Psychomotor Slowing in Mild Cognitive Impairment, Alzheimer's

Original Research Article Dement Geriatr Cogn Disord 2010;29:388–396 DOI: 10.1159/000305095

Accepted: March 23, 2010 Published online: May 20, 2010

© Free Author Psychomotor Slowing in Mild Cognitive Copy – for perImpairment, Alzheimer’s Disease and sonalLewy use onlyBody ANY DISTRIBUTION OF THIS Dementia: Mechanisms and Diagnostic Value ARTICLE WITHOUT WRITTEN Olivier Bailon Martine Roussel Muriel Boucart Olivier Godefroy

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Written permission to distribute the PDF will be granted Department of Neurology and the Laboratoire de Neurosciences Fonctionnelles et Pathologies (UMR CNRS 8160), against payment of a perUniversity Hospital of Lille, Lille, and University Hospital of Amiens, Amiens, France mission fee, which is based on the number of accesses required. Please contact [email protected]

Key Words Attention ⴢ Dementia ⴢ Alzheimer’s disease ⴢ Mild cognitive impairment ⴢ Lewy body dementia ⴢ Perception ⴢ Psychomotor performance ⴢ Neuropsychology

Abstract Background: Although psychomotor slowing is frequent in Alzheimer’s disease (AD) and Lewy body dementia (LBD), its mechanism and diagnostic value have not been examined. Objective: To (i) assess psychomotor speed in patients with mild cognitive impairment (MCI), AD and LBD, (ii) determine the underlying mechanisms, and (iii) examine whether psychomotor slowing constitutes a useful diagnostic marker. Methods: Psychomotor speed was assessed in MCI (n = 11) and mild dementia due to AD (n = 23) or LBD (n = 18) and controls (n = 52) with visual inspection time (VIT), digital tapping, simple reaction time (SRT) and choice reaction time (CRT) tests. Results: MCI did not differ from controls. Both dementia groups showed different patterns. In AD, VIT (p = 0.0001), tapping (p = 0.021), SRT (p = 0.0001) and decision time (p = 0.0001) were impaired as compared to controls. In LBD, VIT (p = 0.0001) was very impaired and correlated with visual hallucinations (p = 0.001); SRT lengthening (p = 0.0001) was related to attentional disorders (p = 0.0001). Conclusions: Psychomotor slowing of AD is due to slower percep-

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tuomotor and decision processes. In LBD, psychomotor slowing is due to visual and attention disorders, and subtle visual disorders contribute to hallucinations. VIT and CRT are useful © diagnostic markers. Copy Copyright 2010sonal S. Karger AG, Baselonly Free Author – for ©per use

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Introduction

With the emergence of disease-modifying therapies, early diagnostic markers for degenerative dementia are becoming increasingly important. Since most patients are referred for cognitive complaints, early cognitive markers are essential. However, most studies in this field have focused on memory rather than psychomotor slowing, despite the fact that the latter constitutes a very frequent impairment. In Alzheimer’s disease (AD) with mild dementia, slowing in simple reaction time (SRT) and choice reaction time (CRT) tasks is already present [1–3]. In mild cognitive impairment (MCI), slowing concerns CRT only [1, 3] and has been observed 3 years before a formal diagnosis of dementia [4]. In Lewy body dementia (LBD), CRT slowing and variability have been reported [5–7]. Reaction time (RT) slowing is usually attributed to attention deficit, but its mechanism has not been specifically addressed. Validation of RT slowing as Dr. O. Godefroy Service de Neurologie, Hôpital Nord FR–80054 Amiens (France) Tel. +33 322 668 240, Fax +33 322 668 244 E-Mail godefroy.olivier @ chu-amiens.fr

a diagnostic marker first requires determination of its mechanism; this is now possible with a validated battery assessing the speed of the four components of RT (perceptual, motor, decision and attention processes) [8]. The aim of the present study was to (i) assess psychomotor slowing in MCI patients and AD and LBD patients with mild dementia, (ii) determine the mechanism behind the slowing (i.e. impairments in the perceptual, motor, decision and/or attentional processes), and (iii) examine whether the psychomotor slowing profile constitutes a useful diagnostic marker.

Method Participants The study was performed in patients referred to the Memory Clinic at Amiens University Hospital for MCI [9] or mild dementia (Mini-Mental State Examination (MMSE) score 120/30) [10] meeting the criteria for AD [11] or probable LBD [12]. The exclusion criteria were as follows: (1) visual impairments likely to compromise letter identification as assessed on the Parinaud optometric scale, in the Albert cancellation test [13] and via identification of the letters used in the RT tests; (2) severe motor difficulties as assessed on the Unified Parkinson’s Disease Rating Scale (UPDRS-motor) [14]; (3) severe deficits in oral comprehension (Shortened Token test !18) [15]; (4) illiteracy; (5) alcoholism or severe comorbidity (severe cardiac, respiratory or renal disease); (6) concurrent neurological and psychiatric disorders (except for depression or anxiety); (7) recent introduction (within the last month) of psychoactive or antiepileptic medication, and (8) lack of informed consent. MRI was performed to exclude patients with focal lesions, including tumor, subdural hematoma and vascular cognitive impairment. Conversely, patients with small stroke or deep infarct revealed by MRI were retained as possible AD or LBD after exclusion of (1) multiple lacunes, (2) clinical stroke or abrupt onset of cognitive disorders, and (3) absence of prominent memory deficit. An associated small infarct was observed in 13 patients (8 in AD group, 3 in LBD group, and 2 in MCI) and its contribution to RT changes was examined in a specific analysis. 52 patients (MCI: n = 11; AD: n = 23; LBD: n = 18) were included. Neuropsychological Performance Testing All subjects were tested by a standardized neuropsychological battery including: the Mattis Dementia Rating Scale [16] for the general intellectual efficiency; oral comprehension by Shortened Token test [15] and oral expression by ‘DO80’ confrontation-naming test [17]; visual and spatial abilities with Albert test [13] and copy of Rey complex geometric figure [18]; verbal and spatial episodic memory with short-term memory with digit span forward [19], verbal and visual long-term memory with the French adaptation of the test of Gröber and Buschke [20] and Doors and People Test [21]; executive functions evaluated with tests from the standardized battery Grefex [22]: Stroop test [23], verbal fluency (literal and category fluency) [24], Trail Making test [25]. Severity of illness was determined by the Clinical Dementia Rating Scale (CDR) [26] and MMSE [10]; the activities of the everyday life by

Psychomotor Slowing in MCI, AD and LBD

the scale Instrumental Activities of Daily Living (IADL) [27]. Psychological aspects were tested with Montgomery-Åsberg Depression Rating Scale (MADRS) [28, 29] for depression and with the French version of the Goldberg Scale [30, 31] for anxiety. When compared with the control and MCI groups, the AD and LBD groups (table 1) had lower MMSE and higher CDR scores [26], greater difficulties in IADL [27] and more impairment in Mattis [16] and verbal fluency [24] tests. In AD, the impairment of episodic memory was more marked [32]. The LBD group had a higher frequency of visual hallucinations, more parkinsonism and greater impairments in digit span [19] and visuoconstructive abilities [18]. The groups did not differ significantly in terms of anxiety [30], depression (MADRS) [28, 29], attentional fluctuation [33] and confrontation-naming ability [17]. Performance on Stroop and Trail Making tests is reported with more details as they are used to assess psychomotor speed in usual clinical practice. Chronometric Tests Chronometric tests were administered on a laptop computer with a 15-inch monitor (resolution: 800 ! 600 pixels; refreshment rate: 60 Hz) using a method described previously [8]. Briefly, white stimuli were displayed on the center of a black screen. Tests were delivered after a practice session in a fixed order (finger-tapping test, SRT and CRT tests, visual inspection time (VIT) test). Subjects were comfortably seated in a quiet room 60 cm from the screen. Four tests were used to assess perceptual VIT, motor (finger-tapping test), attention (SRT distribution) and decision (CRT) processes (fig. 1). The VIT test [34] is a discrimination task requiring the subject to determine which of two vertical lines (left or right) is the shortest. Each trial was initiated by a central fixation point (duration: 500 ms) followed by display of the imperative stimulus, i.e. the two vertical lines. The lengths of the short and long lines did not change during the test (21 and 29 mm, respectively). The imperative stimulus was displayed for a variable duration and was then replaced by a mask (duration: 360 ms). All participants had to successfully complete a practice session using stimuli lasting 500 and 200 ms. The minimum display duration required to achieve 80% accuracy was used as dependent variable. The finger-tapping test required the subject to press the response button with the index finger as often and as rapidly as possible for 15 s. The tapping frequency (in Hz) was taken as the dependent variable. In the SRT and CRT tests, the target stimulus was one of four letters (H, T, S or C) subtending a 1.6° visual angle displayed at random (fig. 1). They appeared with randomly varying stimulus onset asynchrony (500, 550, 600, 650 and 700 ms) after a warning stimulus (a fixation cross displayed for 400 ms). The response consisted of pressing one of two buttons with the index or middle finger of the preferred hand. Each trial was separated from the previous response by a 1-second interval. Tests featured 102 trials and the first two trials were not taken into account (test duration: about 160 s). For all tests, subjects were instructed to respond as rapidly and as accurately as possible. Responses occurring within 120 ms of the appearance of the stimulus were considered to be anticipations and the absence of a response within 3 s was considered to be an omission. SRT and CRT tests used the same stimuli but had different instructions. In the SRT test, the subject had to respond to any of the letters by pressing the same response button

Dement Geriatr Cogn Disord 2010;29:388–396

389

Table 1. Demographic, clinical and neuropsychological data

Number Age, years Male/Female Schooling, years MMSE (/30) Disease duration, months UPDRS upper limb/48 Visual hallucination, n (%) Fluctuation scale CDR 0/0.5/1/2–3 Instrumental ADL Anxiety score (/9) MADRS score (/60) Mattis DRS (/144) Shortened Token test (/36) Confrontation naming (/80) Verbal fluency – literal Verbal fluency – category Copy complex figure (/36) Digit span forward (/9) Total 3 free recall (/48) Recognition (/16) Delayed total recall (/16) Stroop/time, s Naming Interference Stroop/errors, n Naming Interference Trail Making test/time Part A Part B Trail Making test/errors Part A Part B

AD

LBD

MCI

Controls

23 75.686.3 7/16 9.382 24.382.1a, b 47.4830.8 4.682.6 0 0.680.9 0/7/13/1b 1688.7b 2.482.4 6.685.9 12588.6 31.283.3 76.383 14.185.1a 15.884.1a 40.083.2 5.380.9 (0) 8.485.3b 14.081.9 8.684.8b

11 73.688.8 4/7 7.881.8 23.783a, b 39.8813.7 14.285.2b, c 8 (73) 0.980.7 0/3/7/1b 23816b 3.282.7 11.887.0 118815.7b 28.183.6b, c 7683.3 9.883.3a 13.485.1a 17.8811.6b, c 4.480.8 (0)c 12.486 14.981.4 12.683.6

18 75.187 6/12 8.881.9 26.981.9 39.1827.2 5.983.8 0 0.480.8 0/15/0/0 683.7 2.782.3 7.185.1 13186.0 33.481.9 75.984.1 11.884.5a 18.986a 3184.0 5.180.9 (0) 14.686.4 15.281.7 12.383.7

52 74.586.8 19/33 9.482 28.281.4

848178 214869

113829 262883

84819 186855

74817 156853

0.6581.2 6.6812.4

3.083.6 13.4815.4

0.3981.0 5.0811.8

0.480.9 1.181.9

78826 3488178

156894 4938280

73824 2268125

55824 141877

0.380.6 1.881.9

181.3 482.2

080.5 281.5

080.5 181.2

1885.9 26.786.5

p 0.8 0.9 0.1 0.0001 0.6 0.0001 0.0001 0.4 0.013 0.004 0.7 0.06 0.003 0.001 0.9 0.0001 0.0001 0.0001 0.004 0.005 0.06 0.02

Data are expressed as means (8SD) except sex, hallucinations and Clinical Dementia Rating Scale (CDR). AD = Alzheimer’s disease; LBD = Lewy body dementia; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; UPDRS = Unified Parkinson’s Disease Rating Scale; MADRS = Montgomery-Åsberg Depression Rating Scale; IADL = Instrumental Activities of Daily Living; Mattis DRS = Mattis Dementia Rating Scale. a Differ from controls. b Differ from MCI. c Difference between LBD and AD.

with the index finger, whereas in the CRT test, the 4 letters were classified into two groups (group 1: letters ‘H’ and ‘T’; group 2: letters ‘C’ and ‘S’) and subjects were instructed to choose which letter group had been displayed by pressing one of the two response buttons with the index or middle finger. In the SRT test, dependent variables were the numbers of anticipations and omissions and the 5th and 50th percentiles of the SRT [8]; for the CRT test, the error rate, the median CRT, the standard deviation and the decision time (estimated by subtracting the SRT from the CRT [35]) were used.

390


Statistical Analyses Between-group comparisons were performed with a one-way analysis of variance (ANOVA) using the group (MCI, AD, LBD, controls) as a between-subjects factor. When necessary (Stroop, Trail Making and SRT tests), ANOVA for repeated measures on the condition factor was performed. Post-hoc analysis used Bonferroni analysis. To rule out the contribution of vascular lesion, the between-group comparisons were repeated after exclusion of 13 patients with small infarct. Correlations between chronometric indexes (VIT, tapping frequency and median SRT and CRT values) on one hand and clinical indexes (presence of visual hal-

Bailon/Roussel/Boucart/Krystkowiak/ Godefroy

Fixation point (500 ms)

+

Warning signal (100 ms)

Imperative stimulus Mask

Ready? Go! End! Time (ms)

Time (ms)

Duration: 200–300 ms

Fig. 1. Chronometric tests: a VIT, b finger tapping, c SRT, and d CRT. a VIT: this per-

ceptual test required subjects to indicate which vertical line (left or right) was the shortest; the VIT corresponded to the minimum display duration required to achieve 80% accuracy. b Finger tapping: this motor test required subjects to press the response button as rapidly as possible. c SRT: this perceptuomotor test required subjects to respond to all letters by pressing the same response button with the index finger. d CRT: this perceptuomotor and decision test required subjects to respond to letter classes by pressing one of the two response buttons with the index or middle finger, respectively.

Tapping 15 s ‘left’

a

b

Warning (400 ms) Imperative stimulus ‘H, T, S or C’

Imperative stimulus ‘H, T, S or C’

SOA: 500–700 ms

c

Results

Stroop and Trail Making Tests Completion time and error rates in the Trail Making and Stroop tests were analyzed using ANOVAs with repeated measures on the subtest (Stroop test: dot-naming and interference subtests; Trail Making test: parts A and B) and group (MCI, AD, LBD, controls) as between-subject factor. Regarding the Stroop test (table 1), the completion time differed between groups (F(3) = 13.7; p = 0.0001): it

+ H

H

lucinations, anxiety score, MADRS score, fluctuation score, upper limb score of the UPDRS III) and dementia severity (CDR and MMSE scores) on the other were analyzed using the Pearson test, with correction for multiple analyses (p ^ 0.01). The diagnostic value of chronometric indexes was analyzed using a logistic regression analysis with stepwise selection. Two analyses examined chronometric predictors of (i) the diagnosis of dementia (present in both AD and LBD, absent in both MCI and controls) and (ii) the diagnosis of LBD (present in LBD and absent in AD). The impairment of VIT, tapping frequency, SRT, CRT and CRT errors were submitted as independent factors. RT and completion time were log-transformed. p values !0.05 were considered to be significant. Statistical analysis was performed with SPSS Version 13.0 software (SPSS Inc., 2001).


Warning signal (400 ms)

+

Time (ms)

Time (ms) SOA: 500–700 ms

d

was longer in the LBD (p = 0.0001) and AD (p = 0.001) groups (compared with controls) and in LBD relative to AD (p = 0.035). The significant effect of the subtest factor (F(2,97) = 478; p = 0.0001) was due to longer completion times in the naming and interference subtests (p = 0.0001, both). The significant group ! subtest interaction (F(6,194) = 2.4; p = 0.03) was due to a more marked increase in completion time in the interference subtest in both AD (p = 0.001) and LBD (p = 0.002) groups. The groups differed significantly in terms of the error rates (F(3) = 7.4; p = 0.0001), which were higher in LBD than in controls (p = 0.0001) and MCI (p = 0.03) groups. The significant effect of the subtest factor (F(2,97) = 26; p = 0.001) was due to higher error rates in both the naming and interference subtests (p = 0.0001, both). The significant group ! subtest interaction (F(3) = 7.6; p = 0.0001) was due to a greater increase in the error rate in the interference subtest in the LBD group. Concerning the Trail Making test, the completion time differed (F(3) = 10.7; p = 0.0001) between groups: it was longer time in both LBD and AD groups (p = 0.0001, both). The significant effect of the subtest factor (F(1,92) = 26; p = 0.0001) was due to longer time in part B. The significant group ! subtest interaction (F(3,92) = 7; p = 0.0001) was due to a greater time increase in part B in Dement Geriatr Cogn Disord 2010;29:388–396

391

Table 2. Chronometric tests

Visual inspection time, ms Finger tapping, Hz SRT, ms P5 P50 Omissions, % Anticipations, % CRT, ms CRT SD, ms Decision latency, ms Errors, %

AD

LBD

MCI

Controls

p

2678183a 3.8581.2a

477875a, b 4.2181.3

1728133 4.2581.4

115874 4.7280.95

0.0001 0.021

256875a 4068126a 0.981.4 5.787.7 9168179a, c 213856 5108144a, c 382.8

236863 4578131a, b 5.488.2a 17.7821.0 8108182a 291889a–c 3538265b 9.787.9a–c

219866 339897 0.481.7 10.8811.2 7398180 176856 4008142 2.382.1

210852 313862 0.2980.9 10.2812.7 6548142 146838 3418130 282.7

0.0001 0.0001 0.0001 0.87 0.0001 0.0001 0.0001 0.0001

Data are expressed as means (8 SD). AD = Alzheimer’s disease; LBD = Lewy body dementia; MCI = mild cognitive impairment; SRT = simple reaction times corresponding to percentiles 5 and 50 (P5 and P50); CRT = choice reaction time; CRT SD = individual standard deviation on the CRT test. a Differ from controls. b Differ from AD. c Differ from MCI.

both LBD and AD groups (p = 0.0001, both). Groups differed significantly in terms of the error rates (F(3) = 10.3; p = 0.0001) which were higher in both the LBD (p = 0.0001) and AD (p = 0.04) groups. The significant effect of the subtest factor (F(1,92) = 98; p = 0.0001) was due to a higher error rate in part B. The significant group ! subtest interaction (F(3,92) = 13; p = 0.0001) was due to higher increase in the error rate in part B for (i) both LBD (p = 0.0001) and AD (p = 0.023), compared with controls, and (ii) LBD relative to AD and MCI (p = 0.002 for both comparisons). These analyses indicate that both LBD and AD groups are slower, commit more errors and are disproportionately sensitive to the effect of interference (Stroop) and shifting (Trail Making test); this pattern was most marked in the LBD group. Chronometric Tests Visual Inspection Time The groups differed significantly in terms of the VIT (F(3) = 31.9; p = 0.0001), due to longer time in AD and LBD groups (p = 0.0001 for both) (table 2). In addition, VIT was longer in LBD than in AD (p = 0.0001) and MCI (p = 0.0001). As a control measure, the analysis was repeated with visual acuity as a covariate and generated similar results, with longer VITs in LBD than AD and MCI (p = 0.0001, both). This result indicates slower perceptual speed in AD and even more severe impairment in LBD.

392


Finger-Tapping Test Tapping frequency differed between groups (F(3) = 3.4; p = 0.02), due to a lower tapping rate in AD (p = 0.02) (table 2). Hence, this analysis indicated slower motor speed in AD. Simple Reaction Time Test SRTs were analyzed using ANOVA with repeated analyses on index (5th percentile SRT, 50th percentile SRT) and group (MCI, AD, LBD, controls) as betweensubjects factors. The SRT differed between groups (F(3) = 6.5; p = 0.0001), due to a longer SRT in AD (p = 0.002) and LBD (p = 0.014) (table 2). The significant effect of index (F(1,100) = 485; p = 0.0001) was due to a longer 50th percentile SRT. The group ! index interaction was significant (F(3,100) = 4.7; p = 0.004) and was due to a more marked increase in the 50th percentile SRT in the LBD group (p = 0.0001). In addition, an inter-group comparison of the 5th percentile SRT using a one-way ANOVA showed that it differed between groups (F(3) = 3.1; p = 0.03), due to a longer 5th percentile SRT in AD (p = 0.03). Omissions and anticipations were compared across groups using two one-way ANOVAs with group factor (MCI, AD, LBD, controls). Groups did not differ in terms of anticipations (F(3) = 2.3; p = 0.9) but did for omissions (F(3) = 10; p = 0.0001), due to a higher rate in LBD (p = 0.0001). To examine whether this difference accounted for SRT slowing in the LBD group, the 50th percentile SRT was compared between groups using the Bailon/Roussel/Boucart/Krystkowiak/ Godefroy

The error rate differed between groups (F(3) = 14.4; p = 0.0001) and was higher in the LBD group than in all other groups (p = 0.0001). These analyses indicate longer and more variable (individual standard deviation) CRT in both AD and LBD with different patterns of impairment; in LBD, the association of a longer CRT and a higher error rate indicates an impaired decision process; conversely, a slower decision time and a stable error rate in AD suggest that the decisional process was slowed but not damaged.

500 ab 450 a

Simple reaction time (ms)

400 350 300 250

a

200 150 AD LBD MCI Controls

100 50 0 C5

C50

Fig. 2. Distribution of SRT (ms) between centiles 5 and 50. AD =

Alzheimer’s disease; LBD = Lewy body dementia; MCI = mild cognitive impairment. ‘a’ differ significantly from controls, ‘b’ differ significantly from AD patients.

omission rate as a covariate. This generated similar results with longer SRTs in AD (p = 0.005) and LBD (p = 0.02). These analyses indicate that SRT was longer in both AD and LBD but that the respective patterns differed. In AD, the SRT lengthening concerned both the 5th and 50th percentiles and hence was uniform across the distribution – a pattern that is suggestive of slower perceptuomotor processes [8]. In contrast, LBD patients were able to perform a few rapid responses (as shown by the lack of change in the 5th percentile) but were unable to sustain this ability throughout the test (as shown by longer 50th percentile SRTs) (fig. 2). This latter pattern is suggestive of impaired attention [8, 36]. Choice Reaction Time Test CRT differed between groups (F(3) = 15; p = 0.0001) due to slower CRTs in both AD (p = 0.0001) and LBD (p = 0.02) (table 2). Individual standard deviation on the CRT test differed between groups (F(3) = 15; p = 0.0001) due to higher standard deviation in LBD than all other groups (p ! 0.004, all) and to higher standard deviation in AD (p = 0.005) than controls and MCI (p ! 0.005, both). Decision latency also differed between groups (F(3) = 7.4; p = 0.0001) due to a longer time in AD (p = 0.0001). Psychomotor Slowing in MCI, AD and LBD

Between-Group Comparisons in Patients without Small Infarct These analyses performed in 39 patients (MCI: n = 9; AD: n = 15; LBD: n = 15) generated the same results: (1) VIT (F(3) = 30.8; p = 0.0001) was longer in AD (198 8 141 ms) and LBD (469 8 88 ms) groups (p = 0.03, both) and in LBD than all other groups (p = 0.0001, all, MCI: 162 8 111 ms); (2) tapping frequency (F(3) = 4.83; p = 0.004) was lower in AD (3.6 8 1.1 Hz) than other groups (LBD: 4.1 8 1.5; MCI: 4.1 8 1.4 Hz); (3) the 5th percentile SRT (F(3) = 3.3; p = 0.03) was longer in AD (230 8 85 ms) than other groups (LBD: 230 8 68; MCI: 241 8 72 ms), and (4) the 50th percentile SRT (F(3) = 7.2; p = 0.0001) was longer in AD (414 8 129 ms) and LBD (421 8 127 ms) groups (p = 0.004, both) than other groups (MCI: 371 8 106 ms); (5) CRT (F(3) = 16.3; p = 0.0001) was slower CRTs in AD (193 8 33 ms) and LBD (286 8 89 ms) (p = 0.01, both) (MCI: 187 8 58 ms). Correlations Considering clinical indexes, (1) visual hallucinations correlated with VIT (R = 0.44; p = 0.001) and (2) UPDRS III upper limb score correlated with the VIT (R = 0.51; p = 0.0001) and SRT (R = 0.37; p = 0.008). When considering indexes of dementia severity, (1) MMSE score correlated with the VIT (R = 0.47; p = 0.0001), SRT (R = –0.48; p = 0.0001) and CRT (R = –0.375; p = 0.0001) and (2) the CDR correlated with the SRT (R = 0.49; p = 0.0001). Diagnostic Value Logistic regression for assessing predictors of dementia identified (1) the VIT (OR 52; 95% CI 9.8–277; p = 0.0001) and (2) the CRT (OR 15.4; 95% CI 4.1–58; p = 0.0001). The analysis of factors predicting LBD selected the VIT only (OR 20; 95% CI 2–189; p = 0.01).


393

Discussion

The present study showed that (1) the MCI group’s chronometric indexes did not differ from controls; (2) the AD and LBD groups were slower in most chronometric tests but displayed different slowing patterns; (3) in AD, SRT lengthening was uniform across the distribution (i.e. the 5th and 50th percentile SRTs were both affected); (4) conversely, in LBD, the lengthening did not affect the 5th percentile SRT; (5) in AD, CRT lengthening was related to a longer decision time; (6) conversely, CRT impairment in the LBD group associated a combination of CRT lengthening and a higher error rate; (7) the chronometric indexes correlated with dementia severity and VIT correlated with visual hallucinations, and (8) longer VITs and CRTs predicted a clinical diagnosis of dementia, whereas a longer VIT alone predicted a clinical diagnosis of LBD. The maintenance of psychomotor speed in MCI was consistent across neuropsychological and chronometric tests. The few previous studies have variously showed slowing in the Trail Making and Stroop tests [37, 38], longer CRTs [3] and VITs [39] and maintenance of performance in the tapping test [40]. The discrepancy between our findings and those of previous studies is probably due to the selection of very early MCI subjects in the present study, although we cannot exclude a type II error. The important point is that when psychomotor slowing is present in MCI, it is very mild and concerns only a few patients, leaving open the possibility that it may indicate a risk of conversion to dementia. This warrants further investigation in a large unselected population. In mild dementia, the present study emphasizes the importance of psychomotor slowing, which was observed in all tests. Our study reveals that the mechanism of psychomotor slowing varies according to the etiology of the dementia. The contribution of associated small infarct revealed by MRI in 13 patients was ruled out as an additional analysis performed in patients without vascular lesions yielded exactly the same results. In AD, the slowing was uniform across the SRT distribution (since both the 5th and 50th percentile SRTs were lengthened) and was thus suggestive of impaired perceptual and motor processes [8]. This interpretation is fully supported by the observed slowdown in finger tapping and a longer VIT. This finding was unexpected and suggests that AD impairs subtle perceptuomotor processes event in the early stages of dementia. The observed CRT lengthening was related to a longer decision time which, in combination with an unaffected error rate, indicates that AD patients adopted a more conservative approach and took more 394


time to select their response. Hence, these results indicate that psychomotor slowing in AD is related to slower perceptuomotor processes and to a slower decision-making process, due (at least in part) to the adoption of a more conservative approach to decision-taking. The pattern of psychomotor slowing was different in LBD. First, the major impairment concerned the VIT and indicated the presence of severe slowing of visual processes; it could not be attributed to a difference in visual acuity, since a covariance analysis yielded the same result. The sparing of finger-tapping performance in LBD was unexpected and can probably be explained by the very mild intensity of parkinsonian disorders affecting the preferred hand. SRT lengthening was mainly related to slower 50th percentile SRT values, since there was no significant impairment of the 5th percentile. This pattern indicates that patients were able to perform a few rapid responses but they had trouble sustaining rapid responses throughout the test and thus indicates a deficit in sustained alertness [36], as previously reported [8]. Lastly, CRT lengthening was associated with a higher error rate and indicated impairment of the decision-making process, which can partly be explained by a visual disorder. Hence this pattern suggests that psychomotor slowing in LBD is mainly due to the slowing of visual processes and to impaired attention. Our results extend previous reports of difficulties in neuropsychological tests with a strong visual component [41], as the deficit was observed with a pure and elementary visual test. This could be related to dysfunction of the prefrontal and cingulate cortices which have been found to be involved in sustained alertness using a similar SRT paradigm [42]. It could also be related to the cholinergic dysfunction in the medial occipital cortex which has been found to be more severe in LBD than in AD [43]. Interestingly, the slowing of visual processes correlated strongly with visual hallucinations which cannot be explained by poor eyesight [44], suggesting the role of visual disorders. The variability of CRT indexed by individual standard deviation was found to be higher in LBD but did not differ from AD in contrast with previous studies [5, 6]. As RT variability correlates with mean RT [35, 45], this indicates that higher standard deviation cannot be used as diagnostic index in patients with lengthened CRT. Lastly, we found that chronometric indexes provide diagnostic clues. Lengthened VIT and CRTs discriminated between demented and nondemented subjects, indicating that these two tests may be useful for separating MCI from dementia and, possibly, for identifying MCI patients at risk of conversion. In demented patients, a severe impairment in visual inspection was associated with Bailon/Roussel/Boucart/Krystkowiak/ Godefroy

a diagnosis of LBD. This suggests that analysis of the VIT may help to distinguish between these frequent causes of dementia and to identify LBD patients at risk of hallucinations. This warrants further investigation in a large unselected population.

Acknowledgements The authors thank A. Rahnema, L. Eloy, D. Peyserre and P. Despretz for their invaluable help.

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