SEMIAUTOMATIC ANALYSIS OF SLEEP MICROSTRUCTURE PARAMETERS: AROUSAL, CYCLIC ALTERNATING PATTERN AND REM MUSCLE ATONIA.

This thesis project is focused on systems of automatic analysis of sleep parameters and it is composed by two main parts: the first is focused on the process of creation of a software for the analysis of Cyclic Alternating Pattern (CAP) a particular parameter of sleep microstructure and the second part is focused on the use of automatic analysis of muscle activity during sleep. CAP is defined as periodic EEG activity of NREM sleep characterized by sequences of transient electrocortical events, that are distinct from the background electroencephalogram (EEG) activity and occurs at up to 1-minute intervals. CAP represents the microstructure of sleep, and its analysis gives fundamental information that are otherwise neglected with the analysis of sleep macrostructure (sleep staging) alone. CAP is considered a marker for the evaluation of sleep stability and its oscillatory presence is fundamental preservation of sleep stability through the night and in response to arousal stimuli. Analysis of CAP is a very time consuming procedure and it is still used mainly for research purpose rather than in the clinical practice. The development of a software for the analysis of CAP was the main focus of the work in collaboration with Micromed® (an international company for the manufacturing of hardware and software for neurophysiology based in Mogliano Veneto (TV)). During the months spent at Micromed® the PhD student worked with the software programmers and engineers for the creation and validation of the software, individuating all the clinical parameters from guidelines and verifying their correct application and the validity of the results. In the first part of this thesis all the creation process is described in detail. The second part of this thesis is focused on the automatic analysis of muscle EMG tone during both REM and NREM sleep. Muscle tone during sleep gradually diminishes throughout the different sleep stages reaching its minimum with REM muscle atonia. Evaluation of muscle tone during REM sleep is fundamental for the diagnosis of REM sleep Behavior Disorder (RBD) in which there is loss of muscle atonia during REM associated to dream enacting behavior. Muscle activity is measured in polysomnography (PSG) through the recording of different EMG channels. This activity is evaluated almost exclusively during REM sleep using a manual method of visual scoring that require high expertise is highly time consuming. A validated method developed by R. Ferri and co. allows automatic analysis of chin EMG activity through the calculation of Atonia index. Few studies evaluated muscle tone during NREM sleep, and little is known about the neurophysiology of muscle control. Manual methods would be difficult to apply to NREM sleep; the method developed by Ferri is capable to perform an analysis of muscle tone for all sleep stages. RBD is associated to neurodegenerative disorders, synucleinopathies such as Parkinson disease (PD), Multiple System Atrophy (MSA). MSA patients have a more severe loss of atonia during REM sleep compared to PD with RBD. Starting from the fortuitous observation of a prominent facial activity during NREM sleep, we decided to evaluate the facial activity recorded in vPSG in patients with PD, MSA and controls and to evaluate the muscle tone in both REM and NREM sleep using the automatic method for the calculation of atonia index. Our results showed that MSA have a more sustained muscle tone compared to healthy controls in all sleep stages and compared to PD in all NREM stages. Moreover a particular facial expression was noted to be significantly more frequent in MSA compared to PD. This results may help the differential diagnosis between PD and MSA. This is the first study to evaluate muscle tone during all sleep stages using Atonia index and this analysis may open to different perspectives for the understanding of REM behavior disorder and the mechanism underlying the control of muscle tone in NREM slee

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial

Background: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer’s disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. Methods: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. Discussion: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer’s disease

Disorders of Sleep and Motor Control During the Impaired Cholinergic Innervation in Rat – Relevance to Parkinson’s Disease

The medical profession has been generally very slow to acknowledge the importance of sleep medicine and sleep research. Disorders of sleep are related to anxiety, many mental and neurodegenerative diseases, cardiovascular and respiratory disorders, and obesity

Neurophysiological basis of rapid eye movement sleep behavior disorder:Informing future drug development

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by a history of recurrent nocturnal dream enactment behavior and loss of skeletal muscle atonia and increased phasic muscle activity during REM sleep: REM sleep without atonia. RBD and associated comorbidities have recently been identified as one of the most specific and potentially sensitive risk factors for later development of any of the alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and other atypical parkinsonian syndromes. Several other sleep-related abnormalities have recently been identified in patients with RBD/Parkinson’s disease who experience abnormalities in sleep electroencephalographic frequencies, sleep–wake transitions, wake and sleep stability, occurrence and morphology of sleep spindles, and electrooculography measures. These findings suggest a gradual involvement of the brainstem and other structures, which is in line with the gradual involvement known in these disorders. We propose that these findings may help identify biomarkers of individuals at high risk of subsequent conversion to parkinsonism

Considering REM Sleep Behavior Disorder in the Management of Parkinson's Disease

Rapid eye movement (REM) sleep behavior disorder (RBD) is the result of the loss of physiological inhibition of muscle tone during REM sleep, characterized by dream-enacting behavior and widely recognized as a prodromal manifestation of alpha-synucleinopathies. Indeed, patients with isolated RBD (iRBD) have an extremely high estimated risk to develop a neurodegenerative disease after a long follow up. Nevertheless, in comparison with PD patients without RBD (PDnoRBD), the occurrence of RBD in the context of PD (PDRBD) seems to identify a unique, more malignant phenotype, characterized by a more severe burden of disease in terms of both motor and non-motor symptoms and increased risk for cognitive decline. However, while some medications (eg, melatonin, clonazepam, etc.) and non-pharmacological options have been found to have some therapeutic benefits on RBD there is no available treatment able to modify the disease course or, at least, slow down the neurodegenerative process underlying phenoconversion. In this scenario, the long prodromal phase may allow an early therapeutic window and, therefore, the identification of multimodal biomarkers of disease onset and progression is becoming increasingly crucial. To date, several clinical (motor, cognitive, olfactory, visual, and autonomic features) neurophysiological, neuroimaging, biological (biofluids or tissue biopsy), and genetic biomarkers have been identified and proposed, also in combination, as possible diagnostic or prognostic markers, along with a potential role for some of them as outcome measures and index of treatment response. In this review, we provide an insight into the present knowledge on both existing and future biomarkers of iRBD and highlight the difference with PDRBD and PDnoRBD, including currently available treatment options

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Peer reviewedPostprin

The deubiquitylase TRABID coordinates sex-specific neurodegeneration in drosophila melanogaster

Ubiquitin-related post translation modification (PTM) plays an important role in cellular signalling. TRABID is a deubiquitylase that preferentially hydrolyses Lys29 and 33 ubiquitin chains and is known to affect inflammation and consequently, neurodegeneration as the latter is considered functionally linked to the former. However, sex differences are widely observed in both inflammation as well as neurodegeneration phenotypes. In this study, I investigated sex dimorphism, in ubiquitination at the intersection of inflammation and neurodegeneration. I demonstrated Drosophila TRABID has similar enzymatic activity as human TRABID and generated an enzymatically inactive TRABID (trbdC518A) in Drosophila flies. I discovered that trbdC518A has a sexually dimorphic impact in the insect’s locomotor activity, sleep pattern, lifespan, cerebral cells count, brain volume and NF-κB signalling. When blocking female development in astrocytes or immunocompetent cells, sex dimorphisms in locomotor activity and NF-κB signalling are partially eliminated. Further evidence ubiquitinomics and proteomics of fly heads, provided insight into the sex-specific impact of trbdC518A