RESEARCH ARTICLE

Memantine improves attention and episodic memory in Parkinson’s disease dementia and dementia with Lewy bodies Keith A. Wesnes1,2,3, Dag Aarsland4, Clive Ballard5 and Elisabet Londos6 1

Wesnes Cognition Ltd, Streatley on Thames, UK Department of Psychology, Northumbria University, Newcastle, UK 3 Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia 4 The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway 5 Wolfson Centre for Age Related Diseases, Institute of Psychiatry, King’s College London, London, UK 6 Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden Correspondence to: K. A. Wesnes, E-mail: [email protected] 2

In both dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), attentional dysfunction is a core clinical feature together with disrupted episodic memory. This study evaluated the cognitive effects of memantine in DLB and PDD using automated tests of attention and episodic memory. Methods: A randomised double-blind, placebo-controlled, 24-week three centre trial of memantine (20 mg/day) was conducted in which tests of attention (simple and choice reaction time) and word recognition (immediate and delayed) from the CDR System were administered prior to dosing and again at 12 and 24 weeks. Although other results from this study have been published, the data from the CDR System tests were not included and are presented here for the first time. Results: Data were available for 51 patients (21 DLB and 30 PDD). In both populations, memantine produced statistically significant medium to large effect sized improvements to choice reaction time, immediate and delayed word recognition. Conclusions: These are the first substantial improvements on cognitive tests of attention and episodic recognition memory identified with memantine in either DLB or PDD. Copyright # 2014 John Wiley & Sons, Ltd. Objective:

Key words: memantine; dementia with Lewy bodies; Parkinson’s disease dementia; attention; episodic memory; CDR System; automated cognitive tests History: Received 15 December 2013; Accepted 4 March 2014; Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4109

Introduction Dementia with Lewy bodies (DLB) and dementia associated with Parkinson’s disease (PDD) are considered to share major similarities and together account for up to 25% of the global incidence of dementia (Auning et al., 2012). The complex courses of DLB and PDD include cognitive, attentional, motor and psychiatric symptoms; making these forms of dementia particularly challenging in terms of quality of life (QOL) for patients and carers, admission to nursing homes and health-related costs (Lippa et al., 2007).

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DLB patients have been shown to have greater attentional deficits than disease severity-matched Alzheimer’s disease (AD) patients, but with smaller deficits to episodic memory (Ayre, 1998; Calderon et al., 2001). Since Donders (1868) developed automated tests of simple reaction time (SRT) and choice reaction time (CRT), these tests have been central to attention testing in psychology and clinical research. The CDR System is an automated set of tests of attention (including SRT and CRT) and memory, developed for repeated use in clinical trials and validated for use in dementia (Simpson et al., 1989,

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K. A. Wesnes et al.

1991; Nicholl et al., 1995). Using the CDR System, Ayre (1998) identified impairments in AD patients on SRT and CRT compared with controls, but established greater impairment to both tasks in DLB patients, despite the DLB patients having smaller deficits to episodic memory than the AD patients. Further, he established that the DLB to AD deficit on CRT was significantly greater than that on SRT, showing a greater impairment to information processing over and above the increased disruption to the ability to focus attention. A widely prevalent symptom in DLB is fluctuating cognition, identified in 80–90% of patients (Byrne et al., 1989; McKeith et al., 1992). Walker in a series of studies demonstrated that in DLB patients, clinically rated cognitive fluctuations correlated strongly with increased variability of the reaction times on the CDR System attention tests and that such increased variability could reliably distinguish DLB from AD and vascular dementia patients (Walker et al., 1999, 2000a, 2000b). Ballard et al. (2002) replicated the profile of poorer focussed attention, disrupted information processing and greater variability in reaction times in DLB using the CDR System; but importantly demonstrated that the same profile could be seen in PDD patients, compared with AD patients and controls. This characteristic profile of impairment to attentional processes has been used in current consensus guidelines for DLB (McKeith et al., 2005) and PDD (Emre et al., 2007) as evidence to support these impairments as core clinical features of both dementias. Memantine is an N-methyl-D-aspartate receptor (NMDA) receptor antagonist that affects glutamatergic neuronal transmission and prevents the toxic effects of raised concentrations of the excitatory neurotransmitter glutamate. Memantine has proven effective in treating the symptoms of AD (McShane et al., 2006). The first randomised, double-blind, placebocontrolled trial of memantine in DLB and PDD involved 72 patients (32 DLB and 40 PDD) recruited from four sites who were studied over 24 weeks (Aarsland et al., 2009). The primary outcome was the Alzheimer’s Disease Cooperative Study Clinical Impression of Change (ADCS-CGIC), secondary outcomes including mini mental state examination (MMSE), a quick test of cognitive speed (AQT; Andersson et al., 2007), the Neuropsychiatric Inventory (NPI) and the disability assessment for dementia (DAD; Gelinas et al., 1999). At 24 weeks, a significant improvement was seen with memantine in the study population on the ADCS-CGIC, no differences in response being seen between the DLB and PDD patients. Whereas none of the other clinical scales showed effects, one of the three AQT subtests (the time taken to name 40 shapes) showed a significant benefit with memantine. Copyright # 2014 John Wiley & Sons, Ltd.

Emre et al. (2010) reported a second randomised, double-blind, placebo-controlled, 30 site trial of memantine in 78 patients with DLB and 121 with PDD. There were no pre-specified primary end points, the outcome measures including the ADCS-CGIC, the ADCS-activities of daily living scale, Zarit burden interview, NPI and 20 measures from 16 cognitive tests. At 24 weeks, memantine significantly improved the ADCS-CGIC and the NPI in the DLB patients, but not in the PDD patients or in the total population. There were no effects seen on the majority of the other assessments. For the 20 cognitive measures, memantine had no effects in the PDD population, but in DLB improved a single measure, the congruent part of the Stroop test. Thus to date, there is evidence from two randomised double-blind trials that DLB patients treated with memantine for 24 weeks have superior ADCS-CGIC scores to controls, and in one trial PDD patients also. Matsunaga et al. (2013) reviewed the area and identified these two double-blind studies and five unblinded trials, concluding that memantine does not benefit cognition or motor function, but does improve the ‘overall impression’ of the disorders. There is clearly a paucity of evidence of improvements to objective tests of cognitive function; the only reliable effect so far reported being to one of three measures from the AQT in both DLB and PDD (Aarsland et al., 2009). Thus, there is evidence of change with memantine from these studies which the clinicians are able to detect, but which is largely unsupported by measurable changes in cognitive function. The study of Aarsland et al. (2009) also used cognitive tests from the CDR System, but the analyses of data from these tests were not available at the time of publication. As these tests have contributed to the consensus criteria for both dementias and have additionally proven sensitive in identifying cognitive enhancements in the major randomised double-blind, placebo-controlled trials with rivastigmine in DLB (McKeith et al., 2000) and PDD (Emre et al., 2004); the data from the CDR System tests are reported here for the first time to determine if they can also identify beneficial cognitive effects in these two dementias with memantine. Methods Patients

Patients with mild or moderate PDD or DLB, having MMSE scores of 12 and higher, were recruited at three psychiatric and neurological outpatient clinics in Norway, Sweden and the UK. Patients were included Int J Geriatr Psychiatry 2014

Memantine in Parkinson’s dementia and dementia with Lewy bodies

if they fulfilled the UK Parkinson’s Disease Society Brain Bank clinical diagnostic criteria for Parkinson’s disease and subsequently developed dementia at least 1 year after the onset of motor symptoms (PDD) according to the DSM-IV criteria or if they met the revised consensus operationalised criteria for DLB (McKeith et al., 2005). The study was approved by an ethics committee at each centre; patients gave informed consent and were accompanied on study visits. Other details have been reported previously (Aarsland et al., 2009). Procedures

Patients were randomised to receive either placebo or memantine, using lists generated by the study statistician. The initial dose was 5 mg taken in the morning, with a planned gradual increase to the maintenance dose of 20 mg (10 mg morning and evening) from week 4. Participants were assessed at baseline, at week 12 and at week 24. The CDR System is administered via a notebook computer, and during each task, patients respond to various visual stimuli using a response box containing a yes and a no button. The notebooks were delivered to each site with all software preloaded, and the staff thoroughly trained in the use of the CDR System. Four tests from the system, which have been widely used in these and other populations with dementia, were administered in the following order: immediate word recognition (IWR), SRT, CRT and delayed word recognition (DWR; Wesnes et al., 2002, 2005). In IWR, a list of 12 words is presented one at a time at the rate of 1 every 3 s. Immediately afterwards, the patient is instructed that the 12 words will be represented mixed together with 12 other words (distractors), and for each word, the patient must decide whether or not it was from the original list by pressing the yes or no button as quickly as possible. In DWR, which is performed after SRT and CRT had been completed, the original 12 words are again presented mixed with 12 novel distractors, and again, the patient must decide whether or not each was from the original list using the response box and responding as quickly as possible. In SRT, the word yes appears on the screen at unpredictable intervals and remains there until the patient presses the yes button as quickly as possible. The patient is instructed that only the word yes will appear and must just have a finger resting lightly on the yes button, this being monitored by administrator throughout the test. During CRT, the patient is instructed that that they must rest a finger Copyright # 2014 John Wiley & Sons, Ltd.

on each button, that either the word yes or no will appear at unpredictable intervals, and they must respond as accurately and quickly as possible. The four tests took around 8 min to complete, all aspects of stimulus selection being controlled by the computer, and the data were recorded, stored and processed automatically. Validated language versions of the tests were used for each country, and different but equivalent sets of stimuli in all tasks were used in each successive testing session. During the screening period, the patients underwent two familiarisation sessions on the tasks to overcome any initial practice effects, and to ensure that they were both comfortable with the procedures and fully understood the performance requirements (Wesnes and Pincock, 2002). The scores derived for SRT were the average and standard deviation of the reaction times. For CRT, the same reaction time scores were derived, as well as the percentage of correct responses. For the two recognition tests (IWR and DWR), the percentage of correct responses for original words and distractor words were recorded, as well as the average reaction times for correct responses. All randomised patients received at least one dose of mediation, and those with cognitive data at pre-dose and at least one post-dose visit were included in the analysis. In the occasional instance of missing data, no substitutions were made. Baseline scores were compared between the placebo and active treatment groups using analyses of variance. Changes from baseline (pre-dose) scores were submitted to mixed model repeated measures analyses of covariance (ANCOVA) using SAS version 9.2 (SAS Institute, Cary, NC, USA). Fixed terms were fitted to the model for treatment (placebo or memantine), type-of-dementia (DLB or PDD), week (12 or 24) and the following interactions: treatment × week, treatment × type-of-dementia and treatment × week × type-of-dementia. Visit was fitted as a repeated measure, and patients nested within treatment as a random term. The baseline scores were fitted as covariates. To identify and contrast the degrees of cognitive impairment in the two dementias prior to initiation of treatment, data were taken for cognitively normal agematched controls (n = 373) from the CDR System normative database (Wesnes et al., 2002, 2005). Two further measures shown to be characteristically impaired in DLB and PDD (Ballard et al., 2002) were also derived: cognitive reaction time (the difference between CRT and SRT) and reaction time variability, which is the sum of the coefficients of variation for SRT and CRT (Wesnes et al., 2005). Contrasts were made using analyses of variances, and effect sizes were calculated using Cohen’s d method (Cohen, 1988). Int J Geriatr Psychiatry 2014

K. A. Wesnes et al.

Relationships between the cognitive tests and the various clinical scales used in the study were examined using Pearson’s correlation coefficients. Results Fifty-nine patients performed the computerised tests during the study, and both baseline and post-dosing data were available for 51 patients (21 DLB and 30 PDD). All 51 patients had test data available at week 12, and 48 had data available at week 24. The groups were balanced as to clinical and demographic characteristics at baseline (Table 1), no significant differences being detected for any measure. The cognitive data and results of the ANCOVAs are summarised in Table 2. It can be seen that prior to dosing, there were numeric differences between the groups on some measures, but none were significant (all p > 0.1). However, baseline scores were included as covariates in the analyses to adjust for these numeric differences. None of the interaction terms from the ANCOVAs was significant (all p > 0.1), and thus, the combined effects of the two dementias over the post-dosing study period became the foci of interest. Compared with placebo, memantine produced favourable effects on all the measures from all four tests. Although the numeric benefit on SRT with memantine was not statistically significant, the benefits of the compound over placebo on CRT (Figure 1) and the accuracy scores from the two-word recognition tests were statistically reliable (Figure 2). Further, CRT declined significantly from baseline Table 1 Baseline characteristics of study population Placebo (n = 24) Age (years) Men : Women Duration of disease (years) PDD : DLB Duration of PD before onset of dementia MMSE NPI total score Cholinesterase inhibitors Antiparkinson medication Levodopa dose (mg/day)a Antipsychotics

Memantine (n = 27)

76.2 (4.8) 18:6 8.5 (4.7) 16:8 5.2 (3.7)

76.1 (6.5) 22:5 6.6 (5.3) 14:13 4.6 (3.7)

20.8 (3.7) 13.0 (10) 16 (67%) 22 (92%) 437 (255) 9 (37%)

20.4 (3.6) 15.1 (14.6) 11 (41%) 21 (78%) 574 (366) 5(18%)

Data are mean (SD) or number (%). SD, standard deviation; PDD, Parkinson’s disease dementia; DLB, dementia with Lewy bodies; PD, Parkinson’s disease; MMSE, mini mental state examination; NPI, neuropsychiatric inventory. a Placebo = 21, memantine = 18.

Copyright # 2014 John Wiley & Sons, Ltd.

under placebo but not memantine; whereas recognition accuracy for both the IWR and DWR tests was significantly improved over the baseline level with memantine, but not placebo. The supportive measures from these tests provided support for the benefits of memantine, accuracy on CRT showing a numeric improvement and recognition times on the two memory tasks that both became numerically faster. Cohen classified effect sizes of 0.5 and 0.8 to be medium and large, respectively (Cohen, 1988). The effect sizes of the three statistically significant improvements ranged from 0.75 to 0.79, and thus approached large effects. The significant improvements to attention with memantine as assessed by CRT in this study may have contributed to the improved recognition accuracy in the two memory tasks. To examine this, the major ANCOVAs for IWR and DWR accuracy were re-run, fitting CRT reaction time as an additional covariate. For IWR, this moved the previously significant main effect to a trend (p = 0.0645) and reduced the overall benefit slightly (13.3% from 14.2%). However, for DWR, the significant difference remained (p = 0.0031), and the beneficial effect of memantine actually improved (20.2% from 16.6%). This suggests that the beneficial effects of memantine in DLB and PDD on the delayed recognition task were largely independent to the benefits seen to attention. From Table 3, it can be seen that at the start of the study, all measures from the four tasks were impaired in both dementias compared with age-matched normals, with large effect sizes (0.95–2.7). The profiles of impairment over the measures were fairly consistent between DLB and PDD. Further, the significant impairments to CRT and reaction time variability support previous findings that these are characteristic deficits of the two dementias (e.g. Ballard et al., 2002). An advantage of having normative data on tests used in dementia trials is that it is possible to estimate the degree to which treatment has moved patients towards ‘normal’ levels (Wesnes et al., 2002, 2005; Vellas et al., 2005). In this trial, over the 24-week treatment period, memantine moved patients towards controls by 43% on CRT (33% on accuracy), 36% on IWR accuracy (23% on speed) and 41% on DWR accuracy (24% on speed). The CDR System scores at baseline were correlated with those of four clinical scales used in the study (Table 4). For the MMSE, all CDR System measures except accuracy on the CRT task correlated significantly, and superior scores on each measure correlated with higher MMSE scores. The same pattern was seen on DAD, all CDR System measures except CRT Int J Geriatr Psychiatry 2014

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RT

RT

22

25

Memantine

25

Memantine

Placebo

22

25

Memantine

Placebo

22

25

Memantine

Placebo

22

27

Memantine

Placebo

24

Placebo

27

Memantine

2204 (2340)

38.3 (32.2) 1483 (510)

50.0 (33.8)

46.7 (34.4) 1374 (405) 2078 (1952)

51.1 (29.7)

874 (335) 995 (527)

89.4 (12.4)

563 (298) 715 (447) 84.0 (12.2)

Mean (SD)

159 (189)

74 (210)

14.4 (5.7)

3.23 (6.5)

33 (234)

238 (256)

8.3 (5.4)

3.87 (5.9)

61 (70)

71 (80)

3.89 (2.4)

0.11 (2.7)

89 (97)

41 (110)

Change at 12 weeks LS means (SEM)

94 (194)

343 (210)

18.41 (6)

1.69 (6.4)

268 (240)

468 (260)

9.15 (5.6)

7.09 (6)

68 (74)

217 (80)

2.1 (2.5)

0.82 (2.7)

58 (101)

187 (110)

Change at 24 weeks LS means (SEM) 114 ( 43 to 272) 73 ( 68 to 215) 0.46 ( 4.39 to 3.47) 2.98 ( 0.56 to 6.51) 144 (31 to 258)a 65 ( 167 to 38) 5.48 ( 14 to 3.1) 8.73 (0.9 to 16.6)a 353 ( 17 to 724) 117 ( 222 to 456) 0.77 ( 8.5 to 10) 16.41 (8 to 24.8)a 135 ( 167 to 436) 127 ( 400 to 147)

LS means (CI)

Overall change

261 ( 672 to 149)

15.6 (3.1 to 28.2)

236 ( 744 to 273)

14.2 (2.6 to 25.8)

209 ( 373 to 81)

3.44 ( 1.91 to 8.79)

41 ( 255 to 173)

LS means (CI)

Overall difference

0.2059

0.0161

0.3546

0.0176

0.0086

0.2017

0.7019

p

Treatment

0.2996

0.7410

0.6592

0.3574

0.4323

0.5385

0.7723

p

Type

0.3852

0.4720

0.8868

0.7250

0.3182

0.8305

0.4019

p

Treatment * Week

0.3357

0.6066

0.5636

0.3645

0.6138

0.4672

0.6964

p

Treatment * Type

0.7053

0.9534

0.8678

0.9914

0.1135

0.4707

0.8033

p

Treatment * Week * Type

0.39

0.76

0.28

0.75

0.79

0.37

0.11

Cohen’s d effect size

SD, standard deviation; SEM, standard error of the mean; CI, 95% confidence intervals; LS, least squares; SRT, simple reaction time test; CRT, choice reaction time test; IWR, immediate word recognition test; DWR, delayed word recognition test; RT, reaction time; ms, milliseconds. a Change statistically significant compared with baseline (p < 0.05)

DWR RT (ms)

DWR accuracy (%)

IWR (ms)

IWR accuracy (%)

CRT (ms)

CRT accuracy (%)

24

27

Memantine

Placebo

24

Placebo

RT

SRT (ms)

n

Treatment

Measures

Baseline

Table 2 Results of the efficacy analysis

Memantine in Parkinson’s dementia and dementia with Lewy bodies

Int J Geriatr Psychiatry 2014

Immediate Word Recognition

-20

Delayed Word Recognition

Figure 2 Effects of memantine on immediate and delayed word recognition accuracy scores. Scores are least squares means from the analyses of covariances of the change from baseline scores over the 24 weeks of the study. Ascending scores reflect improvements. The error bars are 95% confidence intervals.

accuracy correlated significantly, and superior scores on each measure correlated with higher DAD scores. A comparable pattern was also seen on a 13-item

Copyright # 2014 John Wiley & Sons, Ltd. 396 (35) 77.5 (44)

184 (9) 35.4 (1.7)

43)

212 (115 to 283) 42.1 (119 to 51.9)

1300 (148 to 1646)

35 ( 26 to

1266 (141 to 1617)

115 119

148

43

141

114 11 115 43

1.26 1.85

1.59

1.65

1.53

2.40 1.62 2.70 2.04

299 (30) 77.6 (3.7)

1822 (154)

39.4 (4)

1684 (156)

621 (26) 86.4 (1.2) 920 (37) 46 (3.4)

49.4)

114 (53 to 175) 42.1 (33.8 to 50.5)

941 (619 to 1264)

41.1 ( 32.7 to

786 (460 to 1113)

305 (251 to 359) 10.2 ( 7.7 to 12.7) 419 (343 to 495) 40.7 ( 33.6 to 47.9)

Impairment LS mean (95% CI)

62 119

107

51

88

96 11 84 47

% impairment

-100

0

0.69 1.94

1.15

1.94

0.95

2.05 1.53 2.00 2.24

Cohen’s d

LS, least squares; CI, confidence intervals, SEM, standard error of the mean; ms, milliseconds; SRT, simple reaction time test; CRT, choice reaction time test; CV%, Coefficient of Variance.

2181 (167)

45.5 (4.3)

80.4 (1.4) 881 (55)

2164 (169)

10

897 (55)

20

362 (300 to 424) 10.8 ( 8 to 11) 574 (115 to 662) 37.2 ( 29.5 to 43)

30

678 (31) 85.8 (1.4) 1075 (42) 49.5 (3.7)

LS mean (SEM)

Choice Reaction Time

316 (8) 96.6 (0.4) 501 (11) 86.7 (1.2)

Figure 1 Effects of memantine on simple reaction time and choice reaction time. Scores are least squares means from the analyses of covariances of the change from baseline scores over the 24 weeks of the study. Descending scores reflect impairments. The error bars are 95% confidence intervals. Cohen’s d

300

% impairment

200

Impairment LS mean (95% CI)

Placebo Memantine

SRT (ms) CRT accuracy % CRT (ms) Immediate word recognition (%) Immediate word recognition time (ms) Delayed word recognition (%) Delayed word recognition time (ms) Cognitive reaction time (ms) Reaction time variability (CV%)

-10

LS mean (SEM)

100

Parkinson’s disease dementia

-200

LS mean (SEM)

Placebo Memantine

Dementia with Lewy bodies

Reaction Time Change from Pre-Dose (ms) 0

Controls

Simple Reaction Time

Table 3 Comparisons to normal controls

Words Correct Change from Pre-Dose (%)

K. A. Wesnes et al.

Int J Geriatr Psychiatry 2014

Memantine in Parkinson’s dementia and dementia with Lewy bodies Table 4 Pearson’s correlation coefficients between the CDR System scores of the study population at baseline with four clinical scales

CDR System measure SRT (ms) CRT accuracy % CRT (ms) Immediate word recognition (%) Immediate word recognition time(ms) Delayed word recognition (%) Delayed word recognition time (ms)

MMSE

DAD

13QOL

NPI

Mean 20.6, SD 3.6

Mean 12.5, SD 4.6

Mean 33.7, SD 6.7

Mean 14.1, SD 12.6

0.53* 0.2 0.43* 0.49*

0.48* 0.02 0.44* 0.31*

0.28 0.11 0.4* 0.45*

0.25 0.24 0.24 0.04

0.43*

0.6*

0.31*

0.07

0.51*

0.35*

0.38*

0.01

0.37

0.46*

0.41*

0.16

MMSE, mini mental state examination; DAD, disability assessment for dementia; 13-QOL, 13-item quality of life; NPI, Neuropsychiatric Inventory; SD, standard deviation; SRT, simple reaction time; CRT, choice reaction time; ms, milliseconds. *p < 0.05.

self-rating of QOL (Logsdon et al., 1999); all measures except CRT accuracy and SRT correlated with the ratings and superior scores on each performance measure correlated with higher QOL scores. No significant correlations between the cognitive scores and the NPI were identified. To examine the relationship between the improvements on the three cognitive tests and the ADCS-CGIC scores reported previously (Aarsland et al., 2009), correlations were performed at week 24. CRT alone was found to show a correlation with ADCS-CGIC at this time (r = 0.33, p < 0.025). To further examine the relationship, three groupings of ADCS-CGIC scores were created: ‘Improved’ (scores 1–3; ‘substantial to minimum improvement’), ‘No change’ (score 4) and ‘Worsened’ (scores 5–7, ‘minimum to substantial worsening’). These three groupings were used instead of treatment in the same ANCOVA model used to assess treatment efficacy. A statistically significant main effect of ADCS-CGIC groupings was identified (p = 0.0057), but no simple or higher order interactions were seen (all p > 0.27). Speed on CRT was non-significantly enhanced in the ‘Improved’ ( 52 ms) and ‘No change’ groupings ( 34 ms). However, in the ‘Worsened’ grouping, CRT declined significantly (p = 0.0013; 265 ms, 95% CI 116–413). Thus, changes in ADCS-CGIC ratings were associated meaningfully with changes to CRTs in this study. Copyright # 2014 John Wiley & Sons, Ltd.

Discussion Although other data from this study have already been published (Aarsland et al., 2009), this is the first reporting of the data from the CDR System. The major finding from this analysis was that memantine produced significant improvements on three of four tests of cognitive function in both DLB and PDD. SRT was not statistically significantly improved, although there was a small numeric benefit. CRTs showing a significant shortening combined with a numeric pattern of improved accuracy, suggesting that attentional testing with greater information processing requirement benefits from memantine. This effect is consistent with the improvement in the AQT with memantine in this study (Aarsland et al., 2009). Memantine also statistically significantly improved accuracy on immediate and DWR tests, with speed of recognition showing numerical improvements on both. The improvements on the three tasks approached large effect sizes and are thus likely to be of clinical and everyday relevance. They also compare favourably with the benefits of anticholinesterases in AD, a systematic review of 20 trials (including all pivotal studies) identifying Cohen’s d effect sizes on the Alzheimer’s Disease Assessment Scale Cognitive subscale which ranged from 0.01 to 0.3 (Rockwood, 2004). The findings of this study are in agreement with previous efficacy trials with rivastigmine and donepezil in both dementias using the same CDR System tests, attention being improved by the two anticholinesterases in DLB (McKeith et al., 2000; Wesnes et al., 2002; Rowan et al., 2007) and also in PDD (Emre et al., 2004; Wesnes et al., 2005; Rowan et al., 2007). Further, a score comprising the accuracy scores from IWR and DWR plus a picture recognition task (not used in this study) showed significant improvements with rivastigmine in DLB (Wesnes et al., 2002). Previous work with the CDR System in therapeutic dementia trials has employed the technique of evaluating treatment response in terms of the degree that pre-dosing deficits are reversed towards the levels of normals. In two randomised trials with rivastigmine, a CDR System measure, which combines speed on three attention tests (including SRT and CRT), was moved towards the scores for normals by 50% in DLB (Wesnes et al., 2002) and 24% in PDD (Wesnes et al., 2005). In a trial of galantamine in AD, CRT was moved 30% towards normal scores after 12 weeks of treatment (Vellas et al., 2005). Overall, the 43% identified in the present study with Int J Geriatr Psychiatry 2014

K. A. Wesnes et al.

CRT is in the same range as these effects. Further, in the present study, the movements towards control levels on the IWR and DWR accuracy of 40% and 43%, respectively, are also treatment effects which are arguably clinically relevant. The relationship established in the present study between the improved attention with memantine (as assessed by CRT) and the ADCS-CGIC at 24 weeks suggests that enhanced attention played a role in the improved clinical ratings. As the ADCS-CGIC raters did not have access to the data from the computerised tests, this strengthens the possible association. Finally, the relationships identified at baseline between CRT (and the other cognitive tests) and MMSE, QOL and activities of daily living also support the possibility that the cognitive benefits contributed to the improved ADCS-CGIC scores with memantine in this study. Further CDR System attention tests have been shown to be strong predictors of activity of daily living in both DLB (Ballard et al., 2001) and PDD (Bronnick et al., 2006). The larger trial of Emre et al. (2010) used SRT and CRT tasks from the CogState battery; for both tests, the mean (standard error of the mean) changes from baseline after 24 weeks were 0 (0) for both the placebo and memantine groups. This contrasts notably with the effects seen in the present study, particularly on CRT. Possible explanations for this difference could relate to differences in the two study populations, for example, the patients in the study of Emre et al. were not taking anticholinesterases, whereas 70% of those in the present study were on stable therapy. Another could be that not all SRT and CRT tasks have equivalent sensitivity in dementia trials. The mechanisms by which memantine may have produced the improvements to attention and episodic memory in the present study deserve consideration. The additional ANCOVAs of the memory scores fitting the improved CRTs as covariates strongly suggested the benefits on DWR to be largely independent of attentional improvements. NMDA antagonists can promote hippocampal neurogenesis (Nacher et al., 2003), which may be a potential mechanism for the improvements in episodic memory in this study and also in that seen previous AD trials. It is relevant to such a mechanism that memantine improved memory above baseline levels in this study. The major effect of memantine on CRT in this study was to prevent the decline which occurred in placebo-treated patients over 24 weeks. Such an effect may be more consistent with the neuroprotective properties of memantine. Of possible relevance is a previous finding in first-time diagnosed previously unmediated epilepsy patients treated with remacemide (Wesnes et al., 2009), which, Copyright # 2014 John Wiley & Sons, Ltd.

like memantine, is a low-affinity NMDA receptor antagonist. In that study, the CDR System SRT and CRT tests were employed, and remacemide significantly prevented declines on these measures over 48 weeks, which occurred in patients randomised to carbamazepine. Further, at baseline, attention was identified to be compromised in the epilepsy patients compared with healthy controls, potentially because of the negative neural effects of seizures, and remacemide actually improved attentional performance above the baseline levels in the study. This suggests that low-affinity NMDA antagonists can protect against neurotoxicity to favourably influence aspects of attention; which could be a possible mechanism for the effects of memantine seen in the present study. In conclusion, the present analysis suggests that memantine produces worthwhile cognitive benefits in DLB and PDD; evidenced by the large effect sizes, the movement of the test scores of the patients towards normal levels and the prior established relevance of the attention tests to everyday activities. This possibility is further supported by the association of enhanced attention to the improvement in ADCS-CGIC detected in the study (Aarsland et al., 2009). Furthermore, the effects seen in the two dementias with memantine are comparable in magnitude to the cognitive benefits in these conditions identified previously with anticholinesterase treatment. Overall, these findings indicate that larger future trials of memantine and related compounds are warranted both in DLB and PDD. Conflict of interest KW developed the CDR System and provided it as a scientific service to the clinical trials industry at the time of this trial. The CDR System is now owned by Bracket Inc., Wayne, PA, USA, and KW was employed by them until recently. Key points

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Patients with DLB and PDD besides having episodic memory deficits have a characteristic profile of attentional dysfunction. Memantine produced significant improvements in both populations to attentional performance involving information processing and to verbal episodic recognition memory. These benefits compare favourably with the effects of anticholinesterases in both dementias. This is the first demonstration using cognitive tests of improvements to attention and episodic memory in these two dementias.

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Memantine in Parkinson’s dementia and dementia with Lewy bodies

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