Pochi studi hanno indagato il profilo dei sintomi non-motori nella malattia di Parkinson associata al gene glucocerebrosidasi (GBA). Questo studio è mirato alla caratterizzazione dei sintomi non-motori, con particolare attenzione alla valutazione delle funzioni neurovegetativa, cognitiva e comportamentale, nel parkinsonismo associato a mutazione del gene GBA con la finalità di verificare se tali sintomi non-motori siano parte dello spettro clinico di questi pazienti. E’ stato condotto su una coorte di pazienti affetti da malattia di Parkinson che erano stati tutti sottoposti ad una analisi genetica per la ricerca di mutazioni in uno dei geni finora associati alla malattia di Parkinson. All’interno di questa coorte omogenea sono stati identificati due gruppi diversi in relazione al genotipo (pazienti portatori della mutazione GBA e pazienti non portatori di nessuna mutazione) e le caratteristiche non-motorie sono state confrontate nei due gruppi. Sono state pertanto indagati il sistema nervoso autonomo, mediante studio dei riflessi cardiovascolari e analisi dei sintomi disautonomici, e le funzioni cognitivo-comportamentali in pazienti affetti da malattia di Parkinson associata a mutazione del gene GBA. I risultati sono stati messi a confronto con il gruppo di controllo. Lo studio ha mostrato che i pazienti affetti da malattia di Parkinson associata a mutazione del gene GBA presentavano maggiore frequenza di disfunzioni ortosimpatiche, depressione, ansia, apatia, impulsività, oltre che di disturbi del controllo degli impulsi rispetto ai pazienti non portatori. In conclusione, i pazienti GBA positivi possono esprimere una sintomatologia non-motoria multidominio con sintomi autonomici, cognitivi e comportamentali in primo piano. Pertanto l’impostazione terapeutica in questi pazienti dovrebbe includere una accurata valutazione dei sintomi non-motori e un loro monitoraggio nel follow up clinico, allo scopo di ottimizzare i risultati e ridurre i rischi di complicazioni. / Few studies have investigated the non-motor symptoms profile in Parkinson disease (PD) associated with the glucocerebrosidase gene (GBA). This study is aimed at characterizing non-motor features, with particular attention to the evaluation of autonomic, cognitive and behavioral functions, in PD associated with mutations in the GBA gene with the aim to verify if these symptoms are part of the clinical spectrum of these patients. A study has been conducted on a cohort of patients with PD who had all been subjected to genetic analysis for the detection of mutations in one of the genes so far associated with PD. Within this homogeneous cohort, two different groups were identified in relation to the genotype (patients carriers of GBA mutation and patients noncarriers of genes associated with PD) and the non-motor characteristics were compared in the two groups. We have therefore investigated the autonomic nervous system, through the study of cardiovascular reflexes and analysis of autonomic symptoms, and cognitive-behavioral functions in patients with PD associated with mutations in the GBA gene. The results were compared with the control group. The study showed that patients with PD associated with mutations in the GBA gene had higher frequency of sympathetic dysfunction, depression, anxiety, apathy, impulsivity, as well as disorders of impulse control compared to noncarriers patients. In conclusion, patients GBA positive can manifest a multidomain non-motor symptom profile with autonomic, cognitive and behavioral symptoms. Therefore, the therapeutic approach in these patients should include a thorough assessment of non-motor symptoms and their monitoring in the follow-up, in order to optimize the results and reduce the risk of complications.

Nocturnal Frontal Lobe Epilepsy (NFLE) is characterized by onset during infancy or childhood with persistence in adulthood, family history of similar nocturnal episodes simulating non-REM parasomnias (sleep terrors or sleepwalking), general absence of morphological substrates, often by normal interictal electroencephalographical recordings (EEGs) during wakefulness. A family history of epilepsy may be present with Mendelian autosomal dominant inheritance has been described in some families. Recent studies indicate the involvement of neuronal nicotinic acetylcholine receptors (nAChRs) in the molecular mechanisms of NFLE. Mutations in the genes encoding for the α4 (CHRNA4) and ß2 (CHRNB2) subunits of the nAChR induce changes in the biophysical properties of nAChR, resulting generally in a “gain of function”. Preclinical studies report that activation of a nuclear receptor called type peroxisome proliferator-activated receptor (PPAR-α) by endogenous molecules or by medications (e.g. fenofibrate) reduces the activity of the nAChR and, therefore, may decrease the frequency of seizures. Thus, we hypothesize that negative modulation of nAChRs might represent a therapeutic strategy to be explored for pharmacological treatment of this form of epilepsy, which only partially responds to conventional antiepileptic drugs. In fact, carbamazepine, the current medication for NFLE, abolishes the seizures only in one third of the patients. The aim of the project is: 1)_to verify the clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant NFLE and ADNFLE patients; focousing on the analysis of the polysomnographic action of the PPAR- agonist (fenofibrate). 2)_to demonstrate the subtended mechanism of efficacy by means of electrophysiological and behavioral experiments in an animal model of the disease: particularly, transgenic mice carrying the mutation in the nAChR 4 subunit (Chrna4S252F) homologous to that found in the humans. Given that a PPAR-α agonist, FENOFIBRATE, already clinically utilized for lipid metabolism disorders, provides a promising therapeutic avenue in the treatment of NFLE\ADNFLE.

Aim: To assess if the intake of levodopa in patients with Parkinson’s Disease (PD) changes cerebral connectivity, as revealed by simultaneous recording of hemodynamic (functional MRI, or fMRI) and electric (electroencephalogram, EEG) signals. Particularly, we hypothesize that the strongest changes in FC will involve the motor network, which is the most impaired in PD. Methods: Eight patients with diagnosis of PD “probable”, therapy with levodopa exclusively, normal cognitive and affective status, were included. Exclusion criteria were: moderate-severe rest tremor, levodopa induced dyskinesia, evidence of gray or white matter abnormalities on structural MRI. Scalp EEG (64 channels) were acquired inside the scanner (1.5 Tesla) before and after the intake of levodopa. fMRI functional connectivity was computed from four regions of interest: right and left supplementary motor area (SMA) and right and left precentral gyrus (primary motor cortex). Weighted partial directed coherence (w-PDC) was computed in the inverse space after the removal of EEG gradient and cardioballistic artifacts. Results and discussion: fMRI group analysis shows that the intake of levodopa increases hemodynamic functional connectivity among the SMAs / primary motor cortex and: sensory-motor network itself, attention network and default mode network. w-PDC analysis shows that EEG connectivity among regions of the motor network has the tendency to decrease after the intake the levodopa; furthermore, regions belonging to the DMN have the tendency to increase their outflow toward the rest of the brain. These findings, even if in a small sample of patients, suggest that other resting state physiological functional networks, beyond the motor one, are affected in patients with PD. The behavioral and cognitive tasks corresponding to the affected networks could benefit from the intake of levodopa.

Aims of the study: To assess the prevalence of Antiepileptic Drug (AED) exposure in pregnant women with or without epilepsy and the comparative risk of terminations of pregnancy (TOPs), spontaneous abortions, stillbirth, major congenital malformations (MCMs) and foetal growth retardation (FGR) following intrauterine AED exposure in the Emilia Romagna region (RER), Northern Italy (4 million inhabitants). Methods: Data were obtained from official regional registries: Certificate of Delivery Assistance, Hospital Discharge Card, reimbursed prescription databases and Registry of Congenital Malformations. We identified all the deliveries, hospitalized abortions and MCMs occurred between January 2009 and December 2011. Results: We identified 145,243 pregnancies: 111,284 deliveries (112,845 live births and 279 stillbirths), 16408 spontaneous abortions and 17551 TOPs. Six hundred and eleven pregnancies (0.42% 95% Cl: 0.39-0.46) were exposed to AEDs. Twenty-one per cent of pregnancies ended in TOP in the AED group vs 12% in the non-exposed (OR:2.24; CI 1.41-3.56). The rate of spontaneous abortions and stillbirth was comparable in the two groups. Three hundred fifty-three babies (0.31%, 95% CI: 0.28-0.35) were exposed to AEDs during the first trimester. The rate of MCMs was 2.3% in the AED group (2.2% in babies exposed to monotherapy and 3.1% in babies exposed to polytherapy) vs 2.0% in the non-exposed. The risk of FGR was 12.7 % in the exposed group compared to 10% in the non-exposed. Discussion and Conclusion: The prevalence of AED exposure in pregnancy in the RER was 0.42%. The rate of MCMs in children exposed to AEDs in utero was almost superimposable to the one of the non-exposed, however polytherapy carried a slightly increased risk . The rate of TOPs was significantly higher in the exposed women. Further studies are needed to clarify whether this high rate reflects a higher rate of MCMs detected prenatally or other more elusive reasons.

Background. MicroRNAs (miRNAs) are small non-coding RNAs of 20-22 nucleotides, involved in transcriptional and post-transcriptional regulation of gene expression and involved in Parkinson’s disease. Objective. Identification of a suitable gene set to use as normalizers in expression analysis in PBMCs PD study. Assessment of the potential role as PD biomarker of miR-29a-3p, miR-29b-3p, miR-30a-5p, miR-30b-5p, and miR-103a-3p in PBMCs and plasma samples from L-dopa treated PD and drug-naïve PD patients. MiRNAs discovering through deep sequencing analysis and creation of in silico miRNAs target prediction. Methods. Plasma and PBMCs miRNAs from L-dopa treated PD, drug-naïve PD patients, and controls were analyzed (qRT-PCR), data normalized using RNU24/Z30 for PBMCs, and synthetic spike-in for plasma. Statistical significance of miRNA expression differences calculated by computing a two-tailed paired t-test. Illumina MiSeq NGS platform analysis was performed. MiRNA resources were combined to detect putative miRNA targets. Results. RNU24/Z30 as reliable normalizer for expression analysis in PBMCs PD study were identified. An over-expression of miR-103a-3p, miR-29a-3p and miR-30b-5p in PBMCs PD samples were found. Over-expression trend of miR-30a-5p in plasma PD samples and over-expression trend of miR-30b-5p in plasma drug-naїve PD samples were detected. NGS analysis data were not sufficient to generate meaningful biological results. A sophisticated in silico target prediction model were elaborated. Discussion. We showed for the first time an over-expression of miR-103a-3p in PD patients and replicated a documented deregulation in PD, albeit opposite to published data, of miR-29a-3p and miR-30b-5p. The trend of higher expression of miR-30b-5p in plasma drug-naïve PD samples suggested an involvement of the treatment in the plasma miRNA expression. The in silico analysis identified putative candidate target genes, including genes related to neurodegeneration and PD, such as LRRK2 for miR-30b-5p and miR-103a-3p, PARK7/DJ-1 for miR-29a-3p, Bcl-2 as common target for all miRNAs.

Huntington’s disease (HD) is a progressive, fatal, neurodegenerative disorder caused by an abnormal expansion of a CAG repeat sequence in the gene encoding the protein huntingtin (HTT) on chromosome 4. Clinical features of HD include progressive motor dysfunction, cognitive decline, and psychiatric disturbance. Sleep disturbances are frequent in HD patients. However, sleep alterations as well as their association with other symptoms and signs of the disease have not been systematically studied in large groups of HD patients.The aim of the study was to objectively evaluate sleep features in a large, single-center, population of HD patients by means of nocturnal, laboratory based video-polysomnography (V-PSG), and to correlate PSG findings with clinical parameters;evaluate subjective sleep-related symptoms by subjective sleep evaluation and compare the results with those obtained with the gold standard diagnostic tool, namely V-PSG;finally, evaluate the EEG modifications in HD patients during the sleep-wake cycle, by means of the exact LOw REsolution Tomography (eLORETA) software.The results suggest that sleep is severely disrupted in HD patients.Taken together,our data may suggest that the caudate degenerative process observed in HD account for the increased arousability, increased motor activity during wake and sleep (originating periodic limb movements), reduction of REM sleep and, overall, a general sleep disruption.As concerns the subjective sleep evaluation, our data suggest, overall, that the subjective evaluation of sleep in HD patients shows a poor correlation with PSG results. Our EEG data suggest a defined pattern of motor cortex dysfunction during wake and sleep, which correlates with the clinical and polysomnographic evidence of increased motor activity during wake and NREM, and nearly absent motor abnormalities in REM. It could be hypothesized that EEG modifications reflect motor cortex impairment or, conversely, an effort to counterbalance abnormal motor output.

In questo studio è con un grande campione di pazienti con emorragia cerebrale (111 soggetti) in cui è stata verificata una aumentata prevalenza di sospetto disturbo respiratorio del sonno valutat tramite la scala Berlin Questionnaire rispetto ad altrettanti con ischemia cerebrale (111 soggetti) e altrettanti controlli (n111). La metodica di appaiamento per variabili quali età, sesso, BMI e CCI ha permesso di escludere una eventuale influenza da parte di queste variabili. Dallo studio di variabili di outcome funzionale è risultata significativa la correlazione tra positività per disturbo respiratorio del sonno e un peggior outcome funzionale sia in termini di disabilità (mRS ≥ 3) che di mortalità (mRS =6) nei pazienti con BQ positivo, sia ischemici che emorragici. A riprova di questo ruolo prognosticamente negativo della sospetta OSAS nei pazienti con emorragia cerebrale anche un aumento della durata globale del ricovero in giorni dei pazienti nel gruppo dei positivi. Nel tentativo di esplorare il legame tra disturbi respiratori del sonno ed emorragia cerebrale sono state valutate le neuroimmagini e le caratteristiche di ipertensione arteriosa. E’ stato così riscontrato un tasso complessivo di peggioramento delle lesioni al controllo a 10 giorni circa, aumentato significativamente nei pazienti BQ positivi, con associata inoltre una tendenza all’aumento dell’edema perilesionale. L’ipotesi più probabile rimane comunque che il meccanismo principale con cui il disturbo respiratorio del sonno influisce sull’insorgenza e il peggioramento dell’emorragia cerebrale sia legato all’ipertensione arteriosa. Tale legame, facilmente intuibile considerate le discrete conoscenze sui tre fenomeni, è stato qui dimostrato tramite il riscontro di un tasso notevolmente e significativamente aumentato di ipertensione arteriosa, di profilo pressorio notturno alterato con prevalenza di pazienti non dipper e di aumentata pressione arteriosa farmaco resistente nei pazienti emorragici BQ positivi. / Background: Obstructive sleep apnea (OSA) is currently undertaken to impair ischemic stroke risk especially by intracranial pressure, blood flow, glucose metabolism, atherogenesis, blood coagulation, cardiac arrhythmia and arterial hypertension. In OSA patients hypertension is often related to drug resistance and modification in nocturnal blood pressure profile. In stroke patients with OSA has been observed an impairment of functional outcome. About OSA and intra cranial haemorrhage (ICH) few data are available in literature and most of them are anecdotal. We can speculate that OSA can affect on ICH by arterial hypertension. Methods: in this study we sought to test whether suspected OSA is more prevalent in ICH group than in control. In order to limit potential confounding variables associated with acute ICH, we tested by Berlin Questionnaire (BQ) and Epworth Sleepiness Scale (ESS) referring to the previous 3 months before ICH. Secondarily, we tried to assess if OSA in ICH could affect on functional outcome (mRS) like disability or mortality, as described in ischemic stroke. For these purposes we recruited 111 ICH patients matched by sex, age, Body Mass Index (BMI) and Charlson Comorbidity Index (CCI) with 111 ischemic stroke patients and 111 controls. Results: In ICH patients we found BQ positivity in 30,6% vs 25,2% in ischemic stroke patients vs 13,5% in controls (p 0.01). Moreover BQ positive ICH patients had more disability, mortality, length of recovery, arterial hypertension, drug resistance hypertension and nocturnal blood pressure profile alteration, especially non dipper pattern, than BQ negative ICH. Conclusion: The results suggest that OSA can be considered a risk factor and a negative prognostic factor in ICH patients, as described before in ischemic stroke patients. Moreover we can considered this fenomena probably related to blood pressure alteration caused by sleep breathing disorder.

Background: cognitive impairment is one of the non motor features widely descripted in parkinsonian syndrome, it has been related to the motor characteristics of the parkinsonian syndrome, associated with neuropsychiatric dysfunction and the characteristic sleep and autonomic features. It has been shown to be highly prevalent at all disease stages and to contribute significantly to disability. Objectives: aim of this study is to evaluate longitudinally the cognitive and behavioral characteristics of patients with a parkinsonian syndrome at onset; to describe the cognitive and behavioral characteristics of each parkinsonian syndrome; to define in PD patients at onset the presence of MCI or Parkinson disease dementia; to correlate the cognitive and behavioral characteristics with the features of the parkinsonian syndrome and with the associated sleep and autonomic features. Results: we recruited 55 patients, 22 did not present cognitive impairment both at T0 and at T1. 18 patients presented a progression of cognitive impairment. Progressive cognitively impaired patients were older and presented the worst motor phenotype. Progression of cognitive impairment was not associated to sleep and autonomic features. Conclusion: the evaluation of cognitive impairment could not be useful as a predictor of a correct diagnosis but each non motor domain will help to clarify and characterize the motor syndrome. The diagnosis of parkinsonian disorders lies in building a clinical profile in conjunction with other clinical characteristics such as mode of presentation, disease progression, response to medications, sleep and autonomic features.

The arousal scoring in Obstructive Sleep Apnea Syndrome (OSAS) is important to clarify the impact of the disease on sleep but the currently applied American Academy of Sleep Medicine (AASM) definition may underestimate the subtle alterations of sleep. The aims of the present study were to evaluate the impact of respiratory events on cortical and autonomic arousal response and to quantify the additional value of cyclic alternating pattern (CAP) and pulse wave amplitude (PWA) for a more accurate detection of respiratory events and sleep alterations in OSAS patients. A retrospective revision of 19 polysomnographic recordings of OSAS patients was carried out. Analysis was focused on quantification of apneas (AP), hypopneas (H) and flow limitation (FL) events, and on investigation of cerebral and autonomic activity. Only 41.1% of FL events analyzed in non rapid eye movement met the AASM rules for the definition of respiratory event-related arousal (RERA), while 75.5% of FL events ended with a CAP A phase. The dual response (EEG-PWA) was the most frequent response for all subtypes of respiratory event with a progressive reduction from AP to H and FL. 87.7% of respiratory events with EEG activation showed also a PWA drop and 53,4% of the respiratory events without EEG activation presented a PWA drop. The relationship between the respiratory events and the arousal response is more complex than that suggested by the international classification. In the estimation of the response to respiratory events, the CAP scoring and PWA analysis can offer more extensive information compared to the AASM rules. Our data confirm also that the application of PWA scoring improves the detection of respiratory events and could reduce the underestimation of OSAS severity compared to AASM arousal.

No description available.