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OBJECTIVES To assess the efficacy and safety of sildenafil citrate (Viagra) in men with erectile dysfunction and parkinsonism due either to Parkinson's disease or multiple system atrophy. METHODS Twenty four patients with erectile disease were recruited, 12 with Parkinson's disease and 12 with multiple system atrophy, into a randomised, double blind, placebo controlled, crossover study of sildenafil citrate. The starting dose was 50 mg active or placebo medication with the opportunity for dose adjustment depending on efficacy and tolerability. The international index of erectile function questionnaire (IIEF) was used to assess treatment efficacy and a quality of life questionnaire to assess the effect of treatment on sex life and whole life. Criteria for entry included a definite neurological diagnosis and a standing systolic blood pressure of 90–180 mm Hg and diastolic blood pressure of 50–110 mm Hg, on treatment if necessary. Blood pressure was taken at randomisation (visit 2) and crossover (visit 5) lying, sitting, and standing, before and 1 hour after taking the study medication in hospital. RESULTS Sidenafil citrate was efficacious in men with parkinsonism with a significant improvement, as demonstrated in questionnaire responses, in ability to achieve and maintain an erection and improvement in quality of sex life. In Parkinson's disease there was minimal change in blood pressure between active and placebo medication. In multiple system atrophy, six patients were studied before recruitment was stopped because three men showed a severe drop in blood pressure 1 hour after taking the active medication. Two were already known to have orthostatic hypotension and were receiving treatment with ephedrine and midodrine but the third had asymptomatic hypotension. However, the blood pressures in all three had been within the inclusion criterion for the study protocol. Despite a significant postural fall in blood pressure after sildenafil, all patients with multiple system atrophy reported a good erectile response and were reluctant to discontinue the medication. CONCLUSIONS Sidenafil citrate (50 mg) is efficacious in the treatment of erectile dysfunction in parkinsonism due to Parkinson's disease or multiple system atrophy; however, it may unmask or exacerbate hypotension in multiple system atrophy. As Parkinson's disease may be diagnostically difficult to distinguish from multiple system atrophy, especially in the early stages, we recommend measurement of lying and standing blood pressure before prescribing sildenafil to men with parkinsonism. Furthermore, such patients should be made aware of seeking medical advice if they develop symptoms on treatment suggestive of orthostatic hypotension.

BackgroundParkinsonian syndromes are characterized by a wide spectrum of non-motor symptoms. A few studies explored cognitive deficits and neuropsychiatric symptoms in atypical parkinsonism compared to Parkinson’s disease (PD). The study was performed to identify cognitive and neuropsychiatric differences between PD, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and to evaluate the influence of clinical features, depressive symptomatology and apathy on cognitive performances in the three groups.MethodsFifty-five PD, 44 MSA and 42 PSP patients underwent cognitive tests assessing attention, language, memory, visuospatial and executive functions as well as scales assessing depression and apathy. Out of these patients, 20 PD, 20 MSA and 20 PSP patients were selected to be matched for age, education and global cognitive status. Within each whole patients group, correlational analysis was performed between clinical, behavioural and cognitive parameters.ResultsThe main difference among the groups matched was on cognitive tests exploring verbal learning, executive and linguistic functions. The PSP group was more impaired than the PD and MSA groups on cognitive tests assessing executive functions. On the other hand, MSA group obtained similar cognitive performance to the PD group. As to behavioural symptoms, in whole PSP and MSA groups, apathy and depression were more severe than in PD group, while apathy (but not depression) were more severe in the PSP group as compared to the MSA group.ConclusionsThe present study underlined the pervasiveness of cognitive deficits, apathy and depressive symptoms in PSP, whereas little cognitive differences were found between PD and MSA. The findings indirectly supported a dysfunction of prefronto-subcortical circuitries (i.e., dorsolateral prefrontal and limbic circuits) in PSP and PD. Cognitive similarities between MSA and PD reinforced the pivotal role of altered basal ganglia and corresponding frontal deafferentation in the occurrence of the cognitive deficits.

Many efforts have been tried to evaluate multiple system atrophy (MSA)-related cognitive impairment, however, there is still lacking of effective approach. In this study, for the first time, we developed the individual metabolic radiomics networks (IMRN) using [18F]FDG PET imaging to investigate brain metabolic connectivity patterns of MSA and validated the usefulness of IMRN-based predictive model for MSA-related cognitive impairment. In this retrospective study, we recruited 115 MSA patients with [18F]FDG PET/CT scans. IMRN was constructed by extracting non-redundant radiomics features from each brain region and computing pairwise Pearson correlation coefficients among these features. The validation of IMRN included assessments of small-world properties, test-retest reliability, and metabolic-genetic correlations. Connectome-based predictive modeling (CPM) was implemented to predict Mini Mental State Examination (MMSE) scores, while network-based statistics (NBS) were compared between MSA patients with cognitive impairment (MSA-CI, n = 58; MMSE < 27) and those with normal cognition (MSA-NC, n = 57; MMSE ≥ 27). A support vector machine (SVM) classifier for detecting MSA-CI was developed using discriminative IMRN edges. IMRN showed small-world properties (σ > 1), high reliability (average edge ICC = 0.754), and a significant correlation with gene expression (r = 0.44, P < 0.001). CPM significantly predicted cognitive scores through IMRN edges (positive network: r = 0.27, P = 0.03; negative network: r = 0.28, P = 0.02). NBS revealed decreased cerebellar-cortical connectivity (73 edges) and increased intra-cerebellar/limbic connectivity (24 edges) in MSA-CI compared to MSA-NC. The IMRN-based SVM outperformed SUVR-based SVM in classifying MSA-CI (accuracy: 73.91% vs 62.61%; AUC: 0.80 vs 0.69). This study established a novel approach of IMRN for assessing whole brain metabolic connectivity, uncovering distinct cerebellar connectivity patterns in MSA-CI, which held promise for facilitating personalized cognitive evaluations in MSA.

Background The prognostic impact of dysphagia in multiple system atrophy (MSA) remains controversial. This study aimed to investigate the relationship between dysphagia severity and survival in MSA and to elucidate whether this impact differs between MSA-cerebellar ataxia (MSA-C) and MSA-parkinsonism (MSA-P). Methods This retrospective study included 297 patients with MSA: 251 met criteria for clinically established MSA and 46 for clinically probable MSA. Among them, 171 had MSA-C and 126 had MSA-P. We evaluated symptomatic dysphagia within 3 years of onset and quantified dysphagia severity using the Hyodo score (0 to 12) through fibreoptic endoscopic evaluation of swallowing (FEES) and clinical features, including autonomic dysfunction and vocal cord paralysis. Patients were followed up until death or tracheostomy, and survival factors were analysed using the log-rank test and multivariate Cox proportional hazards model. Results Ninety patients developed symptomatic dysphagia within 3 years of onset, and 75 were evaluated for dysphagia severity using FEES. Survival from onset was shorter in patients with dysphagia within 3 years compared to those without (median: 4.2 years vs. 7.3 years; p  < 0.001). Symptomatic dysphagia within 3 years of onset was an independent predictor of shorter survival in the multivariate Cox analysis. While the Hyodo score was higher in MSA-P than in MSA-C patients ( p  = 0.048), the Hyodo score was associated with survival in both MSA-C and MSA-P patients (log-rank p  < 0.001 and p  = 0.046, respectively). Conclusion Symptomatic dysphagia within 3 years of onset predicts shorter survival in MSA-C and MSA-P patients.

Background Early severe autonomic failure (AF) in multiple system atrophy (MSA) is a risk factor for poor survival. Postmortem studies suggested that AF is related to the degeneration of preganglionic autonomic neurons of the brainstem and spinal cord. Objectives Characterize cerebral alterations on brain imaging associated with cardiovascular AF. Methods Cardiovascular sympathetic failure was evaluated through orthostatic hypotension (OH) based on changes in systolic and diastolic blood pressure during tilt‐test (ΔSBP and ΔDBP). Reduced heart rate (HR) variability reflecting cardio‐vagal impairment was assessed with a composite score formed by the root‐mean square differences of successive R‐R intervals (RMSSD) and HR changes during deep breathing. Voxel‐based morphometry (SPM12), volumetry, and cortical thickness measurements (FreeSurfer 7.0) of T1‐weighted anatomical images were used to assess gray matter (GM) atrophy in sub‐tentorial structures. Multivariate analysis included age, disease severity (UMSARS), and total intracranial volume as confounding factors. Results A total of 62 MSA patients followed at the French Reference Center were retrospectively included, aged 67.3 ± 8.6 years, 69.4% MSA‐P, disease duration 4.2 ± 2.1 years. Medulla atrophy was correlated to OH (p < 0.006). Decrease in GM volume in the left anterior cerebellum (lobule V) was correlated to ΔDBP (pFWEc = 0.017). GM loss in the left interposed nucleus was correlated to ΔSBP (p < 0.003), whereas atrophy of the right dentate was associated with decreased HR variability (p < 0.003). Conclusion Medulla volume was strongly correlated with OH. Cerebellar degeneration was associated with the severity of cardiovascular AF.

Background The progression of sleep disturbances remains unclear in patients with early multiple system atrophy (MSA). We aimed to explore the frequency, severity, and coexistence of 2-year longitudinal changes of sleep disturbances including REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and Parkinson’s disease-related sleep problems (PD-SP) in early MSA. Methods MSA patients with a disease duration < 3 years were enrolled to complete a 2-year follow-up visit. Sleep disturbances including RBD, EDS, and PD-SP were assessed using the RBD Screening Questionnaire, Epworth sleepiness scale, and PD sleep scale-2, respectively. Results A total of 220 patients with MSA enrolled in the study and 90 patients completed the 2-year follow-up visit. The score of all three sleep disturbances significantly increased over the 2-year follow-up in MSA and MSA with the predominant parkinsonism group (all p  < 0.05). The frequency of PD-SP (from 14.5 to 26.7%) and EDS (from 17.7 to 37.8%) was progressively increased (all p  < 0.05) except for RBD (from 51.8 to 65.6%, p  = 0.152) over the 2-year follow-up in MSA. The frequency of coexistence of two or three sleep disturbances also increased over time. The most common sleep disturbance was RBD, followed by EDS and PD-SP over the 2-year follow-up. Conclusions The present study demonstrated that the frequency of different types of sleep disturbances progressively increased except for RBD and the coexistence of two or three sleep disturbances became more common over time in early MSA. Our study suggested that the assessment and management of sleep disturbances should begin early in MSA.

In this multiparametric, cross-sectional study, we aimed to investigate cognitive impairment and brain structural changes in patients with multiple system atrophy (MSA)-parkinsonian variant (MSA-p). Twenty-six MSA-p patients and 19 controls underwent clinical and neuropsychological evaluation and 1.5 T brain MRI scan. Cortical thickness measures and volumes of deep grey matter structures were obtained. A regression analysis correlated MRI metrics with clinical features in MSA-p patients. Almost 46% of MSA-p patients showed a mild cognitive impairment involving mainly attentive–executive and memory domains. Apathy and depression were found in half of MSA-p patients. MSA-p patients showed significant cortical thinning of fronto-temporal–parietal regions and atrophy of periaqueductal grey matter, left cerebellar hemisphere, left pallidum and bilateral putamen, compared to controls. Cortical thinning in temporal regions correlated with global cognitive status and memory impairment. Grey matter cerebellar atrophy correlated with motor deficits. MSA-p patients showed a multidomain cognitive impairment with a prominent cortical damage in anterior more than posterior brain regions and grey matter volume reduction in subcortical structures. Cortical and subcortical structural changes might lead to cognitive dysfunction in MSA-p.

Abstract We aimed to determine patterns of α-synuclein (α-syn) pathology in multiple system atrophy (MSA) using 70-µm-thick sections of 20 regions of the central nervous system of 37 cases with striato-nigral degeneration (SND) and 10 cases with olivo-ponto-cerebellar atrophy (OPCA). In SND cases with the shortest disease duration (phase 1), α-syn pathology was observed in striatum, lentiform nucleus, substantia nigra, brainstem white matter tracts, cerebellar subcortical white matter as well as motor cortex, midfrontal cortex, and sensory cortex. SND with increasing duration of disease (phase 2) was characterized by involvement of spinal cord and thalamus, while phase 3 was characterized by involvement of hippocampus and amygdala. Cases with the longest disease duration (phase 4) showed involvement of the visual cortex. We observed an increasing overlap of α-syn pathology with increasing duration of disease between SND and OPCA, and noted increasingly similar regional distribution patterns of α-syn pathology. The GBA variant, p.Thr408Met, was found to have an allele frequency of 6.94% in SND cases which was significantly higher compared with normal (0%) and other neurodegenerative disease pathologies (0.74%), suggesting that it is associated with MSA. Our findings indicate that SND and OPCA show distinct early foci of α-syn aggregations, but increasingly converge with longer disease duration to show overlapping patterns of α-syn pathology.

Background and objectives Patients with synucleinopathies such as multiple system atrophy (MSA) and Parkinson’s disease (PD) frequently display speech and language abnormalities. We explore the diagnostic potential of automated linguistic analysis of natural spontaneous speech to differentiate MSA and PD. Methods Spontaneous speech of 39 participants with MSA compared to 39 drug-naive PD and 39 healthy controls matched for age and sex was transcribed and linguistically annotated using automatic speech recognition and natural language processing. A quantitative analysis was performed using 6 lexical and syntactic and 2 acoustic features. Results were compared with human-controlled analysis to assess the robustness of the approach. Diagnostic accuracy was evaluated using sensitivity analysis. Results Despite similar disease duration, linguistic abnormalities were generally more severe in MSA than in PD, leading to high diagnostic accuracy with an area under the curve of 0.81. Compared to controls, MSA showed decreased grammatical component usage, more repetitive phrases, shorter sentences, reduced sentence development, slower articulation rate, and increased duration of pauses, whereas PD had only shorter sentences, reduced sentence development, and longer pauses. Only slower articulation rate was distinctive for MSA while unchanged for PD relative to controls. The highest correlation was found between bulbar/pseudobulbar clinical score and sentence length ( r = −0.49, p = 0.002). Despite the relatively high severity of dysarthria in MSA, a strong agreement between manually and automatically computed results was achieved. Discussion Automated linguistic analysis may offer an objective, cost-effective, and widely applicable biomarker to differentiate synucleinopathies with similar clinical manifestations.

Abstract Study Objectives Patients with Parkinson’s disease and multiple system atrophy may be subject to sleep state dissociation. Motivated by the fortuitous observation of prominent facial muscle activity during video-polysomnography in patients with multiple system atrophy, we assessed facial motor activity and chin muscle tone during sleep in multiple system atrophy compared to Parkinson’s disease and controls. Methods A sleep expert blinded to pathology and sleep stage retrospectively analyzed facial activity in 62 video-polysomnography (11 multiple system atrophy, 38 Parkinson’s disease, and 13 controls). Facial movements were classified into six categories: “Eyes closing/opening,” “Eyebrows frowning,” “Raising eyebrows,” “Smiling,” “Other mouth movements,” and “Strained face,” an expression involving both the superior and inferior parts of the face. Chin electromyography activity was quantified during Rapid Eye Movement (REM) and Non-Rapid Eye Movement (NREM) sleep using the atonia index, a validated algorithm. Results Multiple system atrophy patients had an increased number of all facial movements compared to controls during NREM. “Strained face” was significantly more frequent in multiple system atrophy compared to Parkinson’s disease, even after adjusting for the presence of REM sleep behavior disorder (RBD). Atonia index was lower in multiple system atrophy compared to controls and Parkinson’s disease during REM and NREM sleep. This difference remained significant compared to Parkinson’s disease in NREM sleep during N1 and N2 after adjusting for the presence of RBD. Conclusions Facial movements during sleep are frequent in multiple system atrophy, “strained face” appears to be a hallmark of this condition. The presence of increased facial activity and elevated muscle tone during all stages of sleep in multiple system atrophy may be a manifestation of sleep state dissociation, reflecting more severe neurodegeneration. Graphical Abstract