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Visual perception in Parkinson disease
dementia and dementia with Lewy bodies
U.P. Mosimann, MD; G. Mather, PhD; K.A. Wesnes, PhD; J.T. O’Brien, DM; D.J. Burn, MD; Abstract—Objective: To quantify visual discrimination, space-motion, and object-form perception in patients with Parkin-
son disease dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD). Methods: The authors used
a cross-sectional study to compare three demented groups matched for overall dementia severity (PDD: n ϭ 24; DLB: n ϭ
20; AD: n ϭ 23) and two age-, sex-, and education-matched control groups (PD: n ϭ 24, normal controls [NC]: n ϭ 25).
Results: Visual perception was globally more impaired in PDD than in nondemented controls (NC, PD), but was not
different from DLB. Compared to AD, PDD patients tended to perform worse in all perceptual scores. Visual perception of
patients with PDD/DLB and visual hallucinations was significantly worse than in patients without hallucinations.
Conclusions: Parkinson disease dementia (PDD) is associated with profound visuoperceptual impairments similar to
dementia with Lewy bodies (DLB) but different from Alzheimer disease. These findings are consistent with previous
neuroimaging studies reporting hypoactivity in cortical areas involved in visual processing in PDD and DLB.
Parkinson disease (PD) is associated with a higher visual impairment in DLB11 and a recent study risk of developing dementia compared to healthy el- found similar impairments in pentagon copying in derly controls; longitudinal studies suggest that up DLB and PDD.12 Some of these studies used con- to 78% of PD patients will develop dementia after struction tasks as evidence, but this may not be le- nearly two decades of motor symptoms.1 Once de- gitimate given the motor impairments in these mentia is established, clinical symptoms of PD de- patients. Studies quantifying visual perception of mentia (PDD) may show, apart from a longer DLB and PDD using tasks without motor require- duration of motor features, considerable overlap with dementia with Lewy bodies (DLB). The postural Peripheral structures such as the retina, the optic nerve and tract, and primary visual cortex are mul- represented in PDD and DLB2 and both disorders timodal in their function, whereas the visual associ- show similar fluctuation of attention3 and response ation cortex is more specialized.13 Low-level visual discrimination is mainly processed in visual area V1/ Studies comparing visual perception and visual V2, whereas high-level visual functions require addi- construction of PDD with Alzheimer disease (AD) tional activation of large extrastriatal cortical have revealed contradictory results. Some studies re- networks.14 Two visual pathways can be distin- port PDD to be more impaired,6,7 whereas other stud- guished: the ventral occipito-temporal pathway, ies found no differences.8,9 Similar inconsistencies which is required for detailed analysis and identifi- have been found when perception of PD patients was cation of objects and forms, and the dorsal occipito- compared with healthy controls.10 Since operational- parietal pathway, required for spatial vision and ized criteria to define the clinical boundaries be- motion perception.14 Task selection of the present study took these theoretical considerations into ac- refinement, these inconsistencies may be partly due count. We aimed to quantify perceptual differences to diagnostic heterogeneity. When DLB was com- in PDD, DLB, and AD patients matched for overall pared with AD, studies consistently reported greater dementia severity, and in non-demented controls(PD and NC). We tested visual discrimination, Additional material related to this article can be found on the Neurology object-form perception, and space-motion perception Web site. Go to www.neurology.org and scroll down the Table of Con- to assess impairments in different visual cortical tents for the December 14 issue to find the title link for this article.
pathways. Since PDD and DLB have combined motor From the Institute for Ageing and Health (Drs. Mosimann, O’Brien, Burn, and McKeith), Newcastle upon Tyne; Psychology Department (Dr. Mather), LifeSciences School, University of Sussex, Brighton; and Cognitive Drug Research Ltd. (Dr. Wesnes), Oxon, UK.
Supported by the UK Medical Research Council, the Swiss National Science Foundation, and the Swiss Parkinson Foundation. Cognitive Drug Research(CDR) provided the test battery and computers required for free.
G.M. received a research grant in excess of $10,000 from CDR for the programming of the test battery used in the present study. K.A.W. is the Chiefexecutive of CDR. I.G.M. has previously received research support from CDR.
Received May 8, 2004. Accepted in final form August 13, 2004.
Address correspondence and reprint requests to Dr. Urs P. Mosimann, Institute for Ageing and Health, Wolfson Research Centre, Newcastle GeneralHospital, Newcastle upon Tyne NE4 6BE, UK; e-mail: [email protected] Copyright 2004 by AAN Enterprises, Inc.
Table 1 Demographics and clinical description of the sample
Post-hoc Bonferroni tests compared NC vs PD, PDD vs PD, PDD vs DLB, PDD vs AD, and DLB vs AD, and significant group differ-ences are reported.
* PDD vs AD: p ϭ 0.047; DLB vs AD: p ϭ 0.001.
† PDD vs PD Ͻ 0.0001.
‡ PD vs NC Ͻ 0.0001; PDD vs AD: p Ͻ 0.0001; DLB vs AD: p Ͻ 0.0001.
§ PDD vs PD Ͻ 0.0001; PDD vs AD: p ϭ 0.001; DLB vs AD: p ϭ 0.027.
¶ PDD vs PD Ͻ 0.0001; DLB vs AD: p ϭ 0.026.
NC ϭ normal controls; PD ϭ non-demented Parkinson disease; PDD ϭ Parkinson disease dementia; DLB ϭ Dementia with Lewy bod-ies; AD ϭ Alzheimer disease; NS ϭ not significant (p Ͼ 0.05); MMSE ϭ Mini-Mental State Examination; UPDRS ϭ Unified ParkinsonDisease Rating Scale; NPI ϭ Neuropsychiatric Inventory; Fluctuation ϭ One Day Fluctuation Assessment Scale; Bristol-ADL ϭ BristolActivities of Daily Living scale.
and visuoperceptual impairments, all tasks used in cluded spiral, pentagon, three-dimensional house and clock copy- the present study did not require motor responses ing. Parkinsonism in DLB was defined as bradykinesia, plus oneor more of rest tremor, muscular rigidity, and postural instability and were not time driven. Based on previous neuro- without other explanation. Severity of extrapyramidal features imaging findings,15,16 we hypothesized similar visual was assessed with the Unified PD Rating Scale (UPDRS) motor impairments in PDD and DLB and expected impair- score (part III).22 A cutoff score of more than 6 in the one-day ments to exceed those of matched AD patients.
fluctuation assessment scale defined fluctuation.23 The Neuropsy-chiatric Inventory (NPI)24 was used to determine whether a sub-ject was experiencing recurrent visual hallucinations during the Methods.
All subjects were recruited from the New- month previous to the assessment. Analyzing questions 2 or 3 in castle MRC prospective outpatient cohort.2 Characteristics of the the hallucination section of the NPI identified recurrent visual sample are summarized in table 1. The UK PD Society Brain hallucinations. In patients with recurrent visual hallucinations, Bank Clinical Diagnostic Criteria17 were used to make the diagno- the caregiver agreed with either of these questions and reported a sis of PD, the National Institute of Neurologic and Communicative frequency and severity of at least one. The Bristol Activities of Disorders and Stroke and AD and Related Disorders Association Daily Living Scale (Bristol ADL)25 was used to assess impairments (NINCDS-ADRDA)18 for AD, and the DLB Consensus guidelines in activities of daily living. The neuro-ophthalmologic assessment for DLB,19 following the recommendation that patients with par- included external inspection of the eyes, assessment of pupil reac- kinsonian features preceding cognitive impairment for more than tions, light reflex (penlight), measurement of near vision (Landolt 12 months should be diagnosed with PDD.19 PDD patients had to broken rings, test distance 40 cm), assessment of ocular move- have PD for more than 12 months before developing dementia.19 ments, and estimation of the visual field by confrontation test.
Patients were required to have a caregiver providing regular care The red reflex and ocular fundus were assessed with direct and support and to score at least 10 on the Mini-Mental StateExamination (MMSE).
20 Subjects with coexisting medical illness or a history of visual impairment due to cataract, glaucoma, or macular degeneration were excluded. The only antiparkinsonian presented in a multiple-choice format on a 14-inch computer medication allowed was levodopa. Patients stabilized on cholines- screen in a standardized, darkened environment. Subjects sat 40 terase inhibitors (ChE-I) were eligible for the study provided they cm in front of the computer screen. Tasks were not time driven, were on a stable dose for more than 3 months. The percentage of subjects responded verbally, and the examiner handled all but- demented patients on long-term ChE-I was not different between tons. The instruction of each task was read while an example was the diagnostic groups (PDD: 58%, DLB: 65%, and AD: 69%). All presented on the screen. Once the correct answer was given, the patients with PDD were treated with levodopa, but only 43% of task started and no further feedback was given. Different random DLB were on dopaminergic treatment. Of 146 subjects invited, arrangements of stimulus presentation were used in each task.
118 gave written informed consent; 2 patients had to be excluded The assessment lasted about 30 to 45 minutes. Figure E-1 on the because they did not understand the task instructions. The local Neurology Web site (www.neurology.org) gives an overview of all research ethics committee granted ethical approval.
Global cognitive impairment was assessed with Length and size discrimination tasks.
the Cambridge Cognitive Examination (CAMCOG)21 and for the Pairs of lines/circles were presented side-by-side on the screen and purpose of this study, tests assessing apraxia were analyzed sepa- subjects had to decide which of the lines/circles, left or right, were rately from tests measuring visuoconstructional ability, i.e., longer/larger. The stimulus field dimensions were 140 mm wide praxis and construction scores. CAMCOG visual construction in- and 150 mm tall. Reference stimulus (70 mm) and comparison December (1 of 2) 2004
stimulus were separated by 70 mm and the position of the longer pathway (space-motion perception score). The Statistical Package line/larger circle varied randomly. To eliminate cues based on the for Social Sciences (SPSS Version 11) was used for statistical absolute position of the stimulus features such as end-lines, the analysis. The distribution of the data was examined for normality position of each stimulus was randomly jittered from trial to trial (Kolmogorov-Smirnov test). Provided the data did not deviate with a diameter of 7 mm. The test used an adaptive psychophysi- from normal distribution, the five groups were compared with cal procedure to find the stimulus difference required for a subject parametric tests (i.e., one-way analysis of variance [ANOVA]) and to achieve reliable discrimination. Each correct response led to a subsequently post hoc Bonferroni tests were used for two-group decrease in the stimulus difference for the next trial (by 1 mm), comparisons. Means and SD were calculated to represent central and each incorrect response led to an increase in the difference for tendency and dispersion. Pearson-rank-correlation was used for the next trial (by 3 mm). As a result, the test converged on an correlative analysis. All reported p values were two-tailed and a p estimate of the threshold, expressed as difference of size or length value of less than 0.05 was considered statistically significant.
(in %), that the subject detected with 75% accuracy.26 Thirteentrials were presented in each task.
Results.
were well matched with respect to age, sex, and education of Benton’s task.27 Our task used 5 (instead of 11) standard linesat 30 deg (instead of 18 deg) intervals, with subjects judging one and the three dementia groups did not differ in global comparison line (instead of two) in each trial. The stimulus field cognitive impairment (see table 1). Compared to the AD dimensions were 180 mm wide and 150 mm tall. Twenty trials group, the DLB and PDD groups had higher UPDRS motor were presented. Subjects were required to match the angle of the scores, higher fluctuation scores, shorter dementia dura- single line to one of five lines forming a semicircle.
tion, and greater impairment in activities of daily living overlapping figures task was described by De Renzi et al.28 In each (Bristol ADL). No differences in these scores were found trial a series of four unique pictures of animals, utensils, clothing, when DLB was compared with PDD. The frequencies of or fruits were presented on the screen and subjects decided which the core clinical features—fluctuation of cognition (PDD of the four pictures was included in the simultaneously presented 54%; DLB 35%; AD 8%), recurrent visual hallucinations overlapping figure. The stimulus field dimensions were 180 mmwide and 150 mm tall. Thirteen trials were presented.
(PDD 75%; DLB 90%; AD 8%), and extrapyramidal fea- tures (PDD 100%; DLB 85%; AD 13%)—were similar in the block design subtest.29 Two boxes with slightly different forms DLB and PDD groups (chi square or Fisher’s exact t-test: were presented side-by-side and the subject had to decide in which p Ͼ 0.05; NS) but different from AD (Fisher’s exact t-test quadrant the two boxes were different. Stimuli were not matchedsystematically for mean luminance. Each box was 60 mm wide for comparison PDD vs AD and DLB vs AD: p Ͻ 0.05).
and 60 mm tall, and the two boxes were separated by 20 mm.
Visual acuity did not differ between groups (controls 0.40 Ϯ 0.16; PD 0.40 Ϯ 0.14; PDD 0.34 Ϯ 0.11; DLB 0.37 Ϯ 0.18; AD 0.42 Ϯ 0.17) (ANOVA: NS) and other neuro-ophthal- based on the dot position task of Warrington and James.30 In eachtrial, two squares were presented side-by-side, one containing a mologic assessments did not reveal impairments interfer- dot and the other five different numbers at random position. The position of the dot exactly matched the position of a number and Table 2 summarizes CAMCOG data. One-way ANOVA the subject was required to name this number. Each square was revealed significant group differences in all except the 70 ϫ 70 mm and the squares were separated by 30 mm. Thirteen praxis score. PD was similar to controls and different from PDD in all but the CAMCOG abstract thinking score. In signed to match those used in Vaina31 as closely as possible. In abstract thinking PD were similar to PDD and more im- each trial, two black squares (70 ϫ 70 mm) were presented side by paired than controls. Group comparison did not reveal any side on the screen, separated by 30 mm. Each square contained 12 differences between PDD and DLB. Compared to AD, PDD small (3 mm diameter) white dots in random positions, moving inrandom directions and bouncing off the sides of the square. Within and DLB patients were significantly less impaired in mem- a square all dots moved with the same velocity, but the dots ory scores, but more impaired in the visual construction moved with different velocities in the two squares. Four velocities scores, and the DLB group scored lower in the perception were presented: 15 mm/second, 20 mm/second, 44.8 mm/second, score compared to AD. Visual construction CAMCOG and 60 mm/second. The velocity ratios were the ratio of two differ- scores did not correlate with UPDRS-motor scores in PDD ent velocities presented in a trial: 1.33 ϭ 20/15; 2.24 ϭ 44.8/20; 3 ϭ 60/20. When the ratio was 3, for example, all dots in one square group (Pearson correlation: r ϭ Ϫ0.190, p Ͼ 0.05, NS) but moved at three times faster than the dots in the other square. The correlated in the DLB group (Pearson correlation: r ϭ side on which each velocity appeared was selected randomly.
There were 12 trials—i.e., four presentations of each velocity ra- tio—and subjects determined which of the two squares containedthe faster moving dots.
form, and space-motion perception are summarized in the figure, A through C. Visual discrimination scores (z- visual counting task used by Fujimori et al.32 The stimulus in each values) were different between the groups (ANOVA: p Ͻ trial consisted of 10 to 12 colored shapes (white, green, blue, 0.0001) and DLB and PDD patients were more impaired triangles and squares). There were between 1 and 5 target stimuli than AD (post-hoc Bonferroni tests: DLB vs AD: p ϭ 0.007; in each trial (average 3.5). In each of the 13 trials the subjectneeded to count the number of shapes containing one of five pos- PDD vs AD: p ϭ 0.051), but were not different from each sible attributes (e.g., how many squares). The stimulus field di- other (post-hoc Bonferroni tests PDD vs DLB: NS) (see figure 1A). Between-group differences were also found in Outcome measures were errors (in percent) in object-form and space-motion perception (ANOVA: p Ͻ all tasks except the line and size discrimination tasks. Standard-ized z-values were calculated to compare thresholds in the size/ 0.0001). The impairment in object-form perception (see fig- length discrimination tasks and percentage of errors in the angle ure 1B) of PDD and DLB patients was greater compared discrimination task. The mean of the three z-values was the dis- with AD patients (post-hoc Bonferroni tests: DLB vs AD: crimination score. To get a measure of the impairment in the p ϭ 0.003; PDD vs AD: p ϭ 0.001), but not different in ventral visual pathway, mean errors of the overlapping figure and DLB and PDD patients (post-hoc Bonferroni tests PDD vs form perception tasks were calculated (object-form perceptionscore). The mean errors in motion, dot position, and visual count- DLB: NS). Space-motion perception (see figure 1C) re- ing tasks were a measure of the impairment in the dorsal visual vealed a similar pattern of impairment in that the DLB December (1 of 2) 2004
Table 2 CAMCOG data
Post-hoc Bonferroni tests compared NC vs PD, PDD vs PD, PDD vs DLB, PDD vs AD, and DLB vs AD, and significant group differ-ences are reported: * PDD vs PD: p Ͻ 0.0001; PDD vs AD: p ϭ 0.004.
† PDD vs PD: p Ͻ 0.0001.
‡ NC vs PD: p ϭ 0.01.
§ PDD vs PD: p Ͻ 0.0001; PDD vs AD: p ϭ 0.006; DLB vs AD: p ϭ 0.002.
¶ PDD vs PD: p Ͻ 0.0001; DLB vs AD: p Ͻ 0.0001.
࿣ PDD vs PD: p Ͻ 0.0001; PDD vs AD: p Ͻ 0.001; DLB vs AD: p ϭ 0.003.
CAMCOG ϭ Cambridge Cognitive Examination Scale; NC ϭ normal controls; PD ϭ non-demented Parkinson disease; PDD ϭ Parkin-son disease dementia; DLB ϭ Dementia with Lewy bodies; AD ϭ Alzheimer disease; NS ϭ not significant (p Ͼ 0.05).
group did not differ from PDD but tended to be more im- ble 3. Global cognitive impairment of patients with visual paired compared to AD (post-hoc Bonferroni tests: DLB vs hallucinations (MMSE) was not different from patients AD: p ϭ 0.074). PD was similar to controls but less im- without hallucinations and the two groups did not differ paired than PDD in all scores (post-hoc Bonferroni tests for with regard to education, frequency of extrapyramidal all: p Ͻ 0.0001). The PDD group made more errors in symptoms, or fluctuation. Patients with RVH were signifi- object-form perception compared to space-motion percep- cantly more impaired in visual discrimination, space- tion (paired sample t-test: p Ͻ 0.0001), a difference also motion perception, and object-form perception compared to found in the DLB group (paired sample t-test: p Ͻ 0.0001) patients without visual hallucinations.
but not in the AD group (paired sample t-tests: NS). The Within each dementia group, patients on ChE-I did not raw data of all tasks are summarized in table E-1 on the perform differently compared to patients not taking ChE-I in visual discrimination, object-form perception, or space- There were few patients without recurrent hallucina- motion perception. DLB patients taking levodopa did not tions (RVH) in the DLB and PDD groups; therefore the differ in any visual score compared to those patients not PDD and DLB groups were pooled to compare patients taking levodopa; such comparison was not feasible in PDD, with and without hallucinations. Results are shown in ta- since all patients were taking levodopa.
Figure. (A through C) Mean and 95% CI of the discrimination score (A), of errors in object-form perception (B), and er-rors in space-motion perception (C). There was no difference in any of these scores between the DLB and PDD groups, butDLB and PDD tended to perform worse compared to AD patients. PDD and DLB patients made more errors in object-form perception than in space-motion perception. NC ϭ normal controls; PD ϭ Parkinson disease; PDD ϭ PD dementia;DLB ϭ Dementia with Lewy bodies; AD ϭ Alzheimer disease. December (1 of 2) 2004
Table 3 Comparison of DLB/PDD patients with and without recurrent visual hallucinations (RVH)
Values are mean Ϯ SD.
DLB ϭ Dementia with Lewy bodies; PDD ϭ Parkinson disease dementia; NS ϭ not significant (p Ͼ 0.05); MMSE ϭ Mini-Mental StateExamination.
Discussion.
Visual impairments in DLB patients with visual tients with PDD and DLB compared with AD and hallucination exceed those without hallucination, es- two control groups—NC and nondemented PD pa- pecially in the overlapping figure task39 and in the tients. PDD and DLB had similar visuoperceptual line orientation task.40 Barnes and David41 compared impairments but were more impaired compared to visual imagery, visual perception, and recognition patients with AD. Visual perception of PDD/DLB pa- memory in nondemented PD patients with and with- tients with visual hallucinations was worse than in out hallucinations and found that PD patients with visual hallucinations were more impaired in object Combined retinal and cortical changes need to be perception. In the present study, hallucinating DLB/ addressed to understand the extent of perceptual im- PDD patients were more impaired in all visual pairment affecting all test scores. PDD and DLB are scores compared to patients without hallucinations.
both associated with profound cortical cholinergic The interpretation of this finding needs caution, be- deficits and cortical Lewy body pathology in areas cause as in previous studies,39,40 the number of de- involved in visual perception33,34 and functional im- mented patients without hallucinations in this study aging studies have reported hypoperfusion in the oc- The neuropsychological (CAMCOG) data confirm consistently exceeding those found in AD.15,16 These previous findings showing that visuoconstructional findings suggest abnormal function of visual cortical abilities are more impaired in PDD and DLB com- areas. Additional retinal changes cannot be ex- pared to AD and that memory function is relatively cluded, since some visual abnormalities, such as im- preserved.11,42,43 In contrast to most previous studies, paired contrast vision, are mediated by disruption of which reported additional frontal impairment in dopaminergic processes in the retina35,36 and are un- PDD and DLB, we did not find differences in the likely to be discovered during routine neurologic ex- attentional scores. The numerical tasks used to as- amination or by ordinary high contrast visual acuity sess attention in the CAMCOG battery may be in- The dissociation between performance in object- demented patients. One study44 which compared the form and space-motion perception found in PDD and cognitive profile of AD and DLB patients using the DLB but not in AD patients may indicate a deficit in CAMCOG battery also did not find attentional differ- the ventral visual pathway in these groups. This ences. Since CAMCOG visual construction scores in finds support in studies reporting profound cholin-ergic deficits and greater Lewy body density in the DLB also correlated with the severity of extrapyra- temporal lobes.34,37,38 However, it is possible that the midal motor symptoms, it is likely that some of the differences observed are partly related to non- visual constructional impairment is related to motor specific visuocognitive deficits. Object-form percep- impairment in the DLB group. This underpins the tion tasks may be more sensitive than space-motion need for tasks that are independent of motor func- perception tasks because they may contain more vi- tion when testing visual perception in patients with sual information or require more complicated solu- combined extrapyramidal and cognitive impairment.
tion strategies.10 The better perfusion seen onSPECT imaging in DLB/PDD in the ventral stream Acknowledgment
compared with the dorsal stream16 does not necessar-ily equate with better function, since it may reflect The authors thank the patients and controls for their participa-tion, Lorraine Bowman for help with testing, Daniel Collerton for compensatory increase in activity in structurally al- help with data analysis, Simon Kometa for statistical advice, and Jordan Bowen for help with recruiting.
December (1 of 2) 2004
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