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8.2 Evaluation de la cognition et du sommeil chez les patients parkinsoniens

Sleep and cognition in Parkinson’s disease patients: A one year follow-up study

Lucie Plomhause MSc ^1,2, Kathy Dujardin PhD ^1,3, Alain Duhamel PhD ⁴,Marie Delliaux MSc ^1,3, Philippe Derambure MD, PhD ^1,2, Luc Defebvre MD, PhD ^1,3, Christelle Monaca Charley MD, PhD ^{1,2 *}

1 EA 4559, Lille Nord de France University, Lille, France

2 Department of Clinical Neurophysiology, Lille University Medical Center, Lille, France

3 Movement Disorders Department, Lille University Medical Center, Lille, France

4 EA 2694, Lille Nord de France University, Lille, France

Keywords: Parkinson’s disease, antiparkinsonian drugs, sleep, rapid-eye-movement sleep behavior disorder, excessive daytime sleepiness, cognition

Abstract:

Objective: Beside motor symptoms, Parkinson’s disease (PD) leads to behavioral disorders, cognitive dysfunctions and sleep disturbances such as rapid-eye-movement sleep behavior disorder (RBD). RBD and cognitive impairments have been showed to be associated with a higher risk of dementia in PD patients. One possible confounding factor when evaluating PD patients is the antiparkinsonian drugs intake. There is a need to quantify the effect of PD treatments on sleep and cognition. First, this study aimed to evaluate antiparkinsonian drugs effects on sleep and cognition in PD patients after one year on medication. Second, to

compare the evolution of two sub-groups of patients: with or without RBD at the time of diagnosis.

Methods: Thirty-six of the fifty-seven newly diagnosed PD patients previously recruited and evaluated at the Lille university medical center (T1) underwent a second evaluation session after one year of treatment (T2). One overnight polysomnography (PSG) session was used to assess night sleep. Daytime sleepiness was measured in a multiple sleep latency test (MSLT).

Cognition and behavior were assessed in a standard neuropsychological examination. The Lille Apathy Rating Scale (LARS) was used to evaluate apathy. A specific evaluation of visual attention and perception was based on 2 computerized tasks.

Results: At the second evaluation session, patients showed a significantly shorter total sleep time (390 vs 346 min, p=0.019) and percentage of REM sleep (18 vs 14 %, p=0.002)

associated with a significantly shorter sleep onset at the MSLT (16 vs 13 min, p=0,006). No changes were observed on cognitive parameters for the whole group. RBD patients showed longer response time at the visual attention task at the T2 compared to T1, whereas non- RBD patients did not. At T2, RBD patients had a significant higher LARS score than non-RBD patients (-24.9 ± 5.3 vs -27.7 ± 5.7, p=.044), which was not the case at T1.

Conclusion: Antiparkinsonian drugs intake (dopaminergic and non-dopaminergic) induces sleep modification in parkinsonian patients with a disease duration of one year. These modifications include a decreased total sleep time and percentage of REM sleep associated with an increased daytime sleepiness. After 15-month of disease progression, RBD patients did not massively decline on cognition or sleep quality compared to non-RBD patients. Some yet isolated results (on apathy and cognitive slowing) might reflect a trend towards a

potential decline in RBD patients. A longer follow-up study (5 years) will determine whether the presence or not of RBD at the time of diagnosis influences disease progression.

Introduction

Parkinson’s disease (PD) is characterized by motor but also non-motor symptoms such as behavioral disorders, cognitive dysfunctions and sleep disturbances (for review see

1). The latter include excessive daytime sleepiness (EDS), insomnia, parasomnias, obstructive sleep apnea ², restless legs syndrome ³. Rapid eye movement sleep behavior disorder (RBD), is a frequent parasomnia characterized by an abnormal sustain of chin muscle tone during REM sleep associated with sudden motor activities and sometimes elaborated complex behaviors described as “acted-out dreams” ⁴. RBD is a risk factor for dementia in PD ⁵.

The cognitive impairment severity at the early stage of PD has also been associated with a more important decline during the evolution of the disease and with a higher risk of developing dementia ^6,7. Cognitive dysfunctions, reaching mainly executive functions, already exist in drug-naïve PD patients at the time of diagnosis ^8–12.

Patients with a specific profile of the disease, characterized by the presence of RBD and poorer cognitive functioning might reflect an underlying pathophysiology more likely to progress to dementia. The link between the presence of RBD and the severity of cognitive dysfunctions in de novo PD patients remains to be established.

In a recent study, we aimed to determine if drug-naïve PD patients with and without RBD differed in terms of cognition and overall sleep parameters. We concluded that at this early stage in the disease, RBD was not associated with other sleep disorders or cognitive decline ¹³. A longitudinal follow-up will provide data on the impact of RBD in the progression of PD. Prior assessments are needed as a first step of this follow-up study to quantify the effect of PD treatments on sleep and cognition.

In the present study we sought to evaluate PD patients on sleep and cognition parameters, after one year on medication. The first objective is the evaluation of antiparkinsonian effects on sleep and cognition. The second objective consists of the comparison of cognitive functions changes in PD patients with and without RBD.

Subjects and methods

In an initial study, 57 treatment-naïve PD patients were prospectively and

consecutively recruited between June 2008 and January 2012 in the Movement Disorders Department at the Lille Medical University Center (France). A first examination session (T1) occurred within 2 months of PD diagnosis and focused on sleep and global cognitive

parameters. The detailed results are presented in a previous article ¹³. The patients were then followed up for a second examination session (T2) after one year of antiparkinsonian treatment. The study protocol was approved by the local institutional review board and all patients gave their informed, written consent to participation.

The second session (T2) included one overnight polysomnography (PSG) with time synchronized video-PSG, multiple sleep latency tests (MSLTs), a neuropsychological examination and a motor evaluation (the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS-III)¹⁴ and a motor subtype assessment (tremor, akinetic-rigid, mixed)).

No first habituation night was mandatory since the patients were already used to the sleep laboratory at the baseline session.

The polysomnographic recording consisted of a standard montage: an electroencephalogram, electro-oculograms, submental and bilateral anterior tibialis

electromyography, an electrocardiogram and nasal and oral air-flow, oxygen saturation and thoracic and abdominal movement monitoring. To assess objective daytime sleepiness, multiple sleep latency tests were performed after the night if the total sleep time was over 6 hours and consisted in 4 naps at 10:00 AM, 12:00 AM, 02:00 PM and 04:00 PM. Subjective daytime sleepiness was evaluated with the Epworth Sleep Scale ¹⁵.We calculated parameters for sleep structure (total sleep time, sleep latency, sleep efficiency and percentage sleep stage), breathing (mean oxygen saturation during sleep and the apnea-hypopnea index (AHI)) and sleepiness (mean sleep latency in the MSLT, the number of sleep-onset REM periods (SOREMPs) and the number of patients with a mean sleep latency below 8 minutes).

The neuropsychological examination included tests of global cognitive efficiency (the Mini Mental State Examination (MMSE, ¹⁶) and the Mattis Dementia Rating Scale (MDRS, ¹⁷)), attention and processing speed (the Symbol Digit Modalities Test, ¹⁸), working memory (the backward digit span subtest of the WAIS-III, ¹⁹), executive functions (the Stroop color word

test ²⁰ and part B of an oral version of the Trail Making Test(21)), verbal memory (a 16-item free/cued recall test, ²¹) and naming ability (a confrontation naming test). In terms of behavior, apathy and depression were respectively evaluated according to the Lille Apathy Rating Scale (LARS, ²²) and the Montgomery and Asberg Depression Rating Scale (MADRS, ²³).

As described elsewhere (Plomhause et al, neuropsychology in press) a specific evaluation of visuo-spatial processing was used to test visual attention (Posner task) and visuoperceptive abilities (Biederman task). Briefly, in the Posner task the mean response times (ms) to detect a target are compared as a function of the type of cue previously presented: at the center of the screen (neutral), at the same side of the target (valid), at the opposite side of the target (invalid). The parameters calculated were: the mean neutral response time (ms), the cost of invalid cues, and the benefit of valid cues on response times.

In the Biederman task, participants had to name fragmented pictures (with half the contours of each picture deleted) as quickly as possible. After twenty three learning trials, participants had to name 23 fragmented pictures (block 1). Next, a second block of trials consisted in naming 69 randomly presented, fragmented pictures (block 2). Three types of pictures defined the three experimental conditions: 23 pictures were exactly the same pictures as in block 1 (the “identical” condition), 23 pictures were formed by deleting 50% of the contours of the original intact object (yielding a pair of complementary images that, when superposed, formed an intact picture with no overlap - the “complementary”

condition) and 23 pictures corresponded to different views of the objects presented in block 1 (the “different” condition).The parameters calculated were: the mean response times for block 1 and the 3 conditions of block 2.

Statistical analysis

Non parametric Mann-Whitney tests were used to study between-group effects (RBD vs. non-RBD) on cognitive, sleep and PD-related parameters at T2. Chi-squared tests were applied for categorical variables. Covariance analyses adjusted on baseline value (at T1) were used to test for group x time interaction. The threshold for statistical significance was set to p=0.05.

Results

Demographic and disease-related data

Of the 57 patients, 36 completed the second session (15 women, mean age= 64.2 ± 10.0), 12 patients refused it, 4 patients had to cancel it because they could not get free from their jobs, and 2 patients were not able to complete it due to health problem unrelated to PD. One patient was excluded at the diagnosis of possible dementia with Lewy Body and 2 other patients were excluded after PD diagnosis has been questioned (see flow chart). The mean interval duration between the 2 sessions in months was 15.2 ± 2.9.

All patients received antiparkinsonian drugs, either dopaminergic: pramipexole (n=13), ropinirole (n=8), L Dopa (n=15), or non-dopaminergic: selegiline (n=3), rasagiline (n=22). The mean daily L-Dopa equivalent dose was 267.5 ± 181.3 mg. The mean score at the UPDRS 3 on drug was 14 ± 6.8.

Effect of disease progression

Regarding sleep and vigilance parameters, at T2, parkinsonian patients had a

significant decrease of TST and % of PS compared to T1. They had more daytime sleepiness, with a significant increase of ESS score and a significant decrease of mean sleep latency in MSLT (table 1). The other sleep parameters were not significantly different between T2 and T1.

No cognitive decline was found at T2 compared to T1. The MDRS score did not differ between T1 and T2 (respectively 139.0 ± 3.6 and 139.0 ± 3.4). The cost at the Stroop test was significantly lower at T2 than at T1 (respectively 0.88 ± 0.41 and 0.70 ± 0.31, p=0.0477).

No significant difference was found for any of the other cognitive parameters. No significant change was found at the Posner task and the Biederman task between T2 and T1.

Effect of RBD at T2

At T2, non-RBD patients showed a higher body mass index (BMI) than RBD patients (respectively 28.4 ± 4.7 and 24.3 ± 3.5; p =0.018). This difference was already present at T1, non-RBD patients had a BMI of 27.5 ± 3.6 and RBD patients of 23.5 ± 2.6 (p=0.003).

At T2, 13 patients were diagnosed with RBD. Those patients already had RBD at T1.

Between-groups comparisons showed that the percentage of PS with tonic activity was significantly different between RBD and non-RBD patients (41.5 ± 18.3 and 5.9 ± 2.9;

p<.001). None of the other comparisons was significant.

RBD patients had a significantly higher score at the LARS than the non-RBD patients (- 24.9 ± 5.3 vs -27.7 ± 5.7, p=.044). Although these scores were still within the normal range (cut-off: -22/-21), it reflects a greater frequency of apathetic symptoms in the RBD group. No between-group effect was found at the MADRS scores.

Regarding cognition, none of the inter-group comparisons reached the significant threshold.

Group x Time Interaction

No group x time interaction was found for the sleep parameters.

There was a trend toward a significant group x time interaction for the mean response time in the neutral condition of the Posner test (p=0.053). The effect of time was then studied for the 2 group separately. These analysis revealed a significantly higher response time at T2 compared to T1 for RBD patients (p=0.027) but not for non-RBD patients. The other comparisons regarding cognition did not show any significant interaction effect between groups.

Discussion

The first objective of this study was to evaluate the antiparkinsonian effects on sleep and cognition in the first year of PD. Regarding sleep, our follow-up study shows a decrease in TST and in the percentage of PS as well as increased EDS. Both night sleep quality and daytime vigilance modifications are revealed.

It is well known that dopatherapy induces sleep modifications ^24,25. These modifications can have two types of effects: sedation or arousal. L-dopa intakes might worsen sleep quality in mild, early-stage Parkinson's disease, while improving it in later stages of PD ²⁶. A decrease of REM sleep quantity and a delayed REM sleep onset in animals

27, as well as in PD patients ²⁸ has been described following L-dopa intakes. The poorer quality of night sleep quantified in the present study bring important information about the link between antiparkinsonian drugs and this arousal effect.

As regards the sedation effect of dopaminergic treatment, PD patients frequently complain about daytime sleepiness: 33 % to 50 % ^29,30 of PD patients report such a complaint versus 11% of matched healthy volunteers. What is less known is the time of EDS onset during the course of the disease. The increased EDS measured in our patients is in line with the hypothesis of a role of antiparkinsonian drugs in EDS. In a previous study, 15 drug-free newly diagnosed PD patients were evaluated on sleep (PSG and MSLT) and clinical outcome before and after antiparkinsonian medication ³¹. Daytime sleepiness was only present in treated PD patients but not in newly diagnosed drug-free patients. Dopaminergic drugs induced an increase of sleep stages 1 and 2 but no effect on SP. Objective EDS was found in 7 (47 %) patients after medication, when only 1 patient before medication. The severity of objective daytime sleepiness was explained the best by the daily L-dopa dose.

The present study thus provides more data on the link between dopaminergic treatments and EDS but more data are needed to address the issue sleep onset in REM sleep period (SOREMP). In the present study no patient showed SOREMP, while it has been showed around 20 % in patients at an early stage of the MP ³¹ and up to a third of PD patients in an advanced stage of disease ^32–34. Whether SOREMP is due to the PD pathophysiology or to a higher L-dopa equivalent dose remains an open question.

Regarding cognition, no significant change was found between both evaluations for the whole group of parkinsonian patients except an improvement of inhibition capacities (decrease of the cost at the Stroop test) at T2 compared to the first evaluation session. This result must be taken carefully since it could be due to a practice effect ³⁵.

The second objective was to compare the progression of sleep, cognition and behavior in PD patients with and without RBD. Only one parameter progressed differently over time in RBD and N-RBD patients. Only RBD patients but not non-RBD patients showed a cognitive slowing at the visual attention test. RBD patients may also have a trend toward apathy. At T2, RBD patients had more signs of apathy than non-RBD patients, which was not the case at T1, but the interaction did not reach the significant level. In previous studies, the presence of RBD in PD has been associated with more severe cognitive impairments ^36,37. Those evaluations have been done in treated PD patients, several years since disease onset.

Our patients were evaluated at earlier stages of the disease, so a follow-up study is needed and will bring more solid data on the effect of RBD in PD progression.

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