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December 10, 2002; 59 (11) Articles

Fluctuations in attention

PD dementia vs DLB with parkinsonism

C.G. Ballard, D. Aarsland, I. McKeith, J. O’Brien, A. Gray, F. Cormack, D. Burn, T. Cassidy, R. Starfeldt, J.-P. Larsen, R. Brown, M. Tovee
First published December 10, 2002, DOI: https://doi.org/10.1212/01.WNL.0000036908.39696.FD
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Abstract

Background: Marked impairments in and fluctuation of attention are characteristic of dementia with Lewy bodies (DLB). The comparative impairment of these cognitive domains in PD and PD dementia (PD dementia) has not been studied, and is important to the conceptual understanding of parkinsonian dementias.

Method: Detailed evaluations of attention and fluctuating attention (Cognitive Drug Research computerized battery) were undertaken in 278 subjects (50 DLB, 48 PD dementia, 50 PD, 80 AD, 50 elderly controls) from the Newcastle dementia register and the Stavanger PD register (controls, PD, and PD dementia patients were recruited from both centers). DLB, AD, PD, and PD dementia were diagnosed using operationalized criteria.

Results: Impairments in reaction time, vigilance, and fluctuating attention were comparable in patients with DLB and PD dementia, but were less substantially impaired in patients with DLB without parkinsonism. Patients with PD had significantly greater impairment of cognitive reaction time than elderly controls, and comparable impairments of cognitive reaction time to patients with AD. Patients with PD, however, did not exhibit fluctuation of attention.

Conclusion: The profile of attentional impairments and fluctuating attention is similar in PD dementia and DLB with parkinsonism. The current findings do not support the current arbitrary distinctions between these patient groups. Importantly, patients with PD do not experience fluctuating attention.

Lewy body disease is a spectrum of disorders related to PD that overlaps considerably with AD. Patients with PD have severe loss of nigrostriatal dopaminergic neurons1,2⇓ and some neocortical cholinergic deficits, which are greatest in the context of cognitive impairment.3-5⇓⇓ Diffuse cortical Lewy bodies are the main substrate of dementia.6 Patients with familial parkinsonism (chromosome 4p15) exhibit dopa-responsive parkinsonism and cognitive impairment with cortical Lewy bodies, further emphasizing the overlap of presentations within the PD spectrum.7,8⇓ Two of the key clinical diagnoses applied within this spectrum are PD dementia (25 to 40% of patients with PD)9-12⇓⇓⇓ and dementia with Lewy bodies (DLB; 10 to 25%13-19⇓⇓⇓⇓⇓⇓ of patients with dementia). Features of DLB13 include fluctuating cognition, visual hallucinations, and parkinsonism, but the diagnosis cannot be made if parkinsonian symptoms developed more than 1 year before the onset of dementia. A key question is whether this is a meaningful distinction between different clinical entities.

Fluctuating attention measured on a computerized choice reaction time task correlates significantly with clinician and informant ratings of fluctuating cognition20 and with variability of cortical arousal from EEG recordings,21 indicating that fluctuating attention is probably related to fluctuating cognition.20,21⇓ Typically, patients with PD have attentional impairments with slowed reaction times,22-34⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ but fluctuation of attention has not been studied. The current article is the first to compare attention and fluctuating attention among patients with DLB, PD dementia, and PD.

Method.

The study sample consisted of 278 subjects (50 DLB, 48 PD dementia, 50 PD, 80 AD, 50 elderly controls). Patients were recruited from a dementia register of consecutive referrals to old age psychiatry services in Tyneside, UK (DLB, PD dementia, PD, AD) and a community register of patients with PD (including patients with PD with dementia) in Stavanger, Norway. Spouses of patients from both centers were recruited as healthy elderly volunteers. From the total patient registers, matched groups were selected (dementia patients matched for Mini-Mental State Examination scores [MMSE]35; all groups matched for age and sex). Good diagnostic accuracy has been achieved in Newcastle for the first 50 patients coming to postmortem from the overall sample of 338 individuals within the patient register (DLB: sensitivity, 0.83; specificity, 0.91; AD: sensitivity, 0.87; specificity, 0.83).36 There has been no neuropathologic validation of diagnostic accuracy in Stavanger, although the same method was applied. Subjects older than 85 or younger than 60 were excluded. All patients were assessed with a standardized physical examination that incorporated an operationalized evaluation of parkinsonism (Newcastle: the modified Unified PD Rating Scale (UPDRS)37 and Hoehn & Yahr scale38; Stavanger: UPDRS39 and Hoehn & Yahr scale38) and a validated instrument to evaluate psychotic symptoms (Newcastle: Columbia University Scale of psychopathology in AD40; Stavanger: the Neuropsychiatric Inventory41). Patients with DLB were diagnosed according to the internationally agreed consensus criteria,13 which require that the patient must have a dementia syndrome and two out of three core features: 1) fluctuating cognition with pronounced variations in attention and alertness, 2) recurrent visual hallucinations that are typically well formed and detailed, and 3) spontaneous motor features of parkinsonism. In addition, the criteria stipulate that the diagnosis cannot be applied if the onset of parkinsonism occurs more than 1 year before the onset of dementia.

PD was diagnosed according to the UK brain bank criteria42 and dementia in these patients was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., rev. (DSM-III-R)43 criteria in both centers. In both Newcastle and Stavanger, these criteria were applied to information from a standardized evaluation (Stavanger: a semi-structured interview based on the DSM-III-R dementia criteria, MMSE,42 Dementia Rating Scale [DRS],44 Stroop test,45 visual memory [Benton Visual Retention Test],46 visuospatial functioning [Judgment of Line Orientation test]47; Newcastle: Cambridge assessment of mental disorders in the elderly, section B CAMCOG,48 MMSE, History and Etiology Schedule49). AD was diagnosed using the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria.50

The Joint Ethics Committee of Newcastle and North Tyneside Health Authority, University of Newcastle upon Tyne, and The Committee for Ethics in Medical Research, University of Bergen, granted ethical approval. Following full explanation and discussion of the study, patients and healthy volunteers gave their consent to the test, with additional assent from the next of kin for all cognitively impaired patients.

Neuropsychological evaluations of reaction time, vigilance, and fluctuations of reaction time were assessed in both centers using the Cognitive Drug Research51 computerized system. Specific tasks were as follows: simple reaction time—each time “yes” was presented in the center of the screen the participant was required to press the “yes” button as quickly as possible; choice reaction time—each time “yes” or “no” was presented in the center of the screen the participant was required to press the corresponding “yes” or “no” button as quickly as possible; cognitive reaction time—calculated by subtracting the simple reaction time from the choice reaction time; digit vigilance—a digit was displayed constantly on the right hand side of the screen and 90 digits were serially presented (80 min−1) in the middle of the screen. Participants were required to press “yes” every time that digit matched the digit constantly displayed on the right side of the screen.

Within-trial variability (SD) in the measures of choice reaction time was assessed in single trials, lasting approximately 90 seconds. These computerized methods of assessment have the advantage of ensuring excellent inter-rater reliability,51 which is essential in a two-center study. The tests were applied using exactly the same format in the two centers, with the exception of the simple reaction time and choice reaction time tasks, where the words “yes” and “no” were presented in Norwegian at the Stavanger center.

Statistical analysis.

The mean scores and the measures of variability on the reaction time and vigilance tasks were compared between patients with DLB and AD using the independent sample t-test. The primary hypotheses related to greater differences in performance among the DLB, PD dementia, and PD groups and the age-matched controls on the choice reaction time and fluctuating cognition measures and a similar level of performance on these tasks between the DLB and PD dementia patients, representing a total of eight comparisons. The Bonferroni correction therefore requires a p value of 0.006 to indicate significance for the primary evaluations. Other comparisons were considered as secondary evaluations to put the primary comparisons into the context of overall attentional performance. Additional comparisons were made of the choice reaction time performance of controls and patients with PD in Newcastle and Stavanger to determine between-site differences. The pattern of change in performance with increasing cognitive impairment is described. Although the SD was used as the primary measure of fluctuating cognition as this is the method that has been previously validated (in a study that also examined coefficient of variation),20-21⇓ an additional evaluation was undertaken for the key comparison between DLB and PD dementia using the coefficient of variation, dividing the SD by mean choice reaction time, to control for differences in the mean performance. Data were analyzed using the SPSS computer software program (Chicago, IL).52

Results.

A total of 278 patients (50 DLB, 48 PD dementia, 50 PD, 80 AD, 50 elderly controls) were assessed. The demographic comparisons are shown in table 1. The main characteristics of the dementia groups were broadly similar, although patients with LB and AD were significantly older than those with PD dementia and the patients with PD dementia had significantly higher MMSE scores than the patients with DLB (see table 1). As expected, the controls had the highest MMSE scores, whereas the MMSE scores of the PD group were intermediate between those of the controls and the patients with dementia. The PD dementia group had experienced a mean of 13.6 (±5.3) years of parkinsonism before the onset of dementia.

View this table:

Table 1 Sample characteristics

The mean performance on the reaction time tasks in the DLB, PD dementia, and PD groups and the elderly controls are shown in figure 1. The patients with DLB and PD dementia were significantly more impaired than the elderly controls on all primary and secondary comparisons (table 2). The patients with PD without dementia had significant impairments of both choice reaction time and cognitive reaction time compared to elderly controls but did not exhibit any greater fluctuation of choice reaction time (see table 2). In secondary comparisons of vigilance accuracy, the patients with DLB and PD dementia had greater impairments than elderly controls (DLB 59.5 ± 33.3 vs PD dementia 56.9 ± 28.6, elderly controls 98.9 ± 2.8; DLB vs controls t = 8.3, p < 0.0001, PD dementia vs controls t = 10.6, p < 0.0001) and the patients with PD without dementia (PD 92.9 ± 17.0; DLB vs PD t = 6.3, p < 0.0001, PD dementia vs PD t = 7.7, p < 0.0001). Only slight differences in vigilance accuracy were evident between patients with PD without dementia and controls (PD 92.9 ± 17.0 vs controls 98.9 ± 2.8, t = 2.5, p = 0.015).

Figure

Figure 1. Comparisons of reaction times (msec) in patients with dementia with Lewy bodies (DLB) (n = 50), PD dementia (PDD) (n = 48), PD (n = 50), and AD (n = 80), and elderly controls (n = 50). Embedded Image = DLB 50; = ▪ PDD 48; Embedded Image = PD 50; Embedded Image = AD 80; Embedded Image = CON 50. Standard deviations are as follows—DLB: simple reaction time (SRT), 643.1; choice reaction time (CRT), 1,127.1; cognitive reaction time (COGRT), 883.7; choice reaction time standard deviation (CRTSD), 679.4. PDD: SRT, 861.2; CRT, 994.6; COGRT, 632.4; CRTSD, 627.3; PD: SRT, 222.9; CRT, 260.1; COGRT, 241.0; CRTSD, 126.4. AD: SRT, 361.6; CRT, 372.0; COGRT, 408.6; CRTSD, 308.2. Controls: SRT, 101.2; CRT, 79.3; COGRT, 145.0; CRTSD, 166.2.

View this table:

Table 2 Pairwise statistical comparison of attention and fluctuating attention in DLB, PD dementia, PD, and elderly control groups

Patients with DLB and PD dementia had a similar overall profile of reaction time impairments, both with respect to overall deficits and the magnitude of fluctuation. The two groups of patients also had comparable impairments of vigilance accuracy (t = 0.55, p = 0.58). In an additional comparison of patients with DLB and PD dementia using coefficient of variation to control for the overall severity of attentional impairments, the magnitude of fluctuation remained similar in the two groups (DLB 0.47 ± 0.49 vs PD dementia 0.41 ± 0.20, t = 0.80, p = 0.42).

Both patients with DLB and PD dementia had significantly slower reaction times and greater fluctuation than did patients with AD. In contrast, the deficits in simple reaction time were greater in the AD group than the PD group, with trends in the same direction for choice reaction time, although cognitive reaction time was comparable. Patients with AD had substantially greater fluctuation of choice reaction time than did those with PD (statistical comparisons shown in table 3). Vigilance accuracy was more impaired in patients with DLB and PD dementia than in those with AD (AD 85.0 ± 21.6, DLB vs AD t = 4.8, p < 0.0001, PD dementia vs AD t = 6.3, p < 0.0001), but did not differ between patients with PD without dementia and patients with AD (t = 1.8, p = 0.07).

View this table:

Table 3 Secondary statistical comparisons vs AD

Fluctuating choice reaction time.

In order to further characterize fluctuators, the 95th centile of fluctuation scores in the elderly control group was determined, indicating a threshold of 550 msec, which was identical to the previously published optimal threshold for discriminating patients with DLB and AD.23 Applying this threshold to the DLB, PD dementia, and PD groups, 21 (42%), 14 (29%), and 2 (4%) were identified as fluctuators. There were too few fluctuators in the PD group to undertake further evaluations, but the neuropsychological profile of fluctuators was examined in the patients with DLB and PD dementia. Within the PD dementia group, fluctuators had greater impairments of simple reaction time (1,638.5 ± 826.8 vs 544.4 ± 260.3, t = 6.7, p < 0.0001), vigilance accuracy (33.8 ± 22.1 vs 67.5 ± 23.8, t = 4.5, p < 0.0001), and choice reaction time (2,394.5 ± 1,220.0 vs 928.5 ± 339.0, t = 6.3, p < 0.0001), with a trend toward a lower overall MMSE score (17.5 ± 5.1 vs 21.1 ± 4.8, t = 2.3, p = 0.03). There was no significant difference in cognitive reaction time (t = 1.9, p = 0.07). Examining the characteristics, there were no differences in age (t = 0.38, p = 0.71), years of parkinsonism (t = 1.5, p = 0.15), or severity of parkinsonism (t = 0.73, p = 0.47) between fluctuators and nonfluctuators. Within the DLB patient group, there were again differences between fluctuators and nonfluctuators across a range of reaction time and vigilance tasks (simple reaction time, 935.6 ± 702.9 vs 467.7 ± 288.4, t = 3.2, p = 0.002, vigilance accuracy, 43.2 ± 32.1 vs 71.9 ± 29.6, t = 3.2, p = 0.003, choice reaction time, 2,093.2 ± 1,450.7 vs 761.7 ± 181.7, t = 4.9, p < 0.0001, cognitive reaction time 1,184.7 ± 264.9 vs 295.5 ± 148.1, t = 3.8, p < 0.0001) and a trend toward an association with overall MMSE (14.2 ± 4.3 vs 17.4 ± 4.6, t = 2.4, p = 0.02). In addition there was an association with the severity of parkinsonism (1.8 ± 0.83 vs 0.7 ± 0.86, t = 4.0, p < 0.0001). There were no differences in age (t = 1.1, p = 0.27). To put the differences in the severity of parkinsonism into context, 20 (95%) of the fluctuators had parkinsonism, 16 (76%) of moderate severity or greater. Among the nonfluctuators only 13 (45%) had parkinsonism, 7 (24%) with moderate severity or greater.

PD dementia/DLB.

In a joint evaluation of the PD dementia and DLB groups (excluding DLB patients without parkinsonism), the severity of parkinsonism was significantly correlated with the fluctuation of choice reaction time and the overall level of impairment of both choice reaction time and cognitive reaction time. MMSE was significantly associated with fluctuation of choice reaction time and vigilance accuracy. There was, however, no significant association between the duration of parkinsonism and any of the key measures of attention or fluctuation. In the patients with PD without dementia the only significant association was between duration of parkinsonism and simple reaction time.

A detailed breakdown of these results is shown in table 4.

View this table:

Table 4 Relationship between attention/fluctuating cognition and severity of PD and MMSE in PD dementia, DLB, and PD

Differences between patients with DLB with and without parkinsonism.

To further emphasize the potential importance of parkinsonism, the 17 patients with DLB without parkinsonian symptoms had significantly less impairments of choice reaction time variability (t = 3.1, p = 0.003) and choice reaction time (t = 3.2, p = 0.002), with trends toward less impairment of simple reaction time (t = 2.4, p = 0.02) and cognitive reaction time (t = 2.2, p = 0.03) than those with parkinsonism. Vigilance accuracy was 12% higher in the patients with DLB without parkinsonism, although the difference did not attain significance (DLB with PD 55.6 ± 31.6 vs DLB without PD 67.1 ± 35.9, t = 1.4, p = 027). Details are shown in figure 2.

Figure

Figure 2. Patients with dementia with Lewy bodies (DLB) with and without parkinsonism (reaction times in milliseconds). Dark gray bars = DLB with parkinsonism (n = 33); black bars = DLB without parkinsonism (n = 17); light gray bars = PD dementia (PDD) (n = 48). Standard deviations are as follows—DLB + PD: simple reaction time (SRT), 742.0; choice reaction time (CRT), 1,279.5; cognitive reaction time (COGRT), 1,030.8; choice reaction time standard deviation (CRTSD), 717.4. DLB − PD: SRT, 217.5; CRT, 403.5; COGRT, 341.1; CRTSD, 427.0. PDD: SRT, 861.2; CRT, 994.6; COGRT, 632.4; CRTSD, 627.3.

Between-site comparisons.

As a measure of between-site comparability, the choice reaction time measures were compared between the control patients and patients with PD dementia at each center. For the comparison between controls, there was no difference but the Stavanger controls had reaction times that were 40 msec longer (Stavanger 562.5 ± 105.1 vs Newcastle 520.2 ± 59.9, t = 1.8, p = 0.08). There were no differences between patients with PD dementia at the two sites (Stavanger 1,637.3 ± 875.8 vs Newcastle 1,353.1 ± 1,014.0, t = 0.60, p = 0.55).

Discussion.

As hypothesized, patients with PD dementia had a similar profile of impairments in reaction time and fluctuating choice reaction time to those with DLB, with no significant differences between the groups. Overall, the similarity of reaction time and vigilance impairments and fluctuations of cognition in PD dementia and DLB are striking, particularly for patients with DLB with parkinsonism. The deficits of both reaction time and vigilance in the patients with DLB and PD dementia were substantially greater than those seen in AD. Taken together with emerging data regarding the neuropsychiatric and overall cognitive profiles of the two syndromes,53 this indicates that the clinical and neuropsychological characteristics of DLB and PD dementia are similar, which of course is what would be expected given emerging evidence that diffuse cortical Lewy bodies are prominent in patients with PD dementia6 and the overlap of parkinsonism and cognitive impairment with prominent visuospatial dysfunction in familial parkinsonism related to mutations on chromosome 4p15.7,8⇓ There is hence no clinical or scientific rationale to support a distinction between dementias based on the duration of parkinsonism before dementia, further supported by the absence of an association between the duration of parkinsonism and the severity of impairments of attention or fluctuation in the patients with PD dementia and patients with DLB with parkinsonism. These data strongly indicate that definitional distinctions between DLB and PD dementia should be dropped.

Patients with DLB with parkinsonism did experience significantly greater impairments of attention and more severe fluctuation of attention than those without parkinsonism. The presence or absence of parkinsonism in patients with DLB may reflect important clinical and neuropathologic differences and may therefore be a more meaningful distinction.

It is evident that neither parkinsonism nor impairments of cognition are in themselves sufficient to explain the pattern of deficits of reaction time or vigilance. For example, patients with AD with lower MMSE scores have less severe impairments than patients with DLB or PD dementia, and patients with PD with more severe parkinsonism do not experience greater deficits than patients with PD dementia. In addition, the relative preservation of simple reaction time and the impairments of cognitive reaction time in patients with PD emphasize that the deficits are not just related to motor slowing.

Consistent with the hypotheses, patients with PD without dementia had significantly greater global impairment of choice reaction time than elderly controls. In secondary evaluations, however, with the exception of cognitive reaction time, patients with PD without dementia had better preservation of reaction time and vigilance than patients with AD.

There were no major between-site differences in reaction time; hence, whether patients came from the Newcastle or Stavanger center was not a significant confounder.

Fluctuation of choice reaction time was significantly more pronounced in patients with PD dementia and DLB than in patients with AD or elderly controls. This has a fundamental importance for our conceptual understanding of these conditions, as it indicates that fluctuating attention is prominent in PD dementia. Given previous studies indicating a correlation between fluctuating attention and fluctuating cognition, it is hence likely that fluctuating cognition is also a prominent feature in these patients, although this needs to be verified with clinical measures.

There was no evidence of significantly greater fluctuation of choice reaction time in patients with PD without dementia compared to elderly controls. To further clarify the neuropsychological profile of fluctuators, the 95th centile of choice reaction time variability was derived for the control cohort. The identified threshold of 550 msec was identical to the cut-off recommended for the identification of significant fluctuation in previous work from our group focusing on a different patient cohort, indicating the consistency of this measure.20 Fluctuators had slower reaction times, impaired vigilance, and a tendency toward lower MMSE scores. The impairment of vigilance accuracy is important, as it indicates a broad deficit of attentional performance and not just a slowing of cognitive processing. Patients with AD experienced an intermediate level of fluctuating cognition.

In the current study, a standardized computerized battery of attentional tasks was successfully completed by the study participants, including a number of people with MMSE scores below 10. This battery can be completed in 15 minutes and appears highly suitable for use in clinical practice, and clearly has sufficient sensitivity to distinguish between different dementia groups. The highly significant differences in performance on tasks of reaction time and vigilance between patients with DLB or PD dementia and those with PD or AD suggests that detailed neuropsychology could provide an important component of the diagnostic workup.

There are a number of points that have important implications for treatment. Most obviously, the similarity of neuropsychological deficits in PD dementia and DLB, together with encouraging results from preliminary studies,54,55⇓ indicates the urgent need for double-blind placebo-controlled trials of cholinesterase inhibitors in PD dementia. In addition, however, considering that reaction time and vigilance are particularly sensitive to cholinergic enhancement,56-58⇓⇓ there may also be potential benefits of treating patients with PD with these deficits using cholinesterase inhibitors, even in the absence of dementia. This needs to be undertaken cautiously as it is possible that cholinesterase therapy may worsen the motor symptoms of parkinsonism, although this does not appear to occur in PD dementia55 or DLB.59

Acknowledgments

Supported by the Medical Research Council (UK).

  • Received February 26, 2002.
  • Accepted August 27, 2002.

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