Sleep Homeostasis in Parkinson's Disease

April 5, 2018 updated by: Salvatore Galati

Role of Sleep Homeostasis in the Development of the L-Dopa Induced Dyskinesias in Patients With Parkinson's Disease

Parkinson's disease is characterized in the advanced phases by an altered response to dopaminergic therapy for the occurrence of abnormal movements called dyskinesias, that worsens the quality of life of the patient and exposes him to comorbidities. Several data show a reduction in the amount of slow wave sleep that correlates inversely with disease duration. Since this stage of sleep is linked to mechanisms of deletion of superfluous information the investigators hypothesize that the onset of dyskinesias is related to such alteration of sleep.

-This study is aimed to investigate, by means of high-density electroencephalography (hd-EEG), the sleep and in particular the slow wave in order to clarify the relations with the development of dyskinesias.

Study Overview

Status

Completed

Conditions

Parkinson Disease

Detailed Description

Wakefulness in PD is frequently interrupted by sleep episodes, even rapid eye movement sleep (REM), whilst nocturnal sleep is disturbed by abnormal motor activity interference, such as REM sleep behaviour disorder (RBD) or periodic limb movements (PLMS). Several lines of evidence have suggested a close relation between sleep-wake changes and dopaminergic degeneration in PD(1-7) while sleep disorders commonly precede the clinical motor onset by many years (8,9). On the other hand, morning motor performance improvement is frequently mentioned by patients, mainly in those with long disease duration and motor fluctuation (10,11). Of note, the same state of vigilance can profoundly influence some clinical PD features (for instance rigidity) as well as basal ganglia neuronal activity(12).

Few reports have shown changes in sleep architecture: a reduction of the amount of SWS in parallel with disease duration (13-15) has been observed, but no study, so far, has addressed how sleep may impact on LID. Once these abnormal movements develop, they are difficult to treat and negatively affect the quality of life and the treatment costs of PD patients (16,17). Although levodopa represents, so far, the more effective treatment for PD patients (18,19) to ameliorate the cardinal signs such as bradykinesia/akinesia and rigidity (20), as the disease progresses, these benefits are in some measure abolished by the emergence of dyskinesia (21). During the early stages PD patients experience a rather satisfying quality of life that is impeded in the advanced stages by the emerging of these involuntary movements frequently at the peak of the levodopa effect (16,22,23). In other words, when the patients experience these motor complications (shortening motor response and development of dyskinesia) the delivery of levodopa without inducing dyskinesia becomes increasingly difficult (21,24-27).

Several efforts have been made in order to find "pure" anti-dyskinetic drugs that are able to uncouple the anti-akinetic effect from the dyskinetic response. Serotoninergic receptor agonists were claimed to be drugs against dyskinesia (28), however, it was observed that they may also impair levodopa efficacy (29-31). As of today, no clinical effective therapies are able to alleviate dyskinesia without worsening parkinsonism.

Great efforts have been made to clarify LID pathogenesis, emphasizing the role of pulsative stimulation of striatal receptors by dopaminergic treatment (25) and more recently, on molecular changes of postsynaptic (32,33) or presynaptic mechanisms (34). Although no conclusive results on LID pathogenesis have been achieved, indeed disease duration (i.e. the degree of dopaminergic degeneration) rather than long-term use of levodopa, seems to play a crucial role (22,23). This notion can be inferred from clinical practice, but is also evident in MPTP-induced parkinsonism in humans in which the extended dopaminergic lesion caused within a few days the development of dyskinesias undistinguishable from those in the idiopathic form (35).

General Aim:

The study is aimed 1) to define abnormal cortical synaptic homeostasis, measured by means of SWS and waking EEG evoked responses, as key components for the development of LID; 2) to analyse the impact of anti-dyskinetic effect of rTMS on the SWA in additional ten PD patient with LID.

Specific aims:

To compare, in the four groups of subjects (control, de novo, advanced without dyskinesia, and advanced with dyskinesia), changes of the EEG features of NREM sleep: slow wave/slow oscillation and sleep spindles. A significant reduction of the physiological reduction of SWA in dyskinetic patients in comparison with the other groups is expected.
To identify the homeostatic reduction of cortical synaptic strength (downscaling) in the four categories of subjects by comparing late sleep (i.e. towards morning) SWA with early sleep (i.e. at the beginning of the night) SWA as well as by comparing the overnight changes in the amplitude of EEG somatosensory, auditory and visual evoked responses recorded before and after sleep. The study is aimed to demonstrate the reduction/absence of a physiological downscaling in dyskinetic patients versus the other groups.
To analyse the effect of rTMS on SWA of PD patients with LID in order to demonstrate a recovery of physiological downscaling of SWA in these patients parallel to the reduction of dyskinesia.

Study Type

Observational

Enrollment (Actual)

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Switzerland
- Ticino
  - Lugano, Ticino, Switzerland, 6903
    - Ospedale Regionale di Lugano

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Healthy volunteers and patients with parkinson disease

Description

Inclusion Criteria:

clinical characteristics of the patients must be according the UK (United Kingdom) Brain Bank

Exclusion Criteria:

anamnestic obstructive sleep apneas syndrome
known cognitive deterioration or with MMSE (Mini-Mental State Examination) ≤24/30
depression ≥ 20 of the BDI scale (Beck Depression Inventory)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Number of groups / cohorts

Cohorts and Interventions

Group / Cohort
Advanced Parkinsons Disease Polysomnogram
Parkinsons Disease with Dyskinesia Polysomnogram
De novo Parkinsons Disease Polysomnogram
Healthy Volunteers Polysomnogram

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Slow wave sleep Time Frame: 1 night	Percentage of total sleep classified as slow wave sleep	1 night

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amplitude of slow waves during sleep Time Frame: 1 Night	Reduction of homeostatic synaptic plasticity during the time of sleep	1 Night

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Salvatore Galati

Investigators

Principal Investigator: Salvatore Galati, MD, Ospedale Regionale di Lugano

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2013

Primary Completion (Actual)

June 1, 2015

Study Completion (Actual)