Auditory long latency event-related potentials in Alzheimer's disease and multi-infarct dementia

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1 Journl of Neurology, Neurosurgery, nd Psychitry 1988;51: Auditory long ltency event-relted potentils in Alzheimer's disese nd multi-infrct dementi RYUJI NESHIGE, GEOFF BARRETT,* HIROSHI SHIBASAKI From Division ofneurology, Deprtment ofinternl Medicine, Sg Medicl School, Nbeshim, Sg City, Jpn SUMMARY An uditory discrimintion prdigm ws employed to elicit event-relted brin potentils in 13 ptients with Alzheimer's disese nd 14 ptients with multi-infrct dementi. The P3 ltency ws significntly prolonged in 12 ptients with dementi compred with ge-mtched controls nd showed significnt negtive correltion with the score of Wechsler Adult Intelligence Scle (WAIS), especilly with tht of Digit Spn subtest. There ws no disese specificity. After physostigmine tretment, P3 ltency decresed nd WAIS score incresed in 6 mong 1 cses. A long-ltency component of the event-relted potentil (ERP), especilly P3, occurs when subject ttends nd discrimintes stimulus events which differ from one nother long some dimension (for exmple intensity, durtion or modlity).' P3 hs been reported to be ssocited with cognitive processing,2 nd the temporl lobes including hippocmpus nd mygdl hve been proposed s its possible genertor sites.34 Thus, ny fctor which modifies the timing of neurl mechnisms underlying perception nd cognition my led to chnges in the morphology or ltency of P3. There is generl consensus tht P3 ltency evoked by n uditory trget stimulus increses with ge by 1- to 1-8 m s per yer for ges rnging from 2 to 8 yers. Goodin et l' demonstrted tht P3 ltency in demented ptients ws significntly prolonged s compred with norml controls regrdless of the etiology of dementi. This finding hs been supported by other subsequent studies.7" Furthermore, Goodin nd Aminoff'2 distinguished between corticl nd subcorticl dementi by compring ech component of event-relted potentils. The purpose of this study ws to exmine the utility of P3 s dignostic test of dementi both in Alzheimer's disese (AD) nd in multi-infrct *Visiting scientist from Medicl Reserch Council Externl Scientific Stff, The Ntionl Hospitl for Nervous Diseses, London, UK. Address for reprint requests: Ryuji Neshige MD, Deprtment of Internl Medicine, Sg Medicl School, Nbeshim, Sg City, Sg, 84-1 Jpn. Received 29 Jnury 1988 nd in revised form 13 April Accepted 15 April 1988 dementi (MID); to clrify whether there is correltion between P3 mesures nd intelligence quotients (IQ) in demented ptients; nd to evlute the effect of physostigmine on IQ s well s P3. Mterils nd methods Subjects Thirteen ptients with cliniclly definite Alzheimer's disese (AD) (9 femles nd 4 mles, men ge 74 yers; rnge 6 to 82 yers, men Wechsler Adult Intelligence Scle (WAIS) score = 69) were dignosed on the bsis of the criteri proposed by the NINCDS-ADRDA work group.13 All ptients showed dementi of insidious onset nd slow progression, nd hd no other systemic or brin diseses tht could ccount for the progressive memory disturbnce nd other cognitive deficits. Other cuses of dementi were eliminted by pproprite lbortory tests. A group of 14 ptients with multi-infrct dementi (MID) consisted of 4 femles nd 1 mles (men ge 74; rnge 66 to 82 yers, men WAIS score = 67) who were dignosed by clinicl, EEG nd CT findings. Hchinski's ischemic score"4 ws 5 or bove in ll cses of MID. Every ptient selected showed only mild to moderte disbility since severely demented ptients were not cpble of performing the test. As norml controls, dt of 27 helthy subjects previously reported by US5 were used to compre the ge-relted prmeters, nd dt of nine oldest subjects mong those 27 were used to compre the non-gerelted prmeters (see Sttisticl nlysis). WAIS ws tested, without knowledge of P3 results, on the dy of P3 recording or no more thn 2 dys prt. The bttery consisted of Verbl Scle determined by six subtests nd Performnce Scle determined by five subtests. Five ptients ech with AD nd with MID were given physostigmine with the initil dily dose of 2 mg by mouth divided into four doses during the dytime. The dose ws 112

2 Auditory long ltency event-relted potentils in Alzheimer's disese nd multi-infrct dementi grdully incresed up to 1mg per dy nd ws mintined li. Correltion between P3 prmeters nd WAIS on tht level for week. Approximtely 2 weeks fter Liner regressions were performed between the ltencies s strting the mediction, tests of P3 nd WAIS were well s mplitudes of P3 nd the scores obtined from repeted. Ech test ws ctully initited 3 minutes fter the WAIS tests for ech ptient group. first or the second dose of the test dy. Tsk nd recording procedures Ech subject prticipted in n oddbll prdigm using udi: tory stimultion. The stimulus ws pure tone delivered binurlly through light hedphones t n intensity of 75 db SPL nd with the interstimulus intervl of 1-4 s. Tones of two different frequencies, I khz nd 2 khz, were presented t rte of 85 nd 15%, respectively, in rndom order. The subject responded to the trget stimulus by pressing pushbutton with his right index finger. The push-button ws connected to lmp which ws observed by the experimenters to ssess the response cpbility nd ccurcy. When ptients were unble to mintin their ttention to the tones, frequent reminders to perform the tsk were given by one of the exminers. Two hundred rtifct-free trils were verged in ech of two runs of n experiment. Responses from two runs were combined so tht verges were bsed on pproximtely 34 sweeps for frequent stimuli nd 6 sweeps for trgets. EEG ctivity ws recorded from sclp electrodes t Fz, C3, Cz, C4, P3, Pz nd P4 (Interntionl 1-2 system) which were referred to linked er lobe electrodes. An electrooculogrm (EOG) ws recorded by referring n electrode t the glbell to lterl suborbitl electrode below the right eye. Inter-electrode impednce ws reduced to below 3K ohm. Time constnt of mplifiers ws 3 s nd the high frequency cut-off ws set to I khz. Trils including rtifct were excluded from the verges. Activity ws smpled for totl of 768 ms (including 75 ms pre-stimulus period) t n ordinte period of 1-5 ms. The pek mplitude ws mesured with respect to the prestimulus bseline. STATISTICAL ANALYSIS L Criteri for bnormlities 1. Amplitude of ll components nd ltencies of Ni nd P2 We hve studied P3 in 27 helthy subjects ofvrious ges,5 nd found tht the bove prmeters were not relted to ge. In the present study, therefore, nine oldest subjects mong those 27 were used s ge-mtched norml control for intergroup comprison. Student's t test with one-wy nlysis of vrince ws used for sttisticl nlysis. 2. Ltencies of N2 nd P3 N2 nd P3 ltencies in individul ptients were defined s bnorml if the vlues were outside the 95% confidence limits bsed on the regression eqution of ltencies on ge obtined from our previously studied 27 norml subjects.5 As these prmeters were found to be relted to ge,5 the intergroup differences were tested with n nlysis of covrince by using dt stndrdised with respect to ge. In other words, the ctul ltency vlues for ech individul subject were stndrdised to the vlues for the ge 61 yers ccording to the regression eqution of norml group. This stndrd ge ws determined s the men ge of ll subjects, ptients nd helthy controls inclusive. III. Comprison before nd fter physostigmine tretment P3 ltencies nd WAIS scores before nd fter physostigmine tretment were compred by pired t test for ll of the 1 ptients treted. Results L Comprison oferp wveforms mong three groups Helthy control Freq. Nil Rre N2 SW P1 \X -AI P2 AD Freq. Rre MID Freq. Rre P3 L I * * I * *. t. 3 6 Stim Tifme (ms) I I 1.25,uV Fig 1 Grnd men wveforms of event-relted potentils in response to frequent nd rre (trget) tones in the uditory oddbll stimulus prdigm for helthy ged controls nd ptients with Alzheimer's disese (AD) nd multi-infrct dementi (MID). Helthy ged controls were selectedfrom our normtive dt pool.5 P1, NJ nd P2 showed no difference between the three groups. N2 nd P3 ltencies in the two dementi groups were significntly prolonged compred to the norml group.

3 1122 Tble 1 Component ltency (mis) nd mplitude (pu V) in Alzheiner's disese, multi-infrct dementi nd norml controls. Men (stndrd devition) Component AD (n = 13) MID (n = 14) Norml (n = 9) NI Ltency 94-2 (16-) 89 5 (1-2) 11. (16-9) Amplitude -2-8 (2-1) -2-2 (1-9) -2-7 (2.3) P2 Ltency (27 5) (25-1) 18-4 (25-5) Amplitude 4-2 (29) 3-2 (29) 4-3 (22) N2 Ltency* 252- (25 9)t (25 5)t (28-1) Amplitude 1.1 (1-8) --14 (2 ) --89 (3 8) P3 Ltency* (42-)t (34-5)t 356- (26 4) Amplitude 8-2 (4 2) 6-6 (4-3) 9 5 (5 9) Tsk: Button, Recording: Pz tp < -1 (compred with control). *As these prmeters were found to be relted with ge, the intergroup compnson ws mde with n nlysis of covrince by using the stndrdised dt with respect to ge (stndrd ge = 61). Student's t test ws used for other prmeters. All three groups showed wveforms which were essentilly the sme in mplitude nd morphology (fig 1). In every group, ERPs to trget rre tone stimuli showed prominent P3 component which ws not evident in the ERPs to the frequent tone. P1, NI nd P2 ppered to be different in ltency mong the three groups (fig 1), but the difference did not rech the sttisticl significnce (tble 1). N2 nd P3 ltencies in the two dementi groups were significntly prolonged compred with the norml group (fig 1, tble 1). N2 ltency in ll ptients but one of ech ptient group ws greter thn the predicted men vlue for their ge. N2 ltency ws bove the 95% confidence limits in 17% of AD ptients nd in 38% of MID ptients. P3 ltencies of ll demented ptients were greter thn the predicted men vlue for their ge (fig 2). P3 Tble 2 Degree of ssocition of WAIS with P3 ltency in Ev , o. Neshige, Brrett, Shibski 8 9 r - ---~ *oo _O MID * AD Age Fig 2 P3 ltency of ech individul ptient plotted ginst ge long with prt of the liner regression (solid line) nd 95% confidence limitsfor 27 neurologiclly norml dults tken from our previous study.5 P3 ltency in demented ptients ws bove the 95% confidence limits in 46% of AD ptients nd 43% of MID ptients. ltency ws bove the 95% confidence limits in 46% of AD ptients nd 43% of MID ptients. With regrd to mplitude of N1, P2, N2 nd P3, there were no sttisticlly significnt differences between ptients nd ged controls or between AD nd MID (tble 1). II. Correltion between P3 nd WAIS In the demented ptients P3 ltency showed Both disese n = 27 AD n = 13 MID n =14 r r r Full Scle - 71t - 75* --69 Verbl - 63* I Rnge of informtion Comprehension * -1 3 Arithmetic resoning Similrity - 61* Digit spn --63* Vocbulry Performnce --66* Digit symbol - 6* --75* Picture completion -661* Block design Picture rrngement Object ssembly * * = p < 1. t = p < 1. Tsk: Button, Recording: Pz.

4 Auditory long ltency event-relted potentils in Alzheimer's disese nd multi-infrct dementi E 5- u c 4-4'.I WAIS Fig 3 P3 ltency nd WAIS in ptients with AD nd MID. P3 ltency in demented ptients showed significnt negtive correltion with WAIS score. The negtive correltion with WAIS score ws more significnt in ptients with AD thn in those with MID. AD: r = -747p <1, MID: r =--687p < 5 Totl: r = - 71 p < -1 significnt negtive correltion with WAIS scores, tht is, shorter P3 ltencies were ssocited with higher WAIS scores (fig 3, tble 2). Ptients in the AD group tended to hve higher correltions between P3 ltency nd WAIS scores thn those in the MID group, but only the Comprehension subtest yielded correltion which ws significntly different between the two groups (p < 25). P3 mplitude in demented ptients did not correlte with WAIS scores. III. Chnge fter physostigmine tretment In six mong 1 ptients who were given physostigmine, P3 ltency reduced nd WAIS scores incresed fter the mediction (fig 4). In two cses, mediction mde no difference.to either P3 ltency or WAIS scores. In one MID cse, the WAIS score decresed nd P3 ltency becme longer. The men reduction of P3 ltency ws 18 7ms (pired t = 2-23 NS) nd the men increse in WAIS score ws 3 4 points (pired t = 3.8, p <.1). Thus, in generl, the direction of chnge in P3 ltency nd WAIS scores ws s expected from the regression line shown in fig 3. In fct, seven of 1 ptients showed chnge in P3 ltency in the direction predicted from the chnge in WAIS score (p = -55, Sign test). With regrd to the effect of physostigmine on the WAIS subtests, Picture Arrngement showed the gretest improvement followed by Comprehension. All but two ptients were unwre of chnge in their own performnces. Those two cses showed improvement in both P3 ltency nd WAIS score. Side-effects consisting of nuse nd dirrhoe developed in one * 45 - in >,4. U 9 ; T * AD o MID '7d'1T n Before - - After WAIS Fig 4 P3 ltencies nd WAIS scores in ptients with dementi before nd fter the dministrtion of physostigmine. In generl, the direction of chnge ws comprble in the two mesures. AD ptient t the dily dose of 6 mg. There were no chnges in pulse rte, blood pressure, serum electrolytes or liver function tests. Discussion 1123 The principl findings in this study re (1) significntly incresed ltency in pproximtely 45% of both AD nd MID ptients for the P3 component of the uditory ERP, (2) high correltion between P3 ltency nd WAIS score in demented ptients, nd (3) close correspondence between chnges in P3 ltency nd WAIS scores following the dministrtion of physostigmine. All ptients in the present series hd P3 ltencies greter thn the men vlues expected from the norml regression eqution on ge in spite of the fct tht ll cses hd only mild to moderte disbility. This pttern hs been found cross the previously reported studies7 1 1 nd supports the hypothesis tht P3 ltency is strongly ffected by dementing illness. However, the proportion of cses with significntly delyed P3 ltency ws well below the rte described in those with dementi (8%) (Goodin et ll) nd in those with AD (83%) (Syndulko et l7). Brown et ll' lso reported tht P3 ltency ws significntly prolonged in more thn hlf of 15 demented ptients. However, Pfefferbum et l5 reported tht P3 ltency ws significntly prolonged in fewer thn 5% of demented ptients. The min difference between those reports seem to lie in the response tsk required of the subject. Goodin et l,' Syndulko et l7 nd Brown et l" hd their

5 1124 subjects keep mentl count, wheres Pfefferbum et l5 nd ourselves used button-pressing tsk which might be esier to perform thn the count tsk. N2 ltency in our ptient groups ws lso significntly prolonged compred with the norml control. Ritter et l"6 nd Goodin et l'7 reported tht N2 nd P3 ltencies chnged lmost identiclly with incresing tsk difficulty. Since, in the present study. P3 ltency ws beyond 95% confidence limits in lrger number of demented ptients thn N2 ltency, P3 might be more sensitive to dementing illness thn N2. In the present study, P3 ltency ws shown to be strongly correlted with WAIS score. The highest negtive correltion with P3 ltency mong the subtests of WAIS ws seen for Digit Spn, followed by Digit Symbol. The Digit Spn subtest involves the orl repeting of two series of numbers one forwrd nd one bckwrd. The observed ssocition between P3 ltency nd Digit Spn, therefore, suggests tht these mesures my index common dimensions of disrupted cognitive processing. In the clinicl interprettion of the WAIS, 8 the Digit Spn subtest llows rpid check on verbl short term memory nd ttention. According to Hnsch et l,"9 high correltion between Symbol Digit Modlity test scores nd P3 ltency ws observed in Prkinson's disese. By testing 2 neurologiclly norml subjects, Polich et l2 found negtive correltion between P3 ltency nd Digit Spn. Most recently, Homberg et l2" lso demonstrted in Huntington's disese tht P3 ltency ws highly correlted with neuropsychologic tests especilly requiring concept formtion nd selective ttention. The P3 component hs been ssocited with vriety of cognitive processes. P3 ltency is considered to reflect the speed of neurl events underlying perception nd discrimintion of the trget or rre stimulus; mtching tht prticulr informtion ginst stimulus ctegories in memory; nd mking n pproprite decision whether to respond or not.2223 Thus, slowed neurl processing involved in stimulus evlution or decision-mking functions is postulted to underlie the ssocited impirment of P3 ltency nd Digit Spn. In other words, P3 ltency ppers to be strongly ssocited with ttention nd short term memory but not with generl intelligence nd resoning. One of the purposes of this study ws to test whether P3 ltency might serve s useful tool to evlute the effectiveness of specific drugs. Cnter et l24 reported tht lecithin did not ffect EEG spectr or P3 in Alzheimer's disese, which is consistent with reports tht lecithin dministrtion lone did not improve memory in ptients with Alzheimer's disese.25 We used physostigmine becuse its dmin- Neshige, Brrett, Shibski istrtion hs been reported to show memory improvement trnsiently in demented ptients.' In our study, there ws high correltion between the chnge of P3 ltency nd tht of WAIS score fter mediction. Furthermore, the WAIS score showed significnt improvement fter physostigmine while P3 ltency just filed to show significnt reduction (observed t = 2-23, t vlue for p < 5 = 2.25). In fct, hd we predicted tht P3 ltency would decrese fter tretment then we could hve ccepted our P3 result s significnt t p < 5 on the bsis of one-tiled test. It is still difficult to mke ny conclusion from these findings, however, becuse the comprison ws not performed blind nd the effects of prctice on both the ERP test nd the WAIS need to be tken into considertion lthough most ptients forgot bout the ERP or WAIS tested before. Thus, the question s to whether physostigmine improves cognitive function or not wits further study. However, the results indicte tht ERP tests cn provide useful objective informtion in the evlution of drug effects in demented ptients. We thnk Mr Mkomoto Ski for WAIS testing, Dr R Krmer for his comment, Christine Skibiniski nd Gerld R Beck, Clevelnd Clinic Foundtion, for sttisticl nlysis. References I Sutton S, Brren M, Zubin J, John ER. Evoked potentil correltes of stimulus uncertinty. Science 1965;15: Donchin E, Ritter W, McCllum WC. In: Cllwy E, Tueting P, Koslow S. eds. Cognitive Psychophysiology. The endogenous components of ERP. Event-relted brin potentils in mn. 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