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Gregor K Wenning - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of epigallocatechin gallate in Multiple System Atrophy promesa a randomised double blind placebo controlled trial
Lancet Neurology, 2019Co-Authors: Johannes Levin, Sylvia Maas, Madeleine Schuberth, Armin Giese, Claudia Trenkwalder, Wolfgang H Oertel, Gregor K WenningAbstract:Summary Background Multiple System Atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with Multiple System Atrophy. Methods We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable Multiple System Atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov ( NCT02008721 ) and EudraCT (2012-000928-18), and is completed. Findings Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned—47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference −0·94 [SE 1·41; 95% CI −3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. Interpretation 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with Multiple System Atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. Funding ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Luneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.
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recommendations of the global Multiple System Atrophy research roadmap meeting
Neurology, 2018Co-Authors: Ryan R Walsh, Gregor K Wenning, Phillip A Low, Florian Krismer, Wendy R Galpern, Glenda M Halliday, Walter J Koroshetz, Janice L HoltonAbstract:Multiple System Atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided.
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efficacy of rasagiline in patients with the parkinsonian variant of Multiple System Atrophy a randomised placebo controlled trial
Lancet Neurology, 2015Co-Authors: Werner Poewe, Gregor K Wenning, Klaus Seppi, Sid Gilman, Cheryl Fitzerattas, Nir Giladi, Paolo Barone, C Sampaio, Eli Eyal, Olivier RascolAbstract:Summary Background Multiple System Atrophy is a complex neurodegenerative disorder for which no effective treatment exists. We aimed to assess the effect of rasagiline on symptoms and progression of the parkinsonian variant of Multiple System Atrophy. Methods We did this randomised, double-blind, placebo-controlled trial between Dec 15, 2009, and Oct 20, 2011, at 40 academic sites specialised in the care of patients with Multiple Systemic Atrophy across 12 countries. Eligible participants aged 30 years or older with possible or probable parkinsonian variant Multiple System Atrophy were randomly assigned (1:1), via computer-generated block randomisation (block size of four), to receive either rasagiline 1 mg per day or placebo. Randomisation was stratified by study centre. The investigators, study funder, and personnel involved in patient assessment, monitoring, analysis and data management were masked to group assignment. The primary endpoint was change from baseline to study end in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (parts I and II). Analysis was by modified intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00977665. Findings We randomly assigned 174 participants to the rasagiline group (n=84) or the placebo group (n=90); 21 (25%) patients in the rasagiline group and 15 (17%) in the placebo group withdrew from the study early. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7·2 (SE 1·2) total UMSARS units versus 7·8 (1·1) units in those in the placebo group. This treatment difference of −0·60 (95% CI −3·68 to 2·47; p=0·70) was not significant. 68 (81%) patients in the rasagiline group and 67 (74%) patients in the placebo group reported adverse events, and we recorded serious adverse events in 29 (35%) versus 23 (26%) patients. The most common adverse events in the rasagiline group were dizziness (n=10 [12%]), peripheral oedema (n=9 [11%]), urinary tract infections (n=9 [11%]), and orthostatic hypotension (n=8 [10%]). Interpretation In this population of patients with the parkinsonian variant of Multiple System Atrophy, treatment with rasagiline 1 mg per day did not show a significant benefit as assessed by UMSARS. The study confirms the sensitivity of clinical outcomes for Multiple System Atrophy to detect clinically significant decline, even in individuals with early disease. Funding Teva Pharmaceutical Industries and H Lundbeck A/S.
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Multiple System Atrophy
CNS Drugs, 2014Co-Authors: Gregor K Wenning, Carlo Colosimo, Felix Geser, Werner PoeweAbstract:Multiple System Atrophy (MSA) is a sporadic neurodegenerative disorder characterized clinically by various combinations of parkinsonian, autonomic, cerebellar, or pyramidal symptoms and signs and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in several brain and spinal cord structures. The term MSA was introduced in 1969, however cases of MSA were previously reported under the rubrics of striatonigral degeneration, olivopontocerebellar Atrophy, Shy-Drager syndrome and idiopathic orthostatic hypotension. In the late 1990s, α-synuclein immunostaining was recognized as most sensitive marker of inclusion pathology in MSA: because of these advances in molecular pathogenesis, MSA has been firmly established as α-synucleinopathy along with Parkinson’s disease (PD) and dementia with Lewy bodies. Recent epidemiological surveys have shown that MSA is not a rare disorder (∼5 cases per 100,000 population), and that misdiagnosis, especially with PD, is still common due to variable clinical presentations of MSA. However, the clinical picture of MSA in its full-blown form is distinctive. The patient is hypomimic with orofacial and anterior neck dystonia resulting in a grinning smile akin to “risus sardonicus” and sometimes disproportionate antecollis. The voice is often markedly impaired with a characteristic quivering high-pitched dysarthria. The motor disorder of MSA is often mixed with parkinsonism, cerebellar ataxia, limb dystonia, myoclonus, and pyramidal features occurring at the same time. However, akinesia and rigidity are the predominating features in 80% of patients, and cerebellar ataxia within the remaining 20%. According to the predominant motor presentation, MSA patients may be labeled as parkinsonian or cerebellar variant (MSA-P, MSA-C). The diagnosis of MSA is largely based on clinical expertise, and this is well illustrated by the consensus diagnostic criteria, which comprise clinical features only (divided into four domains including autonomic dysfunction, parkinsonism, cerebellar dysfunction, and corticospinal tract dysfunction). Nevertheless, several autonomic function, imaging, neurophysiological, and biochemical studies have been proposed in the last decade to help in the differential diagnosis of MSA. No drug treatment consistently benefits patients with this disease. Indeed, parkinsonism often shows a poor or unsustained response to chronic levodopa therapy, however, one-third of the patients may show a moderate-to-good dopaminergic response initially. There is no effective drug treatment for cerebellar ataxia. On the other hand, features of autonomic failure such as orthostatic hypotension, urinary retention or incontinence, constipation, and impotence, may often be relieved if recognized by the treating physician. Novel symptomatic and neuroprotective therapies are urgently required.
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premotor signs and symptoms of Multiple System Atrophy
Lancet Neurology, 2012Co-Authors: Milica Jecmenicalukic, Werner Poewe, Eduardo Tolosa, Gregor K WenningAbstract:Diagnostic criteria for Multiple System Atrophy are focused on motor manifestations of the disease, in particular ataxia and parkinsonism, but these criteria often cannot detect the early stages. Non-motor symptoms and signs of Multiple System Atrophy often precede the onset of classic motor manifestations, and this prodromal phase is estimated to last from several months to years. Autonomic failure, sleep problems, and respiratory disturbances are well known symptoms of established Multiple System Atrophy and, when presenting early and preceding ataxia or parkinsonism, should be regarded as evidence of premotor Multiple System Atrophy. An early and accurate diagnosis is becoming increasingly important as new neuroprotective agents are developed.
Phillip A Low - One of the best experts on this subject based on the ideXlab platform.
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recommendations of the global Multiple System Atrophy research roadmap meeting
Neurology, 2018Co-Authors: Ryan R Walsh, Gregor K Wenning, Phillip A Low, Florian Krismer, Wendy R Galpern, Glenda M Halliday, Walter J Koroshetz, Janice L HoltonAbstract:Multiple System Atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided.
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expanding the spectrum of neuronal pathology in Multiple System Atrophy
Brain, 2015Co-Authors: Matthew D Cykowski, Ann M Schmeichel, Eduardo E. Benarroch, Elizabeth A Coon, Suzanne Zeineldin Powell, Sarah M Jenkins, Phillip A Low, Joseph E. ParisiAbstract:Multiple System Atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, Multiple System Atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with Multiple System Atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in Multiple System Atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with Multiple System Atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of Multiple System Atrophy.
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natural history of Multiple System Atrophy in the usa a prospective cohort study
Lancet Neurology, 2015Co-Authors: Phillip A Low, Sid Gilman, Matthew B Stern, Peter Novak, Stephen G Reich, Joseph Jankovic, Clifford W Shults, Caroline M Tanner, Frederick J Marshall, Frederick WootenAbstract:Summary Background Multiple System Atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of Multiple System Atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. Methods We recruited participants with probable Multiple System Atrophy—of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)—at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. Findings We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8–10·7) and median survival from enrolment was 1·8 years (0·9–2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5–9·5 vs 10·3 years, 9·3–11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. Interpretation Probable Multiple System Atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. Funding US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.
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prevalence of rem sleep behavior disorder in Multiple System Atrophy a multicenter study and meta analysis
Clinical Autonomic Research, 2015Co-Authors: Josealberto Palma, Elizabeth A Coon, Phillip A Low, Clara Fernandezcordon, Mitchell G Miglis, Safwan Jaradeh, Arijit K Bhaumik, Praveen Dayalu, Elena Urrestarazu, J IriarteAbstract:Objective Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia frequently affecting patients with synucleinopathies, but its exact prevalence in Multiple System Atrophy (MSA) is unclear. Whether questionnaires alone are sufficient to diagnose RBD is also unknown.
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efficacy and safety of rifampicin for Multiple System Atrophy a randomised double blind placebo controlled trial
Lancet Neurology, 2014Co-Authors: Phillip A Low, Sid Gilman, Wolfgang Singer, David Robertson, Horacio Kaufmann, Italo Biaggioni, Roy Freeman, Susan Perlman, Robert A Hauser, William P CheshireAbstract:Summary Background No available treatments slow or halt progression of Multiple System Atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of Multiple System Atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with Multiple System Atrophy. Methods In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30–80 years with possible or probable Multiple System Atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. Findings Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0·62 points [SD 0·85] per month in the rifampicin group vs 0·47 points [0·48] per month in the placebo group; futility p=0·032; efficacy p=0·76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0·5 points (SD 0·7) per month for rifampicin and 0·5 points (0·5) per month for placebo (difference 0·0, 95% CI −0·24 to 0·24; p=0·82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. Interpretation Our results show that rifampicin does not slow or halt progression of Multiple System Atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with Multiple System Atrophy. Funding National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.
Sid Gilman - One of the best experts on this subject based on the ideXlab platform.
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natural history of Multiple System Atrophy in the usa a prospective cohort study
Lancet Neurology, 2015Co-Authors: Phillip A Low, Sid Gilman, Matthew B Stern, Peter Novak, Stephen G Reich, Joseph Jankovic, Clifford W Shults, Caroline M Tanner, Frederick J Marshall, Frederick WootenAbstract:Summary Background Multiple System Atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of Multiple System Atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. Methods We recruited participants with probable Multiple System Atrophy—of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)—at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. Findings We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8–10·7) and median survival from enrolment was 1·8 years (0·9–2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5–9·5 vs 10·3 years, 9·3–11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. Interpretation Probable Multiple System Atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. Funding US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.
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efficacy of rasagiline in patients with the parkinsonian variant of Multiple System Atrophy a randomised placebo controlled trial
Lancet Neurology, 2015Co-Authors: Werner Poewe, Gregor K Wenning, Klaus Seppi, Sid Gilman, Cheryl Fitzerattas, Nir Giladi, Paolo Barone, C Sampaio, Eli Eyal, Olivier RascolAbstract:Summary Background Multiple System Atrophy is a complex neurodegenerative disorder for which no effective treatment exists. We aimed to assess the effect of rasagiline on symptoms and progression of the parkinsonian variant of Multiple System Atrophy. Methods We did this randomised, double-blind, placebo-controlled trial between Dec 15, 2009, and Oct 20, 2011, at 40 academic sites specialised in the care of patients with Multiple Systemic Atrophy across 12 countries. Eligible participants aged 30 years or older with possible or probable parkinsonian variant Multiple System Atrophy were randomly assigned (1:1), via computer-generated block randomisation (block size of four), to receive either rasagiline 1 mg per day or placebo. Randomisation was stratified by study centre. The investigators, study funder, and personnel involved in patient assessment, monitoring, analysis and data management were masked to group assignment. The primary endpoint was change from baseline to study end in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (parts I and II). Analysis was by modified intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00977665. Findings We randomly assigned 174 participants to the rasagiline group (n=84) or the placebo group (n=90); 21 (25%) patients in the rasagiline group and 15 (17%) in the placebo group withdrew from the study early. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7·2 (SE 1·2) total UMSARS units versus 7·8 (1·1) units in those in the placebo group. This treatment difference of −0·60 (95% CI −3·68 to 2·47; p=0·70) was not significant. 68 (81%) patients in the rasagiline group and 67 (74%) patients in the placebo group reported adverse events, and we recorded serious adverse events in 29 (35%) versus 23 (26%) patients. The most common adverse events in the rasagiline group were dizziness (n=10 [12%]), peripheral oedema (n=9 [11%]), urinary tract infections (n=9 [11%]), and orthostatic hypotension (n=8 [10%]). Interpretation In this population of patients with the parkinsonian variant of Multiple System Atrophy, treatment with rasagiline 1 mg per day did not show a significant benefit as assessed by UMSARS. The study confirms the sensitivity of clinical outcomes for Multiple System Atrophy to detect clinically significant decline, even in individuals with early disease. Funding Teva Pharmaceutical Industries and H Lundbeck A/S.
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efficacy and safety of rifampicin for Multiple System Atrophy a randomised double blind placebo controlled trial
Lancet Neurology, 2014Co-Authors: Phillip A Low, Sid Gilman, Wolfgang Singer, David Robertson, Horacio Kaufmann, Italo Biaggioni, Roy Freeman, Susan Perlman, Robert A Hauser, William P CheshireAbstract:Summary Background No available treatments slow or halt progression of Multiple System Atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of Multiple System Atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with Multiple System Atrophy. Methods In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30–80 years with possible or probable Multiple System Atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. Findings Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0·62 points [SD 0·85] per month in the rifampicin group vs 0·47 points [0·48] per month in the placebo group; futility p=0·032; efficacy p=0·76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0·5 points (SD 0·7) per month for rifampicin and 0·5 points (0·5) per month for placebo (difference 0·0, 95% CI −0·24 to 0·24; p=0·82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. Interpretation Our results show that rifampicin does not slow or halt progression of Multiple System Atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with Multiple System Atrophy. Funding National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.
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potential outcome measures and trial design issues for Multiple System Atrophy
Movement Disorders, 2007Co-Authors: Susanne May, Sid Gilman, Brooke B Sowell, Ronald G Thomas, Matthew B Stern, Amy Colcher, C M Tanner, Neng Huang, Peter Novak, Stephen G ReichAbstract:Multiple System Atrophy (MSA) is a neurodegenerative disorder exhibiting a combination of parkinsonism, cerebellar ataxia, and autonomic failure. A disease-specific scale, the Unified Multiple System Atrophy Rating Scale (UMSARS), has been developed and validated to measure progression of MSA, but its use as an outcome measure for therapeutic trials has not been evaluated. On the basis of twelve months of follow-up from an observational study of 67 patients with probable MSA, we evaluated three disease-specific scores: Activities of Daily Living, Motor Examination, and a combined score from the UMSARS and two general health scores, the Physical Health and Mental Health scores of the SF-36 health survey, for their use as outcome measures in a therapeutic trial. We discuss related design issues and provide sample size estimates. Scores based on the disease-specific UMSARS seemed to be equal or superior to scores based on the SF-36 health survey. They appeared to capture disease progression, were well correlated and required the smallest sample size. The UMSARS Motor Examination score exhibited the most favorable characteristics as an outcome measure for a therapeutic trial in MSA with 1 year of follow-up.
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evolution of sporadic olivopontocerebellar Atrophy into Multiple System Atrophy
Neurology, 2000Co-Authors: Sid Gilman, Larry Junck, Karen J Kluin, Roderick J A Little, Jewel R Johanns, Mary Heumann, Robert A KoeppeAbstract:Objective: To determine the percentage of sporadic olivopontocerebellar Atrophy (sOPCA) patients who later develop Multiple System Atrophy (MSA). Methods: Observations of the course of 51 sOPCA patients 20 years of age or older initially evaluated in an ataxia clinic over 14 years and followed at 3- to 6-month intervals for 3 months to 10 years (median 2.5 years, interquartile range 5 months to 4 years). Results: Seventeen patients evolved to develop MSA, whereas the remaining 34 manifested only progressively worsening cerebellar ataxia. The features of the MSA cases included autonomic failure and parkinsonism in 10 patients, autonomic failure without parkinsonism in six, and parkinsonism without autonomic failure in one. Using survival analysis methods, the authors estimated that 24% of subjects in this population will evolve to MSA within 5 years of the onset of sOPCA symptoms (95% CI 10% to 36%). An older age at onset of symptoms and a shorter time from onset of symptoms to first presentation in a neurology specialty clinic were both highly predictive of evolution to MSA. Six of the 17 patients who evolved to MSA died 4 months to 5 years after they had met diagnostic criteria for MSA. The estimated median survival time from time of transition was 3.5 years. In contrast, death occurred in only one of the 34 patients with sOPCA who did not evolve to MSA. Autopsy examination of all six patients with MSA who died confirmed the diagnosis. Conclusions: Approximately one-fourth of sporadic olivopontocerebellar Atrophy patients will evolve to Multiple System Atrophy within 5 years, and this transition carries a poor prognosis for survival. Older age at onset of ataxia and earlier presentation in a neurologic specialty clinic predicted transition to MSA.
Johannes Levin - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of epigallocatechin gallate in Multiple System Atrophy promesa a randomised double blind placebo controlled trial
Lancet Neurology, 2019Co-Authors: Johannes Levin, Sylvia Maas, Madeleine Schuberth, Armin Giese, Claudia Trenkwalder, Wolfgang H Oertel, Gregor K WenningAbstract:Summary Background Multiple System Atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with Multiple System Atrophy. Methods We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable Multiple System Atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov ( NCT02008721 ) and EudraCT (2012-000928-18), and is completed. Findings Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned—47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference −0·94 [SE 1·41; 95% CI −3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. Interpretation 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with Multiple System Atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. Funding ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Luneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.
Michel Goedert - One of the best experts on this subject based on the ideXlab platform.
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Luminescent conjugated oligothiophenes distinguish between α-synuclein assemblies of Parkinson’s disease and Multiple System Atrophy
Acta Neuropathologica Communications, 2019Co-Authors: Therése Klingstedt, Helen Ling, Janice L Holton, Bernardino Ghetti, K. Peter R. Nilsson, Michel GoedertAbstract:Synucleinopathies [Parkinson’s disease with or without dementia, dementia with Lewy bodies and Multiple System Atrophy] are neurodegenerative diseases that are defined by the presence of filamentous α-synuclein inclusions. We investigated the ability of luminescent conjugated oligothiophenes to stain the inclusions of Parkinson’s disease and Multiple System Atrophy. They stained the Lewy pathology of Parkinson’s disease and the glial cytoplasmic inclusions of Multiple System Atrophy. Spectral analysis of HS-68-stained inclusions showed a red shift in Multiple System Atrophy, but the difference with Parkinson’s disease was not significant. However, when inclusions were double-labelled for HS-68 and an antibody specific for α-synuclein phosphorylated at S129, they could be distinguished based on colour shifts with blue designated for Parkinson’s disease and red for Multiple System Atrophy. The inclusions of Parkinson’s disease and Multiple System Atrophy could also be distinguished using fluorescence lifetime imaging. These findings are consistent with the presence of distinct conformers of assembled α-synuclein in Parkinson’s disease and Multiple System Atrophy.
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filamentous α synuclein inclusions link Multiple System Atrophy with parkinson s disease and dementia with lewy bodies
Neuroscience Letters, 1998Co-Authors: Maria Grazia Spillantini, Ross Jakes, R A Crowther, Nigel J Cairns, Peter L Lantos, Michel GoedertAbstract:α-Synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Here we show that α-synuclein is also the major component of the filamentous inclusions of Multiple System Atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between Multiple System Atrophy and Lewy body disorders and establish that α-synucleinopathies constitute a major class of human neurodegenerative disorder.
