disease: the role of hippocampal atrophy as shown with MRI

50ournal ofNeurology, Neurosurgery, and Psychiatry 1995;58:590-597

Memory disorders in probable Alzheimer'sdisease: the role of hippocampal atrophy as shownwith MRI

Bernard Deweer, Stephane Lehericy, Bernard Pillon, Michel Baulac, Jacques Chiras,Claude Marsault, Yves Agid, Bruno Dubois

AbstractMagnetic resonance based volumetricmeasures of hippocampal formation,amygdala (A), caudate nucleus (CN),normalised for total intracranial volume(TIV), were analysed in relation to mea-sures of cognitive deterioration and spe-cific features of memory functions in 18patients with probable Alzheimer's dis-ease. Neuropsychological examinationincluded the mini mental state examina-tion (MMSE), the Mattis dementia ratingscale (DRS), tests of executive functions,assessment of language abilities andpraxis, the Wechsler memory scale(WMS), the California verbal learningtest (CVLT) and the Grober and Buschketest. The volume of the hippocampal for-mation (HFITIV) was correlated withspecific memory variables: memory quo-tient and paired associates of the WMS;intrusions for the CVLT; delayed recall,intrusions and discriminability at recog-nition for the Grober and Buschke test.By contrast, except for intrusions, nocorrelations were found between memoryvariables and the volume of amygdala(AITIV). No correlations were foundbetween the volume of caudate nuclei(CNITIV) and any neuropsychologicalscore. The volume of the hippocampalformation was therefore selectivelyrelated to quantitative and qualitativeaspects of memory performance inpatients with probable Alzheimer's dis-ease.

(C Neurol Neurosurg Psychiatry 1995;58:590-597)

Keywords: Alzheimer's disease; memory; magneticresonance imaging; amygdala; hippocampal formation

Recent developments in quantitative MRIhave provided a new impetus for anatomo-clinical correlations in living patients, and par-ticularly in patients with probable Alzheimer'sdisease. Until recently, such correlations weregenerally searched for with postmortemnecropsy data and emphasised that severe his-tological changes were invariably encounteredin neocortical areas, particularly in the hip-pocampal formation and entorhinal cortex,'-3structures related to memory functions.45 Inmost cases, however, several months sepa-rated the last neuropsychological examination

from the search for anatomical correlates ofcognitive deficits, thereby limiting the inter-pretations, at least for the early memorychanges that characterise most patients withprobable Alzheimer's disease.More direct correlations between volumet-

ric measures of temporal lobe structures andindices of cognitive functioning have beenshown in diverse populations such as patientswith temporal lobe epilepsy,6 patients withdiencephalic and temporal lobe amnesia,7 ornormal elderly subjects.8 In normal aging,positive correlations have been found betweenthe volume of the hippocampal formation andseveral measures of learning derived from theRey auditory verbal learning test and theBuschke selective reminding test.

Recent studies have also reported signifi-cant relations between MRI measurements oftemporal lobe structures and psychometricperformances in patients with probableAlzheimer's disease: correlations between thevolume of amygdala and the mini mental stateexamination (MMSE) score9; between thevolume of the hippocampal formation and ashort test of mental status, the full scale IQ,the verbal IQ, and the performanceIQI';between the volumes of the hippocampalformation and the parahippocampal gyrus andthe MMSE score and, to a lesser degree, per-formance on olfactory tests"; between medialtemporal lobe atrophy, evaluated semiquanti-tatively, and the delayed recall in object mem-ory evaluation and the MMSE score.'2The aim of the present study was to further

assess the relations between MRI based volu-metric measures of temporal lobe structures(hippocampal formation and amygdala) com-pared with caudate nuclei, and (a) variousindices of global intellectual functioning, and(b) quantitative and qualitative aspects ofexplicit memory." The prediction was thatthe volume of the hippocampus should bepreferentially related to mnemonic perfor-mances; this would provide further clues con-cerning the contribution of the hippocampalformation to memory functions.

Patients and methodsPATIENTSThe study comprised 18 patients with probableAlzheimer's disease (mean age 72-4 (SD1 5) years). Patients were recruited at thememory clinic of the Hopital de la Salpetriere,where they were submitted to neurological,

Departments ofNeurology andNeuropsychologyY AgidB DeweerB DuboisS LehericyB PillonDepartment ofNeuroanatomyS LehericyDepartment ofNeuroradiology,INSERM U289,Hopital de la Pitie-Salpetriere, 47 Bd del'Hopital, 75013 Paris,FranceM BaulacCorrespondence to:Dr Bernard Deweer, InsermU289, Batiment NouvellePharnacie, H6pital de laSalpetriere, 47 Bd del'Hopital, 75013 Paris,France.Received 14 March 1994and in final revised form 12April 1994Accepted5 January 1995

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Memory disorders in probable Alzheimer's disease: the role ofhippocampal atrophy as shown with MRI

neuropsychological, and psychiatric examina-tion before inclusion. All patients had normalneurological examination and serum analyses,and fulfilled the NINCDS-ADRDA14 and theDSM 3-R'5 criteria. The ischaemic score'6was not higher than four in any patient, andnone of them had clinical evidence of strokesor cortical infarcts on T2 weighted MRI. Thepatients were in the mild to moderate stagesof the disease (see MMSE scores, table 1),and the mean duration of the disease was 2-4(0-3) years. Magnetic resonance imagingstudies were performed in the same week asthe neuropsychological evaluation. Patientsand families were informed of the project andasked for their willingness to participate to theneuropsychological and MRI study.

NEUROPSYCHOLOGICAL ASSESSMENTIntellectualfunctions (table 1)Patients with probable Alzheimer's diseasewere submitted to the MMSE,'7 the Mattisdementia rating scale (DRS),'8 and the Ravencoloured progressive matrices (PM 47). Testsof executive functions included the simplifiedversion of the Wisconsin card sorting test(WCST),'9 verbal fluency tests (names of ani-mals in one minute, and names beginningwith "M" in one minute),20 and a graphicseries.2' Behavioural abnormalities (prehen-sion, imitation, utilisation behaviours, inertia,indifference), seen in patients with frontallesions,22 were also assessed. A "frontalscore"23 was defined on the basis of the perfor-

Table I Psychometric performance ofpatients withprobable Alzheimer's disease

Test Mean (SEM) Range

MMSE (/30) 22-3 (0-9) 13-27Mattis DRS (/144) 112-7 (3-5) 67-131

Initiation (/37) 28-7 (1-6) 15-37Memory (/25) 13-8 (1-0) 4-21

PM47 20-5 (1-7) 3-29Frontal score (/60) 37-3 (3-0) 16-58WCST (categories, /6) 3-1 (0 5) 0-6Naming (/20) 13-2 (1-1) 3-20Vocabulary (/70) 37-9 (2 6) 19-62

Table 2 Performance ofpatients with probableAlzheimer's disease on memory tests

Test Mean (SEM) Range

WMS 82-0 (2 4) 65-99Logical memory 4-3 (0-5) 0-8Paired associates 6-8 (0 7) 0-12Drawings 2-8 (0 5) 0-7

California verbal learning test:Total learning (/80) 23-6 (1 9) 6-40Delayed free recall (/16) 1-05 (0 3) 0-4Delayed cued recall (/16) 3-82 (0 5) 0-8Intrusions (number) 17-3 (2 7) 2-47Intrusions (% total) 32-3 (3 6) 11-65Discriminability

(recognition; %) 71-7 (3 4) 41-95

Grober and Buschke test:Short term free recall (/48) 8-7 (1-5) 0-26Short term total recall (/48) 25-6 (2-0) 10-41Delayed free recall (/16) 2-2 (0 6) 0-9Delayed total recall (/16) 8-1 (0-8) 2-13Intrusions (number) 9-3 (2-3) 1-36Intrusions (% total) 27-0 (5-7) 4-78Discriminability

(recognition; %) 86-4 (2-7) 66-100

mance at these tasks. Linguistic tests includedthe vocabulary subtest of the WAIS-R and anaming task (20 pictures from the Bostonnaming test, across all levels of difficulty).Depression was evaluated with both an inter-view by a psychiatrist and the Montgomery andAsberg depression rating scale (MADRS).24None of the patients was depressed accordingto the DSM 3-R criteria, and all scores werebelow 20 out of 60, ranging from 4 to 18 witha mean of 8-3.

Memory testsAll patients were evaluated by the Wechslermemory scale (WMS) with delayed recall forlogical memory, drawings, and paired associ-ates. As well as the WMS, all patients weregiven two additional memory tests: theCalifornia verbal learning test (CVLT,1987)25 and the Grober and Buschke test(1987).26 The first given was the CVLT, inwhich the retention of a 16 item shopping listwas measured by free recall after (a) each offive learning trials, and (b) after one trial withan interfering list, both immediately and after a20 minute delay. The items in both listsbelonged to precise semantic categories,which allowed quantitative assessment oflearning strategies. Comparisons of free recall,cued recall, recognition, and variables such asextra list intrusions or accuracy of recognition(corresponding to the discriminability in table2) were also analysed.27 Such an index (dis-criminability)27 takes into account both missesand false positives.On a different testing session, subjects were

given the Grober and Buschke test with con-trolled encoding and selective reminding.26 Inthis task, the 16 items to be learned are pre-sented to the patient on four different cards,one card with four items at a time. Thepatient is asked to point to and read aloudeach item (for example, grapes) when its cate-gory cue is verbally provided (for example,fruit). When all four items of a card are cor-rectly named, the card is removed and imme-diate verbal cued recall is tested, in the order ofidentification, by providing each category cue(for example, which is the fruit?). If thepatient is unable to recall an item in responseto its cue, the pointing and naming procedureis performed again for this item, and cuedrecall is tested again until a correct answer isobtained. Once immediate cued recall for agroup of four items is completed, the next setof items is presented. The learning phase ofthe 16 items is followed by 20 seconds ofcounting backwards to obtain recall from sec-ondary memory. Each of the three recall trialsconsists of an extended period of free recall(up to two minutes) immediately followed bycued recall for those items not retrieved at freerecall. Items missed at cued recall arereminded by the examiner and repeated bythe patient. Total recall is defined as the sumof free and cued recall and would provide thebest estimate of the amount of informationeach patient is able to encode and retrieve(maximum score for the sum of three trials =48). In our adaptation of the procedure we

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Deweer, Lehericy, Pillon, Baulac, Chiras, Marsault, Agid, Dubois

Figure 1 Definition of the oblique coronal plane perpendicular to the long axis of thehippocampalformation (parasagittal view). A = amygdala; HF = hippocampalformation.

used printed words, rather than labelled pic-tures and we included one delayed free andcued recall after 15 minutes. The yes-no

recognition from semantically related andunrelated foils took place only after delayedrecall. In the same way as the CVLT, intru-sions and accuracy of recognition were alsoanalysed.

VOLUMETRIC MEASUREMENTSMagnetic resonance images were analysedwith an image analysis system (HISTO-RAG,BIOCOM, France). The software employs a

semiautomated technique combining tracingand thresholding.28 Quantitative volume esti-mates of the hippocampal formation, theamygdala, the caudate nucleus and the ventri-cles (consisting of the lateral plus the thirdventricles) were obtained on the Ti weightedcoronal oblique images providing high greyand white matter and brain and CSF contrast.Images were contiguous. Regions of interestthat presented high grey scale contrast (brain-CSF interface) were defined by a grey scalethreshold (ventricular volume). Regions ofinterest that did not present a grey scale con-

trast high enough to allow thresholding were

manually traced with a mouse driven cursor

(hippocampal formation, amygdala, and cau-

date nucleus). The surface areas of all regionsof interest were automatically calculated andthe volume of each structure was derived bymultiplying that value by the interslice dis-tance. Delineation of regions of interest andvolume measurements were performed by an

operator (SL) unaware of the clinical diagno-sis. Within rater reliability was estimated forhippocampal formation and amygdala mea-

surements by measuring these structures 10times in one control and one patient withprobable Alzheimer's disease. Coefficients ofvariation (coefficient of variation = SD/mean)

were estimated at 2-8% and 2-3% for hip-pocampal formation and amygdala measure-ments respectively.Volumes were adjusted for total intracra-

nial volume. Total intracranial volume wasevaluated by tracing the outline of the innertable on every sagittal image from side to sideof the head, multiplying each surface obtainedby interslice distance (8-5 mm) and adding allthe slices up (coronal Ti weighted imageswere not used to estimate total intracranialvolume because this sequence did not spanthe whole brain as it did in the sagittal plane).Within rater reliability for measurements oftotal intracranial volume was estimated bymeasuring total intracranial volume (TIV) 10times in one subject. The coefficient of varia-tion was estimated at 0-8%. Values of eachstructure were normalised for between subjectvariation in head size by dividing each valueobtained by the patient's total intracranial vol-ume. This method has already been used inprevious MR studies.29 Thus HF/TIV, A/TIV,and CN/TIV are ratios expressing the mean ofthe left and right sides of hippocampal forma-tion, amygdala, and caudate nucleus, respec-tively divided by the total intracranial volumefor each patient. V/TIV is a ratio expressingthe volume of the lateral ventricles plus thethird ventricle as a percentage of totalintracranial volume for each patient.

Hippocampalformation, amygdala, and caudatenucleus boundariesA previous study has shown that the main fac-tor of accuracy of volumetric measurements,by tracing or thresholding, seems to be thereliability of within rater measurements.These mostly depend on the rater's detailedknowledge of the anatomy and the repro-ducibility of the boundaries of the structuresmeasured.'0 Precise and reproducible delin-eation of the boundaries of the different struc-tures measured have been based oncomparison with histological sectionsobtained in the same oblique coronal planeas the MR images,28 on neuroanatomyatlases,31-33 and on previous reports of volu-metric MR analysis.29 30 Boundaries of the hip-pocampal formations and the amygdala weredrawn on coronal MR images perpendicularto the long axis of the hippocampus (fig 1).The MR-histological correlations have beenreported previously.28 Measurements of thehippocampal formations at the level of thebody of the structure (about four to five sec-tions spanning a rostrocaudal extent of about3 cm) were generally easy (fig 2A). Thesemeasurements included Ammon's horn, thesubiculum, the dentate gyrus, and the whitematter tracts of the alveus and the fimbria.The limit between the subiculum and theparahippocampal gyrus was arbitrarily definedby a line in continuation with the inferiorborder of the subiculum. Caudally, the poste-rior boundary of the hippocampal formationwas chosen as the last section containingAmmon's horn, which corresponded to thesection where the crus of the fornix was visible.Measurements at this level (one section)

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Figure 2 (A) Coronal oblique MRI of the righthippocampalformation in a control brain. Boundaries ofthe hi,ppocampalformation are outlined with white dots. 1= Ammon 's horn; 2 = subiculum; 3 = parahippocampalgyrus; 4 = transverse (choroid) fissure; 5 = temporal horn;6 = collateral sulcus. (B) Coronal oblique MRI of thehead of the right hippocampalformation (white dots) andposterior part of the amygdala (black dots) in a controlbrain. 1 = Ammon 's horn; 2 = subiculum; 3 =parahippocampal gyrus; 4 = amygdala; 5 = hippocampaldigitations; 6 = uncal recess of the lateral ventricle; 7 =optic tract. (C) Coronal oblique MRI of the head of theright hippocamnpalformation (white dots) and amygdala(black dots) at a more rostral level in one control brain.1 = Ammon's horn; 2 = amygdala; 3 = semilunar gyrus;4 = gyrus ambiens; 5 = parahippocampal gyrus;6 = endorhinal sulcus; 7 = collateral sulcus; 8 = uncalrecess of the lateral ventricle; 9 = uncal notch (scale bar =1 cm).

included the subiculum, the hippocampalformation, the dentate gyrus, the alveus, andthe fimbria, and excluded the parahippocam-pal gyrus and the isthmus of the cingulategyms. Rostrally, the head of the hippocampalformation within the posterior part of theuncus was delineated from both the amygdalaand the parahippocampal gyrus (about twosections). This delineation was guided byvisualising either the characteristic shape ofthe hippocampal digitations and the uncalrecess of inferior horn of the lateral ventricle(fig 2B) or the band of high signal intensitygenerated by the alveus, which demarcatedthe hippocampal head from the overlyingamygdala. When neither the digitations andthe uncal recess of the lateral ventricle nor thealveus were visible, the limit was arbitrarilydrawn as a horizontal line connecting themiddle of the medial border of the lateral ven-tricle to the surface of the uncus (fig 2G).This limit was chosen after careful compari-son with histological sections. The subiculumof the uncinate gyrus was part of the measure-ments. Amygdala measurements (three tofour sections) included the corticomedial,central, and basolateral subgroups, and thegyrus semilunaris that covers the corticalnucleus (fig 2G). The medial border of the

C amygdala is partly covered by the entorhinalcortex, which forms the surface of the gyrusambiens. The entorhinal cortex correspondsto area 28 of Broadmann and constitutes amajor part of the anterior parahippocampalgyrus. The gyrus ambiens was separated fromthe parahippocampal gyrus by the uncal notch(produced by the free edge of the tentoriumcerebelli). Measurements included the cortexof the gyrus ambiens, which could not beaccurately separated from the amygdala, andexcluded the entorhinal cortex inferior to theuncal notch. When the uncal notch was eithernot visible or only poorly visible in the ante-rior amygdaloid area, the demarcationbetween the amygdala and the entorhinal cor-tex was defined by a line in continuation withthe inferior border of the amygdala, thusprobably including a small part of the ento-rhinal cortex. The inferior and lateral bordersof the amygdala were formed by the lateral

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ventricle or the white matter of the temporallobe and were easily demarcated. The supe-rior border of the amygdala was not clear cut.Therefore, the amygdala was demarcatedfrom the above substantia innominata by ahorizontal line, arbitrarily passing at the bot-tom of the endorhinal sulcus (fig 2C). At itsposterior end, the optic tract located themedial and superior borders of the amygdala.At this level, the superior border was definedby a horizontal line passing at the supero-lateral border of the optic tract (fig 2B). Thismethod probably excluded small amounts ofthe medial and central nuclei, but is repro-ducible and easy to determine. The amygdalawas also usually well demarcated from the tailof the caudate nucleus and the putamen. Theanterior pole of the amygdala was the mostdifficult to delineate in part because of partialvoluming. Thus the most anterior sectionmeasured was arbitrarily defined as the sec-tion at the level of the closure of the lateralsulcus to form the endorhinal sulcus.Rostrally, it was not possible to delineateaccurately the amygdala from the surroundingareas such as the prepyriform cortex and theentorhinal cortex. The section including theanterior commissure contained part of thehippocampal head and the posterior part ofthe amygdala. The two or three sections for-ward were analysed mainly for the amygdala,whereas the seven or eight sections backwardwere analysed for the hippocampal formation.The volume of the caudate nucleus was esti-mated on the first nine sections in which itwas contained, from the anterior pole of thehead to the posterior part of the body of thenucleus. Boundaries of the caudate nucleuswere easily demarcated from the surroundingstructures.

Comparison of volumetric measures in patientswith probable Alzheimer's disease and controlvaluesIn a previous study,28 volumetric measure-ments of patients with probable Alzheimer'sdisease were compared with those of eight agematched control subjects (mean age 69-2(2 7) years, P = 0-28). Control subjects hadno history of neurological or psychological ill-ness. Control subjects were only submitted tothe mini mental state evaluation (mean score= 28-7 (0A4), range 28-30). Detailed dataconcerning volumetric measures in patientswith probable Alzheimer's disease and con-trols are reported elsewhere.28 Briefly, thesemeasures (expressed as mean (SEM)) showeda significant atrophy of hippocampal forma-tion (- 30 (3)%, P < 0-01; HF/TIV = 2-38(006) and 1-66 (008) for controls andpatients with probable Alzheimer's diseaserespectively) and amygdala (-37 (2)%, P <0-01; A/TIV = 1-77 (0-09) and 1-12 (004)for controls and patients with probableAlzheimer's disease respectively) v controls.No significant volume difference betweenright and left hippocampal formations oramygdala was found in controls or patientswith probable Alzheimer's disease. The ven-tricles enlarged by 25 (1 1)% in patients with

probable Alzheimer's disease compared withcontrols, but the difference was not significant(V/TIV = 21-42 (3-49) and 26-78 (2-31) forcontrols and patients respectively). A smallbut significant decrease in the volume of thecaudate nucleus (-13 (3)%, P = 0 03) wasalso detected in patients with probableAlzheimer's disease (CN/TIV = 2-71 (0-07)and 2-36 (0 09) for controls and patientsrespectively).

STATISTICAL ANALYSESRegression analyses were performed betweenpsychometric performances and volumetricmeasures. No significant differences in vol-ume between right and left hippocampal for-mations, amygdala, and caudate nuclei wereseen in controls or patients.28 When correla-tion analyses between the volumes of the leftor the right volumes of the hippocampal for-mations and psychometric performances wereperformed separately, the results were thesame as those obtained with the mean of theright and the left volumes (except for thepaired associates subtest of the memory quo-tient and the total delayed recall score of theGrober and Buschke test, which failed toreach significance). Therefore, only the corre-lations between the mean of the right and theleft volumes and psychometric performancesare presented to lower the potential error ofmeasurements. Statistical significance wastaken at P < 0 05. Values are expressed asmean (SEM) unless stated otherwise.

ResultsNEUROPSYCHOLOGICAL TESTS

Intellectualffunctions (table 1)The MMSE and the Mattis DRS scores of thepatients corresponded to mild to moderatedementia. The patients achieved a mean ofthree criteria in the Wisconsin card sortingtest, and displayed some signs of frontal dys-function, with a large variability. Their nam-ing abilities were below the normal range(13-2 out of 20, as opposed to a mean score of18-5 in normal elderly controls).

Memory tests (table 2)Patients with probable Alzheimer's diseasewere significantly impaired for all memorytests in the Wechsler memory scale. All MQvalues were below 100, with substantial loss ofinformation after a short delay, as delayedrecall scores were respectively (mean (SEM))0-9 (0-2) for logical memory, 0-6 (0-2) fordrawings, and 2-4 (0-3) for paired associates.On the CVLT, patients' performances were

characterised by (a) poor initial learning(slope of the learning curve (mean (SD) = 0-6(0.1); normal for this age group 1 3 (0 4); (b)poor free recall (1.05 items out of 16; normal8.2); (c) moderate sensitivity to semantic cue-ing (3-82 items out of 16 at cued recall; nor-mal 9 84); (d) disproportionate numbers ofextra-list intrusions, which represented 32%of the total number of responses, and 53% ofresponses at cued recall (normal 8-3% and14-2% respectively; (e) high numbers of false

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positives at recognition, yielding a lowereddiscriminability index between targets anddistractors (68%; normal 92-9 (6)%).34Normative data provided in the text for theCVLT are still unpublished data for theFrench version (for CVLT normative data forthe American version, see Delis et al25).The data were similar in the Grober and

Buschke test. Despite controlled encodingand selective reminding, patients with proba-ble Alzheimer's disease retrieved only two tothree items on each of the free recall trials,without any significant progression from trialto trial. Semantic cueing yielded larger num-bers of correct responses (5 9 out of 16 v 3-8 inthe CVLT), but also triggered extra list intru-sions, corresponding to 32% of the responsesgiven at cued recall (1 82 (3)% in normalelderly controls35). Recognition performancewas also altered compared with that of normalelderly controls, as both misses (3-3 (0-7) v 0in normal elderly controls35) and false posi-tives (2-7 (1-1) v 0 in normal elderly con-

trols35) were noticed, and the discriminabilityindex was lowered (86-4 (2-7)% v 100% cor-

responding to the maximal possible value innormal elderly controls35).

CORRELATION ANALYSES BET1WEENNEUROPSYCHOLOGICAL AND VOLUMETRICMEASURESTests ofglobal cognitive deterioration andexecutive functions (table 3)Global score for MMSE and its orientationsubscore were significantly and positively cor-

related with the volume of the hippocampalformation (r = 0 59, P = 0-01, slope = 6-9(2 4) and r = 0-68, P = 0-003, slope = 4-8(1 3) respectively). The only score of theMattis dementia rating scale that was signifi-cantly correlated with the volume of hippo-campal formation was the memory subscore (r= 0-62, P = 0-006, slope = 7-9 (2 5).The frontal score was not correlated with

volume of hippocampal formation (r = 0-26,P = 0 30; table 3). The same configurationemerged for linguistic performances: lexicalevocation, naming, and vocabulary of theWAIS-R were not correlated with hippocam-pal formation volume (r = 0 07, P = 0-8; r =

0-13, P=0-62; r = 0-01, P=09, respec-tively).

Performances at the PM 47 were not corre-lated with any volumetric measure (r = 0O03,

P = 0-9; r = 0-31, P = 0-20; r = 0-22, P =

037 for HF/TIV, A/TIV, and CN/TIVrespectively) as well as the MADRS score (r =0-25, P = 0 33; r = 0-14, P = 0 57; r = 0-14,P = 0Q57 for HFITV, A/TIV, and CN/TVrespectively). Lastly, the volumes of theamygdala and caudate nuclei were notcorrelated with any score on these tests(r range = 0-02-0-31 and 0 11-035; P range= 0-21-0-84 and 0-16-0-66 for A/TIV andCN/TIV respectively).

Memory tests (table 3)The Wechsler memory quotient was signifi-cantly and positively correlated with the vol-ume of the hippocampal formation (r = 049,P = 004, slope = 15-3 (6-9)), but not withany other volumetric measure. Within thisscale, the paired associates subtest was themost highly correlated with the hippocampalformation volume (r = 0 53, P = 0-025, slope= 4-7 (1-8)).On the Grober and Buschke test, several

variables were significantly correlated with thehippocampal formation volume: total delayedrecall score (r = 0-48, P = 0-05, slope = 5-2(2-4)), number of extra list intrusions (r =0-60; P = 0 009, slope =-16-8 (5-6)),percentage of intrusions in the total numberof responses at cued recall or total recall (r =0-62 and 0-63, P = 0O006 and 0-005, slope =

-42-9 (13.5) and -43-8 (13-6) respectively),index of discriminability at recognition(r = 0-6, P = 0009, slope = 19-9 (6-7) (fig 3).The volume of the amygdala was only corre-

lated with the number of false positives at

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HF/TIVFigure 3 Regression analysis between the volume of thehippocampalfor,nation correctedfor total intracranialvolume (HFITIV) and the percentage of intrusions at theCVLT.

Table 3 Correlations between volumetnic measures and performance on global scales and memory tests

Global measures Memory measures

Mattis Frontal Matis WMS GBT:LT GBT: CVLT:LT CVLT:%Volumes AMMSE DRS score memory MQ Recall Discrim Recall Intr CR

HFmV r= 059 r= 0-41 r 0-26 r 0-62 r 0-49 r 0-48 r= 0-60 r 0 45 r 0-63P =0-01* P= 009 P= 030 P =0-006* P= 004* P= 0005* P= 0009* P =0-06 P =0-006*s= 6-9 (24) s =18-6 (10-3) s =10-0 (936) s =79 (25) s =15-3 (69) s =5-2 (24) s =199 (67) s =16 (07) s =-352 (110)

A/TNI r 0-22 r 0-29 r= 005 r= 0-03 r= 007 r= < 0-001 r= 0-21 r= 0-01 r= 0-22P =037 P= 0-25 P= 0-84 P= 0-92 P 0-78 P= 099 P= 0-41 P= 0-98 P= 041s= -4-8 (53) s= -243 (202) s = -3-8 (17-9) s= 07 (59) s= -4-2 (14-7)s= -0-01 (59)s= 12-9 (15-2) s =0-06 (1-8) s= -25-1 (292)

CNmV r= 0-29 r= 030 r 0-17 r= 0-41 r= 037 r= 0-12 r 0-02 r= 004 r= 005P=0-24 P=0-23 P=0-48 P=008 P=0-12 P=0-63 P=093 P=0-88 P=0-86s= 2-9 (24) s =11-2 (87) s= -55 (77) s =4-3 (24) s =9-8 (56) s= 11 (23) s =0-6 (73) s = -0-1 (07) s= -2-2 (12-1)

*Significant.HF = hippocampal formation; A = amygdala; CN = caudate nucleus; TIV = total intracranial volume; s = slope; MMSE = mini mental status score; DRS =dementia rating scale; WMS = Wechsler memory scale; MQ = memory quotient; GBT = Grober and Buschke test; LT = long term; Discrim = discriminabilityindex; CVLT = California verbal learning test; Intr = intrusions; CR = cued recall.

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recognition (r = 0 53, P = 0 03, slope =- 14-4 (6 0)), but not with the discriminabilityindex.

In the same way, several variables of theCVLT were correlated with hippocampal for-mation volume measurements, and concernedthe number (r = 0 54, P = 0-02, slope =- 18-5 (7.3)) and proportion of extra listintrusions (r = 0-63, P = 0-006, slope =-35-2 (11 0)). The correlation between hip-pocampal formation volume and delayed cuedrecall scores just failed to reach significance (r= 0A45, P = 0-06, slope = 1-6 (0-7), presum-ably because six patients scored zero on thisvariable. Lastly, there were significant correla-tions between amygdala volume and the num-ber and proportion of intrusions (r = 0A49 and0 54, P = 0-04 and 0-03, slope = -35 0(16-0) and -49 3 (19.9) respectively). Noother correlation approached significance.

DiscussionIn this study, patients with probableAlzheimer's disease were characterised by apronounced atrophy of the hippocampal for-mation and the amygdala compared with agematched normal controls, confirming previ-ous reports." 1229 The clinical diagnosis ofprobable Alzheimer's disease was establishedaccording to the criteria of the NINCDS-ADRDA'4 and the DSM 3-R.'5 The speci-ficity and sensitivity of these criteria have beenevaluated at 65%-91% and 47%-86% respec-tively.36 Although these criteria are not anabsolute guarantee of the diagnosis ofAlzheimer's disease (which is neuropathologi-cal), they are still the best available tools forassessing the diagnosis in clinically basedstudies. The atrophy of the temporal lobestructures was present in the early stages ofthe disease.28 Are these early changes associ-ated with specific features of the cognitivedysfunctions that characterise the disease?The volume of the hippocampal formation

was the only measure related to both quanti-tative assessment of memory, such as theWechsler memory quotient and its pairedassociates subscore, and more qualitativeaspects, such as numbers and proportions ofintrusions, or discriminability between targetsand distractors at recognition, at the CVLT orthe Grober and Buschke test. Moreover,volume of hippocampal formation was alsocorrelated with the memory subscores of theglobal cognitive scales, such as the orientationsubscore of the MMSE and the memory sub-scale of the Mattis DRS. Lastly, regressionanalyses between hippocampal formation vol-ume and performance tended to be more sig-nificant for delayed than for immediate recallon each memory test. Such data strongly sug-gest a crucial role for the damage of the hip-pocampal formation in early memorydisorders of patients with probableAlzheimer's disease. These results are also inagreement with previous human5712 and ani-mal studies3839 reporting a role for the hip-pocampal formation in memory processes.The specific influence of hippocampal forma-

tion atrophy on the decline of memory func-tions in Alzheimer's disease was furtherunderlined by the following dissociation:hippocampal formation volume was notcorrelated with any non-mnemonic neuropsy-chological variable, such as scores on tests ofexecutive functions or linguistic abilities.Analysis of the effect of other volumetric mea-sures or additional factors such as age or dis-ease duration'229 was not done given therelatively small number of patients examined.The fact that the amygdala volume was not

related to any index of memory perfor-mance-except for intrusions and false posi-tives at recognition in the Grober andBuschke test-might seem surprising, as it isknown from animal studies that large bilaterallesions of the medial temporal lobe includingthe hippocampus, the amygdala, and theiradjacent cortical regions trigger severememory impairments.38 39 According toMishkin,3840 combined lesions of both struc-tures and their adjacent cortices are necessaryto obtain amnesia in monkeys. In more recentexperiments, however, monkeys with specificlesions restricted to the amygdaloid complexperformed normally on several memory tasks,whereas they were impaired after isolatedbilateral lesions of the hippocampus.4' Thesedata led to the conclusion that "amygdaladamage alone did not impair memory; nor didit exacerbate the memory impairment associ-ated with damage to the hippocampal forma-tion".442 The fact that the volume of theamygdala was not related to memory perfor-mance in this study suggests that this conclu-sion might be extended to humans.

Lastly, as expected, the volume of the cau-date nuclei was not related to performance onexplicit memory tasks. Basal ganglia, and par-ticularly the caudate nuclei, are generally con-sidered as mediating performance in implicitmemory tasks, and more specifically in proce-dural learning in humans,43 45 and are consid-ered part of the "habit system" in non-humanprimates.4647 Significant relations betweenMR based volumetric measures of the caudatenuclei volume and performance in procedurallearning, which is preserved in patients withAlzheimer's disease, remain to be shown.

In conclusion, these data have shown that asignificant atrophy of the hippocampal forma-tion was present relatively early in the courseof Alzheimer's disease, and that this atrophywas related to memory dysfunction. Twomain hypotheses massive lesion of theascending cholinergic pathways originating inthe nucleus basalis of Meynert,48 or more spe-cific degeneration of the hippocampal forma-tion-have been consistently evoked toaccount for memory dysfunction inAlzheimer's disease. Whereas these data canin no way allow the first to be discarded, theyare clearly consistent with the second.

We thank Dr 0 Granat for contributing to the imagingprotocol and DrM Ruberg for useful discussion. The researchwas supported in part by grants from the Assistance Publiquedes H6pitaux de Paris (Contrat de recherche clinique No912208) and the Ministere de la Recherche et de laTechnologie (MRT).

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shown with MRI.disease: the role of hippocampal atrophy as Memory disorders in probable Alzheimer's

and B DuboisB Deweer, S Lehéricy, B Pillon, M Baulac, J Chiras, C Marsault, Y Agid

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disease: the role of hippocampal atrophy as shown with MRI