Levodopa use and sleep in patients with dementia with Lewy bodies

Brief Reports

Cognitive Decline in EarlyParkinson’s Disease

Nagaendran Kandiah, MBBS, MRCP,1*Kaavya Narasimhalu, BA,2 Puay-Ngoh Lau, BHSc,1,3

Soo-Hoon Seah,1,3Wing LokAu,MBBS,MRCP, FRCP,1,3

and Louis C.S. Tan,MBBS,MRCP, FRCP1,3

1Department of Neurology, National Neuroscience Institute,Singapore; 2Center for Molecular Epidemiology, Departmentof Community, Occupational and Family Medicine, NationalUniversity of Singapore, Singapore; 3Parkinson’s Diseaseand Movement Disorders Centre, Department of Neurology,

National Neuroscience Institute, Singapore

Abstract: Data on the prevalence and severity of cognitiveimpairment among patients with newly diagnosed idio-pathic Parkinson’s disease (PD) is limited. Using a pro-spectively collected clinical database, we studied the longi-tudinal trend of mini-mental state examination (MMSE)change and baseline factors predictive for MMSE decline.One hundred six patients with mean age of 61.2 yearsand mean baseline MMSE of 27.8 ± 2.3 were studied.MMSE increased by 0.4 points/year among patients with-out cognitive decline (n = 73) and decreased by 2.39points/year among patients with cognitive decline (n =33). Univariate analysis demonstrated education, age ofdiagnosis, depression, and diabetes mellitus to be associ-ated with cognitive decline. Motor scores and hallucina-tion were not associated with cognitive decline. Multivari-ate analysis demonstrated higher level of education to beprotective (HR = 0.91, 95% CI 0.82–0.99, P = 0.047) anddepression having borderline significance in predictingcognitive decline (HR = 2.00, 95% CI 0.97–4.15, P =0.061). We found that 31% of newly diagnosed idiopathicPD patients have measurable cognitive decline at an earlystage of disease. Higher education is protective whiledepression may be predictive of cognitive decline. � 2009Movement Disorder Society

Key words: Parkinson’s disease; cognition; mini-mentalstate examination; education; depression

Parkinson’s disease (PD) is a neurodegenerative dis-

order with hypofunction in the dopaminergic and cho-

linergic systems.1 Although dopaminergic deficiency

may lead to the motor symptoms of PD, cholinergic

deficiency has been linked to cognitive and psychiatric

symptoms.2 Cognitive deficits have a wide-ranging

effect on quality of life, nursing home placement and

survival.3 Cognitive deficits in PD may take the form

of overt dementia or mild cognitive impairment.

PD patients have been reported to have up to six-

fold increased risk of dementia.4–6 In elderly PD

patients, the risk may be as high as 80%.4 Data on

cognitive decline in early PD is limited.7–9 In a popula-

tion based cohort study, 22% of newly diagnosed PD

patients had concomitant dementia.10 Factors associ-

ated with poor cognitive outcomes in PD include

increased age at diagnosis, low education, longer dura-

tion of PD, severe motor symptoms, orthostatic hypo-

tension, and presence of visual hallucinations.11–13

Understanding the rate of cognitive decline and

establishing the factors associated with greater cogni-

tive decline will allow clinicians to better manage

patients with PD. We hypothesized that a proportion of

patients with newly diagnosed idiopathic PD will de-

velop measurable cognitive decline, early in their dis-

ease. In this study, we examine the rate of cognitive

decline and evaluate the baseline factors associated

with cognitive decline in a cohort of nondemented

newly diagnosed patients with idiopathic PD.

PATIENTS AND METHODS

Data was obtained from the movement disorder

database of the National Neuroscience Institute, Singa-

pore. The study was approved by the institutional

ethics committee. This database was established in the

year 2000 and contains prospectively collected data.

For the purpose of this study, we selected patients with

the following criteria: (1) diagnosis of idiopathic PD;

(2) having the first cognitive assessment within 2 years

from the initial diagnosis of PD; (3) not demented with

a normal education-adjusted mini-mental state exami-

nation (MMSE); (4) having at least 1 additional post-

baseline MMSE; (5) interval of <2 years between con-

secutive MMSE’s. A diagnosis of idiopathic PD was

Potential conflict of interest: None.Received 22 May 2008; Revised 9 October 2008; Accepted 15

October 2008Published online 3 February 2009 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22384

*Correspondence to: Nagaendran Kandiah, Level 3, Clinical StaffOffice, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Sin-gapore 308433, Singapore. E-mail: [email protected]

605

Movement DisordersVol. 24, No. 4, 2009, pp. 605–616� 2009 Movement Disorder Society

made by movement disorder neurologists based on the

NINDS criteria.14

Data on demographics, MMSE, Hoehn and Yahr

stage (H&Y), Unified Parkinson’s Disease Rating Scale

total motor score (UPDRS), depression, and medication

use at baseline were obtained. A single rater (LPN)

performed all MMSE testing. Normal MMSE was

defined as ‡24 for patients with 6 or more years of for-

mal education and ‡22 for patients with less than 6

years of education. These cut-off scores for MMSE

have been validated in Singapore.15,16 A decrease of 2

or more points on consecutive MMSE was used to

identify PD patients with cognitive decline. Reports of

patients with PD and Alzheimer’s disease (AD) have

demonstrated that a 2 point MMSE decline is more

likely to reflect true cognitive decline rather than test

variability.13,17

A two-sample t-test for continuous variables and

chi-squared test for categorical variables were used to

compare baseline variables. Because of unequal fol-

low-up times, a Kaplan–Meyer survival analysis was

adopted treating an MMSE drop of 2 or more points as

the failure event. Cox proportional hazards regression

was used to identify baseline variables, which were

associated with cognitive decline. Variables which sat-

isfied P < 0.10 on the univariate analysis were further

studied in a multivariate model.

RESULTS

Our database included 238 PD patients having only

one MMSE and 235 patients with 2 or more MMSE’s.

Of the latter 235 patients, 58 were excluded for having

interval between onset and first assessment of >2

years, another 44 patients were excluded for having

MMSE below the specified cut-offs and a further 27

were excluded for having intervals of >2 years

between consecutive MMSE’s. One hundred six

patients satisfied all the inclusion criteria and were fur-

ther studied. Statistical comparison of PD patients hav-

ing only one MMSE and the 106 patients included in

our study did not demonstrate any statistically signifi-

cant difference in baseline MMSE, H&Y score, years

of education, and age at diagnosis.

The mean age at the first visit for the entire cohort

was 61.2 6 10.3 years and the average years of formal

education was 7.1 6 4.8 years. There were 62 (58%)

males and 44 (42%) female patients. There were 92

Chinese patients, 11 Malay patients, and 3 Indian

patients. The mean interval between onset of symptoms

and diagnosis of PD in our cohort was 1.2 6 1.3 years.

The mean baseline H&Y stage was 2.15 (1.5–3) and

baseline UPDRS total motor score was 19.85 (7.5–

51.5). Mean baseline MMSE for the entire cohort was

27.8 (23–30). At baseline 78 patients were receiving

levodopa, 49-dopamine agonist and 14 anticholinergic

medications. There was no significant difference in

mean baseline MMSE, H&Y, and UPDRS total motor

scores between patients with cognitive decline and

those without (Table 1).

Thirty-three (31%) patients had ‡2 point drop on

consecutive MMSE scores and were classified as hav-

ing cognitive decline. Mean duration of follow-up for

all patients was 2.84 6 1.24 years. The annual rate of

change in MMSE among all patients was 20.46 (SD

1.90) points/year. The rate for those with no cognitive

decline was 10.41 (SD 0.97) points/year whereas the

rate for patients with cognitive decline was 22.39 (SD

2.07) points/year (Fig. 1).

Univariate Cox Proportional Hazards Regression

Models demonstrated lower education, higher age at

diagnosis and depression (P < 0.05) to predict cogni-

tive decline. Use of dopamine agonist and presence of

diabetes mellitus showed a trend toward significance.

Multivariate analysis only demonstrated education (HR 50.91, P 5 0.047) as a predictor for cognitive decline

(Fig. 2). Presence of depression showed borderline sig-

nificance (HR 5 2.0, P 5 0.061). Severity of motor

TABLE 1. Baseline features

Total cohort(N 5 106)

No cognitivedecline (N 5 73)

Cognitivedecline (N 5 33) P

Mean age, yr (SD) 61.2 (10.3) 59 (10) 65 (9) 0.007Gender, males (%) 62 (58) 47 (64) 15 (45) 0.067Education, mean yr (SD) 7.1 (4.8) 8.0 (5.0) 5.0 (3.7) 0.003Ethnicity, Chinese N (%) 92 (87) 65 (89) 27 (82) 0.360Baseline HNY, mean (SD) 2.1 (0.4) 2.1 (0.4) 2.2(0.3) 0.754Baseline UPDRS, mean (SD) 19.8 (8.8) 19 (8.9) 20 (8.7) 0.813Baseline MMSE, mean (SD) 27.8 (2.3) 27 (2.3) 27 (2.4) 0.300

The P value reflects significant differences between patients with cognitive decline and those without cognitive decline.

606 N. KANDIAH ET AL.

Movement Disorders, Vol. 24, No. 4, 2009

scores and stage of PD as measured by UPDRS and

H&Y did not influence the rate of cognitive decline

(Table 2).

DISCUSSION

This study examined the rate of decline and factors

predicting cognitive decline among patients with newly

diagnosed idiopathic PD. Our patients had a relatively

early stage of disease as reflected by the mean baseline

H&Y score of 2.1 and mean baseline UPDRS total

motor score of 19.8.The diagnosis of idiopathic PD

was maintained in all patients at the end of the longitu-

dinal study after a mean follow-up period of 2.8 years.

We identified 31% of our 106 patients to have a

decline of 2 or more MMSE points, with a mean an-

nual decline of 2.39 points in this group. The single in-

dependent baseline predictor for cognitive decline was

a low education with depression demonstrating border-

line significance for predicting cognitive decline.

Contrary to the notion that cognitive dysfunction is

not common early in PD; our findings suggest that a

relatively large proportion of PD patients will develop

cognitive difficulties early in the disease. Earlier

reports have demonstrated that PD patients with nor-

mal baseline MMSE to develop significant deficits on

neuropsychological testing compared with elderly con-

trols.18 In a population based cohort study, 22% of

newly diagnosed PD patients had concomitant demen-

tia.10 The annual MMSE decrease of 2.39 points

among our patients with PD and cognitive decline is

comparable with earlier reports. One earlier study of

PD dementia reported an annual MMSE decline of 2.3

points (95% CI 2.1–2.5).13 This magnitude of MMSE

decline is comparable to that of Alzheimer’s disease.10

There is evidence that global cognitive measures such

as the MMSE correlate with the pathological stages of

PD and thus may be a useful measure of cognition in

PD.19 MMSE is also useful in the longitudinal follow-

up of cognition in PD.13

The finding of low education as a predictor for cog-

nitive decline in our study is consistent with earlier

reports. In a recent meta-analysis involving 901 ini-

tially nondemented PD patients, it was found that age

and level of education emerged as important predictors

for global cognitive decline.5 It has been postulated

that higher levels of education is associated with

greater functional brain reserve and thus a higher

threshold to manifest cognitive deficits.5,11 The possi-

bility that education emerged as a protective factor

against cognitive decline due to the ceiling effect of

MMSE in this patient group also needs to be enter-

tained. We also found depression to be of borderline

significance in predicting cognitive decline. EarlierFIG. 2. Kaplan–Meier survival analysis by education levels.

TABLE 2. Results of Cox proportional hazards model

Variable

Univariatemodel Multivariate model

Hazardratio P

Hazardratio

(95% CI) P

Gender 1.67 0.140Ethnicity 1.19 0.587Education 0.88 0.003 0.91 (0.82–0.99) 0.047Age 1.05 0.008 1.01 (0.95–1.07) 0.686Duration of follow-up 1.06 0.690Hoehn and Yahr Stage 1.14 0.723UPDRS total motor score 1.01 0.728Baseline MMSE 0.94 0.379Postural hypotension 1.22 0.568Diabetes mellitus 1.98 0.064 1.68 (0.80–3.53) 0.172Depression 2.03 0.043 2.00 (0.97–4.15) 0.061Visual hallucinations 0.87 0.851Levodopa use 0.99 0.986Dopamine agonist use 0.51 0.062 0.78 (0.31–1.96) 0.598Anticholinergics 0.85 0.785

FIG. 1. Line diagram showing the longitudinal pattern of MMSEchange.

607COGNITION AND PD


reports have shown that 30 to 50% of patients with PD

have depression and that this may influence cognitive

performance in PD.20 One study found that depressed

PD patients performed worse on a neuropsychological

battery compared with a control group matched for se-

verity of depression.21 This relationship between

depression and cognitive impairment in PD may reflect

the involvement of a common pathway for both

depression and cognitive symptoms.22 Although earlier

studies have identified stage of PD and motor scores to

predict dementia,23 we did not find such an association.

We believe this may be related to our selection of

newly diagnosed cases with relatively mild PD. This

may also suggest that the degeneration in the dopami-

nergic and cholinergic systems in patients with PD

occur independent of the other.

The limitations of our study include a retrospective

design, small sample sizes for certain variables such as

medication use and the use of the MMSE as the sole

cognitive assessment tool. The use of specified MMSE

cutoffs for patient selection may have potentially

underestimated the presence of cognitive decline in our

PD population. Despite this, we believe that our find-

ings will add to the understanding of the pattern of

cognitive decline in early PD. The presence of early

cognitive decline in 31% of our patients should alert

clinicians to screen for cognitive decline among

patients with idiopathic PD. The MMSE is useful in

the screening and longitudinal follow-up of cognitive

decline in PD and should be included as part of a

standard battery in the evaluation of PD.

Acknowledgments: We thank all clinicians who contrib-uted patients to our database.

Author contributions: Nagaendran Kandiah: conception,organization, and execution of research project, design andexecution of statistical analysis, writing of first draft; KaavyaNarasimhalu: organization of research project, design andexecution of statistical analysis, manuscript writing andreview; Puay-Ngoh Lau: execution of research project,review of statistical analysis, review of manuscript; Soo-Hoon Seah: execution of research project, review of statisti-cal analysis, review of manuscript; Wing Lok Au: conceptu-alization of research project, review of manuscript; LouisC.S. Tan: conceptualization and execution of research pro-ject, design of statistical analysis, review of manuscript.

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15. Sahadevan S, Tan NJ, Tan TC, Tan S. Cognitive testing of el-derly Chinese from selected community clubs in Singapore. AnnAcad Med Singapore 1997;26:271–277.

16. Sahadevan S, Lim PP, Tan NJ, Chan SP. Diagnostic performanceof two mental status tests in the older Chinese: influence of edu-cation and age on cut-off values. Int J Geriatr Psychiatry2000;15:234–241.

17. Clark CM, Sheppard L, Fillenbaum GG, et al. Variability in an-nual mini-mental state examination score in patients with proba-ble Alzheimer disease: a clinical perspective of data from theconsortium to establish a registry for Alzheimer’s Disease. ArchNeurol 1999;56:857–862.

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608 N. KANDIAH ET AL.


Levodopa Use and Sleep inPatients with Dementia

with Lewy Bodies

Sophie Molloy, MD,1* Thais Minett, MD,2

John T. O’Brien, MD,1 Ian G. McKeith, MD,1 andDavid J. Burn, MD1

1Wolfson Research Centre, Institute for Ageing and Health,Newcastle University, Campus for Ageing and Vitality,Newcastle upon Tyne, United Kingdom; 2Department ofPreventative Medicine, Federal University of Sao Paulo,

Rua Borges Lagoa, Sao Paulo, Brazil

Abstract: Sleep disturbance and excessive daytime somno-lence (EDS) are features of Parkinson’s disease (PD) anddementia with Lewy bodies (DLB) that may be influencedby dopamine replacement therapy. The effect of levodopaon sleep and EDS in DLB is unknown and unclear in PD.The aim of this study is to determine if levodopa treat-ment alters sleep symptoms and EDS in DLB. Dopaminenaıve patients with DLB (n 5 15; mean mini mental stateexamination (MMSE) score 17.7(4.6)) and PD (n 5 9;mean MMSE 25.5(2.2)) were assessed using the Epworthsleep scale, Parkinson’s disease sleep scale, and the neuro-psychiatric inventory prior to initiating treatment withlevodopa. All measures were repeated after 3 and 6months of levodopa therapy. The median final daily levo-dopa dose was 300 mg in both groups. Baseline sleepmeasures were comparable between groups. Levodopatreatment did not affect sleep or lead to increased EDS inDLB patients. The use of levodopa does not appear toadversely affect subjective sleep measures or increaseEDS in DLB patients. � 2009 Movement Disorder Society

Key words: levodopa; sleep; dementia with Lewy bodies

The etiology of sleep disturbance in Lewy body dis-

eases may be multifactorial with the underlying condi-

tion and effects of medication significant contributing

factors. Excessive daytime somnolence (EDS) is com-

mon in PD while nocturnal sleep disturbance occurs in

at least 60% of patients with PD, with sleep fragmenta-

tion, the commonest complaint compared to age-

matched controls.1 Dopamine agonists are used cau-

tiously in patients prone to daytime somnolence and

are generally avoided in the Lewy body dementias (i.e.

DLB and PD with dementia). This is because of con-

cern of precipitating and/or exacerbating neuropsychiat-

ric features, especially hallucinations. Nevertheless, Par-

kinsonism is common in patients with DLB and may

significantly impact on functional ability. The conse-

quence of levodopa (L-dopa) treatment on sleep and day-

time somnolence in PD remains unclear and, to our

knowledge, has not been assessed in DLB. We therefore

undertook a pilot prospective study to investigate this

latter point, as a subsection of a larger study examining

other aspects of the effect of L-dopa in DLB.2,3

METHODS

DLB patients were recruited from hospital and com-

munity dwelling populations under the care of neuro-

logists, old age psychiatrists, and geriatricians. PD

patients were recruited through movement disorder clin-

ics where the diagnosis was made clinically by an expe-

rienced movement disorder neurologist (DJB; no diag-

nostic L-dopa challenge performed). No patient refused

participation, and patients were recruited over a 12-

month period as part of a larger project that has been

reported elsewhere.2,3 Only 1 patient with DLB failed to

complete the 6-month assessment and her data was

excluded. The Newcastle and North Tyneside ethics

committee approved the study, and all patients gave

informed consent to participate or, if unable because of

cognitive dysfunction in the case of DLB patients, assent

was obtained from carers. Diagnosis was confirmed

between experienced clinicians using the consensus cri-

teria for DLB4 and the UK Parkinson’s Disease Society

Brain Bank criteria for Parkinson’s disease (excluding L-

dopa response).5 All patients were L-dopa naıve and not

on dopaminergic therapy at study entry, but all DLB

patients were receiving a stable dose of cholinesterase

inhibition, which did not change during the study. Base-

line data included disease duration that was determined

as time of symptom onset as recalled by the patient in

the case of PD and time of formal diagnosis for DLB.

The motor subsection of the Unified Parkinson’s Dis-

ease Rating Scale (UPDRS III)6 was used to determine

the severity of Parkinsonism, with the 5-item subscore

derived for DLB patients to give a measure of motor

impairment that was independent of cognitive function.7

Global cognitive function was assessed using the MMSE8

whilst severity of depressive symptoms was rated accord-

ing to the geriatric depression scale (GDS).9 A baseline

*Correspondence to: Dr. Sophie Molloy, Department of Neurol-ogy, Imperial Hospitals Trust, Charing Cross Hospital, Fulham Pal-ace Road, London W6 8RF, United Kingdom.E-mail: [email protected]

Potential conflict of interest: SM’s research was funded by PPPhealthcare from August 2001-03.

Received 28 July 2008; Revised 30 October 2008; Accepted 5 No-vember 2008

Published online 3 February 2009 in Wiley InterScience (www.



609LEVODOPA USE AND SLEEP IN PATIENTS WITH DLB

sleep assessment was performed using the self-adminis-

tered Epworth sleep scale (ESS),10 and the Parkinson’s

disease sleep scale (PDSS). The PDSS is a 15 item vis-

ual analogue scale that addresses several aspects of sleep

ranging from nocturnal motor and non motor symptoms

and sleep onset to daytime somnolence. It has a maxi-

mum score of 150 (10 points per question) correspond-

ing to ‘‘best possible’’ with lower scores equating to

greater sleep disturbance. It has not been validated in

patients with known cognitive impairment.11 The carer

completed neuropsychiatric inventory (NPI) which has a

specific sleep subsection (NPI-S) and was completed in

all PD patients and 13 of 15 patients with DLB.12

Patients were then commenced on L-dopa three

times daily, which was gradually titrated up as toler-

ated until motor symptoms improved or side effects

were encountered. The sleep questionnaires were

repeated on L-dopa at 3 and 6 months, when patients

were reassessed by the same principal investigator

(SM). To assess the effect of L-dopa on motor impair-

ment, a fasting L-dopa challenge was performed as pre-

viously described.2,3

Statistical Analysis

SPSS for Windows (version 13.0) was used for data

analysis. All results were tested for normality using

Kolmogorov-Smirnov testing. Fisher’s exact test was

used for categorical data comparison. Mean values

between patient groups were compared using independ-

ent sample t tests (t) and mean values pre and post

treatment were compared with paired sample t tests (t).Because neither the NPI nor the PDSS data were nor-

mally distributed, Mann-Whitney testing (Z) on two in-

dependent samples or Wilcoxon Signed Ranks Test (Z)for paired samples were used. All statistical tests were

two tailed and were regarded as significant at P <0.05, other than those involving the 15 item PDSS,

where multiple comparisons were undertaken and the

subsequent P value was set at less (P < 0.003) accord-

ing to a Bonferroni correction.

RESULTS

Twenty-four L-dopa naıve patients were recruited, 15

with DLB and 9 with PD. Baseline data are displayed

in Table 1. Age, sex distribution, disease duration,

depression scores, and baseline motor function did not

differ between groups but, as expected, MMSE was

lower in DLB patients, and the total mean NPI in these

patients indicated a greater overall neuropsychiatric

burden. The NPI-S did not differ between groups and

both ESS and total PDSS scores were comparable.

DLB patients reported unexpectedly falling asleep dur-

ing the day more than PD patients (PDSS question 15:

DLB median 5 3.5, PD median 5 7; Z 522.2, P 50.025), but this was not significant when the Bonfer-

roni correction was applied.

The median dose of L-dopa at 6 months was compa-

rable between groups at 300 mg with PD patients rang-

ing from 200 to 300 mg total versus 150 to 750 mg/

day in DLB (Z5 20.6, P 5 0.525). This L-dopa dose

resulted in an acute motor benefit for patients who

underwent a fasting L-dopa challenge as part of the

study (t (20) 5 2.57, P 5 0.018; n 5 21(DLB 5 12,

PD 5 9)) although no overall change was noted when

UPDRS –III scores at 6 months for each group were

compared to baseline (t(19)5 0.19, 95% CI5 26.3–

7.6, P 5 0.850) or when 5-item UPDRS scores in

DLB were compared on L-dopa (t(14)5 1.20, 95%

CI5 20.8–3.0, P 5 0.251).

L-dopa did not influence sleep assessment scores

after 6 months of therapy either when the group was

considered as a whole or by diagnosis (Fig. 1; n does

not change). The only change in subscores was that

PD patients reported an increased likelihood of experi-

encing disruptive nocturnal numbness and tingling

compared to DLB patients at 6 months (PDSS question

10: DLB median 5 0.2, PD median 5 20.9; Z 522.0, P 5 0.043) but not compared to baseline PD

scores. This again, however, did not meet the threshold

for significance (P < 0.003) when the Bonferroni cor-

rection was applied. There was no significant correla-

tion between L-dopa dose and change in PDSS, ESS,

or NPI-S scores (data not shown).

CONCLUSIONS

This study suggests that L-dopa can be prescribed to

manage Parkinsonism in DLB without disrupting noc-

TABLE 1. Baseline data

Factor DLB (n 5 15) PD (n 5 9) P

Sex (M:F) 10:5 8:1 0.351Age (yr) 76.5 (6.5) 80.1 (5.4) 0.151DD (yr) 2.7 (1.6) 4.4 (7.4) 0.761MMSE 17.7 (4.6) 25.5 (2.2) <0.001*GDS 6.5 (3.5) 3.8 (4.6) 0.103UPDRS III 35.8 (13.4) 35.9 (7.4) 0.986NPI 13.9 (11.9) 6.0 (3.6) 0.037**

NPI—S 2.2 (3.2) 1.3 (4.0) 0.212ESS 9.6 (4.7) 6.8 (4.8) 0.17PDSS 94.2 (24.7) 95.4 (20.5) 0.903

DD, disease duration.*, significant t-test; **, significant Z test.

610 S. MOLLOY ET AL.


turnal sleep or provoking EDS. This is despite the sug-

gestion that DLB patients reported that they were more

likely to doze during the day than PD patients prior to

treatment according to the PDSS. Similarly, PD

patients did not experience any deterioration in sleep

symptoms or EDS with L-dopa use.

Sleep disorders are common in neurodegenerative

conditions and frequently disruptive to both patient

and carer.13 Sleep disturbance and EDS are reported

more frequently in DLB than Alzheimer’s disease,14

whilst EDS, insomnias, and parasomnias are common

sleep disorders in PD.15 Polysomnography (PSG) and

multiple sleep latency testing (MSLT) are the most

rigorous means of sleep assessment,16 but both the

ESS and PDSS have been validated in PD and the

former is reported to correlate with MSLT and noc-

turnal PSG.10 The ESS has been used in patients

with both DLB and PD dementia14,17 with some sug-

gesting a correlation between dementia and EDS.1

Originally, EDS was suggested as primarily a phe-

nomenon of treated PD patients and/or disease pro-

gression10 but whilst formal studies propose that

EDS emerges because of both these factors, it does

not correlate with either the duration or severity of

disease in treated patients.18 EDS is more common

in men and those on dopamine agonists19 although

the latter has been contested.20 Dopamine agonists

are considered twice as likely to provoke sleep

attacks compared to L-dopa21 (disputed elsewhere).22

L-dopa can precipitate acute sedation in drug naıve

healthy volunteers but it remains unclear whether tol-

erance occurs with chronic use.23 Variable ESS

results are reported in two large studies of treated

PD patients whereby no correlation was identified

between L-dopa dose and sudden onset of sleep in

one24 but another showed a dose effect of L-dopa

(and dopamine agonists) on EDS.25 PD patients(n 515) on L-dopa demonstrated a dose related emer-

gence of EDS as measured by the ESS and PSG,

and although the MSLT showed no influence of vari-

ables such as disease or treatment duration, ESS

change could be explained by these variables.26 The

correlation between MSLT and ESS scores has been

debated elsewhere.27 A further study of 39 PD and

41 DLB patients reported no association with ESS

scores and L-dopa use or baseline dose.17 Therefore,

the influence of dopaminergic treatment on sleep in

PD, let alone DLB, is far from certain. Our pilot

study has shown no detrimental effect of L-dopa use

on sleep or EDS in DLB.

Neurodegenerative conditions with dopamine defi-

ciency are clearly prone to sleep disorders, and the use

of dopaminergic replacement therapy may affect sleep.

Our study specifically assessed how L-dopa use could

impact on sleep and EDS in DLB. The study is limited

by small sample size, relatively low daily L-dopa dose,

absence of a control group, and the lack of a gold

standard objective measure of effect such as PSG. All

DLB patients were on cholinesterase inhibitors prior to

L-dopa treatment. Because PD patients only com-

menced L-dopa as part of this study, their disease dura-

tion was relatively brief; hence, they may not have

experienced as many sleep symptoms as patients with

a more prolonged disease course. Currently, the influ-

ence of dopamine and its replacement on sleep in PD

remains uncertain and, to our knowledge, has never

been clinically assessed in DLB. From a practical and

clinical view point, dopaminergic replacement in these

frail patients may provide a motor benefit in some2

without exacerbating EDS or significantly worsening

sleep disturbance. Our findings clearly need to be repli-

cated in larger cohorts.

Acknowledgments: S. Molloy: research project, organiza-tion, execution and manuscript writing; T. Minett: statisticalanalysis, manuscript review and critique; J.T. O’Brien:research conception and supervision; I.G. McKeith: researchconception and supervision; D.J. Burn: research conceptionand supervision, manuscript review, and critique.

FIG. 1. Sleep data over 6 months. (a) Mean ESS scores in PD andDLB patients from baseline to 6 months (error bars depict standarddeviation). (b) Mean PDSS scores in PD and DLB patients frombaseline to 6 months (error bars depict standard deviation).

611LEVODOPA USE AND SLEEP IN PATIENTS WITH DLB


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1. Comella CL. Sleep disorders in Parkinson’s disease: an over-view. Mov Disord 2007;22:S367–S373.

2. Molloy S, O’Brien JT, McKeith IG, et al. The role of levodopain the management of dementia with Lewy bodies. J Neurol Neu-rosurg Psychiatry 2005;76:1200–1203.

3. Molloy S, Rowan EN, McKeith IG, et al. The effect of levodopaon cognitive function in Parkinson’s diease with and withoutdementia and dementia with Lewy bodies. J Neurol NeurosurgPsychiatry 2006;77:1323–1328.

4. Mc Keith IG, Galasko D, Kosaka K, et al. Consensus guidelinesfor the clinical and pathologic diagnosis of dementia with Lewybodies (DLB): report on the consortium on DLB internationalworkshop. Neurology 1996;47:1113–1124.

5. Gibb WRG, Lees AJ. The relevance of the Lewy body to thepathogenesis of idiopathic Parkinson’s disease. J Neurol Neuro-surg Psychiatry 1988;51:745–752.

6. Fahn S, Elton RL, and the Members of the UPDRS DevelopmentCommittee. Unified Parkinson’s disease rating scale. In: Fahn S,Marsden CD, Calne DB, editors. Recent developments in Parkin-son’s disease. London: Macmillan; 1987. p 153–63.

7. Ballard C, McKeith I, Burn D, et al. The UPDRS scale as a meansof identifying extrapyramidal signs in patients suffering from de-mentia with Lewy bodies. Acta Neurol Scand 1997;96: 366–371.

8. Folstein M, Folstein S, McHugh PR. Mini-mental state. Apractical method for grading the cognitive state of patients forthe clinician. J Psychiatr Res 1975;12:189–198.

9. Yesavage JA, Brink TL, Rose TL, et al. Development and vali-dation of a geriatric depression screening scale: a preliminaryreport. J Psychiatr Res 1982;17:37–49.

10. Johns MW. Sleepiness, snoring and obstructive sleep apnoea: theEpworth sleepiness scale. Chest 1993;101:30–36.

11. Chaudhuri KR, Pal S, DiMarco A, et al. The Parkinson’s diseasesleep scale: a new instrument for assessing sleep and nocturnaldisability in Parkinson’s disease. J Neurol Neurosurg Psychiatry2002;73:629–635.

12. Cummings JL, Mega M, Grey K, et al. The Neuropsychiatryinventory: comprehensive assessment of psychopathology indementia. Neurology 1994;44:2308–2314.

13. Boeve BF, Silber MH, Ferman TJ. Current management of sleepdisturbances in dementia. Curr Neurol Neurosci Rep 2002;2:169–177.

14. Grace JB, Walker MP, McKeith IG. A comparison of sleep pro-files in patients with dementia with Lewy bodies and Alzhei-mer’s disease. Int J Geriatr Psychiatry 2000;15:1023–1033.

15. Pal PK, Calne S, Samii A, et al. A review of normal sleep andits disturbances in Parkinson’s disease. Park Relat Disord 1999;5:1–17.

16. Bhatt MH, Podder N, Chokroverty S. Sleep and neurodegenera-tive diseases. Semin Neurol 2005;25:39–51.

17. Boddy F, Rowan EN, Lett D, et al. Subjectively reported sleepquality and excessive daytime somnolence in Parkinson’s diseasewith and without dementia, dementia with Lewy bodies andAlzheimer’s disease. Int J Geriatr Psychiatry 2006;21:1–7.

18. Fabbrini G, Barbanti P, Aurilia C, et al. Excessive daytime sleep-iness in de novo and treated Parkinson’s disease. Mov Disord2002;17:1026–1030.

19. Ondo WG, Vuong D, Khan H. Daytime sleepiness and othersleep disorders in Parkinson’s disease. Neurology 2001;57:1392–1396.

20. Arnulf I, Konofal E, Merino-Andreu M, et al. Parkinson’s dis-ease and sleepiness. Neurology 2002;58:1019–1024.

21. Arnulf I. Sleep and wakefulness disturbances in Parkinson’s dis-ease. J Neural Transm Suppl 2006;70:357–360.

22. Gomez-Esteban JC, Zarranz JJ, Lezcano E, et al. Sleep com-plaints and their relation with drug treatment in patients sufferingfrom Parkinson’s disease. Mov Disord 2006;21:983–988.

23. Andreu N, Chale JJ, Senard JM, et al. L-dopa induced sedation: adouble blind cross-over controlled study versus triazolam and pla-cebo in healthy volunteers. Clin Neuropharmacol 1999;22:15–23.

24. Hobson DE, Lang AE, Wayne Martin WR, et al. Excessive day-time sleepiness and sudden-onset sleep in Parkinson disease.JAMA 2002;287:455–463.

25. O’Suilleabhain PE, Dewey RB. Contributions of dopaminergicdrugs and disease severity to daytime sleepiness in Parkinson dis-ease. Arch Neurol 2002;59:986–989.

26. Kaynak D, Kiziltan G, Kaynak H, et al. Sleep and sleepiness inpatients with Parkinson’s disease before and after dopaminergictreatment. Eur J Neurol 2005;12:199–107.

27. Comella C. Sleep episodes in Parkinson’s disease: more ques-tions remain. Sleep Med 2003;4:267–268.

612 S. MOLLOY ET AL.


The TOR1A Polymorphismrs1182 and the Risk of Spreadin Primary Blepharospasm

Giovanni Defazio, MD,1* Mar Matarin, PhD,2

Elizabeth L. Peckham, DO,3 Davide Martino, PhD,1

Enza M. Valente, PhD,4 Andrew Singleton, PhD,2

Anthony Crawley, BS,3 Maria Stella Aniello, MD,1

Francesco Brancati, PhD,4 Giovanni Abbruzzese, MD,5

Paolo Girlanda, MD,6 Paolo Livrea, MD,1

Mark Hallett, MD,3 and Alfredo Berardelli, MD7

1Department of Neurological and Psychiatric Sciences,University of Bari, Italy; 2Molecular Genetics Unit,

Laboratory of Neurogenetics, National Institute on Aging,National Institutes of Health, Bethesda, Maryland, USA;

3Human Motor Control Section, NINDS, National Institutesof Health, Bethesda, Maryland, USA; 4Neurogenetics Unit,IRCCS CSS-Mendel Institute, Rome, Italy; 5Department

of Neurosciences, Ophthalmology, and Genetics, Universityof Genoa, Italy; 6Department of Neurosciences, Psychiatry,

and Anesthesiology, University of Messina, Italy;7Department of Neurological Sciences and NEUROMED

Institute, ‘‘Sapienza’’ University, Rome, Italy

Abstract: We studied the influence of the rs1182 polymor-phism of the TOR1A gene on the risk of dystonia spreadin two representative cohorts of patients presenting withprimary blepharospasm (BSP), one from Italy and theother from the United States of America. The relationshipbetween rs1182 polymorphism and spread was estimatedby Kaplan-Meier survival curves and Cox proportionalhazard regression models adjusted by age and sex, ageof BSP onset. In both series, patients carrying the T allele(G/T or T/T) in the rs1182 polymorphism were more likelyto have dystonia spread as compared with the homozy-gous carriers of the common G allele. The comparablefindings obtained in two independent cohorts support agenetic contribution to BSP spread. � 2009 MovementDisorder Society

Key words: TOR1A; single-nucleotide polymorphisms;blepharospasm; primary adult-onset; dystonia; spread

A single mutation in TOR1A, the gene encoding tor-

sin A protein, is responsible for most cases of early-

onset generalized primary dystonia but has no signifi-

cant role in primary late-onset dystonia.1 Recent case-

control studies in Icelandic and Italian populations

nevertheless raised the possibility that the 191G/T sin-

gle nucleotide polymorphism (SNP) located at the

3_untranslated region of the TOR1A gene (SNP ID:

rs1182) influences the risk of developing late-onset

dystonia.2–4 However, these findings were not con-

firmed in other series from Germany or the United

States of America.3,5

Previous studies did not take into account that late-

onset dystonia may remain focal or spread to adjacent

body regions,6,7 and left open the question whether

normal TOR1A variants affect the susceptibility to

spread. Because primary blepharospasm (BSP) have a

higher risk of spread and spread faster (usually within

the first 5 yr of history) than focal cervical dystonia

(CD) or hand dystonia (FHD),2–4 we tested whether

the rs1182 SNP affects the risk of spread in two inde-

pendent Italian and U.S. cohorts of cases presenting

with primary BSP.

PATIENTS AND METHODS

Italian patients were consecutive outpatients periodi-

cally seen at the movement disorder clinics of the par-

ticipating centres between 2002 and 2007. The major-

ity of the United States of America patients were

members of the Benign Essential Blepharospasm

Research Foundation and were examined in nine major

cities across the USA in a two-yr period. A smaller

number of patients were seen in outpatient visits at the

National Institutes of Health (NIH) in Bethesda, Mary-

land. Two-thirds of patients had already been included

in our previous genetic studies.2,3 The study was

approved by local ethical committees.

Inclusion criteria were focal BSP or BSP as part of

a segmental/multifocal dystonia diagnosed according to

standard criteria;1 BSP as the onset manifestation of

dystonia; age at BSP onset >20 yr; and duration of

disease >5 yr for patients with focal BSP. Exclusion

criteria were features suggesting secondary or heredo-

degenerative dystonia,1 Most patients were receiving

botulinum toxin which seemed to have no effect on

spread.8 No patient was exposed to neuroleptic drugs

after BSP onset.

Spread of dystonia to oromandibular region -mouth,

jaw and tongue-, neck, larynx, and limbs was assessed

by standardized examination including triggering

manoeuvres for dystonic movements or postures in

*Correspondence to: Dr. Giovanni Defazio, Department of Neuro-logical and Psychiatric Sciences, University of Bari, Policlinico,Piazza Giulio Cesare 1 70124 Bari, Italy.E-mail: [email protected]

Potential conflict of interest: None reported.

Received 7 October 2008; Revised 8 December 2008; Accepted 4January 2009

Published online 6 February 2009 in Wiley InterScience (www.



613TOR1A POLYMORPHISM rs1182 AND SPREAD OF BLEPHAROSPASM

apparently asymptomatic subjects. Dystonia was diag-

nosed when slow dystonic movements and definitely

abnormal postures occurred at rest or were activated

by specific tasks. Subtle signs like unusual tight hand

gripping during writing (three cases) and shoulder ele-

vation without significant limitation of shoulder move-

ment (five cases) were not considered dystonic.9,10 No

patient had hand tremor.11 Assessors were unaware of

study hypothesis.

In the Italian series, information on age at BSP onset

and date of spread (approximated to 1 yr) obtained at

the initial clinical evaluation was supported by records

from other physicians whenever available. In about

half of cases, however, the date of spread was obtained

from our own observation at follow-up visits. We,

therefore evaluated the agreement of the diagnosis of

dystonia at different body sites among the examiners

from the participating centers by k statistics12 using

viderecordings from 20 patients with late-onset dysto-

nia, 10 patients with movement disorders other than

dystonia, and 10 healthy controls. According to the

Landis classification,13 substantial (k index between

0.6 and 0.8) to almost perfect (k > 0.8) interobserver

agreement was obtained for the diagnosis of OMD

(k 5 0.71), CD (k 5 0.82), laryngeal dystonia (k 50.73) and FHD (k 5 0.75).

In the United States of America series, information

was obtained from a one time face-to-face examination

performed by the same examiner (EP) who evaluated

BSP patients for spread of dystonia as above reported.

Diagnosis was confirmed by the senior investigator

(MH). The dates of BSP onset and of dystonia spread

were obtained from the patient’s historical report and

records from other physicians whenever available.

The rs1182 SNP was genotyped by real-time poly-

merase chain reaction and a site specific enzymatic

cleavage (primers DYT1-F: 5_TGACAGTCATGATT-

GGCAGCCG-3_; and DYT1-R: 5_ATCTGAGCAG-

TCTCTCATAATG-3_) as reported.2,3

The relationship between rs1182 SNP and spread

was estimated by Kaplan-Meier survival curves and

multivariable Cox proportional hazard regression mod-

els assuming time to spread as the primary end-

point.12,14 The STATA8 package computed survival

curves and hazard ratio (HR), 95% confidence interval

(CI) and p values. Significance was set at the 0.05

level. Statistical power was assessed according to Par-

mar and Marchin.12 Sensitivity of the T allele testing

was the proportion of patients with BSP as part of a

segmental/multifocal dystonia who also carried the T

allele; specificity was the proportion of BSP patients

who remained focal and did not carry the T allele.

RESULTS

A total of 144 Italian patients and 257 USA

patients (all Caucasians) met eligibility criteria. In

both series, females predominated, BSP had its onset

in the fifth to sixth decade and in most cases spread

within the first 5 yr (Table 1, Fig. 1). Age at BSP

onset and frequency of spread were significantly

higher in the Italian series (Table 1). In both series,

age of BSP onset was greater in the patients who

spread (P < 0.01) whereas duration of disease tended

to be longer in those who did not (data not shown).

BSP spread to one body site in 40 Italian and 38

United States of America patients and to a second

body site in 12 Italian and 22 United States of Amer-

ica patients (P 5 0.12). Dystonia spread more fre-

quently to the oromandibular region, less frequently to

neck, larynx and upper limb (Table 1). The genotype

frequency for the rs1182 SNP was similar in Italian

and United States of America patients (Table 1).

In both series, patients carrying the T allele (GT or

TT) were significantly more likely to experience spread

than those without (Fig. 1). Multivariable Cox analysis

taking into account age, sex, and age at BSP onset

(and referral center in the Italian series) confirmed a

significantly higher risk of spread in patients carrying

the T allele as compared with homozygous carriers of

the common G allele (Italian series: adjusted HR, 1.9;

95%CI, 1.1–3.2; P 5 0.03. USA series: adjusted HR,

2.1; 95%CI, 1.1–3.9; P 5 0.02). Stratification by geno-

type yielded an increased risk of spread in GT patients

(Italian series: adjusted HR, 1.8; 95%CI, 1.1–3.3; P 50.04. USA series: adjusted HR, 2.2; 95%CI, 1.1–4.2;

P 5 0.02). whereas the TT group failed to reach statis-

tical significance (Italian series: adjusted HR, 1.8;

95%CI 0.7–4.8; P 5 0.25. USA series: adjusted HR,

1.7; 95%CI, 0.7–4.7; P 5 0.50). The study had an esti-

mated <80% chance of detecting a two-fold change in

the risk of spread for the TT genotype with 50.05

(two-sided).

United States of America patients carrying the T al-

lele yielded a higher risk of spread to either the oro-

mandibular region (adjusted HR, 2.0; 95%CI, 1.1–3.9;

P 5 0.03) or extracranial sites (neck, larynx, and upper

limb) (adjusted HR, 2.1; 95% CI, 1.1–4; P 5 0.03).

Non significant trends towards increased risk of spread

were observed in the Italian series (Oromandibular

region: adjusted HR, 1.7; 95%CI, 0.9–3.1; P 5 0.11.

Extracranial sites: adjusted HR, 2.0; 95%CI, 0.8–4.9;

P 5 0.14), but study power was <80%.

The T allele testing yielded 50% (26/52) sensitivity

and 71% (65/92) specificity in the Italian series, 45%

614 G. DEFAZIO ET AL.


(27/60) sensitivity and 70% (137/197) specificity in the

United States of America group.

DISCUSSION

In our samples, the risk of spread was higher in

patients carrying the T allele than in homozygous car-

riers of the common G allele. The association between

T allele and spread was independent of possible con-

founders and, probably, of the site of spread. The com-

parable findings obtained in two independent cohorts

add an extra validation to the association of the rs1182

polymorphism to dystonia spread in patients presenting

with primary BSP. This finding also receives support

from current knowledge. Although the effect of the

rs1182 SNP upon the expression and functioning of

torsin A is unknown and we cannot exclude that

rs1182 might be the tagging SNP for a different causa-

tive variant in the haplotype block, dystonia associated

FIG. 1. Kaplan–Meier survival analysis of spread of dystonia in the Italian (A) and USA (B) series according to the presence of the T allele inthe TOR1A single nucleotide polymorphism rs1182. Censored observations are displayed by ticks. In the Italian series, number of at risk patientswas 144 at time zero, 92 at 5 yr, 50 at 10 yr, 23 at 15 yr, and 12 at 20 yr. In the USA series, there were 257 patients at time zero, 209 at 5 yr,132 at 10 yr, 84 at 15 yr, 49 at 20 yr, and 20 at 30 yr.

TABLE 1. Demographic and clinical features, and genotype distribution of theTOR1A single nucleotide polymorphism rs1182 in Italian and United States of America series

Italian series USA series P*

Number of patients 144 257Sex (men/women) 42/102 57/200 0.12Mean age (yr) 6 SD. 68.6 6 10.2 66.2 6 9.3 0.90Mean age (yr) of blepharospasm onset 6 SD 57.2 1 7.9 52 6 8.7 <0.0001Mean years of follow up 6 SD 11.4 6 5.7 14.5 6 8.4 <0.0001Number of patients (%) who experienced spread 52 (36%) 60 (23%) 0.006Mean time to initial spread (years) 6 SD 2.8 6 2.8 2.9 6 3.8 0.6Number of patients who experienced spread**toOromandibular region 42 40 0.22Larynx 4 10Neck 15 25Upper limb 4 7

rs 1182 - genotype distribution (%)GG 91 (63%) 170 (66%) 0.50GT 41 (28%) 73 (28%)TT 12 (9%) 14 (6%)

*P by by Student’s t test and Chi-square test.**Blepharospasm spread to only one body site in 40 Italian and 38 United States of America patients, to a

second body site in 12 Italian and 24 United States of America patients.

615TOR1A POLYMORPHISM rs1182 AND SPREAD OF BLEPHAROSPASM


with the TOR1A_GAG mutation has a high tendency

to generalize within few years from onset.1,7

Our study may have limitations. This was not a pop-

ulation-based study, but recruiting criteria yielded case

series resembling the general population of cases in

both demographic and clinical features.1,6,7,15 The dif-

ference in the frequency of spread between Italian and

United States of America populations probably

reflected the different age at dystonia onset. In patients

presenting with BSP, the higher the age at BSP onset,

the higher was the tendency to spread.6,7,15 The satisfy-

ing levels of interobserver agreement on the diagnosis

of dystonia at different body sites minimized an ob-

server bias causing misclassification of spread events.

Assessing self-reported age at dystonia onset and tim-

ing to spread in half of the Italian patients and in the

majority of the United States of America patients

might expose to recall bias. Nevertheless, we showed

that age at dystonia appearance may be reliably deter-

mined from retrospective reports in primary late-onset

dystonia.6 The sample size did not allow us to examine

the influence of the rs1182 polymorphism on the risk

of second spread, and to adequately investigate the

effect of the TT genotype. We calculated15 that about

700 patients would be needed to detect a two- to three-

fold change in the risk of spread for the TT genotype

with 50.05 (two-sided), b > 80%, 30% frequency of

spread events at 5 yr, and 10% frequency of TT geno-

type. A study of such size may be difficult to perform

in reasonable time owing to BSP prevalence.16

In conclusion, this study provides new informa-

tion suggesting that genetic factors may contribute to

the spread of primary BSP. The low sensitivity of the

T allele testing indicates that spread of dystonia is

probably a multi-factorial event. The 70% specificity

also indicates that excluding the T allele may help to

identify BSP patients who are less likely to have

spread.

Acknowledgments: This work was funded by the Comi-tato Promotore Telethon, Italy (Grant No. GGP05165); theBenign Essential Blepharospasm Research Foundation, Beau-mont, TX, USA; and the Intramural Research Programs ofthe National Institute on Aging and National Institute of Neu-rological Disorders and Stroke, National Institutes of Health:Department of Health and Human Service(project numberZ01 AG000957-05), Bethesda, MD, USA.

Author Roles: Giovanni Defazio: Conception and organi-zation of the research project; design and execution of thestatistical analysis; writing of the first draft and revision ofthe manuscript; Mar Matarin: Organization and execution ofthe research project; review and critique of the manuscript;Elizabeth L Peckham: Organization and execution of theresearch project; review and critique of the manuscript;

Davide Martino: Organization and execution of the researchproject; execution and revision of the statistical analysis;review and critique of the manuscript; Enza M Valente: Or-ganization and execution of the research project; review andcritique of the manuscript; Andrew Singleton: Organizationand execution of the research project; review and critique ofthe manuscript; Anthony Crawley: Execution of the researchproject; Maria Stella Aniello: Execution of the research pro-ject; Francesco Brancati: Execution of the research project;Giovanni Abbruzzese: Execution of the research project;review and critique of the manuscript; Paolo Girlanda: Exe-cution of the research project; review and critique of themanuscript; Paolo Livrea: Review and critique of the manu-script; Mark Hallett: Conception and organization of theresearch project; design, review and critique of the statisticalanalysis; review and critique of the manuscript; AlfredoBerardelli: Conception, organization and execution of theresearch project; review and critique of the manuscript.

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616 G. DEFAZIO ET AL.


Levodopa use and sleep in patients with dementia with Lewy bodies

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