SCOPOLAMINE-INDUCED COGNITIVEIMPAIRMENT AS A PREDICTOR OF COGNITIVEDECLINE IN HEALTHY ELDERLY VOLUNTEERS:

A 6-YEAR FOLLOW-UPANDREW BARKER1*, ROY JONES2, JACKIE PRIOR2 AND KEITH WESNES3

1Senior Research Fellow/Honorary Consultant in Old Age Psychiatry, Thornhill Research Unit,Moorgreen Hospital, Southampton, UK

2Director, The Research Institute for the Care of the Elderly, St Martin's Hospital, Bath, UK3Director, Cognitive Drug Research Ltd, Reading, UK

ABSTRACT

Objective. To determine if scopolamine-induced cognitive impairment in healthy elderly people predicts cognitivedecline 6 years later.

Design. Prospective cohort study.Setting. Elderly care research unit.Participants. Healthy elderly people who were part of a volunteer panel of research subjects.Interventions. Scopolamine 0.2 mg administered subcutaneously at baseline.Main outcome measures. Cognitive drug research computerized cognitive testing battery pre- and post-scopolamine,

with repeat testing over 6 years later.Main results. 16/24 subjects were retested. Although marked decrements in cognitive functioning were seen with

scopolamine, there was little change in performance over 6 years, and no signi®cant association was seen betweenscopolamine-induced decrement and change over time.

Conclusions. The scopolamine challenge test is not likely to play a role in the preclinical diagnosis of Alzheimer'sdisease. # 1998 John Wiley & Sons, Ltd.

Int. J. Geriat. Psychiatry, 13: 244±247, 1998.

KEY WORDSÐscopolamine; aged; prognosis; diagnosis; cognition; memory; Alzheimer's disease; cholinergicantagonists; muscarinic antagonists

Currently available anti-Alzheimer's drugs arepalliativeÐthey were not designed to a�ect thepathogenesis of the disorder. However, there isincreasing evidence that some commonly usedmedications such as NSAIDs (Stewart et al., 1997)and hormone replacement therapy (Tang et al.,1996) may have disease-modifying e�ects in Alz-heimer's disease, and at the time of writing the®rst agent likely to demonstrate a reduction indisease progression (propentofylline) is awaitinglicence approval with the European MedicinesEvaluation Agency. In order to maximize the

therapeutic bene®t of such compounds, early andpreferably preclinical diagnosis of the disorder willbe needed.

One potential marker is scopolamine-induceddecrement in cognitive function. Since a reductionin central cholinergic function is implicated in thecognitive impairments found in Alzheimer's dis-ease, it may be possible to probe the functionalreserve of the cholinergic system with an anti-cholinergic drug. Elderly people are more sensitiveto the cognitive e�ects of anticholinergics thanyoung (Molchan et al., 1992), and people withAlzheimer's disease more sensitive than normalelderly controls (Sunderland et al., 1985).

In 1995 we reported in this journal a 3-yearfollow-up of a group of healthy elderly volunteerswho had undergone a scopolamine challenge test

CCC 0885±6230/98/040244±04$17.50 Received 10 September 1997# 1998 John Wiley & Sons, Ltd. Accepted 16 December 1997

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 13: 244±247 (1998)

*Correspondence to: Dr A. Barker, Thornhill Research Unit,University of Southampton, Moorgreen Hospital, Botley Road,West End, Southampton SO30 3JB, UK. Tel: 01703 475216.Fax: 01703 463022.

as part of a study involving a putative antidementiaagent (Barker et al., 1995). In two out of a batteryof 10 computerized cognitive tests there wasa signi®cant correlation between scopolamine-induced decrement and subsequent decline. How-ever, the subjects were high performers at baselineand there was very little overall change in cognitivefunction in the group over the 3 years on which toassess decline. The current study retested the samesubjects 6 years after baseline.

METHODS

In 1990, 24 healthy elderly subjects received 0.2 mgsubcutaneous scopolamine prior to either oralcycloserine or placebo (Jones et al., 1991). Baselineand serial measurements of cognitive function wereperformed throughout the day to assess maximalscopolamine-induced decrement using the cogni-tive drug research computerized assessment system(CDR battery) (Wesnes et al., 1987). Baseline per-formance on the Mini-Mental State Examination(MMSE) (Folstein et al., 1975) was also assessed.

The version of the CDR battery that was usedproduces 10 subtest scores: simple reaction time,choice reaction time, choice reaction time accuracy,vigilance accuracy, vigilance false alarms and thevigilance reaction time, delayed recognition reac-tion time, delayed recognition sensitivity index,memory scanning reaction time and memoryscanning sensitivity index. A detailed descriptionof these tests is given in our previous article(Barker et al., 1995). Parametric techniques (pairedt-tests and Pearson correlation) were used forstatistical analysis for all variables except vigilanceaccuracy and vigilance false alarms, for which

non-parametric tests (Wilcoxon matched-pairssigned-ranks test and Spearman rank correlation)were more appropriate. p-values quoted are basedon a two-tailed test of signi®cance and a value ofp5 0.05 set for statistical signi®cance.

RESULTS

Of the 24 subjects originally studied, 16 were seenat follow-up (three had died, two moved away, onewas ill and two declined to consent). There was nodi�erence at baseline between those seen and lost tofollow-up in age (mean 70.6 vs 70.2), sex (6/16 malevs 10/24 male) or MMSE score (mean 29.75 vs 30).Mean time between baseline and follow-up assess-ments was 6.5 years (range 6.3±6.8). The MMSEscore of the 16 subjects remained high (baselinemean 29.75, follow-up mean 29.5) and no-onescored less than 28 at baseline or follow-up.

The decrements on CDR subtests produced byscopolamine for these 16 subjects were comparablewith results presented previously (Barker et al.,1995): in all except vigilance false alarms, there wasa marked and statistically signi®cant reductionin cognitive performance (Table 1). Cognitiveperformance of this high-performing group hadchanged little over 6 years, with only two testsshowing any statistically signi®cant deterioration(Table 2).

A comparison of scopolamine-induced cognitivedecrement with subsequent decline in perform-ance on the CDR battery showed no statisticallysigni®cant relationship on any of the subtests,though two trends in the direction of decrementbeing associated with decline over the 6-yearfollow-up (Table 3).

Table 1. Scopolamine-induced decrement in cognitive performance on the CDR battery

CDR test scoresÐmean (SD) Baseline Post-scop. Statistic/p

Simple reaction time 281 (45) 327 (58) t� 5.3 p� 0.000

Choice reaction time 448 (56) 501 (84) t� 3.9 p� 0.002

Choice reaction time accuracy 97.2 (2.0) 96.1 (2.6) t� 2.6 p� 0.02

Delayed recognition reaction time 769 (102) 861 (148) t� 3.3 p� 0.005

Delayed recognition sensitivity index 0.71 (0.17) 0.51 (0.19) t� 6.3 p� 0.000

Memory scanning reaction time 645 (118) 675 (136) t� 1.8 p� 0.097

Memory scanning sensitivity index 0.92 (0.06) 0.88 (0.07) t� 2.2 p� 0.045

Vigilance accuracy* 99.5 (99±100) 97 (98.3±99.8) z� 2.1 p� 0.04

Vigilance false alarms* 0.5 (0±0.9) 0.4 (0.3±1.0) NS

Vigilance reaction time 433 (40) 480 (47) t� 5.6 p� 0.000

*Wilcoxon matched-pair signed-ranks test based on median (interquartile range).

# 1998 John Wiley & Sons, Ltd. INT. J. GERIAT. PSYCHIATRY, VOL. 13: 244±247 (1998)

SCOPOLAMINE-INDUCED COGNITIVE IMPAIRMENT AND COGNITIVE DECLINE 245

DISCUSSION

Anticholinergic challenge has been used to demon-strate cognitive dysfunction and hypersensitivepupillary dilation in people with Alzheimer'sdisease (Sunderland et al., 1985; Scinto et al.,1994). Sensitivity to anticholinergics has also beendemonstrated in people with Down's syndrome(Sacks and Smith, 1989), a disorder which isoften used as a model for Alzheimer's disease. Inthe present study, a moderate and consistentcorrelation coe�cient was demonstrated betweenscopolamine-induced cognitive decrement withsubsequent decline for memory scanning sensitivityindex, vigilance accuracy and vigilance false alarmsat 3 years and 6-years follow-up. The correlation isnow non-signi®cant due to reduction in numbers ofremaining subjects. There was little decline inoverall cognitive test performance over the 6 yearsand this limits the possible predictive power of thescopolamine challenge in this group of patients. Its

use in a group with mild cognitive impairment mayachieve even better results.

There are a number of markers which may helpdistinguish people with early Alzheimer's disease,including psychological (Christensen et al., 1991),neuroimaging (Jobst et al., 1992), biochemical(Van Nostrand et al., 1992; Jensen et al., 1995)and genetic (Blesa et al., 1996). Of particularinterest is the possibility of a protein measurable inserum which is positive preclinically (Kennardet al., 1996). In view of these developments, it isunlikely that a scopolamine challenge test will playa diagnostic role clinically in Alzheimer's disease. Itis, however, likely to continue to be useful inscreening potential anti-Alzheimer's medications.

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Table 2. Change in cognitive scores on the CDR battery over 6 years

CDR test scoresÐmean (SD) Baseline Follow-up Statistic/p

Simple reaction time 281 (45) 287 (55) NS

Choice reaction time 448 (56) 440 (47) NS

Choice reaction time accuracy 97.2 (2.0) 96.9 (2.8) NS

Delayed recognition reaction time 769 (102) 929 (452) NS

Delayed recognition sensitivity index 0.71 (0.17) 0.77 (0.19) NS

Memory scanning reaction time 645 (118) 682 (116) t� 2.8 p� 0.02

Memory scanning sensitivity index 0.92 (0.06) 0.94 (0.07) NS

Vigilance accuracy* 99.5 (99±100) 96.7 (84.8±100) z� 2.3 p� 0.02

Vigilance false alarms* 0.5 (0±0.9) 0 (0±1.0) NS

Viligance reaction time 433 (40) 470 (106) NS

*Wilcoxon matched-pairs signed-ranks test based on median (interquartile range).

Table 3. Correlation coe�cients for decline with changeover time (baseline7 follow-up) for CDR tests

R p

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Delayed recognition sensitivity index 0.03 NS

Memory scanning reaction time ÿ0.15 NS

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Vigilance accuracy ÿ0.40 NS

Vigilance false alarms ÿ0.41 NS

Vigilance reaction time ÿ0.44 (0.08)

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246 A. BARKER ET AL.

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