Serum miR-96-5P and miR-339-5P Are Potential Biomarkers for Multiple System Atrophy and Parkinson's Disease

Parkinson's disease (PD) and Multiple System Atrophy (MSA) are progressive neurodegenerative diseases with overlap of symptoms in early stages of disease. No reliable biomarker exists and the diagnosis is mainly based on clinical features. Several studies suggest that miRNAs are involved in PD and MSA pathogenesis. Our goal was to study two serum circulating microRNAs (miR-96-5p and miR-339-5p) as novel biomarkers for the differential diagnosis between PD and MSA. Serum samples were obtained from 51 PD patients, 52 MSA patients and 56 healthy controls (HC). We measured levels of miRNAs using quantitative PCR and compared the levels of miR-96-5p and miR-339-5p among PD, MSA and HC groups using a one-way analysis of variance. Correlations between miRNA expression and clinical data were calculated using Pearson's rho test. We used the miRTarBase to detect miRNA targets and STRING to evaluate co-expression relationship among target genes. MiR-96-5p was significantly increased in MSA patients compared with HC (Fold change (fc): 3.6; p = 0.0001) while it was decreased in PD patients compared with HC (Fold change: 4; p = 0.0002). Higher miR-96-5P levels were directly related to longer disease duration in MSA patients. We observed a significant increase of miR-339-5p in MSA patients compared with PD patients (fc: 2.5; p = 0.00013). miR-339-5p was increased in MSA patients compared with HC (fc: 2.4; p = 0.002). We identified 32 target genes of miR-96-5p and miR-339-5p, some of which are involved in neurodegenerative diseases. The study of those miRNAs could be useful to identify non-invasive biomarkers for early differential diagnosis between PD and MSA

Brain Communications

Brain charts for the human lifespan have been recently proposed to build dynamic models of brain anatomy in normal aging and various neurological conditions. They offer new possibilities to quantify neuroanatomical changes from preclinical stages to death, where longitudinal MRI data are not available. In this study, we used brain charts to model the progression of brain atrophy in progressive supranuclear palsy – Richardson syndrome (PSPRS). We combined multiple datasets (n=8170 quality controlled MRI of healthy subjects from 22 cohorts covering the entire lifespan, and n=62 MRI of PSP-RS patients from the 4 Repeat Tauopathy Neuroimaging Initiative) to extrapolate lifetime volumetric models of healthy and PSP-RS brain structures. We then mapped in time and space the sequential divergence between healthy and PSP-RS charts. We found six major consecutive stages of atrophy progression: (i) ventral diencephalon (including subthalamic nuclei, substantia nigra, and red nuclei), (ii) pallidum, (iii) brainstem, striatum and amygdala, (iv) thalamus, (v) frontal lobe and (vi) occipital lobe. The three structures with most severe atrophy over time were the thalamus, followed by the pallidum and the brainstem. These results match the neuropathological staging of tauopathy progression in PSP-RS, where the pathology is supposed to start in the pallido-nigro-luysian system and spreads rostrally via the striatum and the amygdala to the cerebral cortex, and caudally to the brainstem. This study supports the use of brain charts for the human lifespan to study the progression of neurodegenerative diseases, especially in the absence of specific biomarkers as in PSP.Apprentissage profond pour la volumétrie cérébrale : vers le BigData en neuroscienceInitiative d'excellence de l'Université de Bordeau

Falls in ambulatory non-demented patients with Parkinson's disease

This study aimed at determining the prevalence of falling in PD patients, to assess generic and disease-specific clinical and pharmacological factors, relationship with health-related quality of life (HR-QoL) and changes in falls from OFF to ON in patients with motor fluctuations. Six-hundred and eighty-three PD patients of the COPARK survey were evaluated (11 had missing data and were excluded from the analysis). Patients with falls were identified as those with a UPDRS Item 13 ¡Ý 1 in the ON condition. All patients were assessed in a standardized manner [demographics, treatments, Unified PD Rating Scale (UPDRS), Hospital Anxiety and Depression Scale, Pittsburg questionnaire and HR-QoL scales (SF36, PDQ39)]. Falling was reported by 108/672 (16 %) PD patients during the ON state and prevalence increased according to PD severity, from 5 % in Hoehn and Yahr stage 1-60 % in stage 4. Falling was significantly related to lower HR-QoL. Falling correlated with (1) generic factors such as female gender, age at the end of academic studies and diuretics consumption, (2) motor PD-specific factors including disease severity, frozen gait, difficulties when arising from a chair, dyskinesia and higher levodopa daily equivalent dose and (3) non-motor PD-specific factors such as orthostatic hypotension and hallucinations. Falling was more frequent in OFF than in ON in 48/74 (64 %) patients with motor fluctuations and remained unchanged in 27 patients (36 %). In summary, falling affected a significant proportion of PD patients, especially in advanced stages. It was associated with a variety of generic and PD-specific factors and was related to reduced HR-QoL.Fil: Rascol, Olivier. NS-Park Network; Francia. Université Paul Sabatier; Francia. Inserm; FranciaFil: Pérez Lloret, Santiago. Université Paul Sabatier; Francia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Damier, Philippe. Hôpital Laënnec; Francia. NS-Park Network; Francia. Inserm; FranciaFil: Delval, Arnaud. Seul Centre Hospitalier Universitaire; FranciaFil: Derkinderen, Pascal. Hôpital Laënnec; FranciaFil: Destée, Alain. NS-Park Network; Francia. Inserm; Francia. Seul Centre Hospitalier Universitaire; FranciaFil: Meissner, Wassilios G.. Universite de Bordeaux; Francia. Institut des Maladies Neurodégénératives; Francia. Centre Hospitalier Universitaire de Bordeaux; FranciaFil: Tison, Francois. Universite de Bordeaux; Francia. Centre Hospitalier Universitaire de Bordeaux; Francia. Institut des Maladies Neurodégénératives; Francia. NS-Park Network; FranciaFil: Negre Pages, Laurence. Inserm; Francia. NS-Park Network; Franci

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation

Patient-perceived progression in multiple system atrophy: natural history of quality of life

Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improving patient care, and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients, and identify informative items using a four-step statistical strategy.We leveraged the data of the French MSA cohort comprising annual assessments with the MSA-QoL questionnaire for more than 500 patients over up to 11 years. The four-step strategy (1) determined the subdimensions of Hr-QoL in MSA; (2) modelled the subdimension trajectories over time, accounting for the risk of death; (3) mapped the sequence of item impairments with disease stages; and (4) identified the most informative items specific to each disease stage.Among the 536 patients included, 50% were women and they were aged on average 65.1 years old at entry. Among them, 63.1% died during the follow-up. Four dimensions were identified. In addition to the original motor, nonmotor, and emotional domains, an oropharyngeal component was highlighted. While the motor and oropharyngeal domains deteriorated rapidly, the nonmotor and emotional aspects were already slightly to moderately impaired at cohort entry and deteriorated slowly over the course of the disease. Impairments were associated with sex, diagnosis subtype, and delay since symptom onset. Except for the emotional domain, each dimension was driven by key identified items.Hr-QoL is a multidimensional concept that deteriorates progressively over the course of MSA and brings essential knowledge for improving patient care. As exemplified with MSA, the thorough description of Hr-QoL using the 4-step original analysis can provide new perspectives on neurodegenerative diseases' management to ultimately deliver better support focused on the patient's perspective

Study protocol: Care of Late-Stage Parkinsonism (CLaSP): a longitudinal cohort study

Background: Parkinson's disease (PD) is a chronic progressive disorder leading to increasing disability. While the symptoms and needs of patients in the early stages of their disease are well characterized, little information is available on patients in the late stage of the disease.Methods/designThe Care of Late-Stage Parkinsonism (CLaSP) study is a longitudinal, multicenter, prospective cohort study to assess the needs and provision of care for patients with late stage Parkinsonism and their carers in six European countries (UK, France, Germany, Netherlands, Portugal, Sweden). In addition, it will compare the effectiveness of different health and social care systems. Patients with Parkinsonism with Hoehn and Yahr stage IV in the On-state or Schwab and England stage 50% or less are evaluated at baseline and three follow-up time-points. Standardised questionnaires and tests are applied for detailed clinical, neuropsychological, behavioural and health-economic assessments. A qualitative study explores the health care needs and experiences of patients and carers, and an interventional sub-study evaluates the impact of specialist recommendations on theiroutcomes.Discussion: Through the combined assessment of a range of quantitative measures and qualitative assessments of patients with late stage parkinsonism, this study will provide for the first timecomprehensive and in-depth information on the clinical presentation, needs and health care provision in this population in Europe, and lay the foundation for improved outcomes in these patients.Trial registrationThe protocol was registered at ClinicalTrials.gov as NCT02333175 on 07/01/2015

Alterations in electrochemical skin conductance as a marker of autonomic dysfunction in multiple system atrophy

BACKGROUND: Multiple System Atrophy (MSA) is a rare neurodegenerative disease with pronounced autonomic failure (AF). Severe cardiovascular AF is associated with poor prognosis. Since sweating dysfunction is less well known, we investigated the interest of a quick and non-invasive assessment of sweating using electrochemical skin conductance (ESC) as a marker for AF in MSA. METHODS: 138 MSA patients of the French Reference center for MSA with an annual follow-up including the Unified MSA Rating Scale (UMSARS), COMPASS (autonomic symptoms) and measurements of foot and hand ESC (Sudoscan®) participated to this study (age 65 ± 8 years, 66% probable MSA, 72% AMS-P). Statistical analysis included: (i) correlations between ESC and MSA type, age, disease duration, severity, blood pressure (BP), COMPASS, (ii) comparisons between groups with normal or abnormal ESC, and (iii) multivariate analysis by logistic regression. Relationships between severity progression during follow-up with ESC and other variables were modeled by Generalized Estimating Equation. RESULTS: Hands and feet ESCs were abnormal in 81/138 (59%) and 93/138 (67%) cases, respectively. Abnormal ESCs were significantly correlated to disease severity and several features of AF. ESCs worsening over time was more pronounced than other autonomic features such as orthostatic hypotension. Abnormal ESCs at baseline were significantly associated with a higher progression of UMSARS's score during follow-up. CONCLUSION: Sweating dysfunction assessed by ESC is frequent in MSA and is significantly related to disease severity and AF. The gradual decrease in ESC with disease duration could be useful as a quantitative marker of autonomic dysfunction

A comparative study on vowel articulation in Parkinson's disease and multiple system atrophy

International audienceAcoustic realisation of the working vowel space has been widely studied in Parkinson's disease (PD). However, it has never been studied in atypical parkinsonian disorders (APD). The latter are neurodegenerative diseases which share similar clinical features with PD, rendering the differential diagnosis very challenging in early disease stages. This paper presents the first contribution in vowel space analysis in APD, by comparing corner vowel realisation in PD and the parkinsonian variant of Multiple System Atrophy (MSA-P). Our study has the particularity of focusing exclusively on early stage PD and MSA-P patients, as our main purpose was early differential diagnosis between these two diseases. We analysed the corner vowels, extracted from a spoken sentence, using traditional vowel space metrics. We found no statistical difference between the PD group and healthy controls (HC) while MSA-P exhibited significant differences with the PD and HC groups. We also found that some metrics conveyed complementary discriminative information. Consequently, we argue that restriction in the acoustic realisation of corner vowels cannot be a viable early marker of PD, as hypothesised by some studies, but it might be a candidate as an early hypokinetic marker of MSA-P (when the clinical target is discrimination between PD and MSA-P)

New insights into orthostatic hypotension in multiple system atrophy: a European multicentre cohort study

Objectives: Orthostatic hypotension (OH) is a key feature of multiple system atrophy (MSA), a fatal progressive neurodegenerative disorder associated with autonomic failure, parkinsonism and ataxia. This study aims (1) to determine the clinical spectrum of OH in a large European cohort of patients with MSA and (2) to investigate whether a prolonged postural challenge increases the sensitivity to detect OH in MSA. Methods: Assessment of OH during a 10 min orthostatic test in 349 patients with MSA from seven centres of the European MSA-Study Group (age: 63.6±8.8 years; disease duration: 4.2±2.6 years). Assessment of a possible relationship between OH and MSA subtype (P with predominant parkinsonism or C with predominant cerebellar ataxia), Unified MSA Rating Scale (UMSARS) scores and drug intake. Results: 187 patients (54%) had moderate (>20 mm Hg (systolic blood pressure (SBP)) and/or >10 mm Hg (diastolic blood pressure (DBP)) or severe OH (>30 mm Hg (SBP) and/or >15 mm Hg (DBP)) within 3 min and 250 patients (72%) within 10 min. OH magnitude was significantly associated with disease severity (UMSARS I, II and IV), orthostatic symptoms (UMSARS I) and supine hypertension. OH severity was not associated with MSA subtype. Drug intake did not differ according to OH magnitude except for antihypertensive drugs being less frequently, and antihypotensive drugs more frequently, prescribed in severe OH. Conclusions: This is the largest study of OH in patients with MSA. Our data suggest that the sensitivity to pick up OH increases substantially by a prolonged 10 min orthostatic challenge. These results will help to improve OH management and the design of future clinical trials.Fil: Pavy Le Traon, Anne. University Hospital of Toulouse; Francia. Inserm; FranciaFil: Piedvache, A.. Université Paul Sabatier; FranciaFil: Pérez Lloret, Santiago. University Hospital of Toulouse; Francia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Calandra Buonara, G.. Università di Bologna; Italia. Istituto delle Scienze Neurologiche di Bologna; ItaliaFil: Cochen De Cock, V.. University Hospital of Toulouse; Francia. University of Montpellier; FranciaFil: Colosimo, C.. Sapienza Università di Roma; ItaliaFil: Cortelli, P.. Università di Bologna; Italia. Istituto delle Scienze Neurologiche di Bologna; ItaliaFil: Debs, R.. University Hospital of Toulouse; FranciaFil: Duerr, S.. Universidad de Innsbruck; AustriaFil: Fanciulli, A.. Universidad de Innsbruck; AustriaFil: Foubert Samier, A.. Centre Hospitalier Universitaire de Bordeaux; Francia. Universite de Bordeaux; FranciaFil: Gerdelat, Angela. University Hospital of Toulouse; FranciaFil: Gurevich, T.. Tel-Aviv University; IsraelFil: Krismer, F.. Universidad de Innsbruck; AustriaFil: Poewe, W.. Universidad de Innsbruck; AustriaFil: Tison, Francois. Universite de Bordeaux; Francia. Centre Hospitalier Universitaire de Bordeaux; FranciaFil: Tranchant, C.. University Hospital Hautepierre; FranciaFil: Wenning, G.. Universidad de Innsbruck; AustriaFil: Meissner, Wassilios G.. Universite de Bordeaux; Francia. Centre Hospitalier Universitaire de Bordeaux; FranciaFil: Rascol, Olivier. University Hospital of Toulouse; Franci