_Journal ofNeurology, Neurosurgery, and Psychiatry 1994;57: 1503-1509

Extrapyramidalism in Alzheimer's disease:prevalence, psychiatric, and neuropsychologicalcorrelates

Marcelo Merello, Liliana Sabe, Alejandra Teson, Ricardo Migliorelli, Martin Petracchi,Ramon Leiguarda, Sergio Starkstein

AbstractThe prevalence and clinical correlates ofextrapyramidal signs in a consecutiveseries of 78 patients with Alzheimer's dis-ease attending a neurology clinic, and 20age comparable normal controls, wereexamined. Based on the unifiedParkinson's disease rating scale(UPDRS) findings, 18 patients (23%) metcriteria for parkinsonism, 44 (56%) hadisolated extrapyramidal signs, and 16(21%) had no extrapyramidal signs.Whereas the control group showed a sim-ilar prevalence of isolated extrapyrami-dal signs (57%), none of them showedparkinsonism. No significant differenceswere found for age, sex, duration of ill-ness, and severity of dementia among thethree Alzheimer's disease groups.Patients with Alzheimer's disease-parkinsonism, however, showed a signifi-candy higher frequency of majordepression and dysthymia and signifi-candy higher Hamilton depression scoresthan patients with isolated or noextrapyramidal signs. Patients withAlzheimer's disease-parkinsonism alsoshowed significantly more deficits onfrontal lobe related tasks such as theWisconsin card sorting test, trail makingtest, and verbal fluency, as well as ontests of constructional praxis andabstract reasoning than patients withAlzheimer's disease but no extrapy-ramidal signs. In conclusion, the studyshowed a specific association betweenAlzheimer's disease and parkinsonism,as well as significant relations betweenparkinsonism, deficits in executive func-tions, and depression among patientswith Alzheimer's disease.

(7 Neurol Neurosurg Psychiatry 1994;57: 1503-1509)

Extrapyramidal signs are well known featuresof Alzheimer's disease. Molsa et aP' examined143 patients with probable Alzheimer's dis-ease for the presence of extrapyramidal signsand found that only 8% of them had no signs.A limitation of this study, however, was that agroup of normal controls was not assessed,and whether the prevalence of extrapyramidalsigns in Alzheimer's disease was comparablewith that found in non-demented people of asimilar age could not be determined. In arecent community based study, Funkensteinet a!2 showed that diminished spontaneous

movements of the limbs or face, reduced armswing in walking, and gait abnormalities wereassociated with a substantially increasedprobability of having clinically diagnosedAlzheimer's disease. Whether this increasedfrequency of extrapyramidal signs was part of aparkinsonian syndrome or only consisted ofisolated extrapyramidal signs was not estab-lished. The delineation of a subgroup ofpatients with Alzheimer's disease andextrapyramidal signs has important clinicalimplications, as this group was reported tohave a faster cognitive decline and a highermortality.3The mechanism of extrapyramidal signs in

Alzheimer's disease is poorly understood.Whereas some studies have shown neuro-pathological similarities between Parkinson'sdisease and Alzheimer's disease withextrapyramidal signs,4-5 others showed neitherdysfunction of the nigrostriatal dopaminergicterminals6 nor response to levodopa treat-ment.7 The apomorphine test is regularly usedfor the diagnosis of Parkinson's disease, with asensitivity of 70-90%." To the best of ourknowledge, this test has not been assessed inpatients with Alzheimer's disease andextrapyramidal signs. Whether this group ofpatients shows either a positive or a negativeresponse to apomorphine may shed more lighton the mechanism of extrapyramidal signs inAlzheimer's disease.

Depression is also a frequent findingamong patients with Alzheimer's disease, andhas been reported in 30-40% of consecutivepatients.9 A similar prevalence of depressionhas been documented in patients withParkinson's disease,'0 but the possibility thatAlzheimer's disease with extrapyramidal signsmay be significantly associated with depres-sion has rarely been examined. Bakchine et al Ihave recently reported that depressed patientswith Alzheimer's disease had significantlyhigher akinesia scores than patients withAlzheimer's disease but without depression.This study had limitations, as the diagnosis ofdepression was not based on clinical criteria, astructured psychiatric interview was not car-ried out, and patients with Alzheimer's dis-ease taking neuroleptics were not excluded.

Although several studies showed thatpatients with Parkinson's disease, even in theabsence of dementia, have deficits in specificcognitive functions, such as planning, setshifting, and abstract reasoning,'2 neuro-psychological differences between patientswith Alzheimer's disease and with or with-out extrapyramidal signs have rarely been

Department ofClinical NeurologyM MerelloR LeiguardaS StarksteinDepartment ofBehaviouralNeurology, RaulCarrea Institute ofNeurologicalResearch, BuenosAires, ArgentinaL SabeA TesonR MigliorelliM PetracchiS StarksteinCorrespondence to:Dr Marcelo Merello, RaulCarrea Institute ofNeurological Research-FLENI, Montaneses2325, 1428 Capital Federal,Argentina.Received 20 December1993 and in revised form17 June 1994.Accepted 23 June 1994

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examined. Girling and Berrios'3 assessed agroup of 146 patients with Alzheimer's dis-ease and found a significant associationbetween extrapyramidal signs and deficits infrontal lobe related functions, such as verbalfluency and perseverations. Patients takingneuroleptics or other drugs that could poten-tially induce extrapyramidal signs were notexcluded, however, and a comprehensive neu-ropsychological battery was not used.We examined a consecutive series of

patients with Alzheimer's disease for the pres-ence of extrapyramidal signs. Our main goalswere to determine the prevalence ofextrapyramidal signs in Alzheimer's disease,to assess the response of patients withAlzheimer's disease and extrapyramidal signsto apomorphine, and to examine the associa-tions between Alzheimer's disease, extrapyra-midal signs, the pattern of cognitive deficits,and the prevalence of depression.

Patients and methodsPATIENTSA consecutive series of 103 patients whoattended the neurology clinic of our Institutebecause of progressive cognitive decline werescreened for inclusion in this study. Theinclusion criteria were (a) NINCDS-ADRDA'4 criteria for probable Alzheimer'sdisease; (b) no history of closed head injurieswith loss of consciousness, strokes or otherneurological disorders with CNS involve-ment; (c) normal results on laboratory tests;(d) no focal lesions on CT; (e) a Hachinskiischaemic score 415; and (I) no past or pre-sent intake of drugs that could produceextrapyramidal signs (neuroleptics, calciumchannel blockers, chronic use of antiemetics).Seventy eight patients met the criteria andwere included. We also examined 20 agecomparable healthy subjects with no history ofneurological or psychiatric disorders and nopast or present intake of drugs that could pro-duce extrapyramidal signs.

NEUROLOGICAL EXAMINATIONAfter informed consent patients and controlswere assessed with the unified Parkinson'sdisease rating scale (UPDRS).'6 This scale hasthree sections: (a) activities of daily living; (b)motor examination; and (c) complications ofantiparkinsonian treatment. Items scoresrange from 0 to 4, and higher scores indicatemore severe impairments. Based on themotor section scores of the UPDRS, patientswere divided into the following groups: (a)Alzheimer's disease-Parkinsonism: patientsincluded in this group had rigidity,bradykinesia, and resting tremor, rigidity plusbradykinesia only, or resting tremor only.Bradykinesia was defined as a score >1 onthe finger tapping, rapid hand movements,and alternating movements of the hands sec-tions of the UPDRS. Rigidity was defined as ascore >1 in the UPDRS (only cogwheelrigidity was considered); (b) Alzheimer's dis-ease-extrapyramidal signs: patients includedin this group had extrapyramidal signs other

than bradykinesia, rigidity, or resting tremor(flexed posture, gait disorders, masked face);and (c) Alzheimer's disease-no extrapyramidalsigns: patients included in this group scored 0on every item on the motor section of theUPDRS.

APOMORPHINE TESTPatients who met the criteria for Alzheimer'sdisease-parkinsonism received 60 mg of dom-peridone daily for at least 48 hours before thetest.8 A basal examination was carried out inthe fasting state at 0900 and included theWebster scale (a scale that measures motordisabilities),'7 the number of taps producedwhen patients were asked to tap alternativelyon two keys situated 20 cm apart with themore affected hand in 30 seconds, and thetime to rise from an armless chair, walk 6metres, come back, and sit down. We decidedto use the Webster scale instead of theUPDRS as the first has usually been used toassess motor changes after apomorphineinjection. After the basal assessment, 3 mg ofapomorphine were injected subcutaneously,and the neurological assessment was repeatedevery 15 minutes for one hour. Criteria for apositive response were an increase in tapping>15% and of walking speed >20% and adecrease in the Webster score > 3 points.'8

PSYCHIATRIC EXAMINATIONThe psychiatric evaluation included the fol-lowing assessments:

Structured clinical interview for DSM-III(SCID) 19The SCID is a semistructured diagnosticinterview for making the major axis I DSM-III-R diagnoses. The SCID was given by apsychiatrist blind to the remaining clinicaldata, and the interview was carried out withthe patient and at least one first degree rela-tive. Based on the SCID responses, DSM-III-R diagnoses of major depression anddysthymia were made.

Hamilton depression scale (HAM-D)20The HAM-D is a 17 item interviewer ratedscale that measures psychological and auto-nomic symptoms of depression.

NEUROPSYCHOLOGICAL EXAMINATIONPatients received a comprehensive neuropsy-chological evaluation that consisted of the fol-lowing tasks:

Mini mental state exam (MMSE)2'The MMSE is an 11 item examination thathas been found to be reliable and valid inassessing a limited range of cognitive func-tions in patients with dementia.

Buschke selective reminding test22This test measures verbal learning and mem-ory during a multiple trial list learning task.The patient listens to a list of words, and has torecall as many words as possible. Each subse-quent learning trial involves the selective pre-sentation of only those words that were not

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recalled on the immediately preceding trial.The outcome measures are the long termretrieval and the delayed recall scores.

Benton visual retention test23This test assesses visual perception and non-verbal memory. Patients are exposed to geo-metric designs for 10 seconds and areimmediately presented with a card containingthe correct design among three different foils.The patient has to select the correct one.

Apraxia subtest of the western aphasia battery24This test assesses the presence of ideomotorapraxia.

Block design (WAIS)25This test examines the presence of construc-tional apraxia. Patients are presented with redand white blocks and are asked to constructreplicas of printed designs. Time to comple-tion was not considered in the final score.

Digit span25This test examines auditory attention andincludes two parts. Both consist of seven pairsof random number sequences that the exam-iner presents at the rate of one per second. Inthe first part (digits forward), the patient isasked to repeat a string of numbers (from 2 to8) exactly as it is given, and in the second(digits backwards) the patient is asked torepeat a string of numbers (from 2 to 8) inreverse order.

Wisconsin card sorting test (WCST)26This test measures the ability to develop newconcepts and shift sets, and also requires thesubjects to suppress a previously correctresponse and produce a new one. Assessmentof the overall proficiency of the test wasjudged by the number of categories achieved(maximum 6). Because of the rather largenumber of cognitive tests assessed, wedecided to use number of categories as thesingle endpoint for this task.

Trail making test27This test examines visual, conceptual, andvisuomotor tracking. The patient is instructedto draw lines to connect consecutively num-bered circles on a paper (part A), and thenconnect the same number of consecutivelynumbered and lettered circles on anotherpaper by alternating between the two

Table 1 Demographic and psychiatric findings

Alzheimer's Alzheimer's Alzheimer'sdisease- disease- disease-noparkinsonism extrapyramidalism extrapyramidalism

Patients (n) 18 44 16Age (y) 74 9 (6 6) 72-4 (7 6) 71-8 (7-2)Sex (M/F) 4/14 11/33 4/12Education (y) 9-4 (5-3) 10 (5 3) 10-5 (4-1)Duration of illness (y) 4-1 (2 8) 4-2 (2 6) 4-7 (2 6)HAM-D scale** 15-3 (9-8) 10-6 (6 5) 5-8 (4 9)Major depression*** 6 (34%) 9 (20 5%) 0Dysthymia 8 (44%) 15 (34 5%) 4 (25%)No depression 4 (22%) 20 (45%) 12 (75%)

Values are mean (SD) or No (%).**p < 0-01; ***p < 0-001.

sequences (part B). The patient is urged toconnect the circles as quickly as possible. Tocontrol for graphomotor speed and visualscanning the final score was the time to com-plete part A minus the time to completepart B.

Controlled oral word association test28This test examines access to semantic infor-mation with time constraint. Patients wereinstructed to name as many words beginningwith the letter F as they could in one minute.People's names and proper nouns were notpermitted. The letters A and S were thenpresented successively, one minute beingallowed for each letter. The score was thenumber of words produced in one minute.

Boston naming test29This test measures the ability to name pic-tured objects. Line drawings of high and lowfrequency objects are presented one at a timeon cards, which the patient has to name.

Token test30This test measures verbal comprehension ofcommands of increasing complexity.

Raven's progressive matrices3'This test measures visuospatial reasoning.Patients are presented with a pattern problemwith one part removed and several picturedinserts, one of which contains the correct pat-tern. The patient has to select the missingpiece to complete the pattern.The whole testing session lasted between

60 and 120 minutes. Because some of thepatients showed fatigue during the assess-ment, they were allowed to split the cognitiveassessment into two or three sessions.

STATISTICAL ANALYSISStatistical analysis was carried out onmeans and SDs by analysis of covariance(ANCOVA), and post hoc t tests. Regressionswere calculated with a stepwise forwardregression analysis (F to enter = 1 0), and fre-quency distributions were calculated withcontingency tables, Fisher's exact tests, and x2tests with a Yates' correction for cell sizes

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Table 2 Neurologicalfindings

Alzheimer's Alzheimer'sdisease- disease-isolated Normalparkinsonism extrapyramidalism controls

Resting tremor 8 (44) 0 0Masked face 12 (66) 24 (54) 5 (25)Abnormal speech 8 (44) 5 (11) 0Finger tapping 14 (77) 13 (29) 2 (10)Action tremor 8 (44) 8 (18) 1 (5)Rigidity 15 (83) 17 (38) 8 (40)Hand movements 17 (94) 9 (20) 1 (5)Alternating movements 17 (94) 12 (27) 1 (5)Leg agility 15 (83) 12 (27) 1 (5)Rising from a chair 13 (68) 19 (43) 1 (5)Abnormal posture 13 (68) 24 (54) 5 (25)Abnormal gait 9 (50) 18 (40) 2 (10)Postural instability 7 (38) 18 (40) 1 (5)Body bradykinesia 12 (66) 25 (56) 1 (5)UPDRS (total motor score) 14-1 (7-7) 4-5 (4 8) 2-8 (1-8)

Values are No (%) except for UPDRS which is mean (SD).

Table 3 Mean (SD) neuropsychologicalfindings

Alzheimer's Alzheimer's Alzheimer'sdisease- disease-isolated disease-noparkinsonism extrapyramidalism extrapyramidalism

Buschke LTR 165 (9-1) 19-4 (18-7) 197 (242)Buschke delayed 2 4 (1-7) 2-2 (3-1) 1-4 (2 7)Apraxia (WAB) 56 2 (4 1) 56 (7-8) 58-0 (3 8)Digits backward (WAIS)* 3 0 (0 9) 3 0 (1-2) 4-0 (1-0)Wisconsin card sorting* 1 1 (1 5) 1-8 (2-1) 3-2 (1-9)Trail making test (A-B)* -339 (150) -254 (141) -181 (142)Block design* 2-2 (2 2) 2-3 (2 2) 4-9 (1-9)Controlled oral word

association 23-0 (6 4) 28-2 (10-5) 30-6 (10-8)Boston naming test 12-0 (4 0) 12-5 (5 8) 14-0 (4-2)Token test 17-3 (6 8) 15-7 (8 0) 19-4 (7 9)Raven's progressive matrices* 22-8 (27 7) 30 4 (29 8) 55-7 (32-7)Mini mental state exam 18-3 (5 3) 18-5 (6 6) 20-5 (6-1)Benton visual retention test 4-5 (2 0) 4 1 (2 3) 5-3 (2 8)

*p < 0*05.

10K4, df = 2, p < 0.005). This difference wasaccounted for by the significantly higherprevalence of parkinsonism in patients withAlzheimer's disease compared with normalcontrols X2 Yates = 5-41 df= 1, p < 0.02).On the other hand there were no significantbetween group differences in the frequencyof isolated extrapyramidal signs (X2 = 1 27,df= l,p = 0.25).

Only eight patients (10%) showed restingtremor, which was bilateral, mild, andvariable in five patients, and persistent inthe other three. Bradykinesia or rigiditywere always present in the Alzheimer'sdisease-parkinsonism group. The remainingmotor signs were also significantly morefrequent in the Alzheimer's disease-parkin-sonism group than in the Alzheimer's disease-isolated extrapyramidal signs group (table 2).

APOMORPHINE TESTEleven of the 18 Alzheimer's disease-parkin-sonism group patients underwent the apo-morphine test (five patients refused and twopatients could not be localised). The mean(SD) Webster scores, tapping scores, andwalking speed at basal examination were 9 9(3-8), 37-6 (12-1), and 17-4 (3 3), respec-tively. There were no clinical improvementsafter the apomorphine injection. Thirty min-utes after apomorphine injection, mean (SD)Webster scores, tapping scores, and walking

speed were 9-7 (4), 36-3 (10-5), and 17-4(3-3) respectively, and none of these differ-ences were significant (t = 1-4, 1-4, and 1-0respectively; p > 0K10). Side effects were pre-sent in all the 11 patients, and consisted ofmild and transient nausea, yawning, and som-nolence, which started five to 10 minutes afterthe injection and lasted for 15 to 30 minutes.

PSYCHIATRIC FINDINGSA one way analysis of variance (ANOVA) forHAM-D scores showed significant betweengroup differences (F(2,75) = 7-56, p <0-001). On individual comparisons, patientswith Alzheimer's disease-parkinsonism hadsignificantly higher HAM-D scores thanpatients with either isolated extrapyramidalsigns (p < 0.02), or no extrapyramidal signs(p < 0 0002), whereas patients with isolatedextrapyramidal signs showed significantlyhigher HAM-D scores than patients withAlzheimer's disease and no extrapyramidalsigns (p < 0 02). A hypothesis of equal fre-quency of dysthymia and major depressionbased on the presence of parkinsonism, iso-lated extrapyramidal signs, or no extrapyrami-dal signs was statistically rejected (X2 = 13,df = 4, p = 0 007). On individual compar-isons, patients with Alzheimer's disease-parkinsonism showed a significantly higherfrequency of major depression and dysthymiathan the Alzheimer's disease-no extrapyrami-dal signs group (Fisher's exact test p = 0-002and p = 0-03 respectively).To determine those factors that most sig-

nificantly correlated with parkinsonism inAlzheimer's disease, we carried out a stepwiseregression analysis in which the motorUPDRS score was the dependent variable andage, duration of illness, age at onset of demen-tia, MMSE, and HAM-D scores were theindependent variables. The regression analy-sis was significant (R2 = 0-26, F(4,73) = 6(5,p = 0-0004), and the variables that accountedfor most of the variance were the HAM-Dscores (R2 = 0-03, p < 0-0001), and age (R1 =0X07, p < 0X0001).

NEUROPSYCHOLOGICAL FINDINGSA multiple analysis of covariance (MAN-COVA) for the neuropsychological evaluation(group: Alzheimer's disease-parkinsonism,Alzheimer's disease-isolated extrapyramidalsigns, Alzheimer's disease-no extrapyramidalsigns; covariate: Hamilton depression scalescores; independent variables: neuropsycho-logical tasks) showed a significant main effect(Wilks' A (28,122) = 0 55, p < 0-05). Inde-pendent MANCOVAs for each neuropsycho-logical test showed significant between groupdifferences on the following: Wisconsin cardsorting test (F(2,74) = 6-59, p < 0-01), con-trolled oral word association test (F(2,74) =3-88, p < 0 05), Raven's progressive matrices(F(2,74) = 6(40, p < 0.01); digits backward(F(2,74) = 4A46, p < 0-05); block design(F(2,74) = 8&15, p < 0.001), and trail makingtest (F(2,74) = 6-92, p = 0.01). No signifi-cant between group differences were found onthe Bushke selective reminding test, Benton

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visual retention test, token test, Boston nam-ing test, digits foward, and ideomotor apraxia.On individual comparisons, the Alzheimer'sdisease-parkinsonism group showed signifi-cantly lower scores than the Alzheimer's dis-ease-normal group on the Wisconsin cardsorting test (F(1,31) = 18-2, p < 0-001), trailmaking test (F(1,31) = 19 3, p < 0 00 1), con-trolled oral word association test (F(1,3 1) =11-2, p < 0-001), Raven's progressive matri-ces (F(1,31) = 8'13, p < 0-01), digits back-ward (F(1,31) = 11-5, p = 0-001), and blockdesign (F(1,31) = 8-86, p < 0-01). TheAlzheimer's disease-isolated extrapyramidalsigns group showed significantly lower scoresthan the Alzheimer's disease-normal group onthe Raven's progressive matrices (F(1,57) =8&13, p < 0-01), Benton visual retention test(F(1,57) = 4-45, p

Merello, Sabe, Teson, MiglioreUli, Petracchi, Leiguarda, Starkstein

examined. Whereas our study showed that theprevalence of parkinsonism was significantlyhigher in the Alzheimer's disease group, theprevalence of isolated extrapyramidal signswas similar to that found in non-dementedage comparable controls. Although futurestudies should examine the prevalence ofextrapyramidal signs in young controls, thisfinding suggests that the high frequency ofisolated extrapyramidal signs in patients withAlzheimer's disease is related to age and notto the presence of dementia. On the otherhand parkinsonism (as defined in the presentstudy) was a specific finding restricted to asubgroup of patients with Alzheimer's disease.Based on these findings, future studies thatexamine extrapyramidal signs in Alzheimer'sdisease should be restricted to patients withAlzheimer's disease with tremor or rigidityand bradykinesia. It should also be stressedthat, in agreement with a recent report byKischka et al,33 we found that rigidity and aki-nesia but not tremor were the most prevalentextrapyramidal signs in patients withAlzheimer's disease and parkinsonism.

Another finding of our study was the signif-icant association between depression andextrapyramidal signs in Alzheimer's disease.Extrapyramidal signs have also been reportedin patients with primary (no known braininjury) depression. In a study that examinedthe presence of extrapyramidal signs in non-depressed patients with Parkinson's disease,primary depression, and normal controls,Rogers et al found that depressed patients hadsignificantly more extrapyramidal signs thannormal controls (significantly higher scores onthe Webster scale).34 These signs improvedafter depressed patients were successfullytreated with antidepressant medications. Fewstudies have examined the neuropathologicalcorrelates of depression in patients withAlzheimer's disease. Zweig et alP reported asignificantly greater neuronal loss in both thelocus coeruleus (which provides noradrener-gic innervation to most of the cortex) and thedorsal raphe nuclei (where serotonergic neu-rons are located) in patients with Alzheimer'sdisease and depression compared with non-depressed patients with Alzheimer's disease.Zubenko et al'6 confirmed the significant neu-ronal depletion in the raphe nuclei ofdepressed patients with Alzheimer's disease,but they also reported a significant neuronalloss in the substantia nigra of depressed com-pared with non-depressed patients withAlzheimer's disease. In a recent study, Forstlet al7 reported a significant associationbetween loss of noradrenergic and cholinergicneurons and depression scores in Alzheimer'sdisease. Thus it is possible that the associationbetween depression and extrapyramidal signsfound in the present study may result fromsignificant depletions of biogenic amines.

In a recent study, Girling and Berrios'3examined the association between extrapyra-midal signs and cognitive deficits inAlzheimer's disease, and found a significantcorrelation between higher scores on theWebster scale and more deficits on the con-

trolled oral-word association test, a test con-sidered to be sensitive to frontal lobe dysfunc-tion. Our study had methodologicalimprovements compared with the report ofGirling and Berrios because we excludedpatients taking neuroleptics or other medica-tions that could potentially induce extrapyra-midal signs, and we assessed patients with amore comprehensive neuropsychological bat-tery. Although patients with and withoutextrapyramidal signs did not show significantdifferences on the MMSE (a measure ofglobal cognitive decline), patients withAlzheimer's disease-parkinsonism showed sig-nificant deficits in frontal lobe-related tasks,such as the Wisconsin card sorting and thetrail making tests (which measure shiftingabilities), the controlled oral word associationtest (which measures verbal fluency), and theRaven's progressive matrices (which assessesabstract reasoning). We also found signifi-cantly more severe constructional apraxia inpatients with Alzheimer's disease-parkinson-ism, which some authors consider may also bepresent in patients with frontal lobe relateddeficits.40 Whereas significant between groupdifferences in specific cognitive tasks may berelated to the higher sensitivity of these taskscompared with the MMSE, no significantbetween group differences were found on ver-bal and visual memory tasks, which werereported to be the most sensitive tests for thediagnosis of dementia.'9 Thus our study repli-cates that of Girling and Berrios-namely, thefinding of frontal lobe related cognitivedeficits in patients with Alzheimer's diseaseand extrapyramidal signs. Moreover, we alsofound that deficits in frontal lobe related tasksmostly correlated with rigidity and bradykine-sia, but not with tremor.The question that now arises is what is the

mechanism of parkinsonism in Alzheimer'sdisease? This question may be answered fromclinical, neuropathological, and pharmacolog-ical perspectives. We have already discusseddiscrepancies between neuropathological andneuroradiological reports. Thus for the pre-sent study, we decided to examine the mecha-nism of extrapyramidal signs in Alzheimer'sdisease by a pharmacological approach (theapomorphine test). In patients withParkinson's disease the administration of apo-morphine is usually followed by a dramaticimprovement in extrapyramidal signs.8 Thisindicates a good response to levodopa treat-ment, and may be a marker of presynapticnigrostriatal dysfunction. In the present studynone of the 11 patients with Alzheimer's dis-ease and parkinsonism who underwent theapomorphine test showed a positive motorresponse, suggesting that parkinsonism inAlzheimer's disease may not result fromnigrostriatal dysfunction. Another possibilityis that the Alzheimer's disease-parkinsonismgroup has a diffuse Lewy body disease, aspatients with this disease may show extrapyra-midal signs that do not respond to dopamin-ergic agonists.40 Several findings argue againstthis possibility. Perry et al described the clinicalfeatures of pathologically confirmed senile

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dementia of the Lewy body type, and reportedthat the onset of illness was characterised byan acute or subacute confusional state, theextrapyramidal signs were mild, and patientsdid not meet the clinical criteria for probableAlzheimer's disease.35 On the other hand allour patients with Alzheimer's disease-parkin-sonism met the criteria for probableAlzheimer's disease, and none of them haddelirium at the onset of dementia. Regardlessof the final neuropathological outcome, wefind a significant association between parkin-sonism in Alzheimer's disease and specificpsychiatric and cognitive changes.

In conclusion, we found that about onequarter of a consecutive series of patients withAlzheimer's disease had parkinsonism. Thesepatients did not improve from their motordeficits with dopaminergic agonists, andshowed a high frequency of depression.Patients with Alzheimer's disease and parkin-sonism had significantly more severe deficitsin frontal lobe related tasks and constructionalpraxis than patients with Alzheimer's diseasebut without parkinsonism. Whether theparkinsonism in Alzheimer's disease improvesafter treatment with antidepressant drugs, andwhether this subgroup of patients withAlzheimer's disease show metabolic deficits inspecific brain areas will have to be examinedin future studies.

This study was partially supported by funds from the Institutode Investigaciones Neurologicas Raul Carrea-FLENI, theSandoz Foundation, and Qualitas Medicina. We thank JasonBrandt, PhD, for his most valuable suggestions, and LauraJason, MA, and Mariela Juejati, MA, for helping with the neu-ropsychological evaluation.

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7 Duret M, Goldman D, Messina J, Hildebrand J. Effect ofL-dopa on dementia related rigidity. Acta Neurol Scand1989;80:64-7.

8 Hughes AJ, Lees AJ, Stern GM. Apomorphine test to pre-dict dopaminergic responsiveness in parkinsonian syn-dromes. Lancet 1990;ii:32-4.

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