Sleep dysfunction and EEG alterations in mice overexpressing alpha-synuclein.

BackgroundSleep disruptions occur early and frequently in Parkinson's disease (PD). PD patients also show a slowing of resting state activity. Alpha-synuclein is causally linked to PD and accumulates in sleep-related brain regions. While sleep problems occur in over 75% of PD patients and severely impact the quality of life of patients and caregivers, their study is limited by a paucity of adequate animal models.ObjectiveThe objective of this study was to determine whether overexpression of wildtype alpha-synuclein could lead to alterations in sleep patterns reminiscent of those observed in PD by measuring sleep/wake activity with rigorous quantitative methods in a well-characterized genetic mouse model.MethodsAt 10 months of age, mice expressing human wildtype alpha-synuclein under the Thy-1 promoter (Thy1-aSyn) and wildtype littermates underwent the subcutaneous implantation of a telemetry device (Data Sciences International) for the recording of electromyograms (EMG) and electroencephalograms (EEG) in freely moving animals. Surgeries and data collection were performed without knowledge of mouse genotype.ResultsThy1-aSyn mice showed increased non-rapid eye movement sleep during their quiescent phase, increased active wake during their active phase, and decreased rapid eye movement sleep over a 24-h period, as well as a shift in the density of their EEG power spectra toward lower frequencies with a significant decrease in gamma power during wakefulness.ConclusionsAlpha-synuclein overexpression in mice produces sleep disruptions and altered oscillatory EEG activity reminiscent of PD, and this model provides a novel platform to assess mechanisms and therapeutic strategies for sleep dysfunction in PD

Technology in Parkinson's disease:challenges and opportunities

The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society

Placebo analgesia persists during sleep : an experimental study

Although placebo analgesia is a well-recognized phenomenon with important clinical implications, the possibility that placebo effects occur during sleep has received little attention. This experimental study examined whether responsiveness to acute heat pain stimuli applied during sleep could be reduced following a placebo conditioning procedure administered before sleep. Healthy individuals (n = 9) underwent polysomnographic recordings for one habituation night followed by one placebo analgesia night and one control night in counterbalanced order. Conditioning induced robust analgesia expectations before the placebo night. In the morning after the placebo night, participants reported less nocturnal pain, anxiety, and associated sleep disturbance (all p's < 0.05) compared to the control night. Furthermore, placebo induction produced a 10% reduction in brain arousals evoked by noxious stimuli during rapid-eye-movement (REM) sleep (p = 0.03), consistent with our previous findings suggesting that analgesia expectations are reprocessed during REM sleep. In contrast, arousals increased by 14% during slow wave sleep (SWS) (p = 0.02). In the morning after the last recording night, placebo testing administered as a manipulation check confirmed that typical placebo analgesic responses were produced during waking (p's < 0.05). These results suggest that analgesia expectations developed before sleep reduced nocturnal pain perception and subjective sleep disturbances and activated brain processes that modulate incoming nociceptive signals differentially according to sleep stage. These results need to be replicated in future studies exploring how analgesia expectations may be reactivated during different sleep stages to modulate nociceptive responses

Cognitive Impairment and Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a frequent sleep disorder characterized by repetitive interruption of ventilation caused by partial or complete collapse of the upper airway during sleep. OSA is highly prevalent in the world and it has been associated with cardiovascular disease and cognitive impairment in children and adults. The cognitive impairment in individuals with OSA includes deficiencies in attention and constructional abilities, delayed long-term visual and verbal memory, and executive functions. Although, the pathogenesis of cognitive impairment in patients with OSA is complex and remains incompletely understood, several mechanisms, such as hypoxia, inflammation and sleep fragmentation have been proposed. The aim of this chapter is to describe some findings reported in the literature to explain the association between OSA and cognitive impairment

"A great perturbation in nature" : Parkinson's disease and sleep disorders

The diagnosis of Parkinson's disease has remained essentially a clinical one. The diagnostic criteria consist of cardinal motor symptoms and signs, such as bradykinesia and at least one of the following: rest tremor, muscular rigidity or postural instability. However, non-motor symptoms (i.e. cognition, mood, sleep, pain, dysautonomy) constitute a major clinical challenge. The total burden of non-motor symptoms is likely to be more important than the motor symptoms in determining the quality of life across all stages of the disease. The current study aims to evaluate, by means of a structured questionnaire approach, the occurrence of sleep disorders, sleeping difficulties, health-related quality of life and other comorbidities in a non-selected population of Finnish Parkinson patients. The response rate was 59% (N=854). The occurrence of rapid eye movement sleep behavior disorder was 39.0%, restless legs syndrome 20.3%, chronic insomnia disorder 36.9%, narcolepsy like symptoms 11.0%, sleep disordered breathing 22.1%, respectively. Low quality of life occurred in 45.0% of the participants, depression in 20.9%, excessive daytime sleepiness in 30.2%, fatigue in 43.9%.Parkinsonin tauti luetaan kuuluvaksi liikehäiriösairaudeksi. Tautidiagnostiikassa muita Parkinsonin tautiin liittyviä oireita ei oteta huomioon. Myös jatkossa ne voivat jäädä pienelle huomiolle. Muita oireita on koetettu luokitella jaotuksella kognition, mielialatekijöiden ja ahdistuksen, unen, kivun, fatiikin ja autonomisen hermoston oireisiin. Käsillä olevassa tutkimuksessa keskitytään Parkinsonin tautiin liittyviin unihäiriöihin. Niiden käytännön merkitystä potilaalle selvitettiin kysymällä potilaiden unihäiröiden vaikutusta koettuun elämän laatuun. Vuonna 2011 Suomen Parkinson Liiton jäsenille postitettiin kohdistettu kysely univaikeuksista. Kyselyn kohortti oli 1447 henkilöä, joista osallistui 854 henkilöä. Vastattujen lomakkeiden määrä oli riittävän suuri tilastollisesti merkitsevien johtopäätösten esittämiseen. Suomalaisessa unihäiriöiden esiintyvyys kyselytutkimuksessa olivat behavioraalinen unioireyhtymä esiintyi 39.0% kyselyyn vastanneista. Vastaavasti kroonista unettomuutta oli 36.9%, päiväaikaista väsymystä 30.6%, levottomat jalat oireyhtymää 20.3%, mahdollista uniapneaa 22.1% ja narkolepsian kaltaisia oireita 11.0%. Masennusta esiintyi 20.9%:lla, koettua huonoa elämänlaatua 45.0%:lla, fatiikkia 43.9%:lla ja liiallista päiväaikaista väsymystä 30.2%:lla vastanneista

The Objective Measurement of Sleep-Wake Disturbance in Parkinson's Disease

Parkinson’s disease (PD) is an increasingly prevalent neurodegenerative disease affecting older adults. Motor symptoms, including tremor, rigidity and tremor were classically predominant. However, troublesome non-motor symptomatology are known to impair quality of life for patients with PD and there carers. Sleep-wake disturbances are gaining attention in PD encompassing disturbances of the circadian, homeostatic and ultradian sleep systems. These symptoms have been linked to the troublesome problems of cognitive deficits, mood disturbance and visual hallucinations. Mechanisms exploring the interaction of sleep-wake disturbance and other non-motor symptoms in PD are not well understood. Bidirectional causality between sleep-wake disturbance and concomitant symptoms in PD provide insights into common chemical and neural mechanisms which prior to the development of therapy, must be understood. Furthermore, sleep-wake disorders in PD at present provide a maker of early diagnosis for which future disease modifying treatment can be targeted. However objective and reliable measurement techniques are yet to be devised in this field. This thesis aims to utilise the objective measurement of sleep-wake disturbances across the circadian, homeostatic and ultradian sleep systems in PD through four empiric experiments to help inform our understanding of these critical symptoms. While the usefulness of self-report data is not doubted as a means of engaging the patient and hearing their voice they cannot serve the same identification and measurement uses of objective data. Given our ageing population, the need for diagnostic, predictive and sensitive monitoring biomarkers in Parkinson’s disease has never been greater. Objective, accurate and reliable measurement techniques, as demonstrated in this thesis, underpins further research in this field

Autonomic Nervous System and Rem Behavior Sleep Disorder: a new tool to identify Idiopathic or Parkinsonians patients through Heart Rate Variability Polysomnography Analysis

Objective: RBD is a sleep disorder known to be associated in a very high percentage of cases with alfa-synucleopathies. During rapid eye movement (REM) sleep, the cardiovascular system is unstable and greatly influenced by sympathetic activity. Heart Rate Variability (HRV) indirectly tests functions and activities of the ANS during sleep. We evaluate whether HRV and Hypnogram Indices are polysomnographic valid biomarkers to distinguish subjects with idiopathic RBD from those with Parkinson's Disease. METHODS: Our study examines HRV linear and non-linear indices of 37 patients aged 53 years and older (median 72.7; mean 72.3 ± 7.4; range 53-84), 7 women (18.9%) and 30 men (81.1%). 22 pts were idiopathic REM sleep behavior disorder (59.5%; age: median 72.5; mean 74.5 ± 5.2; range 68 83), of which 3 women (13.6%) and 19 men (86.4%); 15 pts had REM Sleep Behavior Disorder secondary to Parkinson's disease (40.5%; a ge: median 73; mean 69.5 ± 9 ; range 53 84), including 4 women (26.7%) and 11 men (73.3%). A parallel Analysis was made on Hypnogram Parameters. RESULTS: The REM sleep phase allowed to record the greatest number of significant differences in HRV Index between the two groups of patients. Among the Frequency HRV Linear Indices, VLF signal band recorded the highest number of significant results suggesting that the sympathetic component may be the one most compromised in the autonomic neurodegeneration process of RBD. HRV Complexity Non-Linear Indices (LZC and KC) have the highest number of statistically significant results so that could be the right parameter to use to distinguish our two RBD populations. Hypnogram Indices Analysis showed no significant value for not even a parameter. CONCLUSIONS: HRV can be a valid biomarker to distinguish the two populations of patients affected by RBD, both idiopathic and affected by Parkinson's disease. It could represent a new and easy tool to identify, among the REM Behavior Sleep Disorder, patients affected or not by Parkinson’s desease or could be even useful when an early diagnosis is needed or it is necessary monitoring a probable conversion from idiopathic form to PD or evaluate the effectiveness of RBD therapies

IMAGING SPECIFIC ABSORPTION RATE WITH MR THERMOMETRY USING PARAMAGNETIC LANTHANIDE COMPLEXES AND IN VIVO GABA MR SPECTROSCOPY IN MOVEMENT DISORDERS

Magnetic Resonance Imaging (MRI) is a popular imaging modality due to its ability to provide excellent soft tissue contrast without exposure to ionizing radiation. It can be used for temperature monitoring (thermometry) as well as for assessing the biochemistry in vivo (MRS). This dissertation focuses separately on the development, application and quantitation issues of these two aspects of MRI