Drevetset a!, 1992), a finding which has echoes of thecontradictory positive association between traceruptake and endogenicity described by Austin et a!(1992b). The contrasting decreases in the samecortical areas described by Bench et a! (1992) aresimilar to the changes seen here in men. The closeparallel between cognitive impairment and tracerdecrements has already been discussed; it may reflectpremorbid impairment rather than the currentreversible state of depression. Further discussion ofthis problem and indeed its relationship to the presentfindings is beyond the scope of the present paper andwill be pursued elsewhere (in preparation).

The relationship of tracer uptake to onset of illnessand immediate outcome

The association of late onset of illness with greaterevidence of structural brain abnormality (Alexopouloseta!, 1992) was not paralleled by the SPECT findingsin this study. There was, however, preliminary evidenceof better outcome in patients with higher traceruptake in subcortical areas and in right parietal andposterior cingulate cortex. Outcome overall was notvery good and reflected that previously reported forelderly depressed patients (Murphy, 1983). Cognitivefunction improved in those patients whose depressionresolved, but the sample was too small for us to

comment on the extent to which cognitive functionnormalised. Further investigation of the relationshipbetween treatment response and SPECT or structuralscan parameters will be of considerable interest.

Conclusions

Where uptake of @“¿�Tc-exametazimeis normal insevere depression in the elderly, this may help toexclude dementia. How this information would bebest used clinically is going to depend upon how theuse of SPECT in dementia itself develops. The potential for combining information from CT or MRI withSPECT data to produce a more sensitive index ofcerebral dysfunction is likely to assume increasingimportance (e.g. Jobst et a!, 1992). Some cognitiveimpairment is a feature of depressive illness inpatients of all ages, and does not itself predictappearances on SPECT like those seen in Alzheimertype dementia. Conversely, where a pattern likeAlzheimer-type dementia is seen, this is unlikely tobe a simple and reversible consequence of beingdepressed. These findings make a preliminary contribution to establishing the value of SPECT in thedifferential diagnosis of dementia.

The results also highlight the importance of patientselection in reaching a balanced view of the relationship between cognitive impairment, regional braindysfunction, and depression. It is an inherent sourceof confusion that cognitive impairment is both acause and a consequence of depression in the elderly.

Acknowledgements

We thank the Gordon Small Trust and the Weilcome Trust for theirgenerous support, and Norma Brearley for the careful preparationof the manuscript.

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S. M. Curran, MBChB,MRCPsych,Senior Registrar in Psychiatry of Old Age; C. M. Murray, RON, RMN,RM, Research Nurse; M. Van Beck, RMN, FPCC,Research Nurse; N. Dougall, BSc, Medical PhysicsTechnician; R. E. Carroll, BSc,PhD,Clinical Scientist; M-P. Austin, MBBS,FRANZCP,Scottish HealthEndowment Research Trust Fellow; K. P. Ebmeier, GerMedStateExam, MRCPsych,Clinical Scientist andHonorary Consultant Psychiatrist; @G,M. Goodwin, DPhil,MRCPsych,Clinical Scientist and HonoraryConsultant Psychiatrist, MRC Brain Metabolism Unit, Royal Edinburgh Hospital, Morningside Park,Edinburgh EHJO SHF

*Correspondence