Just Accepted by International Journal of Neuroscience

Multimodal imaging evaluation of excessive daytime sleepiness in Parkinson’s disease Maria Chondrogiorgi, Loukia C. Tzarouchi, Anastasia K. Zikou, Loukas G. Astrakas, Paraskevi Kosta, Maria I. Argyropoulou, Spiridon Konitsiotis doi:10.3109/00207454.2015.1023437

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Abstract Purpose of the study: The multimodal imaging investigation of excessive daytime sleepiness (EDS) in Parkinson’s disease (PD). The role of dopaminergic treatment and other clinical parameters was also evaluated. Materials and Methods: Seventeen non-demented PD patients with EDS (PD-EDS) and 17 PD patients without EDS were enrolled. Clinical, treatment and MRI data were acquired. Grey matter (GM) volume was examined with voxel based morphometry, while white matter (WM) integrity was assessed with diffusion tensor imaging by means of fractional anisotropy, mean diffusivity, axial diffusivity (AD) and radial diffusivity measures. Results: Increased regional GM volume was found in the PD-EDS group bilaterally in the hippocampus and parahippocampal gyri. Increased AD values were also shown in the PD-EDS group, in the left anterior thalamic radiation and corticospinal tract and bilaterally in the superior corona radiata and the superior longitudinal fasciculus. Levodopa equivalent dose differed significantly between the groups and was the only predictor of EDS, while the only predictor of Epworth sleepiness scale score in the PD-EDS group was the dopamine-agonist dose. Increased frequency of gamblers was also observed in the PD-EDS group. Conclusions: Regional GM increases and increased AD values in certain WM tracts were found in the PD-EDS group. The changes could result from disinhibited signaling pathways or represent compensatory changes in response to anatomical or functional deficits elsewhere. The study findings support also the contribution of the total dopaminergic load in the development of EDS, while the dose of DAs was found to predict the severity of the disorder.

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Title: Multimodal imaging evaluation of excessive daytime sleepiness in Parkinson’s disease

Authors Paraskevi Kostab, Maria I. Argyropouloub, Spiridon Konitsiotisa Affiliations a

Department of Neurology, Medical School, University of Ioannina, Stavrou Niarchou Av.,

University Campus, 45110, Ioannina, Greece b

Department of Radiology, Medical School, University of Ioannina, Stavrou Niarchou Av.,

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University Campus, 45110, Ioannina, Greece c

Department of Medical Physics, Medical School, University of Ioannina, Stavrou Niarchou Av.,

University Campus, 45110, Ioannina, Greece

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Corresponding Author

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Maria Chondrogiorgi, MD Department of Neurology, Medical School, University of Ioannina, StavrouNiarchou Av. , University Campus, 45110, Ioannina, Greece Tel: +30 2651033955 , Fax: +30 2651023910 E-mail address: [email protected]

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Abstract

Purpose of the study: The multimodal imaging investigation of excessive daytime sleepiness (EDS) in Parkinson’s disease (PD). The role of dopaminergic treatment and other clinical parameters was also evaluated.

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Maria Chondrogiorgia, Loukia C. Tzarouchib, Anastasia K. Zikoub, Loukas G. Astrakasc,

Materials and Methods: Seventeen non-demented PD patients with EDS (PD-EDS) and 17 PD patients without EDS were enrolled. Clinical, treatment and MRI data were acquired. Grey matter (GM) volume was examined with voxel based morphometry, while white matter (WM) integrity was assessed with diffusion tensor imaging by means of fractional anisotropy, mean diffusivity, axial diffusivity (AD) and radial diffusivity measures. Results: Increased regional GM volume was found in the PD-EDS group bilaterally in the hippocampus and parahippocampal gyri. Increased AD values were also shown in the PD-EDS

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group, in the left anterior thalamic radiation and corticospinal tract and bilaterally in the superior corona radiata and the superior longitudinal fasciculus. Levodopa equivalent dose differed significantly between the groups and was the only predictor of EDS, while the only predictor of

frequency of gamblers was also observed in the PD-EDS group.

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Epworth sleepiness scale score in the PD-EDS group was the dopamine-agonist dose. Increased

Conclusions: Regional GM increases and increased AD values in certain WM tracts were found in the PD-EDS group. The changes could result from disinhibited signaling pathways or

study findings support also the contribution of the total dopaminergic load in the development of

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EDS, while the dose of DAs was found to predict the severity of the disorder.

Keywords

Parkinson’s disease; Excessive daytime sleepiness; Neuroradiology; Diffusion tensor imaging;

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Introduction

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Axial diffusivity

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As knowledge concerning the multiple faces of Parkinson’s disease (PD) extends, the non-motor symptoms attract an increasing amount of interest due to their significant contribution to the reduction of patients’ quality of life. Excessive daytime sleepiness (EDS) is described as inappropriate and undesirable sleepiness during waking hours and its frequency among PD patients reaches the percentage of 50% [1]. If left untreated, EDS may affect daytime function

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represent compensatory changes in response to anatomical or functional deficits elsewhere. The

and predispose to traffic accidents. The pathophysiology of EDS in PD remains highly unknown and is probably

multifactorial, as the disease itself, the dopaminergic drugs and other disorders frequently accompanying PD, such as depression, insomnia, parasomnias, sleep fragmentation, REM sleep behavior disorder (RBD) and restless legs syndrome (RLS) have all been proposed as etiological factors [2]. The neuropathological substrate of the disorder is largely unknown and few studies

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about cerebral structural abnormalities in PD-related EDS have been reported. In fact, a previous study that used diffusion tensor imaging (DTI) [3], to compare PD-EDS to PD-non EDS patients and controls, showed significantly lower fractional anisotropy (FA) values of the fornix fiber in the PD-EDS group. A more recent study, applying voxel based morphometry (VBM) in groups

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relevant to those of the previously described study, concluded a widespread cortical and

subcortical atrophy that was significantly more pronounced when the PD-EDS group was

compared to healthy controls than to PD-non EDS group [4]. Finally, the morphometry analysis

The purpose of the present study, conducted in a sample of non-demented individuals,

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was the multimodal imaging investigation of the PD-related EDS. VBM was used to detect

regional changes in the grey matter (GM) volume. White matter (WM) was examined with DTI by means of FA and mean diffusivity (MD) measures, but also through axial diffusivity (AD)

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and radial diffusivity (RD) procedures, which estimate water diffusion parallel and perpendicular to axonal bundles respectively, assessing axonal and myelin status. Assessment of WM with

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non-conventional magnetic resonance imaging (MRI) techniques in degenerative diseases has received an increasing amount of interest, since changes in fiber integrity or communication speed have been found to accompany a variety of neuropsychiatric symptoms [6,7]. The role of dopaminergic treatment and other clinical parameters was also evaluated in the present study.

Subjects

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Materials and methods

Seventeen non-demented (Mini Mental State Examination score>25) PD patients with

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in another study revealed middle cerebellar peduncle atrophy in PD patients presenting EDS [5].

EDS (PD-EDS group) and seventeen age-matched PD patients without EDS (PD-non EDS group) were recruited from the movement disorder outpatient clinic at University Hospital of Ioannina. All of the patients fulfilled the United Kingdom PD Society Brain Bank clinical diagnostic criteria for idiopathic PD [8]. Eligible patients should not show any sign of atypical parkinsonism or serious psychiatric disorder. All patients were examined by a movement disorders expertized neurologist and disease severity was graded using the modified Hoehn and Yahr scale. The level of daytime somnolence was rated with the Epworth Sleepiness Scale (ESS)

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[9]. In this eight-item questionnaire the total score ranges from 0 to 24, and EDS is defined as a value greater than 10. In order to increase validity in the diagnosis of EDS and exclude borderline cases we considered as cases the PD patients scoring ≥13 in ESS. As non-EDS we considered the patients with score ≤6 in ESS. The thresholds of 13 and 6 were taken arbitrarily.

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The existence of possible depressive disorder was assessed with Hamilton Depression Scale (HAM-D). Through a direct interview we collected information on the type and duration of

current medication, the presence of RBD and RLS. The patients were also asked for possible vocational consequences (definition according to 4th edition of the Diagnostic and statistical

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Manual of Mental Disorders). We chose to collect this type of information based on previous

research that was suggestive of a possible link between sleep disorders and particularly EDS with impulsivity and specifically gambling [10,11]. Therefore we used gambling as marker of impulsivity, as a full assessment of similar disorders was beyond the scopes of the study. If

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present, accompanying family members were asked to confirm the occurrence of these disorders.

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The presence of PD diagnosis among 1st to 3rd degree relatives was also investigated. In order to create comparable values of the doses of levodopa and DAs and calculate the total load of antiparkinsonian treatments, the daily dose of each treatment was converted to Levodopa Equivalent Dose (LED) [12]. The term “total LED” corresponds to the sum of the daily dose of levodopa and anti-parkinsonian drugs with available validated equivalency with

Ethics

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levodopa [12].

The study followed the principles of the Declaration of Helsinki and was approved by the local

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gambling, defined as failure to resist gambling impulses despite severe personal, family or

ethics committee. Written informed consent was obtained from all participants. Imaging Protocol MR imaging was performed with a 1.5T MR scanner (Intera; Philips Healthcare, Best, the Netherlands), using a quadrature head coil. The imaging protocol consisted of :1) T1-weighted high-resolution (1 Χ 1 Χ 1 mm) 3D spoiled gradient-echo sequence (TR, 25 ms; TE, 4.6 ms), which was used for structural imaging; 2) a single-shot multisection spin-echo-planar sequence 15

(TR, 9807 ms; TE, 131 ms; FOV, 230 mm; matrix, 128 Χ 128; slice thickness, 3 mm; maximum b-value, 700 s/mm2 ; 16 noncollinear diffusion directions; intersection gap, 0), which was used for DTI; and 3) a sagittal T2-weighted FLAIR sequence (TR, 6300 ms; TE, 120 ms; FOV, 250 mm; matrix, 256 Χ 256; ; slice thickness, 6 mm; intersection gap, 0.6mm), which was

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used for evaluation of WM hyperintensities. Image Analysis

SPM 8 (Wellcome Department of Cognitive Neurology, London, UK). The T1-weighted images

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were normalized to the T1 Montreal Neurological Institute (MNI) template and segmented into GM, WM, and cerebrospinal fluid (CSF) compartments. Modulation of the normalized images was performed to preserve regional brain volume. Finally, GM. WM, and CSF partitions were smoothed with a Gaussian filter of 8 Χ 8 Χ 8 mm full-width at half maximum. A t-test at the

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between patients with and without EDS.

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voxel level (p

Multimodal imaging evaluation of excessive daytime sleepiness in Parkinson's disease.

The multimodal imaging investigation of excessive daytime sleepiness (EDS) in Parkinson's disease (PD). The role of dopaminergic treatment and other c...
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