41040ournal ofNeurology, Neurosurgery, and Psychiatry 1997;62:410-413

SHORT REPORT J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.410 on 1 April 1997. Downloaded from

Impairment in dating and retrieving remote events in patients with early Parkinson's disease

Annalena Venneri, Paolo Nichelli, Giacomo Modonesi, Maria Angela Molinari, Riccardo Russo, Carla Sardini

Abstract target event, and only when they failed to Remote has been studied in a it, did we offer a multiple choice recogni- group of 25 non-demented patients with tion procedure. A graded score was thus Parkinson's disease and their perfor- obtained depending on the number of cues mance has been compared with that of 22 needed to recall each event. Because we were healthy control subjects. Only patients interested in the effect of a putative prefrontal who scored > 27 on the mini mental state dysfunction in causing remote memory examination and with no anticholinergic impairment in patients with Parkinson's dis- treatment were included in the sample. A ease we only examined patients with early remote memory questionnaire was given, Parkinson's disease, without any detectable to evaluate memory for public events that sign of dementia. occurred from 1966 to 1990. Each event was probed with five questions concern- ing its content and one for the date. Methods Compared with healthy subjects, patients SUBJECTS with Parkinson's disease were signifi- The subject group comprised 25 patients with cantly impaired both in recalling the con- Parkinson's disease (mean age 60-4 (SD 7 3); tent and in dating remote events. These mean education 5-8 (SD 1-9) years), and 22 results support the claim that remote age matched healthy control subjects (mean memory in patients with Parkinson's dis- age 62-3 (SD 4.7); mean education 6-9 (SD ease is disrupted independently of 2 7) years). The mean duration of disease was dementia. This impairment might result 3 05 (SD 3T0) years. The mean mini mental from a dysfunction at the level of the cir- state score for the patients with Parkinson's cuit connecting the basal ganglia to the disease was 28-7 (SD 1.1), and 29-4 (SD 09) frontal lobes. for the control subjects. Subjects were recruited through the out- http://jnnp.bmj.com/ (7 Neurol Neurosurg Psychiatry 1997;62:410-413) patient clinic of the neurological department of the University of Modena (Italy). Only ambulatory patients with early idiopathic Department of Keywords: remote memory; Parkinson's disease; Parkinson's disease were included. One Psychology, University frontal lobe patient was in stage 1 of the Hoehn and Yahr ofAberdeen, UK were in A Venneri scale.3 The remaining 24 patients stage

2. The diagnosis of idiopathic Parkinson's dis- on September 25, 2021 by guest. Protected copyright. Sezione di Neurologia, Two previous studies have directly considered Dipartimento di the issue of remote memory in patients with ease was made by a neurologist based on the Patologia Parkinson's disease. In the first study, asymmetric onset of bradykinesia associated Neuropsicosensoriale, et all found that only demented with either rigidity or resting tremor. Only UniversitA di Modena, Freedman Italy patients with Parkinson's disease showed an patients with pronounced responsiveness to A Venneri impairment in recognising faces that were in levodopa were included in the study. P Nichelli the news in the years from 1920 to 1979. In a Exclusion criteria were history of neurological G Modonesi M A Molinari second study, Sagar et al2 found defective dat- illness other than Parkinson's disease, psychi- C Sardini ing of both public and personal events in non- atric illness, head trauma with loss of con- Department of demented patients with early Parkinson's dis- sciousness, medical illnesses, or medications Psychology, University ease, whereas content recall was only impaired adversely affecting cognition, and substance of Essex, UK disease. misuse. Patients either taking anticholinergic R Russo in demented patients with Parkinson's However, as information about content was medications or scoring < 27 on the mini mental Correspondence to: Professor Paolo Nichelli, obtained via a recognition task, the testing state examination4 were also excluded from Sezione di Neurologia, could have missed a retrieval the study. All patients were receiving anti- Dipartimento di Patologia procedure Neuropsicosensoriale, deficit. parkinsonian medication at the time of the Universita degli Studi di overcome we devised a study. These comprised carbidopa-levodopa, Modena, Via del Pozzo, 71, To this problem, 41100 MODENA, Italy. questionnaire in which information about benserazide-levodopa, amantadine HC1, L- Received 18 April 1996 public events was requested via a cued recall deprenyl, and bromocriptine. Normal controls and in revised form with progres- were spouses or relatives of patients participat- 15 October 1996 procedure. We provided subjects Accepted 10 December 1996 sively more detailed verbal cues about each ing in the study. Impairment in dating and retrieving remote events in patients with early Parkinson's disease 41

Patients with Parkinson's disease did not formance were separately scored for each J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.410 on 1 April 1997. Downloaded from differ from normal controls with respect to age question. (t45 = 0 99, NS) or years of formal education (t45 = 1 56, NS). Content information score Content information score depended on the MATERIALS AND PROCEDURE number of cues needed to produce the right Stroop test answer. Subjects recalling the target event This test measures cognitive flexibility. We without any cue obtained a score of five. Four, used a 30 item shortened version5 of the origi- three, and two points were assigned to subjects nal test. It comprises three parts: naming the requiring respectively one, two, or three cues. colour of dots, reading black and white colour When subjects could only recognise the correct names, and naming the colour in which colour answer among the alternatives, they scored one names are printed. Performance was evaluated point. Scores on questions concerning five in terms of errors and execution time. consecutive years were summed together. Five scores were hence obtained, one for each of the Wisconsin card sorting test periods: 1966-70; 1971-5; 1976-80; 1981-5; The purpose of this test is to assess the ability 1986-90. to form abstract concepts, and to maintain and shift the set. We used the modified proce- Dating dure of Nelson et al6 which requires subjects Dating performance was evaluated taking into to sort 48 cards one by one according to a cat- account three different variables: egory that must be deduced from the exam- Dating error-The absolute values of the dif- iner's feedback. After six consecutive correct ference between the estimated and the real responses, the subject is informed that the date of the event were clustered and averaged sorting category has changed. Performance across five consecutive years resulting in five was evaluated in terms of percentage of perse- five year period values for each subject. verative errors and number of sorting cate- Dating -The slope of the linear regres- gories that had been identified. sion of estimated versus real dates of the events was computed to measure the so called Public event questionnaire "forward telescoping effect"-that is, the The test explored the subjects' knowledge effect by which subjects tend to report a date about 25 events which occurred between 1966 more recent than the real one. and 1990. This period was chosen to match Dating precision-From the linear regression adulthood of the patients and normal subjects. of estimated versus real dates we computed a We selected one event for each year. Only score defined by the following formula: events that were likely to be familiar to most of 1-(residual variance/total variance) the Italian population were chosen. For each This score was used to indicate the close- event we prepared a question asking for infor- ness with which dates provided agreed with mation related to the event. If the subject one another (they were consistent with any could not respond correctly, information specific bias). about the target event was provided with a

progressive cueing method. For example, a STATISTICS http://jnnp.bmj.com/ question was the following: "A bomb The distribution of data points did not always destroyed the waiting room of a train station in conform to a normal distribution and vari- an Italian town. What is the name of the ances were not homogeneous between data town?" If the subjects could not remember the sets. Therefore, unless stated otherwise, P val- correct answer (Bologna), we added the fol- ues reported were obtained by means of the lowing cue: "Several 10s of people died and non-parametric Mann-Whitney two tailed U many were wounded as a consequence of the test. Results are presented as means (SEM) explosion". If there was no correct response, on September 25, 2021 by guest. Protected copyright. two further cues were added, one at a time: "The event occurred at 10 25 am" (a photo- Results graph of the event depicting the station clock Patients with Parkinson's disease showed no at the precise time of the explosion had been interference effects on the Stroop test. Their printed by the main Italian newspapers and performance did not differ either in terms of shown on television) and "A neofascist group errors (patients 3-2 (0 53); normal controls was charged with having placed the bomb". If 1-5 (0 4), NS) or in terms of execution time none of these cues triggered the production of (patients 25-9 (3 42); normal controls 21-2 the correct answer, subjects were offered four (2-57), NS). choices among which they had to select the On the Wisconsin card sorting test, patients correct response. In the example these were: with Parkinson's disease identified fewer cate- "Milan, Brescia, Florence, Bologna". Finally, gories (2-80 (0 252)) than controls (4 05 in the case of wrong recognition, subjects were (0-341), P = 0 009) and made a larger num- asked ifthey had any recollection of the event at ber of perseverative errors (4-92 (0 750)) than all. Whenever subjects either provided the cor- controls (2-14 (0-595), P = 0-006). rect response or could recollect the event but Scores on the public event questionnaire were unable to come up with the correct distributed normally and data were assessed answer, they were asked to recall the year in by analysis of variance (ANOVA). Patients which the event had occurred. with Parkinson's disease recalled fewer events Both content information and dating per- without any cueing than controls (8-56 412412~~~~~~~~~~~~~~~~~~~~~~Venneri,Nichelli, Modonesi, Molinari, Russo, Sardini

1 content Figure Mean 25 o patient with Parkinson's disease) obtained a J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.410 on 1 April 1997. Downloaded from scores in each Controls information a) m bias value than .1 and five year period. PD = PD patients dating greater unity (1 Parkinson's disease. Co 20 1-0, respectively). All the remaining subjects 0 showed a "forward telescoping effect" (they a) 15 tended to record events as more recent than 0 they actually were). Dating bias was 0-68 (0-045) in normal subjects and 0-56 (0-054) in 10 patients with Parlinson's disease. There was 0 (-) no significant difference between the two 5 groups (P = 0-20). was greater in controls 0 II ~~~~~Dating precision 1966-70 1971-75 1976-8 1981-85 1986-90 (0-63 (0-033)) than in patients with Five year period Parkinson's disease (0-48 (0-042); P = 0-01). The total content information score was related both to the number of categories (r = (1-066) v 12-86 (0-910), P = 0-004). WVhen 0-40; P = 0-006) and to the number of perse- groups were compared for number of items verative errors (r = 0-45; P = 0-001) on the recalled in , cued recall (one, two., or Wisconsin card sorting test, which is com- three cues), and recognition, there was a very monly considered to be a task sensitive to highly significant effect (F = 1 15-028, df 4, frontal lobe impairmient.6 P < 0-0001) of recall condition, but there was also a very highly significant interaction betwee,.n recall condition and group (F= Discussion 5-467., df 4, P = 0-0004). Post hoc compar- Different from previous findings,' our results isons showed that there was no difference showed that non-demented patients with betwee.-n the two groups for cued response and Parkinson's disease are impaired both in recogniition., but they differed in performance retrieving the content and in dating old memo- in free recall. Figure 1 shows the average con- ries. In the experiments of Freedman et al!' tent iniformation scores obtained by control and Sagar et a!', recall of public events was subject:s and patients with Parkinson's disease tested by means of pictures, either of famous on the five five-year periods of the public event faces' or of famous scenes.2 This supposedly questic)nnaire. Results of ANOVA on these might have provided powerful visual cues that scores showed that events concerning more led to the underscore of a defective recall of recent time periods were better recalled than content information. The procedure we earlier ones (F = 26-932; df 4,180; adopted, providing graded scores for sponta- P < Q.()OO 1). patients with Parkinson's disease neous and cued recall, might have permitted were vvorse than control subjects at recalling us to detect subtler impairments in remote the eNvent content (F = 9-297; df 1,45; memory. P < O.()038) but there was no interaction Several studies8-1 have provided evidence betwee,-n group and content score (F = 1 548, that prefrontal structures play a key part in df 4,1E30, NS)-that is, the temporal gradient planning a systematic search for old .

was sinniilar in the two experimental groups. The frontal lobes are directly connected to the http://jnnp.bmj.com/ Figuire 2 shows dating errors averaged basal ganglia through a complex circuit includ- acrossJfive year periods in normal controls and ing the caudate nucleus, thalamus, substantia in pat::ients with Parkinson's disease. The nigra, and globus pallidum. It has been sug- results of the two groups were compared by gested""1 that reduction in dopamine in this ANOVrA. As expected, dating errors were complex circuit-especially in the caudate greater for earlier than for more recent events nucleus-added to dopamine depletion in the (F = 50-67 1; df 4,180, P < 0-000 1). Patients corticomesial limbic system, causes decreasing with Pharkinson's disease were significantly less dopamine concentrations in the frontal cortex, on September 25, 2021 by guest. Protected copyright. accuraite than normal controls in dating (F = which clinically results in deficit in the so called 6-612; df 1,45 p = 0-01). However, there was "frontal tasks". Indeed, as shown in other stud- no inte-raction between group and dating error ies,"4''9 we found non-demented patients with (F =C)-28 1, df 4,180, NS). Parkinson's disease to be defective on the Onl'y two subjects (one control and one Wisconsin card sorting test, which is commonly held to be sensitive to frontal lobe dys:function. Previous work'5 20 has shown that patients Figure 2 Mean dating 10I o Controls with Parkinson's disease are impaired on recall errors in each five year * PD patients but not recognition memory tests, suggesting period. PD Parkinson's that the effort demanding retrieval processes disease. necessary for recall may result in imnpaired per- formance. Accordingly, the remote memory

5 impairment we found in patients with Parkinson's disease may be the result of their a) 0) difficulty in planning the retrieval of old memo- nies. As a consequence, patients with Parkinson's disease were able to recall fewer I ~~~~events spontaneously and needed a larger num- 1966-70 1971-75 1976-8 1981-85 1986-90 ber of cueing aids for reaching the correct Five year period answer compared wit-h normal subjects. Impairment in dating and retieving remote events in patients with early Parkinson's disease 413

Baddeley and Wilson21 argued that patients 8 Cohen NJ, Squire LR. Retrograde and remote J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.410 on 1 April 1997. Downloaded from memory impairment. Neuropsychologia 1981;19:337-56. with frontal lesions are incapable of activating 9 Kopelman MD. in clinical the problem solving component of memory research and practice. In: Conway MA, Ruben DC, Spinnler H, Wagenaar W, eds. Theoretical perspectives on retrieval. Following an alternative explana- autobiographical memory. The Netherlands: Kluwer tion,22 the prefrontal cortex stores complex Publications, 1992:427-50. 10 Squire LR, Cohen NJ. Remote memory, , knowledge units (managerial knowledge units and the neuropsychology of memory. In: Cermak LS, ed. (MKUs)), which unite a series of events that Human memory and amnesia. Hillsdale, NJ: Erlbaum, 1982:275-303. occur or occurred in our life. Remote memory 11 Kopelman MD. The neuropsychology of remote memory. deficits might follow prefrontal damage In: Spinnler H, Boller F, eds. The handbook of neuropsy- chology. Vol 8. Amsterdam: Elsevier, 1993:215-38. because of a loss of these representations. 12 Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid Y. We argue that Parkinson's disease may Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson's disease. Brain Res cause a similar impairment because of failure 1983;275:321-8. in accessing MKUs, which might parallel their 13 Hornykiewicz 0, Kish SJ. Neurochemical basis of dementia in Parkinson's Disease. Can J Neurol Sci 1984;11: impairment in accessing motor representa- 185-90. tions. 14 Lees AJ, Smith E. Cognitive deficits in the early stages of Parkinson's disease. Brain 1983;106:257-70. 15 Taylor AE, Saint-Cyr JA, Lang AE. Frontal lobe dysfunc- We thank Augusto Scaglioni who referred some of the patients tion in Parkinson's disease: the cortical focus of neostri- with Parkinson's disease. PN was funded by the Italian atal outflow. Brain 1986;109:845-83. National Research Council; AV was supported by the 16 Taylor AE, Saint-Cyr JA, Lang AE. Parkinson's disease: European Science Foundation. cognitive changes in relation to treatment response. Brain 1987;110:35-51. 1 Freedman M, Rivoira P, Butters N, Sax DS, Feldman RG. 17 Taylor AE, Saint-Cyr JE. Executive functions. In: Huber Retrograde amnesia in Parkinson's disease. Can J7 Neurol SJ, Cummings JL, eds. Parkinson disease: neurobehavioral Sci 1984;11:297-301. aspects. New York: Oxford University Press, 1990. 2 Sagar HJ, Cohen NJ, Sullivan EV, Corkin S, Growdon JH. 18 Gotham AM, Brown RG, Marsden CD. "Frontal" cogni- Remote memory function in Alzheisner's disease and tive function in patients with Parkinson's disease "on" Parkinson's disease. Brain 1988;111:185-206. and "off" levodopa. Brain 1988;111:299-321. 3 Hohen MM, Yahr MD. Parkinsonism: onset, progression, 19 Canavan AGM, Passingham RE, Marsden CD, Quinn N, and mortality. Neurology 1967;17:427-42. Wyke M, Polkey CE. The performance on learning tasks 4 Folstein MF, Folstein SE, McHugh PR. "Mini-mental of patients in early stages of Parkinson's disease. state": a practical method for grading the cognitive state of Neuropsychologia 1989;27: 141-56. patients for the clinician. J7 Psychiatr Res 1975;12: 20 Brown RG, Marsden CD Cognitive function in Parkinson's 189-98. disease: from description to theory. Trends Neurosci 1990; 5 Venneri A, Molinari MA, Pentore R, Cotticelli B, Nichelli P, 13:21-29. Caffarra P. Shortened Stroop color-word test: its applica- 21 Baddeley A, Wilson B. Amnesia, autobiographical memory, tion in Alzheimer's disease. In: Nicolini M, Zatta PF, and . In: Rubin DC, ed. Autobiographical Corain B, eds. Alzheimer's disease and related disorders. memory. Cambridge: Cambridge University Press, 1986: London: Pergamon Press, 1993:81-2. 225-52. 6 Nelson HE. A modified card sorting test sensitive to frontal 22 Grafman J. Alternative frameworks for the conceptualiza- lobe defects. Cortex 1976;12:313-24. tion ofprefrontal lobe functions. In: Boller F, Grafman J, 7 Milner B. Effects of different brain lesions on card sorting eds. The handbook of neuropsychology. Vol 9. Amsterdam: test: the role offrontal lobes. Arch Neurol 1963;9:100-10. Elsevier, 1994:187-201. http://jnnp.bmj.com/ on September 25, 2021 by guest. Protected copyright.