Focal cerebral hypoperfusion deficit dementia Alzheimer type · by the Protocole MT-85 d'Examen Linguistique de l'Aphasie-version alpha."6 Gnosic activities, involving bothbodyimageandperceptiveas

Journal of Neurology, Neurosurgery, and Psychiatry 1987;50:1602-1612

Focal cerebral hypoperfusion and selective cognitivedeficit in dementia of the Alzheimer type

PIERRE CELSIS, ALAIN AGNIEL, MICHELE PUEL, ANDRt RASCOL,JEAN-PIERRE MARC-VERGNESFrom LHEC-INSERM U 230 and Service de Neurologie CHU PURPAN, Toulouse, France

SUMMARY Regional cerebral blood flow was investigated using single photon emission computedtomography and xenon-133 intravenous injection in six patients with dementia of the Alzheimertype (DAT) with atypical focal clinical presentation, and in 20 age-matched healthy volunteers. Thepatients had a progressive and preponderant cognitive deficit and a focal hypoperfusion that cor-related with the neuropsychological findings, whereas the average flow did not significantly differfrom that of controls. The assessment of concordant haemodynamic and neuropsychological focalabnormalities could be useful in the diagnosis of atypical cases of DAT.

Alzheimer's disease (AD) and dementia of theAlzheimer type (DAT) have long been considered ascharacterised by a progressive, diffuse and ratherhomogeneous impairment of cognitive functions.However, isolated or prominent cognitive dys-function, especially language alterations, have beendescribed in the disease' 3 or related to a selectivecerebral degeneration.4 Histopathological changesespecially in the temporoparietal regions have beenreported too.5 Measurements of local cerebral glu-cose metabolism by positron emission tomography(PET) or isopropylamphetamine distribution bysingle photon emission computed tomography(SPECT) have pointed to a bilateral temporoparietalmetabolic decrease in Alzheimer's disease.6-9 Re-cently, Friedland et al'0 and Haxby et al" empha-sised hemispheric asymmetries in demented patients.We studied six patients with DAT and focaloligaemia. In this paper, we compare their haemo-dynamic status with that obtained from a controlgroup and report the relationships between theregional cerebral blood flow (rCBF) of the patientsand their performances on specific cognitive tests.

Address for reprint requests: P Celsis, LHEC-INSERM U 230,Service de Neurologie, CHU PURPAN F31059 Toulouse Cedex,France

Received 25 November 1986 and in revised form 18 March 1987.Accepted 26 March 1987

Material and methods

PatientsOut of a series of 36 patients with DAT who underwent arCBF evaluation by SPECT, we studied six right-handedsubjects aged 57 to 75 years (mean age 66 + 81). Whenreferred for the first time to the Department of Neurology,three ofthem exhibited an elective cognitive deficit, the otherthree a more diffuse alteration with, however, a dispro-portionate impairment of one of the cortical functions.Along with the duration of symptoms, that ranged from 1 to7 years, successive medical evaluations included physicaland neurological examinations, neuropsychological testing,laboratory tests, EEGs and CT scans. None of the patientshad a family history of DAT. Subjects were free from anymotor or sensory deficit. None had a history of cerebro-vascular disease (Hachinski ischaemic score"2 of three orless) and in the two cases where it was performed, the digitalangiography was normal. The cerebrospinal fluid (CSF) wasstudied in three patients and the results were within normallimits. In all cases, folic acid deficiency, hypothyroidism, ter-tiary neurosyphilis and pernicious anaemia were excluded.EEGs were normal or without obvious focal abnormality.CT scans were normal or showed mild, diffuse cerebral atro-phy, sometimes predominating in one of the hemispheres. Ineach case, neuropsychological evaluation demonstrated aprogressive deterioration of intellectual and mnesic abilitiesin addition to the selective or prominent cognitive deficit. Atan early stage of the disease, the symptoms met the criteriafor the clinical diagnosis of possible Alzheimer's disease, asgiven in the report of the NINCDS-ADRDA Work Groupon the diagnosis of Alzheimer's disease. 3 At the time of theflow study, the patients met the criteria of the Work Groupfor the diagnosis of probable Alzheimer's disease and all six

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Focal hypoperfusion in dementia of Alzheimer type

patients exhibited symptoms that met the diagnostic criteriafor Primary Degenerative Dementia given in the Diagnosticand Statistical Manual of Mental Disorders.14

Before the CBF study, informed consent was obtainedfrom the patients or their relatives. Three of them (cases 1, 2and 6) were retested 8 to 12 months later.

ControlsWe measured cerebral blood flow at rest in 20 age-matchedcontrols (mean age 65 + 5 2 years). They underwent clinicaland neuropsychological evaluations in order to exclude cere-brovascular disease and cognitive impairment. Ten controlswere retested 1 year later. Written informed consent wasobtained from the normal volunteers.

CBF measurementRegional cerebral blood flow was assessed using a singlephoton emission tomograph (Tomomatic 64, Medimatic,Copenhagen) and intravenous injection of xenon 133 (2220MBeq, 60 mCi). Data were collected from three transverseslices simultaneously, each of 2cm thickness, parallel andcentred at 1, 5 and 9cm above the canthomeatal planerespectively. The in-plane resolution was 1-7 cm. During the4 minute data collection, patients were kept at rest, eyesclosed, and pCO2 was continuously recorded using acutaneous electrode and a Kontron 634 pCO2 monitor. Theaccuracy of transcutaneous pCO2 recordings had beenassessed previously. The values obtained in seven patientsboth by transcutaneous measurement and from arterialblood samples were compared. Mean value from arterialblood samples was 30 4 + 5-3 mm Hg (range 22.8-35.9) andmean value from transcutaneous technique was 31 + 6-2(range 22-38). The correlation coefficient was equal to 0 979,

Fig 1 Regions ofinterest in slice 2 (5 cm abovecanthomeatalplane). F = frontal; S = sylvian;PT = parietotemporal; MF = middle-frontal;MO = middle-occipital; ASC = anterior sub-cortical;PSC = posterior sub-cortical.

1603thus showing the accuracy of the transcutaneous methodwhen correctly applied (that is, when the electrode is heatedup to 44-45°C). A small blood sample was withdrawn forhaematocrit determination. CBF was calculated using amethod described previously.15 Hemispheric flow was deter-mined in slices 2 and 3. From slice 2, a mean value wasderived for the regions of interest (ROI) shown in fig 1,namely the right and left frontal (F), Sylvian (S) and pari-etotemporal (PT) cortical regions, the middle frontal (MF)and middle occipital (MO) cortical regions, and the rightand left anterior and posterior subcortical regions (ASC andPSC respectively). The ROIs were determined using a semi-automatic method, which first consisted in delimiting theouter contour of the brain by thresholding. Then, the lengthof the saggital axis (that is, the distance between the frontaland occipital poles), expressed in pixels, was automaticallycalculated. Two horizontal lines were drawn on the screen:the first at a distance from the most anterior point of thefrontal pole equal to 25% of the saggital length; the secondat a distance equal to 60% of the saggital length. The firstline corresponded to the limit between the frontal (F) andSylvian (S) regions and gave the anterior limit of the ASCregion. The second line corresponded to the limit betweenthe Sylvian (S) and parietotemporal (PT) regions and gavethe posterior limit of the PSC region. Then, according to thisscheme, the ROIs were drawn using predefined templates.Asymmetries, expressed as the percent difference betweenhemispheres or homologous ROIs were calculated accordingto the formula:

dif%/o = 200 x Left-Right /lLeft + Right

Neuropsychological testingExtensive neuropsychological tests were performed in orderto appreciate which of the cognitive functions were impairedand to what extent. Owing to the existence of a prepon-derant mental alteration, the evaluation was adapted to eachpatient by varying some of the subtests.Corticalfunctions For the language evaluation, spontane-ous speech, repetition, naming, auditory comprehension,oral reading, reading comprehension and writing were testedby the Protocole MT-85 d'Examen Linguistique del'Aphasie-version alpha."6 Gnosic activities, involvingboth body image and perceptive as well as associative visualgnosias, were tested by the Protocole Montreal-Touloused'evaluation des gnosies visuelles (PEGV).17 Constructivepractic abilities were evaluated using spontaneous drawing,Rey-Osterrieth complex figure (ROCF) test,18 Bender-gestalt test19 and WAIS block design subtest.20 Ideationaland ideomotor praxias were tested by imitation of gesturemade by the examiner and by ability to perform complexactions.Mnesic capacities This investigation was based on inter-viewing the patient, who was asked to describe the mainstages of his life or to recall historical and social events, andon the performance on specific tests: Weschler's MemoryScale,2" Benton Visual Retention Test,22 memory drawingof the Rey-Osterrieth complex figure (ROCF)'8 and "144"Memory Battery Scale."Intellectual and operative abilities Oral and written arith-metic calculation was tested as well as logical-deductive



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Table 1 Computed tomographicfindings, cognitive impairment, pCO2 and regional cerebral bloodflow values in six patients with dementiaofthe Alzheimer type

Durationof Focal hypoperfusion

Age symptomsCase (yr) (yr) CT Prominent deficit pCO2 ROI CBFml/lOOg/min

Left Right Dif(%)1 59 7 Left cortical atrophy Global aphasia 41 Left frontal subcort. 32 37 152 57 3 Left cortical atrophy Anterior aphasia, right

hemivisual neglect 40 Left frontal 45 63 333 60 5 Mild diffuse atrophy Aphasia 38 Left parieto-temporat 40 48 184 73 6 Mild diffuse atrophy Aphasia 38 Left frontal sylvian 46 54 165 72 1 Normal Constr. apraxia, left

ideomotor aprax. +hemivis. neglect. Leftear relat. extinction 33 Right sylvian 56 50 11

6 75 3 Mild diffuse atrophy Left hemivisual, lefthemimotor neglects 39 Right parieto-temporal 34 29 16

ROI, region of interest; CBF, cerebral blood flow; Dif (%), 200 x ILeft - Rightl/Left + Right.

reasoning (Raven's Progressive Matrices24 and block-formsseriation and classification). The Mini Mental State evalua-tion (MMS)25 was also used as rapid screening test.

Results

The main results of the neuropsychological testingand SPECT study of cerebral perfusion are sum-marised in table 1.

Global CBFfindingsControls Mean flow in the control group was equalto 50 6 + 9-8 ml/lOOg/min. Hemispheric flow was 50+ 9 5 and 51-1 + 10-5 in the left and right hemi-sphere respectively. The average percent differencebetween homologous ROIs never exceeded 6-5 (table2). The average percent difference between hemi-spheres was equal to 3-1 + 2-4, the individualdifference never exceeding 7%. In the group of 10retested controls, mean flow was equal to 52 3 + 9-2ml/100g/min at the first measurement and to 54-6 +8&3 at the second assessment, the difference being notsignificant. Furthermore, there was no correlationbetween the hemispheric asymmetries, expressed inpercent difference, that were observed at the first and

Table 2 Side to side variations in controls

ROI Mean DIF (%)SD

F 55+4-6S 4-6 + 3-5PT 61 + 37ASC 64 ± 34PSC 48 ± 3-8

Hemisphere 3-1 + 2-4

ROI, Region of interest; DIF (%),200 x ILeft - Rightl/Left + Right.

second CBF evaluation, neither for the hemispheresnor for any of the ROIs.Patients All patients exhibited a focal hypo-perfusion in one of the hemispheres. Global meanflow was equal to 47 7 + 8-5 ml/1OOg/min and did notsignificantly differ from the average flow observed incontrols. In the hemispheres with focal hypo-perfusion, flow was equal to 46-3 + 8 2 and, in thehemispheres without focal hypoperfusion, to 50-2 +8-9 ml/100g/min, a value very close to the mean valueobserved in the control group. The average percentdifference between hemispheres equalled 8 + 4a2 andsignificantly differed from the value obtained in con-trols (p < 0.01). All three patients who were retested1 year later still exhibited focal hypoperfusion, thelocalisation and extent of which were quite similar tothose observed at the first examination.

CASE REPORTSCase IA 59 year old woman began in 1978 to have anelective difficulty in expressing herself. In 1979, whenshe was referred to the department for the first time,she presented with expressive aphasia with nonfluentspeech, word-finding difficulties in visual naming anddysorthographia. Auditory comprehension, repeti-tion and reading aloud were preserved. At thistime, practic and gnostic functions were preserved.Patient's score on ROCF copying test was 36. Imi-tation of gesture was correct. Right/left orientationwas normal and there was no finger agnosia. Objects,familiar faces and places were identified correctly.Spatial and temporal orientations were normal andarithmetic calculation was preserved. Yet, memorywas already impaired as revealed by the memorydrawing of the ROCF (5 points over 36). Then, the

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Focal hypoperfusion in dementia of Alzheimer typelanguage disturbance gradually progressed and, in1985, the patient was unable to communicate sincethe deficit resembled a global aphasia. Speech outputexclusively consisted of the stereotyped word "oui".Writing was limited to copying by graphic imitationand reading comprehension was nil. Although theseverity of language disturbance made it difficult toadminister some standard tests, we were able to detecta certain degree of deterioration in practic capacitiesand intellectual abilities. The visuo-constructionalfunction became altered (30 on ROCF copying testand 9 on WAIS block design subtest). An ideomotorapraxia appeared as well as problems in right/left ori-entation and finger gnosia. Also, the patient failedwritten calculation. Mnesic capacities were difficult toappreciate but, according to the family, they did notseem to be severely impaired. A mild intellectualdeficit was noted and the patient was unable to per-form Raven's progressive matrices. The patient con-tinued to perform housekeeping activities althoughshe worked "like an automaton", her husband re-ported. She was fully oriented and never became lost.Thus, at this stage, the patient exhibited a global men-tal impairment, yet with preponderant language dys-function. Physical and neurological examinationswere unremarkable. Digital subtraction angiographyfailed to demonstrate any abnormality on the carotid,vertebral, basilar and great intracranial arteries. TheCT scan showed cortical atrophy, more pronouncedon the left fronto-temporal region (fig 2a). In 1985,the flow study, (fig 2b and table 1), revealed a focalarea of hypoperfusion in the left hemisphere,corresponding to the frontal and anterior subcorticalregions. Flow in the Sylvian and parietotemporalareas was also slightly decreased on the left side.Mean hemispheric values in slice 2 were 38 vs 42ml/lOOg/min on left and right side respectively, and37 vs 39 ml/lOOg/min in slice 3, showing a moderate,global hypoperfusion in this 59 year old patient.

Case 2In 1985, a 57 year old man was seen in neurologicalconsultation for the evaluation ofmarked apathy, un-concern, troubles of elocution and slowing of think-ing and memory. Difficulties were first noted 3 yearsbefore consultation. The patient was cooperative andaware of his difficulties. The MMS score was equal to20: orientation 8/10, registration 3/3, attention andcalculation 0/5, recall 2/3, language 7/9. He presentedwith non-fluent speech: the language evaluationshowed a poor output, short phrase length, a milddysarthria and omissions of the small "grammatical"words of the language (articles, pronouns .. .). Audi-tory and reading comprehension was mildly impairedfor complex sentences only. Written output was

1605strongly paraphasic, tending to jargonagraphia. Thevisuoconstructive activities were mildly impaired andshowed signs of right hemispatial neglect (omissionsand errors in the copy of Rey's figure in the right sideonly, with a score equal to 28). Calculation andmemory were impaired, as shown by MMS evalu-ation (see above) and Benton VRT (3/10). However,the outstanding neuropsychological deficits calledattention to a focal left dysfunction, and moreespecially to the anterior region since the patientpresented with non-fluent aphasia. Yet, the neuro-logical examination, EEG and CSF were strictlynormal and a CT scan showed a mild cortical atro-phy, more pronounced in the left hemisphere (fig 2c).The flow study supported the neuropsychologicalexamination. On the CBF map corresponding to slice2 (fig 2d), a cortical hypoperfusion was clearly seen inthe left frontal region. The local percent differencereached 33%, compared with the opposite ROI (table1). Low flow was also found in the left anterior sub-cortical area (52 vs 59 ml/lOOg/min). In the otherROIs, flow was slightly depressed by about 6% on theleft side but the mean left and right hemisphericvalues, 58 and 64 ml/lOOg/min respectively, showedthat the brain, as a whole, was correctly perfused.

Case 3In 1980, a 60 year old woman first experienceddifficulty in expressing herself and in understanding.She was aware of her troubles and depressed. Twoyears after onset, she was admitted to the departmentof neurology for a neuropsychological evaluationthat showed a global impairment: word-findingdifficulties, impoverishment in grammatical compe-tence, mild dysorthographia, constructional apraxia,mild ideomotor apraxia, body image alteration andmemory impairment (69 on Wechsler memory scale,10 over 15 on Benton VRT given in form F). Over thenext 3 years, her language gradually worsened, withnon-fluent speech, verbal paraphasias and impairedauditory comprehension while the extra-linguisticdeficits remained stable. Four successive CT scans,between 1981 and 1984, only showed mild corticalatrophy without focal changes. The cerebrospinalfluid was normal. In 1985, the EEG showed somedelta waves in the left temporal lobe. Intravenous an-giography showed no abnormality of the carotid, ver-tebral and basilar arteries. At this stage, the MMSscore was found equal to 22: orientation 8/10, regis-tration 2/3, attention and calculation 3/5, recall 2/3,and language 7/9. In contrast to the rather un-remarkable results of the physical and laboratorytests mentioned above, the tomographic data showeda 17% decrease in CBF in the left parietotemporalregion, compared with the contralateral ROI (table1). Left frontal flow was also slightly diminished



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1608(-8%). In slice 2, CBF was equal to 48 and 52ml/lOOg/min in left and right hemisphere respectively.

Case 4In 1978, a 73 year old man noted the progressive on-set of speech disability. One year later, at the firstexamination, we found word-finding difficulties, se-mantic and phonemic paraphasias. Practic abilitieswere normal (35 on ROCF copying test). No gnosticdisorder was found at the PEGV. Memory functionsand intellectual abilities were slightly impaired (6/10on Benton VRT, 17/36 on the memory drawing ofROCF). The patient was cooperative and customaryactivities were preserved. Neurological and EEGfindings were normal. During the next years, repeatedexaminations showed a gradual worsening. Oral read-ing and reading comprehension became impaired andthe deterioration progressively resembled a trans-cortical sensory aphasia, with fluent but often inco-herent speech and numerous paraphasias. Verbalcomprehension of complex sentences was impaired.Repetition was normal. Oral activities were relativelymore preserved than writing and reading comprehen-sion. Gnosic and operative abilities were preserved.Practic activities, both ideomotor and constructive,were normal but slow. Six years after onset, the audi-tory comprehension was severely impaired. Thepatient required several repetitions before compre-hending the questions and the responses were de-layed. Reading comprehension and writing weredeeply affected. Difficulty in arithmetic calculationwere noted. Perceptive and associative visual gnosiaswere strictly normal. The patient performed per-centile 50 on PM38 Raven's test. Although difficult toassess because of language alterations, mnesic capaci-ties did not appear more impaired than they were atthe previous examination. The patient was oriented todate, place and persons. He was frustrated about hispoor language abilities but he continued to performsocial and household activities. Thus, in this patient,language was the most impaired function from thebeginning and worsened most all through theprogression of the disease. EEG showed somebilateral theta waves and two successive CT scansonly showed a mild, diffuse cerebral atrophy (fig 2e).This was not the case of the CBF map, slice 2, thatshowed a pronounced asymmetry (fig 20). Flowsequalled 47 and 53 ml/100g/min in left and righthemisphere respectively. The hypoperfusion waspreponderant in the left frontal and Sylvian cortices(table 1) but also involved the subjacent white matterand basal ganglia. In slices 1 and 3, the flow was alsodiminished in the left hemisphere (about 10%) but theoverall perfusion level was good since mean flow inthe three slices averaged 50 ml/lOOg/min.

Celsis, Agniel, Puel, Rascol, Marc- VergnesCase 5A 72 year old woman was hospitalised in 1985 forword-finding difficulties, poor memory and mild tem-porospatial disorientation of approximately 3 monthduration. She was aware of her troubles and anxious.Neuropsychological testing evidenced a deficit in anumber of cognitive abilities. MMS score was equalto 23: orientation 6/10, registration 3/3, attention andcalculation 5/5, recall 0/3, and language 9/9. How-ever, an ideomotor apraxia predominating at the leftsuperior limb, a constructional apraxia due to an im-portant deficit in visuospatial perception as well assigns of left visual hemineglect (score on ROCF copy-ing test equal to 28 with most of the errors in the leftside), a left-ear relative extinction on dichotic test anda spatiotemporal disorientation that the patient triedto correct by logical and deductive reasoning, sug-gested that cortical dysfunction was more severe onthe right side. Normal language capacities supportedthis hypothesis. The patient had also some difficultyin recognising ward personnel and exhibited euphoricbehaviour. Neurological examination and cere-brospinal fluid were normal. An EEG showed righttemporal and parietal slowing. CT scan was un-remarkable. The 3-D flow study demonstrated anelective, moderate hypoperfusion of the right Sylvianregion (table 1). In contrast, compared with the leftside, flow was about 5% higher in the other rightROIs. On the average, perfusion was identical forboth hemispheres and equalled 51 ml/100g/min inslice 2, a value that could be considered normal in a72 year old patient.

Case 6In 1982, three years before admission, this 75 year oldwoman started to complain of memory troubles. Atthe time she was hospitalised, neuropsychologicaltesting showed deterioration. Memory was stronglyimpaired: a verbal learning test of 10 words was im-possible. Temporospatial disorientation was com-plete. The patient achieved 16 on MMS score(orientation 1/10, registration 3/3, attention and cal-culation 5/5, recall 0/3, language 7/9). But, sur-prisingly, among signs of diffuse deterioration, lefthemivisual and hemimotor neglects were noted.Moreover, examination demonstrated an importantconstructional apraxia (O on WAIS block design sub-test) and an upper-limb bilateral ideomotor apraxia,more pronounced on the left side. Compared withother functions, language was preserved, fluent, anddifficulty only appeared in elaborating a complex, ab-stract sentence. The patient was partially aware of herdifficulties. The EEG showed theta waves in the righthemisphere and the CT scan was remarkable only formild, diffuse atrophy (fig 2g). 3-D CBF measurementexhibited a global hypoperfusion (39 and 36



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ml/1OOg/min in left and right hemisphere re-spectively), with a reduction in right relative to leftparietotemporal region of about 15% (fig 2h).

Discussion

Obviously, for lack of histopathological evidence, thediagnosis of Alzheimer's disease can be founded onlyon the medical history, clinical examination, neuro-psychological tests and laboratory studies. From theinformation thus recorded from our patients, thediagnosis of primary degenerative dementia could beestablished according to the criteria given in the DSMIII,14 whereas the diagnosis of probable Alzheimer'sdisease would apply, according to the criteria ofMcKhann et al.13 Therefore, taking into accountboth the two possible terms, the age of the patientsand also to comply with current use in recent litera-ture, we chose the term "dementia of the Alzheimertype" (DAT) to describe our patients.

In our patients, the average flow was notsignificantly lower than in controls. Besides, flowcalculated from the hemispheres with focal hypo-perfusion did not differ significantly from the meanvalue obtained in controls. In the hemispheres with-out hypoperfusion, the values were within the rangeof the mean flows observed in controls. Differencesbetween patients and controls only appeared whenlooking for regional asymmetries. Compared withage-matched controls, bilateral symmetrical reduc-tion offlow has been described in Alzheimer's disease,using the xenon- 133 inhalation technique and station-ary detectors.26 27 Tomographic data on CBF inDAT, far from being numerous, essentially consist ofthose produced by Frackowiak et al,28 using ol5,who also found bilateral hypoperfusions. Measure-ment of cerebral glucose rate with PET has alsodemonstrated bilateral significant diminution inpatients with DAT.6 29 30 The differences between ourresults and those reported in the works mentionedabove are not due to the technique, as we also, usingSPECT, have observed global bilateral decrease inother demented patients, but depend on patient selec-tion. This selection also resulted in the fact that onlytwo cases (Nos I and 6) showed a global hypo-perfusion, thus achieving a very atypical grouping ofdemented patients.

All six patients manifested a progressive mentalimpairment that gradually involved several cognitivefunctions, so that they could be termed demented.Indeed, for three of them (cases 3, 5 and 6), the diag-nosis of dementia had been put forward from thebeginning. But they exhibited a disproportionatefailure of a specific cognitive capacity: patients I to 4initially showed preponderant language deficits while

1609patients 5 and 6 evidenced a prominent contructionalapraxia and left visual and motor hemineglects. Someauthors have recently insisted on progressive lan-guage alteration in DAT.1 Kirshner et al2 havesuggested a continuous spectrum from isolated apha-sia to generalised dementia. Mesulam4 suggested thatthis clinical syndrome could result from a preferentialinvolvement of the left perisylvian region, a specialtype of progressive degenerative disorder. Recently,Chawluk et al31 reported two cases of slowlyprogressive aphasia with striking abnormalities ofglucose utilisation in the left hemisphere, without anycontralateral impairment, as demonstrated by PET.They stressed that their patients did not present withgeneralised dementia. Our cases have prompted us toa view close of that of Kirshner et al because ourpatients with prominent language alteration showed afrontal or parietotemporal hypoperfusion andbecause mild signs of memory failure and reasoningimpairment appeared relatively soon in progressionof the disease. Since the first CBF examination, in1985, one of these patients (case 1), whose languagealteration remained by far the most striking-if notthe only appreciable-disorder for the 3 or 4 yearsafter onset, has become incontinent.

Concerning the right hemisphere, Crystal et a132reported a patient with biopsy-proved Alzheimer'sdisease who presented with a right parietal syndrome,2 years before intellectual impairment appeared. Theysuggested that the parietal lobes could be initiallymore affected than other regions. Indeed, two of ourpatients (cases 5 and 6) evidenced a preponderantdysfunction of the right hemisphere involving theparietal region, but including signs of temporal im-pairment in case 5. Also considering all six patients,the frontal and perisylvian regions appeared to be ini-tially affected as well. So, our findings might suggestthat DAT could begin with different kinds of selectivecognitive impairment, related to a left as well as aright hemispheric flow disturbance likely to be shownby haemodynamic studies.The most striking fact was that all six patients

showed a focal cerebral hypoperfusion which wasconsistent with the neuropsychological findings. Thisfocal hypoperfusion was not a simple hemisphericasymmetry, a finding emphasised by Friedland etal,10 and which we observed frequently in the remain-ing patients of our complete series studied by SPECTwho presented as mild to moderate Alzheimer's dis-ease. The decrease in flow was indeed well-circumscribed, sometimes accompanied by a slightglobal reduction in the ipsilateral hemisphere. Such ahaemodynamic pattern resembled those observed instroke patients. But our patients were not strokepatients. First, they experienced a very slowlyprogressive deterioration in cognitive ability. Evi-



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dence of the insidious nature of onset was found inthe time that elapsed from the beginning of the trou-bles to the first neurological consultation (severalmonths or years). The regular progression of the dis-ease, together with the absence of focal motor or sen-sory deficit, also resulted in a Hachinski ischaemicscore of 3 or less. Secondly, none of the patients ex-hibited a focal hypodensity on CT scans. Finally, thedigital cerebral angiography we carried out in twopatients proved the absence of arterial lesions. In theremaining patients, we found an ischaemic disease sohighly improbable that we decided to circumvent therisks of the examination in such weak subjects. Thus,in our series of 36 subjects with DAT, 6 (15%) ex-hibited a localised flow abnormality consistent withthe neuropsychological findings, whereas CT scansonly showed mild atrophy, more or less focal, or didnot correlate at all. Concerning some common fea-tures of Alzheimer's disease and cerebrovascular dis-ease, Benson et al33 have warned against the possiblemisleading diagnosis of degenerative dementia in thepresence of angular gyrus syndrome. Among factorsdistinguishing Alzheimer's disease from the angulargyrus syndrome, they cited the PET study, likely toshow highly contrasted metabolic patterns, de-pending on the disease. Our patients, especially case3, suggested that this was not a reliable means fordifferential diagnosis, as patients with degenerativecognitive disorders (possible or probable DAT) couldexhibit focal flow or metabolic abnormalities and notalways bilateral parietal and/or frontal disturbances.

Friedland et alt' reported hemispheric asym-metries in glucose utilisation in patients withAlzheimer's disease. They found that the per-formance on visuospatial tasks was significantlyworse in patients with preponderant right-side meta-bolic impairment than in patients with predominantlyleft dysfunction. Our results agreed with those of Fos-ter et at34 concerning cortical glucose metabolism inpatients with DAT, with the difference that the hypo-perfusions we observed seemed more focal than themetabolic abnormalities they reported. The authorsfound significant relationships between predominantlanguage deficits and left temporoparietal metabolicalterations as well as between disproportionate vis-uoconstructive dysfunction and right tempo-roparietal hypometabolism. They noted that patientswith a prominent memory failure had no tempo-roparietal asymmetry in glucose metabolism. We alsocould not find a patient with a prominent memorydeterioration coupled with a focal haemodynamic al-teration. Haxby et all' reported significant cor-relations between two neuropsychological indices ofasymmetry of language and visuospatial construc-tion, and regional asymmetry of glucose metabolicrate, whereas Foster et al34 mentioned a close cor-

Celsis, Agniel, Puel, Rascol, Marc-Vergnesrelation between the degree of generalised hypo-metabolism and the reaction time. Indeed, previousstudies with PET have shown a significant re-lationship between the severity of dementia and themean cerebral glucose or oxygen utilisation.28 29 35Using MRI, Besson et at36 found a negative cor-relation between the constructional subscores and thechanges in spin-lattice relaxation time in the parietalregions. The limited number of cases did not allow usto study such quantitative correlations, but it shouldbe remarked that the patient with the greatestmemory and reasoning deficits also exhibited the low-est flows (case 6). To be compared with this findingwere the results of our study on normals that demon-strated a positive significant relationship between theflow changes during memory activation and a short-term memory score.37Our results suggested that CBF measurement using

SPECT is sensitive and reliable enough to demon-strate asymmetries or focal abnormalities in patientswith dementia of the Alzheimer type whereas CT scanusually failed to show such local alterations. Further-more, these alterations strongly correlated withthe neuropsychological tests. As stressed byKhachaturian38 "the validation of diagnostic tests re-mains a crucial problem in all areas of Alzheimer'sdisease research but especially in the area of neu-ropsychology". In our work, measuring cerebralblood flow by SPECT thus appeared a good means ofconsolidating the neuropsychological findings inDAT. In other respects, recent works have empha-sised the variability of cognitive profiles39 or regionalmetabolic rates of glucose40 in DAT. Reviewing themodels currently developed for Alzheimer's disease,Wurtman4' said that each model was supported bysome observational or experimental evidence, andeach seemed to be contradicted by other evidence. In-deed, our work, together with others, 1 34 39 40 pointsto variability in the clinical expression of the disease,which is the reason why none of the models perfectlymatches the observed facts. But it also supports theidea that, combining clinical and neuropsychologicalexaminations with functional mapping of the brain, asubtyping of DAT could be achieved. Thus, for in-stance, the bilateral posterior decrease in flow or me-tabolism, a finding now well established,69 would beascribed in the subgroup of patients presenting withaphasia, apraxia and agnosia, a subgroup actuallydifferent from that of patients with focal abnormalityand selective cognitive deficit (such as those presentedhere), or from that of patients with generalised hypo-perfusion or hypometabolism and preponderantmemory loss.34 To establish such a subtyping wouldreally appear of prime interest as the prognosis couldbe different and as appropriate treatment could beproposed according to the subgroup.



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To fulfill the latter point supposes that the ae-tiology and the pathogenetic mechanisms of the dis-ease be elucidated. In this respect too, a subtypingwould be rewarding. The factors responsible for thelocal development of hypoperfusion or hypo-metabolism have not been determined. The circum-scribed decrease in flow could be due to a localamyloid angiopathy which has been observed inAlzheimer's disease.32 42 Most of the time, a gener-alised process was observed, involving the wholebrain, but recent work has demonstrated unifocal al-terations that could account for our focal hypo-perfusions.43 Besides, in case of amyloid angiopathy,the blood-brain barrier (BBB) might be disrupted, assuggested by Elovaara et al.44 This local disruptioncould in turn lead to neuronal alterations via the in-trusion of neurotoxic proteins. In this case, the focalblood flow changes would represent the early stage ofthe disease. However, Friedland et al,45 usingrubidium-82 and PET failed to demonstrate a localpermeability of the BBB in patients with generalisedDAT. The cortical hypoperfusions we observed mightalso represent the transynaptic consequence of the de-generation of subcortical cholinergic neurons ob-served in Alzheimer's disease or senile dementia.4647However, were the subcortical cholinergic neuronsthe primary focus of the pathological process in-volved in our cases, the unilateral and rather limitedhypoperfusion we observed after years of progressionof the disease would appear somewhat disconcerting.Alternatively, the dysfunctional area might reflect aregional, cortical neuronal loss, as suggested by Brunet al.5 The neuronal loss could mainly affect the so-matostatin neurons, as suggested by Crow et a148 whofound a reduction in somatostatin in the frontal andtemporal cortices of patients with DAT, as well as arelationship between the location of neurofibrilliarytangles and the somatostatin-containing cell bodiesand who considered these cells as a possible site ofprimary disturbance. However, whatever the patho-genetic mechanisms involved in DAT, a local biopsy,whenever possible, would still be needed to establishthe diagnosis.

Nevertheless, assessing regional cerebral bloodflow by SPECT has proved interesting. First, becausethe technique appeared more sensitive than CT and assensitive as the much more costly PET technique forthe visualisation of focal abnormalities. Secondly,because its results correlated very well with theneuropsychological findings which were thus consoli-dated. The conjugate haemodynamic and neu-ropsychological approach might then prove useful inthe early diagnosis of DAT. Finally, because thespecific pattern of flow it could demonstrate in a sub-group might confirm the validity of the pathogeneticmodel proposed.

1611

The authors thank Fransoise Viala, ChristianeDuchein, Gerard Viallard, Therese Pujol and DrBernard Doyon for their assistance.References

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