Fluctuating' Cognition in Dementia with Lewy Bodies And

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Int J Geriatr Psychiatry 2001; 16: 494±498. DOI: 10.1002/gps.368

The characterisation and impact of `¯uctuating' cognition in dementia with Lewy bodies and Alzheimer's disease

Clive BallardÃ, Matthew Walker, John O'Brien, Elise Rowan and Ian McKeith

Institute of Health for the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK

SUMMARY Background Case reports and clinical observations suggest that ¯uctuating cognition >FC) is common in all the major dementias, particularly dementia with Lewy bodies >DLB) where it is one of three core clinical diagnostic features. The pur- pose of this study was to characterise FC and determine its impact upon activities of daily living. Methods Forty matched subjects >15 DLB, 15 AD, 10 elderly controls) were assessed using the activities of daily living scale >ADLD), the cognitive drug research >CDR) computerised neuropsychological test battery and a semi-standardised assessment of FC. The CDR battery was completed three times across a 1-week period, to evaluate variability in attention, visuospatial ability, working memory and delayed recall. Results There was a strong positive correlation between clinical FC scores and total mean ADLD. Measures of cognitive variability also demonstrated strong signi®cant correlations with independent clinical severity ratings of FC across several cognitive domains. These associations were most powerful between attentional measures and clinical FC ratings. Conclusions Although attention is the cognitive domain which ¯uctuates most markedly, other cognitive domains are also affected. FC also has a signi®cant independent impact on activities of daily living. Copyright # 2001 John Wiley & Sons, Ltd.

key wordsÐAlzheimer's disease; dementia with Levy bodies; ¯uctuating cognition; neuropsychology

INTRODUCTION The prevalence of FC is 80±90% in patients with DLB >McKeith et al., 1992; Byrne et al., 1989) and The most common forms of degenerative dementia 10±20% in patients with AD >McKeith et al., 1992, are Alzheimer's disease >AD) which constitute 1994). The importance of FC is evident from anecdotal approximately 60±70% of cases, and dementia with reports that indicate considerable changes in day to day Lewy Bodies >DLB), which accounts for a further functioning >McKeith et al., 1992; Byrne et al., 1989; 15±25% of sufferers >Cummings and Benson, 1992; Gibb et al., 1987; Yamamoto and Imai, 1988; McKeith et al., 1992, 1996). Consensus diagnostic Burkhardt et al., 1988; Crystal et al., 1990; Ballard criteria have been published which describe the clin- et al., 1993; Ishikawa et al., 1997; Wagner and ical syndrome associated with DLB >McKeith et al., Bachman, 1996; Hely et al., 1996; Briel et al., 1999). 1996), the three core clinical features of which are Recent work supports the expert view that these prominent and persistent visual hallucinations, ¯uctu- ¯uctuations in cognition relate closely to variability ating cognitive impairment >FC) and parkinsonism. in attention and to impairments of consciousness FC is by far the least well characterised of these key >Walker et al., 2000a). However, several further key features. questions remain, principally >1) How do these ¯uctuations affect other cognitive domains? >2) Do they have

Ã a signi®cant impact upon activities of daily living? Correspondence to: Dr C. Ballard, Institute of Health for the The current investigation was designed to charac- Elderly, Newcastle General Hospital, Westgate Road, New- castle upon Tyne, NE4 6BE, UK. Tel: +0191-2563327. Fax: terise and compare the variability in cognitive perfor- +0191-2195071. E-mail: [email protected] mance in patients with DLB and AD together with

Received 27 June 2000 Copyright # 2001 John Wiley & Sons, Ltd. Accepted 19 September 2000 ¯uctuating cognition in alzheimer's disease and dementia with lewy bodies 495 elderly controls across a 1-week period. We tested the All tests were started between 10 and 11 a.m. and hypotheses that clinically identi®ed FC would be patients were not allowed caffeine prior to evaluation. associated with ¯uctuations in performance across a Subjects were assessed using the CDR neuropsycho- range of cognitive domains and would have a signi®- logical test battery, a validated, well-tolerated compu- cant impact upon activities of daily living. terised assessment >Simpson et al., 1991). All tests were administered in the subject's place of residence METHODS using a standard portable laptop computer, placed at a standard distance in front of the subject. Participant Subjects responses were recorded using an attached response pad containing two non-latching buttons. If partici- The study cohort consisted of 40 subjects, 15 DLB pants were unable to place their ®ngers >or thumbs) patients, 15 AD sufferers and 10 healthy elderly con- on the buttons due to physical disability, testing was trols. Patients were recruited from a dementia case reg- discontinued and participants excluded. This action ister of consecutive referrals to old age psychiatry was taken to limit the potential for mobility dif®cul- services in Tyneside UK, with spouses of patients ties in¯uencing reaction time data. Participants were recruited as controls. None of the patients were taking initially trained in the use of the response module by cholinesterase inhibitors. Good diagnostic accuracy completing a practice choice reaction time >CRT) task has been achieved for the ®rst 50 patients coming to >see below). All data from this practice CRT were dis- post-mortem from the overall sample of 338 indivi- regarded. If after initial training, the participant was duals within the overall case register >DLB: sensitivity not able to utilise the response box correctly, the prac- of 0.83and a speci®city of 0.91) >McKeith et al., tice CRT task was repeated. If participants failed the 2000). Subjects were matched for age and gender, second practice for any reason, they were omitted with dementia sufferers also matched for cognitive from the study. impairment using the Mini Mental State Examination A version of the CDR battery specially designed for >MMSE) >Folstein et al., 1975). All patients were use in an elderly or demented population was assessed with >i) a structured psychiatric history employed in this study >Simpson et al., 1991). This >history and aetiology schedule) >Dewey et al., included the following: 1992), >ii) a standardised physical examination incor- Immediate verbal recognition ,IREC)±12 words porating the Uni®ed Parkinson's Disease Rating Scale were presented, one every 3s. These words were sub- >UPDRS) >Fahn and Elton, 1987), >iii) a validated sequently represented in random order interspersed instrument to evaluate psychotic symptoms >Columbia with 12 distractor words. Participants responded University Scale Psychopathology in Alzheimer's `YES' or `NO' to indicate whether they saw each Disease, CUSPAD) >Devanand et al., 1992) and >iv) word in the original list. informant interview using the activities of daily Simple reaction time ,SRT)±the word `YES' was living scale >Weintraub et al., 1982), with the addi- presented 30 times in the centre of the screen and tional question regarding verbal abilities taken from the participant was required to press the `YES' the Barthel index. DLB patients were diagnosed response button as quickly as possible. according to the internationally agreed consensus Choice reaction time ,CRT)±the word `YES' or criteria >McKeith et al., 1996) and AD patients `NO' was presented 30 times in the middle of the diagnosed according to NINCDS ADRDA criteria screen, the participant was required to press the corre- >McKhann et al., 1984). sponding response button as quickly as possible. The Joint Ethics Committee of Newcastle and Digit vigilance ,VIG)±a digit was displayed North Tyneside granted ethical approval. Following constantly on the right side of the screen and 90 full explanation and discussion of the study, patients digits were serially presented >80 minÀ1) in the and controls gave their consent to the test, with addi- middle of the screen. Participants were required to tional assent from the next of kin for all cognitively press `YES' every time this digit matched the impaired patients. digit constantly displayed on the right side of the screen. Spatial memory ,SPM)±participants were required Neuropsychological evaluation of ¯uctuating to remember four locations in a 3Â3matrix. cognition Responding involved indicating whether 18 individu- The neuropsychological evaluation was completed by ally presented locations were one of the four `to be Dr Matthew Walker, blind to the clinical FC rating. remembered' locations.

Memory scanning ,MS)±three digits were pre- could not be assumed across in the study group. The sented for the participant to remember. Eighteen coef®cient of variation >CV) was also applied to reac- digits were then individually presented. Participants tion time measures, given the greater mean impair- were instructed to press `YES' or `NO' according to ment of reaction times in DLB patients. Spearman's whether the digit was one of the `to be remembered' rank-order correlations were employed to evaluate digits. the relationship between variability on the ADLD Delayed verbal recognition ,DREC)±as for IREC and FC, and to evaluate the relationship between the except 12 new distractor words were used. mean ADLD performance and FC. A linear regression All participants completed three repeat trials of the analysis was performed to examine potential con- complete test battery across 1 week. The variability founders. Data was analysed using the SPSS compu- >SD) in performance for each individual aspect of ter software program >SPSS, 1992). cognition evaluated by the CDR system was then cal- culated across the three trials in 1 week and used as a RESULTS measure of ¯uctuating neuropsychological performance. Suf®cient parallel forms >50) of the CDR Subject data tasks were utilised to ensure multiple repeat testing occasions were possible and independent. The relia- The demographic and clinical data characteristics of bility and stability of repeat test sessions have been the participants are displayed in Table 1. established for all core tasks. Fluctuating cognition

Clinical evaluation of ¯uctuating Measures of variability >SD and CV) in attentional cognition/consciousness performance on SRT, CRT and VIG across 1 week were signi®cantly correlated with the clinical FC Independent ratings of the severity of FC/conscious- severity ratings >Table 2). The variability in perfor- ness were made using a semi-standardised informant mance level on both immediate verbal recognition interview >Walker et al., 2000a), scored by three and delayed verbal recognition were also strongly experienced geriatric psychiatrists >Dr Clive Ballard, associated with clinical FC scores >IREC: r0.48; Prof. Ian McKeith and Prof. John O'Brien), quantify- p < 0.002; DREC: r0.37; p < 0.01), as were ¯uctua- ing both frequency and duration of such episodes on a tions in numeric working memory ability >r0.55; 0±4 scale over the month leading up to the interview. p < 0.0001) >Table 2). Variability in spatial memory Both scores were then multiplied to produce an over- >SPM) performance demonstrated no correlation with all score of FC from 0 to 16 >0 representing no FC, 12 clinical FC scores >rÀ0.17; p N/S). representing severe FC while a score of 16 signi®ed a In a further correlation analysis focussing speci®- continuous stupor state which, by de®nition, denotes cally on the people with dementia >Table 2), only no ¯uctuation). This method is part of the validated variability in the attentional measures remained sig- DLB clinical diagnostic procedure utilised in New- ni®cantly associated with FC. castle >McKeith et al., 2000). To be rated as present, A regression analysis was performed in the DLB a clear-cut example of FC which in¯uences cognitive cohort to determine the effect of parkinsonian features or practical performance is required. The scale has >using UPDRS scores) upon CRT variability. CRT been concurrently validated against a modi®ed delir- variability >SD) remained strongly associated with ium assessment instrument covering a variety of different domains in¯uenced by FC >Walker et al., a 2000b). Table 1. Group demographic and clinical variables AD patients DLB patients Healthy elderly Study variable >N15) >N15) controls >N10) Statistical analysis Age >years) 78.8 > Æ 3.9) 78.7 > Æ 6.6) 77.5 > Æ 4.5) MMSE 18.0 > Æ 0.9) 17.3> Æ 5.0) 29.4 > Æ 3.2) Individual scores of cognitive test variability were % Females 53.3 40 50 correlated with independent clinical severity ratings Mean clinical of FC >values from 0 to 12) using the Spearmans rank FC score 1.5 > Æ 1.3) 8.6 > Æ 2.7) 0.0 > Æ 0.0) method. Variability >SD) in cognitive performance aValues in parantheses are standard deviations. MMSE, mini mental was compared between DLB, AD and normal con- status examination; FC, ¯uctuating levels of cognition; AD, trols using Mann±Whitney U-test as equal variance Alzheimer's disease; DLB, dementia with Lewy bodies.

Copyright # 2001 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2001; 16: 494±498. ¯uctuating cognition in alzheimer's disease and dementia with lewy bodies 497

Table 2. Spearman's rank correlations analyses between the variability >SD and CV) in CDR cognitive measures across three repeat trials in 1 week and independent clinical severity ratings of FCa CDR measure: across-trial Correlation analyses with clinical FC Correlation analyses with clinical FC variability >SD) ratings for the entire cohort >N40) ratings for the dementia cohort >N30) Simple reaction time r0.58; p < 0.0001Ã r0.52; p < 0.004Ã >CV r0.33; p < 0.03Ã) >CV r0.31; p < 0.09) Choice reaction time r0.68; p < 0.0001Ã r0.62; p < 0.0001Ã >CV r0.57; p < 0.0001Ã) >CV r0.56; p < 0.001Ã) Digit vigilance reaction time r0.71; p < 0.0001Ã r0.70; p < 0.0001Ã >CV r0.38; p < 0.01Ã) >CV r0.62; p < 0.0001Ã) Digit vigilance accuracy r0.61; p < 0.0001Ã r0.48; p < 0.06 Immediate verbal recognition >SI) r0.48; p < 0.002Ã r0.47; p < 0.07 Delayed verbal recognition >SI) r0.37; p < 0.01Ã r0.35; p < 0.06 Spatial memory >SI) rÀ0.17 >N/S) rÀ0.01 >N/S) Numeric working memory >SI) r0.55 p < 0.0001Ã r0.35; p0.05

aSD, standard deviation; CV, coef®cient of variation; N/S, non-signi®cant; SI, sensitivity index. *Statistically Signi®cant

Table 3. Spearman's rank correlation analyses between clinical FC scores and activities of daily living >ADL) measures across 1 week Correlation analyses with Correlation analyses with Diary/schedule assessment independent clinical FC ratings independent clinical FC ratings measure across 1 week for the entire cohort >N40) for the dementia cohort >N30) ADL±variability >SD) r0.14; pN/S r0.53; pN/S ADL±total mean r0.62; p < 0.0001 r0.87; p < 0.0001 clinical ratings of FC >t2.3; p < 0.02), whilst also con®rm expert opinion >McKeith et al., 1996) UPDRS values did not demonstrate a signi®cant rela- that performance on tasks of attention, SRT, CRT tionship with FC severity >UPDRS: t1.9; pN/S). and VIG reaction show the closest relationship with FC. The cohort size was modest, and a larger sample would be required to clarify the exact relationship Impact on ADL between FC and some of the other cognitive domains. The variability in patients' abilities to perform daily Given the broad impact on a range of cognitive activities across 1 week as assessed by the ADLD, functions, it is not surprising that FC should be signif- showed no correlation with clinical FC scores. A icantly associated with the overall mean performance strong positive correlation, however, was demon- of activities of daily living. These results do, however, strated between FC and the total mean ADLD score, have to be interpreted with some caution, as the sam- both overall and amongst the patients with dementia ple was small and it is possible that FC and impair- >Table 3). Linear regression analysis of overall ADLD ment of activities of daily living are both markers of performance within the dementia groups revealed that severity; although both FC and MMSE score contrib- FC and MMSE were important in in¯uencing ADLD uted independently to the level of impairment on >T5.0, p < 0.00001 and T2.5, p0.003, respec- activities of daily living, indicating that this is prob- tively), however, a diagnosis of AD or DLB was not ably not the explanation for the association. The like- >T0.47, p0.64). lihood that FC does add to the level of practical disability also emphasises its importance as a thera- peutic target in intervention trials, and clearly illus- trates that FC is not just of esoteric interest. DISCUSSION Episodes of FC in DLB patients have been The current study demonstrates that variability in a described as `delirium like', and appear to have a number of cognitive domains can be detected over a similar overall pattern of characteristics to delirum period of 1 week using a standardised neuropsycho- per se >Walker et al., 2000a,b). It would certainly be logical assessment, con®rming the broad impact of interesting to pro®le the cognitive ¯uctuations experi- FC on a range of cognitive tasks. These investigations enced by patients with delirium in the same way, and

Copyright # 2001 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2001; 16: 494±498. 498 c. ballard et al. given the more stable long-term course of FC in DLB Dewey ME, Copeland JRM, Lobo A, Saz P, Dia J-L. 1992. Compu- it is an exciting possibility that this may represent a terized diagnosis from a standardized history schedule: a preli- minary communication about the organic section of the HAS- clinical model in which the mechanisms of disturbed AGECAT system. Int J Geriatr Psychiatry 7>6): 443±446. consciousness can be studied, with implications for Fahn S, Elton R. 1987. Uni®ed Parkinson's disease rating develop- our understanding of delirium. ment committee. Uni®ed Parkinson's disease rating scale. In Recent Developments in Parkinson's Disease, vol. 2, Fahn S, Marsden CD, Calne D >eds). Macmillan: New York; 153±163. 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