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Journal of Clinical and Experimental Neuropsychology Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ncen19
Memory and attention in patients with senile dementia of the alzheimer type and in normal elderly subjects a
a
a
b
C. R. Lines , C. Dawson , G. C. Preston , S. Reich , c
C. Foster & M. Traub
a
a
Merck Sharp and Dohme Neuroscience Research Centre , Harlow, U.K. b
St. Thomas' Hospital , London, U.K.
c
Queen Mary's Hospital , Sidcup, U.K. Published online: 04 Jan 2008.
To cite this article: C. R. Lines , C. Dawson , G. C. Preston , S. Reich , C. Foster & M. Traub (1991) Memory and attention in patients with senile dementia of the alzheimer type and in normal elderly subjects, Journal of Clinical and Experimental Neuropsychology, 13:5, 691-702, DOI: 10.1080/01688639108401083 To link to this article: http://dx.doi.org/10.1080/01688639108401083
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content.
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This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sublicensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Journal of Clinical and Experimental Neuropsychology 1991, VOI. 13, NO. 5, pp. 691-702
0168-863419 1/1305-0691$3.W 0 Swets & Zeitlinger
Memory and Attention in Patients with Senile Dementia of the Alzheimer Type and in Normal Elderly Subjects* C.R. Lines’, C. Dawson’, G.C. Preston’, S. Reich’, C. Foster3, and M. Traub’
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‘Merck Sharp and Dohme Neuroscience Research Centre, Harlow, U.K. 2St. Thomas’ Hospital London, U.K. and 3Queen Mary’s Hospital, Sidcup, U.K.
ABSTRACT Previous studies have shown that cholinergic blockade in normal subjects induces impairment of vigilance as well as memory deficits. In the present investigation we have examined the validity of this pharmacological model of dementia by administering a battery of cognitive tasks to patients with mild and moderate senile dementia of the Alztieimer type and to age-matched controls. In contrast to volunteers receiving scopolamine all the mildly demented patients, and half of those moderately affected, performed normally on tests of vigilance whilst exhibiting the expected memory deficits. These data suggest that the mechanism of memory loss in Alzheimer’s disease may differ from that found in scopolamine-induced amnesia.
The postmortem findings of a loss of cholinergic markers in pathways projecting from the basal forebrain to the cortex and hippocampus of patients with Alzheimer’s disease (Bowen, Smith, White, & Davison, 1976; Davies & Maloney, 1976) has led to the proposition that damage to this particular system may be responsible for a number of the major clinical features of Alzheimer’s disease. The ‘cholinergic hypothesis’ has received further support from the observation that anticholinergic agents, such as scopolamine (hyoscine), induce temporary deficits of secondary memory following administration to healthy volunteers (Kopelman, 1986). Although the ‘scopolamine model’ fails to account for a number of features of Alzheimer’s disease, including failures of primary and remote memory, of praxis and of language (Jorm, 1987), it has been claimed that cholinergic blockade induces a selective loss of secondary memory reminiscent of early dementia (Kopelman & Corn, 1988). The postulate that centrally acting anticholinergic agents have specific amnestic properties which are dissociable from their sedative
* The authors would like to thank Mrs. J. Tredinnick for typing this manuscript. Address for correspondence: Dr. M. Traub, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR. U.K. Accepted for publication: November 14, 1990.
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actions has been summarised by Kopelman (1986) as follows: “...the memory impairment produced by hyoscine is unlikely to be accounted for in terms of impaired attention, although performance at tests of attention is affected at higher doses and at tests (e.g. dichotic listening) where the information processing load is relatively great.” However, in a series of studies we have been unable to dissociate the amnestic properties of scopolamine from its sedative effects; even at relatively low doses scopolamine induced drowsiness (on a visual analogue scale) together with a decrease in vigilance (auditory and visual sustained attention) (Broks et al., 1988). In addition, when the effects of cholinergic blockade were reversed by an anticholinesterase, physostigmine (Preston et al., 1988), or diminished by the development of tolerance on chronic treatment (Brazell, Preston, Ward, Lines, & Traub), 1989), there was no evidence of differential effects on sedation, vigilance or secondary memory. Others, too, have found evidence for attentional deficits in the range of doses which produce memory impairment (Parrott, 1986, Wesnes, Simpson, & Kidd, 1988; Wesnes & Warburton, 1983,1984). It is uncertain to what extent the attentional deficits that accompany scopolamineinduced memory loss mimic the symptoms of early Alzheimer’s disease. Although it is a common observation that patients in the later stages of the disorder suffer marked impairment of arousal, there have been relatively few formal studies of attentional processes in mild/moderate dementia. The conclusion by Butters et al. (1988) that patients with probable Alzheimer’s disease show deficits on the attentiow‘concentration index of the Wechsler Memory Scale is in broad agreement with previous reports (Vitaliano, Breen, Albert, Russo, & Prinz, 1984), but these studies have been limited by their use of relatively nonselective psychological tests in groups of patients who have reached a stage of their illness when virtually all cognitive functions are affected to some degree. The main aim of the present investigation was to test the predictive value of the ‘scopolamine model’ of dementia by examining the performance of mildly affected patients on tests of vigilance which have been previously shown to be sensitive to cholinergic blockade (Brazell et al., 1989; Broks et al., 1988; Preston et al., 1988). It is possible that impairment of vigilance may be a relatively early marker of dementia and may contribute to the other well described cognitive deficits. In this case, drugs that appear to improve attention such as nicotine or benzodiazepine inverse agonists may be of benefit in mild dementia (Sahakian, Jones, Levy, Gray, & Warburton, 1989; Sarter, Schneider, & Stephens, 1988).
METHODS Subjects Patients: Eight community-dwelling patients (2 males and 6 females)judged to be suffer-
ing from mild senile dementia of the Alzheimer type (SDAT) were included in the study. (As in previous studies on mild SDAT the group size is relatively small, due to difficulties
693
VIGILANCE IN ALZHEIMER’S DISEASE
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in obtaining patients who are at an early stage of the disease.) The diagnosis was made according to NINCDS-ADRDA criteria for probable Alzheimer’s disease (McKhann et al., 1984) by a geriatrician on the basis of history and routine laboratory and CT investigations to exclude other possible causes of dementia such as multi infarct dementia or dementia due to head injury. The judgement of severity was based on the criteria of the Clinical Dementia Rating (Berg, 1984) for mild dementia and on the score in the MiniMental State Examination (MMSE - Folstein, Folstein, & McHugh, 1975). Eight moderately demented patients (MMSE = 11 - 19) were also examined but they varied considerably in their ability to complete the battery, because of dyspraxia or dysphasia, and their results are only summarised briefly.
Normal Elderly: Eight normal age-matched controls (3 males and 5 females) from the community with no known relevant medical disorder were selected to take part in the study. Table 1 shows the mean age, premorbid or current IQ (as estimated by the National Adult Reading Test (NART - Nelson, 1982)). and MMSE scores for the mild SDAT patients and normal elderly. There were no significant age or IQ differences between the two groups. Vision and hearing was adequate (when corrected if necessary) in all subjects.
Apparatus The apparatus for computer based testing has been described elsewhere (Broks et al., 1988). It consists of an IBM personal computer linked to a touch sensitive colour monitor.
Test Selection The asessments undertaken fell into the following three broad categories: 1 . Tests of overall intellectual function: the Cambridge Cognitive Examination (CAMCOG - part of the Cambridge Examination for Mental Disorders of the Elderly (Roth, Huppert, Tym, & Mountjoy, 1988)) was administered. This consists of 60 items examining a wide range of cognitive functions which are grouped into eight subscales. It incorporates the items of the MMSE. The NART was used to give an estimate of the person’s premorbid or current IQ. In the case of the moderate patients only the MMSE was given.
2. Sustained attention tests: an auditory sustained attention test and visual vigilance test, identical to those we have used with normal young volunteers receiving scopolamine, were administered.
3. Memory tests: these were chosen to examine a variety of aspects of memory such as new learning (verbal free recall and recognition), forgetting (delayed recall and recognition), retrieval from long term memory (verbal fluency test) and immediate short term memory (digit and block spans). Table 1. Demographic Details (means and ranges). Age
NART estimated IQ
MMSE
Normal elderly
78 (70-97)
103 (76- 128)
29 (27-30)
Mild SDAT
82 (75-92)
106 (87- 11 8)
22 (20-26)
694
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Procedure
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For the normal elderly subjects all tests were administered during the same session (approximate duration 2 hours). For the mild SDAT patients all the tests of memory and attention were administered during a single session (approximate duration 1.25 hours). but the other assessments were sometimes undertaken on a separate occasion. Patients and control subjects were given the opportunity to rest between tests but there were no breaks during any individual task. In the moderate patient group it was often necessary either to modify the experimental procedures (e.g., by allowing verbal rather than touchscreen responding and presenting stimuli verbally instead of visually) or to abandon particular tests altogether.
Test Details (in order of administration) I ) Wiikins Auditory Sustained Attention (Wilkins, Shallice, diMcCarthy, 1987) In this procedure the subject was required to listen to trains of bleeps from the computer. At the end of each train the subject was asked to indicate the number of bleeps heard by pointing to a number selected from a choice (1-15) presented on a grid on the touchscreen. Train lengths from 5-14 were given in a random order at a nominal frequency of 0.25 hz. The bleeps in a train had a duration of 50 ms and were separated by a period randomly chosen to be 1 frequency +/- O.S/frequency (i.e., tones could be separated by 2 to 6 s). The measure taken was the number of errors made. This procedure was identical to one which showed deficits in young volunteers receiving scopolamine (Broks et al.. 1988). The test lasted for 10 minutes and was preceded by a practice session. 2 ) Verbal Free Recall and Recognition In this test subjects were presented with a list of 10 high frequency and imageability words (Paivio, Yuille, & Madigan. 1968) (animal, car, child, corn, diamond, factory, meat, window, wine and woman), one at a time, on the monitor. Presentation rates were controlled by the experimenter depending on the time taken by the subject to pronounce the word correctly, although there was a minimum presentation time of 2 s. At the end of the presentation the subject was given a maximum of 60 s to recall as many words as they could, in any order. This procedure was repeated for four trials using the same word list, presented in the same order, each time. Measures taken were the number of words recalled and intrusions. Following the last verbal free recall trial, the subject performed a three-choice recognition test. Three words (consisting of the target word and two semantically related words) were presented on the monitor. The subjects’ task was to indicate (by touching it) which word had been displayed in the original word list. The number of words correctly recognised was recorded. 3 ) Visual Vigilance This procedure was adapted from that reported by Nuechterlein, Parasuraman, and Quiyan (1983). Digits were presented briefly on the computer screen against a random visual noise background, in which each pixel was set to either black or to the colour and intensity of the target with a probability of 0.5. The digits were presented at a rate of ]/second for 5 minutes. The subject was required to press a hand-held push-button whenever a particular target digit (7) appeared on the screen. In each minute block of 60 trials there were 15 targets and 45 non-targets (each stimulus being exposed for 240 ms). which were chosen from the remaining digits 1-9. Data collected from this task (for each block of trials) were hit rate and false alarms. This procedure was identical to one which has shown deficits in young volunteers receiving scopolamine (unpublished data; scopolamine deficits using a task
VIGILANCE IN ALZHEIMER'S DISEASE
695
which differed only in the stimulus duration (40 ms) are reported by Preston et al. (1989)). The test was preceded by a practice session.
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4 ) Delayed Recall and Recognition This test was run approximately 15 minutes after the verbal free recall test (during which time the visual sustained attention task was performed and any remaining time was taken up with conversation). The subject was given a minimum of 60 s in which to recall as many items as possible from the original word list. This was followed by a three-choice recognition procedure (the two semantically related words were different from those used in the recognition task given after the immediate free recall procedure).
5 ) Digit Span In this test the subjects were presented with sequences of digits displayed on the screen. At the end of each sequence a grid containing the digits 1-9 were displayed on the touchscreen; the subject was then required to repeat the digit sequence by touching the appropriate numbers on the grid. Digit sequences were given at a frequency of approximately 1 digidsecond. The sequences were chosen randomly with the constraint that no digit could appear more than once on a given sequence. This test always started with a sequence of two digits. Thereafter the sequence length was increased by one each time the subject succeeded. This procedure was adopted until the subject failed at a sequence length. At this point another attempt was given at the same sequence length. The test was terminated once the subject had failed twice at a given sequence length and the span recorded as the maximum number of digits correctly recalled. 6 ) Block Span This computerised version of the Corsi blocks test was analogous to the digit span test, except that the material recalled was spatial rather than verbal. An irregular array of rectangular boxes was displayed on the screen; a number of boxes, corresponding to the sequence length, were then 'lit up' (turned red for 1 s) in order. The subject was required to echo the sequence of boxes by touching them in the appropriate order. All other details were as for the digit span test. 7) Verbal Fluency Both category and letter fluency were examined. For the category fluency task subjects were told they would have a minute to name as many animals as they could. The letter fluency task consisted of an 'easy' letter (S)and a 'hard' letter (J). For each letter subjects were told they would have a minute to say as many words as they could think of beginning with that letter excluding the names of people or places. The measure taken was the number of correct words given (excluding repetitions).
RESULTS Mild Dementia/Normal Elderly Data were analysed by between-groups analysis of variance. The means and standard deviations for the sustained attention and memory tests are given i n Table 2.
I . Overall lntellecrual Function The functioning of normal elderly versus SDAT patients on the various subscales of the C A M C O G are shown in Figure 1. It can be seen that t h e mild S D A T
6%
C.R. LINES ET AL.
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group were significantly impaired on the orientation (F [1,14]= 23.80, p < .0005), language (F [1,14]= 35.10,p c .OOOl), memory (F [1,14]= 15.54,p c .005), praxis (F [1,14]= 12.27,~ < .005) and perception (F [1,14]= 6 . 9 6 , c~ .05) subscales whereas there were no significant group differences on the attention/ concentration (F [1,14]= 3.23), calculation (F [1,14]= 2.33) or abstract thinking (F [1,14]= 2.61) subscales. 2 . Sustained Attention Tests i) Wilkins Auditory Sustained Attention There was no significant difference between groups in the number of errors made (F c 1) with both normal elderly and mild SDAT patients making few errors.
ii) Visual Vigilance Data for this test were analysed with blocks of trials as a factor to determine whether there was any decline in subjects performance over the five, minutelong, blocks. Despite the relative complexity of the task and its sensitivity to the
[=3 Normal
*** 100
p
80
**
***
1
**
=
elderly
Mild SDAT
*
0
V
v,
E 60 3 E ._ X
0
I
40
Lc
0
20 0
Fig. 1. CAMCOG profiles for normal elderly subjects and mild SDAT patients. Asterisks indicate a significant group difference (*** p < .OOO5; ** p < .OO5; * p C .05).
697
VIGILANCE IN ALZHEIMER'S DISEASE
Table 2. Means and Standard Deviations of Test Results.
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Test
Normal elderly
Mild SDAT
Verbal Free Recall
Recall' Intrusions* Recognition
8.1 0.1 10.0
4.4 0.1 8.6
Delayed
Recall Intrusions Recognition
8.2 0.1 9.6
2.4 0.1 8.2
(3.2) *** (0.3) (2.7)
20.2 14.1 8.4
11.0 7.1 5.5
(2.0) ** (3.9) ** (2.3)
Verbal Fluency
Category Easy letter Hard letter
Spans
Digit Block
5.2 4.6
4.9 3.9
Wilkins
Errors
0.5
0.5
Visual Vigilance
% Hits % False alarms
97.9 1.1
97.2
(0.8) (1.1)
1.5
Asterisks indicate a significant group difference (*** p < .0005; ** p < .005). 'Mean of the mean number of words recalled/intrusions over 4 trials.
effects of scopolamine in normal volunteers, there were no significant main effects of group or block and no significant group x block interactions in the number of hits or false alarms (Fs < 1). Both normal elderly subjects and mild SDAT patients responded to nearly all the target stimuli and made very few errors of commission.
3 . Memory Tests i) Verbal Free Recall and Recognition The mild SDAT patients were significantly impaired in the mean number of words correctly recalled over four trials. (F [1,14] = 5 1 . 6 4 , ~< .OOOl). Examination of the mild SDAT patients' pattern of recall for each word over the four trials revealed a serial position curve similar in shape to that found in normal elderly subjects, with the most consistently recalled words tending to be those last in the list. There was no significant group difference in terms of the number of intrusions made (F < 1) or the mean number of words correctly recognised ( F [1,14] = 3.13). ii) Delayed Recall and Recognition Not surprisingly, given the differences between groups in the number of words originally recalled (see above), there was a significant group difference in the
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number of words recalled after a 15-minute delay (F [1,14]= 22.12, p < .0005). There was no significant difference between groups in the number of intrusions made (F < 1) or the mean number of words correctly recognised (F [1,14]= 1.78).
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iii) Verbal Fluency The mild SDAT group produced significantly fewer exemplars of animals ( F [1,14]= 14.45,p
Journal of Clinical and Experimental Neuropsychology Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ncen19
Memory and attention in patients with senile dementia of the alzheimer type and in normal elderly subjects a
a
a
b
C. R. Lines , C. Dawson , G. C. Preston , S. Reich , c
C. Foster & M. Traub
a
a
Merck Sharp and Dohme Neuroscience Research Centre , Harlow, U.K. b
St. Thomas' Hospital , London, U.K.
c
Queen Mary's Hospital , Sidcup, U.K. Published online: 04 Jan 2008.
To cite this article: C. R. Lines , C. Dawson , G. C. Preston , S. Reich , C. Foster & M. Traub (1991) Memory and attention in patients with senile dementia of the alzheimer type and in normal elderly subjects, Journal of Clinical and Experimental Neuropsychology, 13:5, 691-702, DOI: 10.1080/01688639108401083 To link to this article: http://dx.doi.org/10.1080/01688639108401083
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content.
Downloaded by [McMaster University] at 18:30 23 December 2014
This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sublicensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Journal of Clinical and Experimental Neuropsychology 1991, VOI. 13, NO. 5, pp. 691-702
0168-863419 1/1305-0691$3.W 0 Swets & Zeitlinger
Memory and Attention in Patients with Senile Dementia of the Alzheimer Type and in Normal Elderly Subjects* C.R. Lines’, C. Dawson’, G.C. Preston’, S. Reich’, C. Foster3, and M. Traub’
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‘Merck Sharp and Dohme Neuroscience Research Centre, Harlow, U.K. 2St. Thomas’ Hospital London, U.K. and 3Queen Mary’s Hospital, Sidcup, U.K.
ABSTRACT Previous studies have shown that cholinergic blockade in normal subjects induces impairment of vigilance as well as memory deficits. In the present investigation we have examined the validity of this pharmacological model of dementia by administering a battery of cognitive tasks to patients with mild and moderate senile dementia of the Alztieimer type and to age-matched controls. In contrast to volunteers receiving scopolamine all the mildly demented patients, and half of those moderately affected, performed normally on tests of vigilance whilst exhibiting the expected memory deficits. These data suggest that the mechanism of memory loss in Alzheimer’s disease may differ from that found in scopolamine-induced amnesia.
The postmortem findings of a loss of cholinergic markers in pathways projecting from the basal forebrain to the cortex and hippocampus of patients with Alzheimer’s disease (Bowen, Smith, White, & Davison, 1976; Davies & Maloney, 1976) has led to the proposition that damage to this particular system may be responsible for a number of the major clinical features of Alzheimer’s disease. The ‘cholinergic hypothesis’ has received further support from the observation that anticholinergic agents, such as scopolamine (hyoscine), induce temporary deficits of secondary memory following administration to healthy volunteers (Kopelman, 1986). Although the ‘scopolamine model’ fails to account for a number of features of Alzheimer’s disease, including failures of primary and remote memory, of praxis and of language (Jorm, 1987), it has been claimed that cholinergic blockade induces a selective loss of secondary memory reminiscent of early dementia (Kopelman & Corn, 1988). The postulate that centrally acting anticholinergic agents have specific amnestic properties which are dissociable from their sedative
* The authors would like to thank Mrs. J. Tredinnick for typing this manuscript. Address for correspondence: Dr. M. Traub, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR. U.K. Accepted for publication: November 14, 1990.
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CB. LINES ET AL.
actions has been summarised by Kopelman (1986) as follows: “...the memory impairment produced by hyoscine is unlikely to be accounted for in terms of impaired attention, although performance at tests of attention is affected at higher doses and at tests (e.g. dichotic listening) where the information processing load is relatively great.” However, in a series of studies we have been unable to dissociate the amnestic properties of scopolamine from its sedative effects; even at relatively low doses scopolamine induced drowsiness (on a visual analogue scale) together with a decrease in vigilance (auditory and visual sustained attention) (Broks et al., 1988). In addition, when the effects of cholinergic blockade were reversed by an anticholinesterase, physostigmine (Preston et al., 1988), or diminished by the development of tolerance on chronic treatment (Brazell, Preston, Ward, Lines, & Traub), 1989), there was no evidence of differential effects on sedation, vigilance or secondary memory. Others, too, have found evidence for attentional deficits in the range of doses which produce memory impairment (Parrott, 1986, Wesnes, Simpson, & Kidd, 1988; Wesnes & Warburton, 1983,1984). It is uncertain to what extent the attentional deficits that accompany scopolamineinduced memory loss mimic the symptoms of early Alzheimer’s disease. Although it is a common observation that patients in the later stages of the disorder suffer marked impairment of arousal, there have been relatively few formal studies of attentional processes in mild/moderate dementia. The conclusion by Butters et al. (1988) that patients with probable Alzheimer’s disease show deficits on the attentiow‘concentration index of the Wechsler Memory Scale is in broad agreement with previous reports (Vitaliano, Breen, Albert, Russo, & Prinz, 1984), but these studies have been limited by their use of relatively nonselective psychological tests in groups of patients who have reached a stage of their illness when virtually all cognitive functions are affected to some degree. The main aim of the present investigation was to test the predictive value of the ‘scopolamine model’ of dementia by examining the performance of mildly affected patients on tests of vigilance which have been previously shown to be sensitive to cholinergic blockade (Brazell et al., 1989; Broks et al., 1988; Preston et al., 1988). It is possible that impairment of vigilance may be a relatively early marker of dementia and may contribute to the other well described cognitive deficits. In this case, drugs that appear to improve attention such as nicotine or benzodiazepine inverse agonists may be of benefit in mild dementia (Sahakian, Jones, Levy, Gray, & Warburton, 1989; Sarter, Schneider, & Stephens, 1988).
METHODS Subjects Patients: Eight community-dwelling patients (2 males and 6 females)judged to be suffer-
ing from mild senile dementia of the Alzheimer type (SDAT) were included in the study. (As in previous studies on mild SDAT the group size is relatively small, due to difficulties
693
VIGILANCE IN ALZHEIMER’S DISEASE
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in obtaining patients who are at an early stage of the disease.) The diagnosis was made according to NINCDS-ADRDA criteria for probable Alzheimer’s disease (McKhann et al., 1984) by a geriatrician on the basis of history and routine laboratory and CT investigations to exclude other possible causes of dementia such as multi infarct dementia or dementia due to head injury. The judgement of severity was based on the criteria of the Clinical Dementia Rating (Berg, 1984) for mild dementia and on the score in the MiniMental State Examination (MMSE - Folstein, Folstein, & McHugh, 1975). Eight moderately demented patients (MMSE = 11 - 19) were also examined but they varied considerably in their ability to complete the battery, because of dyspraxia or dysphasia, and their results are only summarised briefly.
Normal Elderly: Eight normal age-matched controls (3 males and 5 females) from the community with no known relevant medical disorder were selected to take part in the study. Table 1 shows the mean age, premorbid or current IQ (as estimated by the National Adult Reading Test (NART - Nelson, 1982)). and MMSE scores for the mild SDAT patients and normal elderly. There were no significant age or IQ differences between the two groups. Vision and hearing was adequate (when corrected if necessary) in all subjects.
Apparatus The apparatus for computer based testing has been described elsewhere (Broks et al., 1988). It consists of an IBM personal computer linked to a touch sensitive colour monitor.
Test Selection The asessments undertaken fell into the following three broad categories: 1 . Tests of overall intellectual function: the Cambridge Cognitive Examination (CAMCOG - part of the Cambridge Examination for Mental Disorders of the Elderly (Roth, Huppert, Tym, & Mountjoy, 1988)) was administered. This consists of 60 items examining a wide range of cognitive functions which are grouped into eight subscales. It incorporates the items of the MMSE. The NART was used to give an estimate of the person’s premorbid or current IQ. In the case of the moderate patients only the MMSE was given.
2. Sustained attention tests: an auditory sustained attention test and visual vigilance test, identical to those we have used with normal young volunteers receiving scopolamine, were administered.
3. Memory tests: these were chosen to examine a variety of aspects of memory such as new learning (verbal free recall and recognition), forgetting (delayed recall and recognition), retrieval from long term memory (verbal fluency test) and immediate short term memory (digit and block spans). Table 1. Demographic Details (means and ranges). Age
NART estimated IQ
MMSE
Normal elderly
78 (70-97)
103 (76- 128)
29 (27-30)
Mild SDAT
82 (75-92)
106 (87- 11 8)
22 (20-26)
694
C.R.LINES ET AL.
Procedure
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For the normal elderly subjects all tests were administered during the same session (approximate duration 2 hours). For the mild SDAT patients all the tests of memory and attention were administered during a single session (approximate duration 1.25 hours). but the other assessments were sometimes undertaken on a separate occasion. Patients and control subjects were given the opportunity to rest between tests but there were no breaks during any individual task. In the moderate patient group it was often necessary either to modify the experimental procedures (e.g., by allowing verbal rather than touchscreen responding and presenting stimuli verbally instead of visually) or to abandon particular tests altogether.
Test Details (in order of administration) I ) Wiikins Auditory Sustained Attention (Wilkins, Shallice, diMcCarthy, 1987) In this procedure the subject was required to listen to trains of bleeps from the computer. At the end of each train the subject was asked to indicate the number of bleeps heard by pointing to a number selected from a choice (1-15) presented on a grid on the touchscreen. Train lengths from 5-14 were given in a random order at a nominal frequency of 0.25 hz. The bleeps in a train had a duration of 50 ms and were separated by a period randomly chosen to be 1 frequency +/- O.S/frequency (i.e., tones could be separated by 2 to 6 s). The measure taken was the number of errors made. This procedure was identical to one which showed deficits in young volunteers receiving scopolamine (Broks et al.. 1988). The test lasted for 10 minutes and was preceded by a practice session. 2 ) Verbal Free Recall and Recognition In this test subjects were presented with a list of 10 high frequency and imageability words (Paivio, Yuille, & Madigan. 1968) (animal, car, child, corn, diamond, factory, meat, window, wine and woman), one at a time, on the monitor. Presentation rates were controlled by the experimenter depending on the time taken by the subject to pronounce the word correctly, although there was a minimum presentation time of 2 s. At the end of the presentation the subject was given a maximum of 60 s to recall as many words as they could, in any order. This procedure was repeated for four trials using the same word list, presented in the same order, each time. Measures taken were the number of words recalled and intrusions. Following the last verbal free recall trial, the subject performed a three-choice recognition test. Three words (consisting of the target word and two semantically related words) were presented on the monitor. The subjects’ task was to indicate (by touching it) which word had been displayed in the original word list. The number of words correctly recognised was recorded. 3 ) Visual Vigilance This procedure was adapted from that reported by Nuechterlein, Parasuraman, and Quiyan (1983). Digits were presented briefly on the computer screen against a random visual noise background, in which each pixel was set to either black or to the colour and intensity of the target with a probability of 0.5. The digits were presented at a rate of ]/second for 5 minutes. The subject was required to press a hand-held push-button whenever a particular target digit (7) appeared on the screen. In each minute block of 60 trials there were 15 targets and 45 non-targets (each stimulus being exposed for 240 ms). which were chosen from the remaining digits 1-9. Data collected from this task (for each block of trials) were hit rate and false alarms. This procedure was identical to one which has shown deficits in young volunteers receiving scopolamine (unpublished data; scopolamine deficits using a task
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which differed only in the stimulus duration (40 ms) are reported by Preston et al. (1989)). The test was preceded by a practice session.
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4 ) Delayed Recall and Recognition This test was run approximately 15 minutes after the verbal free recall test (during which time the visual sustained attention task was performed and any remaining time was taken up with conversation). The subject was given a minimum of 60 s in which to recall as many items as possible from the original word list. This was followed by a three-choice recognition procedure (the two semantically related words were different from those used in the recognition task given after the immediate free recall procedure).
5 ) Digit Span In this test the subjects were presented with sequences of digits displayed on the screen. At the end of each sequence a grid containing the digits 1-9 were displayed on the touchscreen; the subject was then required to repeat the digit sequence by touching the appropriate numbers on the grid. Digit sequences were given at a frequency of approximately 1 digidsecond. The sequences were chosen randomly with the constraint that no digit could appear more than once on a given sequence. This test always started with a sequence of two digits. Thereafter the sequence length was increased by one each time the subject succeeded. This procedure was adopted until the subject failed at a sequence length. At this point another attempt was given at the same sequence length. The test was terminated once the subject had failed twice at a given sequence length and the span recorded as the maximum number of digits correctly recalled. 6 ) Block Span This computerised version of the Corsi blocks test was analogous to the digit span test, except that the material recalled was spatial rather than verbal. An irregular array of rectangular boxes was displayed on the screen; a number of boxes, corresponding to the sequence length, were then 'lit up' (turned red for 1 s) in order. The subject was required to echo the sequence of boxes by touching them in the appropriate order. All other details were as for the digit span test. 7) Verbal Fluency Both category and letter fluency were examined. For the category fluency task subjects were told they would have a minute to name as many animals as they could. The letter fluency task consisted of an 'easy' letter (S)and a 'hard' letter (J). For each letter subjects were told they would have a minute to say as many words as they could think of beginning with that letter excluding the names of people or places. The measure taken was the number of correct words given (excluding repetitions).
RESULTS Mild Dementia/Normal Elderly Data were analysed by between-groups analysis of variance. The means and standard deviations for the sustained attention and memory tests are given i n Table 2.
I . Overall lntellecrual Function The functioning of normal elderly versus SDAT patients on the various subscales of the C A M C O G are shown in Figure 1. It can be seen that t h e mild S D A T
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group were significantly impaired on the orientation (F [1,14]= 23.80, p < .0005), language (F [1,14]= 35.10,p c .OOOl), memory (F [1,14]= 15.54,p c .005), praxis (F [1,14]= 12.27,~ < .005) and perception (F [1,14]= 6 . 9 6 , c~ .05) subscales whereas there were no significant group differences on the attention/ concentration (F [1,14]= 3.23), calculation (F [1,14]= 2.33) or abstract thinking (F [1,14]= 2.61) subscales. 2 . Sustained Attention Tests i) Wilkins Auditory Sustained Attention There was no significant difference between groups in the number of errors made (F c 1) with both normal elderly and mild SDAT patients making few errors.
ii) Visual Vigilance Data for this test were analysed with blocks of trials as a factor to determine whether there was any decline in subjects performance over the five, minutelong, blocks. Despite the relative complexity of the task and its sensitivity to the
[=3 Normal
*** 100
p
80
**
***
1
**
=
elderly
Mild SDAT
*
0
V
v,
E 60 3 E ._ X
0
I
40
Lc
0
20 0
Fig. 1. CAMCOG profiles for normal elderly subjects and mild SDAT patients. Asterisks indicate a significant group difference (*** p < .OOO5; ** p < .OO5; * p C .05).
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Table 2. Means and Standard Deviations of Test Results.
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Test
Normal elderly
Mild SDAT
Verbal Free Recall
Recall' Intrusions* Recognition
8.1 0.1 10.0
4.4 0.1 8.6
Delayed
Recall Intrusions Recognition
8.2 0.1 9.6
2.4 0.1 8.2
(3.2) *** (0.3) (2.7)
20.2 14.1 8.4
11.0 7.1 5.5
(2.0) ** (3.9) ** (2.3)
Verbal Fluency
Category Easy letter Hard letter
Spans
Digit Block
5.2 4.6
4.9 3.9
Wilkins
Errors
0.5
0.5
Visual Vigilance
% Hits % False alarms
97.9 1.1
97.2
(0.8) (1.1)
1.5
Asterisks indicate a significant group difference (*** p < .0005; ** p < .005). 'Mean of the mean number of words recalled/intrusions over 4 trials.
effects of scopolamine in normal volunteers, there were no significant main effects of group or block and no significant group x block interactions in the number of hits or false alarms (Fs < 1). Both normal elderly subjects and mild SDAT patients responded to nearly all the target stimuli and made very few errors of commission.
3 . Memory Tests i) Verbal Free Recall and Recognition The mild SDAT patients were significantly impaired in the mean number of words correctly recalled over four trials. (F [1,14] = 5 1 . 6 4 , ~< .OOOl). Examination of the mild SDAT patients' pattern of recall for each word over the four trials revealed a serial position curve similar in shape to that found in normal elderly subjects, with the most consistently recalled words tending to be those last in the list. There was no significant group difference in terms of the number of intrusions made (F < 1) or the mean number of words correctly recognised ( F [1,14] = 3.13). ii) Delayed Recall and Recognition Not surprisingly, given the differences between groups in the number of words originally recalled (see above), there was a significant group difference in the
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number of words recalled after a 15-minute delay (F [1,14]= 22.12, p < .0005). There was no significant difference between groups in the number of intrusions made (F < 1) or the mean number of words correctly recognised (F [1,14]= 1.78).
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iii) Verbal Fluency The mild SDAT group produced significantly fewer exemplars of animals ( F [1,14]= 14.45,p
