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1.
Review: Novel treatment strategies targeting alpha‐synuclein in multiple system atrophy as a model of synucleinopathy
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E. Valera G. Monzio Compagnoni E. Masliah 《Neuropathology and applied neurobiology》2016,42(1):95-106
Neurodegenerative disorders with alpha‐synuclein (α‐syn) accumulation (synucleinopathies) include Parkinson's disease (PD), PD dementia, dementia with Lewy bodies and multiple system atrophy (MSA). Due to the involvement of toxic α‐syn aggregates in the molecular origin of these disorders, developing effective therapies targeting α‐syn is a priority as a disease‐modifying alternative to current symptomatic treatments. Importantly, the clinical and pathological attributes of MSA make this disorder an excellent candidate as a synucleinopathy model for accelerated drug development. Recent therapeutic strategies targeting α‐syn in in vivo and in vitro models of MSA, as well as in clinical trials, have been focused on the pathological mechanisms of α‐syn synthesis, aggregation, clearance, and/or cell‐to‐cell propagation of its neurotoxic conformers. Here we summarize the most relevant approaches in this direction, with emphasis on their potential as general synucleinopathy modifiers, and enumerate research areas for potential improvement in MSA drug discovery. 相似文献
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Nathalie Dutheil PhD Qin Li PhD Matthias Klugmann PhD Wassilios G. Meissner MD PhD Pierre‐Olivier Fernagut PhD 《Movement disorders》2017,32(8):1230-1239
Background : MSA is a fatal neurodegenerative disorder characterized by a combination of autonomic dysfunction, cerebellar ataxia, and l ‐dopa unresponsive parkinsonism. The hallmark of MSA is the accumulation of α‐synuclein, forming cytoplasmic inclusions in oligodendrocytes. Adeno‐associated viruses allow efficient targeting of disease‐associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of α‐synuclein in the substantia nigra in the context of PD. Objectives : We aimed to develop viral‐based models of MSA. Methods : Chimeric viral vectors expressing either human wild‐type α‐synuclein or green fluorescent protein under the control of mouse myelin basic protein were injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor assessment before histopathological analysis at 3 and 6 months. Results : Injection of vectors expressing α‐synuclein in the striatum resulted in >80% oligodendroglial selectivity in rats and >60% in monkeys. Rats developed progressive motor deficits that were l ‐dopa unresponsive when assessed at 6 months. Significant loss of dopaminergic neurons occurred at 3 months, further progressing at 6 months, together with a loss of striatal neurons. Prominent α‐synuclein accumulation, including phosphorylated and proteinase‐K–resistant α‐synuclein, was detected in the striatum and substantia nigra. Conclusions : Viral‐mediated oligodendroglial expression of α‐synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how α‐synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies. © 2017 International Parkinson and Movement Disorder Society 相似文献
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Distinctive distribution of phospho‐alpha‐synuclein in dermal nerves in multiple system atrophy
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Kathrin Doppler MD Jessica Weis Katharina Karl Sönke Ebert Jens Ebentheuer MD Claudia Trenkwalder MD Stephan Klebe MD Jens Volkmann MD Claudia Sommer MD 《Movement disorders》2015,30(12):1688-1692
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Antonio Suppa MD PhD Luca Marsili MD Flavio Di Stasio MD Anna Latorre MD AK. Parvez MBBS Carlo Colosimo MD Alfredo Berardelli MD 《Movement disorders》2014,29(1):97-104
In humans, intermittent and continuous theta‐burst stimulation (iTBS and cTBS) elicit long‐term changes in motor‐evoked potentials (MEPs) reflecting long‐term potentiation (LTP)‐ and depression (LTD)‐like plasticity in the primary motor cortex (M1). In this study, we used TBS to investigate M1 plasticity in patients with MSA. We also assessed whether responses to TBS reflect M1 excitability as tested by short‐interval intracortical inhibition (SICI), intracortical facilitation (ICF), short‐interval intracortical facilitation (SICF), and the input/output curves. We studied 20 patients with MSA and 20 healthy subjects (HS). Patients were clinically evaluated with the Unified Multiple System Atrophy Rating Scale. The left M1 was conditioned with TBS. Twenty MEPs were recorded from the right first dorsal interosseous muscle before TBS and 5, 15, and 30 minutes thereafter. In a subgroup of 10 patients, we also tested MEPs elicited by SICI, ICF, SICF, and input/output curves, before TBS. Between‐group analysis of variance showed that at all time points after iTBS MEPs increased, whereas after cTBS they decreased only in HS. In both subgroups tested, patients with predominant parkinsonian and cerebellar features, iTBS and cTBS left MEPs unchanged. MSA patients had reduced SICI, but normal ICF, SICF, and input/output curves. No correlation was found between patients' clinical features and responses to TBS and M1 excitability variables. These findings suggest impaired M1 plasticity in MSA. © 2013 International Parkinson and Movement Disorder Society 相似文献
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Delineating the sites and progression of in vivo atrophy in multiple system atrophy using fluid-registered MRI. 总被引:1,自引:0,他引:1
Jonathan M Schott Jessica E Simon Nick C Fox Andrew P King M Nadeem Khan Lisa Cipolotti Dominic C Paviour John M Stevens Martin N Rossor 《Movement disorders》2003,18(8):955-958
We describe the pattern and progression of atrophy delineated using fluid registration of serial magnetic resonance imaging scans in a case of multiple system atrophy (MSA). The in vivo findings were consistent with those found at postmortem, including significant supratentorial atrophy concurrent with an unusual degree of cognitive impairment for MSA. 相似文献
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Mathieu Boudes PhD Pieter Uvin MD Silvia Pinto Thomas Voets PhD Clare J. Fowler MD Gregor K. Wenning MD PhD Dirk De Ridder MD PhD Nadia Stefanova MD PhD 《Movement disorders》2013,28(3):347-355
Multiple system atrophy (MSA) is an adult‐onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α‐synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)–human α‐synuclein (hαSyn) transgenic and control wild‐type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age‐related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP‐hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn‐related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA. © 2013 Movement Disorder Society 相似文献
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Ahmed Z Asi YT Sailer A Lees AJ Houlden H Revesz T Holton JL 《Neuropathology and applied neurobiology》2012,38(1):4-24
Multiple system atrophy (MSA) is an unrelenting, sporadic, adult-onset, neurodegenerative disease of unknown aetiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. Neuropathological examination often reveals gross abnormalities of the striatonigral and/or olivopontocerebellar systems, which upon microscopic examination are associated with severe neuronal loss, gliosis, myelin pallor and axonal degeneration. MSA is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies, due to the presence of abnormal α-synuclein positive cytoplasmic inclusions in oligodendrocytes, termed glial cytoplasmic inclusions. These are the hallmark neuropathological lesion of MSA and are thought to play a central role in the pathogenesis of the disease. In this review, neuropathological features of MSA are described in detail, along with recent advances in the pathophysiology and genetics of the disease. Our current knowledge of the expression and accumulation of α-synuclein, and efforts to model the disease in vitro and in vivo, are emphasized in this paper and have helped formulate a working hypothesis for the pathogenesis of MSA. 相似文献
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Matthias Preusser Melitta Kitzwoegerer Herbert Budka Stefan Brugger 《Neuropathology》2007,27(5):453-456
Recently, a family with idiopathic brain calcification was reported, in which one family member was diagnosed with multiple system atrophy (MSA) at autopsy. We report here a case showing similar neuropathological features in a patient with longstanding hypoparathyroidism. Our female patient had a history of hypoparathyroidism with hypocalcaemia and tetany since the age of 9 years. In her 50s she developed dementia and parkinsonism. She died of myocardial infarction aged 65 years. Neuropathology showed severe brain calcifications of the Fahr type in the basal ganglia, thalami, cerebral and cerebellar white matter and dentate nuclei. Additionally, there was prominent alpha‐synucleinopathy of the multiple system atrophy type (MSA). The patient has a healthy identical twin and there is no family history of hypoparathyroidism or neurological disease. Data on alpha‐synuclein accumulation in various cases of Fahr's syndrome are needed to establish the correlation between alpha‐synucleinopathy and bilateral striopallidodentate calcification. 相似文献
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Klaus Seppi Michael F H Schocke Kathrin Prennschuetz-Schuetzenau Katherina J Mair Regina Esterhammer Christian Kremser Armin Muigg Christoph Scherfler Werner Jaschke Gregor K Wenning Werner Poewe 《Movement disorders》2006,21(6):847-852
There is neuropathologic evidence that, in early stages of the Parkinson variant of multiple system atrophy (MSA-P), the putamen shows a distinct topographical pathology affecting predominantly the dorsolateral and caudal regions while leaving the rostral to midparts almost intact. We investigated the topographic profile of putaminal degeneration in MSA-P patients in vivo by means of diffusion-weighted imaging (DWI), which has been shown to reveal abnormalities in the basal ganglia of patients with MSA-P compared to patients with PD and healthy controls. For this purpose, regional trace of the diffusion tensor (rTrace(D)) values were determined in the entire, anterior, and posterior putamen in 15 patients with probable MSA-P, in 20 patients with PD, and in 11 healthy volunteers matched for age and disease duration. MSA-P patients had significantly higher rTrace(D) values in entire, anterior, and posterior putamen compared to both controls and PD patients. Trace(D) values were significantly higher in the posterior compared to the anterior putamen in the MSA-P group. There were no significant differences between posterior and anterior putamen in both the control and PD group. Our study demonstrates prominent involvement of the posterior putamen in early disease stages of MSA-P in vivo by assessing putaminal diffusivity with the help of DWI. 相似文献
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Progression of alpha‐synuclein pathology in multiple system atrophy of the cerebellar type
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J. Brettschneider D. J. Irwin S. Boluda M. D. Byrne L. Fang E. B. Lee J. L. Robinson E. Suh V. M. Van Deerlin J. B. Toledo M. Grossman H. Hurtig R. Dengler S. Petri V. M.‐Y. Lee J. Q. Trojanowski 《Neuropathology and applied neurobiology》2017,43(4):315-329
13.
《Movement disorders》2006,21(6):809-815
Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients' own evaluation of their illness and factors associated with poor health‐related quality of life (Hr‐QoL). We, therefore, assessed Hr‐QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA‐Study Group (EMSA‐SG) Natural History Study: Medical Outcome Study Short Form (SF‐36), EQ‐5D, Beck Depression Inventory (BDI), Mini‐Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), Hoehn & Yahr (H&Y) Parkinson's disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson's Disease Sleep Scale (PDSS). Forty‐six percent of patients had moderate to severe depression (BDI ≥ 17); Hr‐QoL scores on the SF‐36 and EQ‐5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA‐P (predominantly parkinsonian motor subtype) than MSA‐C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr‐QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate‐to‐strong predictors for the SF‐36 physical summary score and the BDI and UMSARS motor scores for the SF‐36 mental summary score. This report is the first study to show that Hr‐QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr‐QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr‐QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease. © 2006 Movement Disorder Society 相似文献
14.
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by the filamentous aggregation of α‐synuclein. We report a case of MSA showing unusual neuropathological findings and review six autopsied cases of MSA. The patient progressively developed parkinsonism and ataxia for the 9 years prior to her death at the age of 72 years. Neuropathological examinations revealed neuronal loss restricted to the olivopontocerebellar and striatonigral region, which was more severe in the putamen. Staining with anti‐α‐synuclein antibody demonstrated widespread occurrence of glial cytoplasmic inclusions, which mainly accumulated in oligodendroglial cells and corresponded closely to the degree of disease progression. In addition, tau‐positive granules were detected within the glial cytoplasm in the neurodegenerative region, which was especially prominent in the putamen and internal capsule. Tau accumulation was also clearly recognized by staining with specific antibodies against three‐repeat or four‐repeat tau. The glia that demonstrated deposition of tau‐positive granules were distinguished from α‐synuclein‐positive oligodendroglia by double immunohistochemical staining. These characteristic glial accumulations of tau were also present in all six cases of MSA. These results indicate that tau‐positive granules in glia are common findings in MSA and that tau aggregation might be another pathway to neurodegeneration in MSA. 相似文献
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Olivier Flabeau MD Wassilios G. Meissner MD PhD Annaig Ozier MD PhD Patrick Berger MD PhD François Tison MD PhD Pierre‐Olivier Fernagut PhD 《Movement disorders》2014,29(3):388-395
Breathing disorders like sleep apnea, stridor, and dysrythmic breathing are frequent in patients with multiple system atrophy (MSA). These observations have been related to neurodegeneration in several pontomedullary respiratory nuclei and may explain the occurrence of sudden death. In this study, we sought to determine whether these functional and neuropathological characteristics could be replicated in a transgenic model of MSA. Mice expressing human wild‐type α‐synuclein under the control of the proteolipid promoter (PLP‐αSYN) were compared with age‐matched controls. Using whole‐body, unrestrained plethysmography, the following breathing parameters were measured: inspiratory and expiratory times, tidal volume, expiratory volume, peak inspiratory and expiratory flows, and respiratory frequency. For each category, the mean, coefficient of variation, and irregularity score were analyzed. Brains were then processed for stereological cell counts of pontomedullary respiratory nuclei. A significant increase in the coefficient of variation and irregularity score was observed for inspiratory time, tidal volume, and expiratory volume in PLP‐αSYN mice (P < 0.05). Glial cytoplasmic inclusions were found in the medullary raphe of PLP‐αSYN mice, together with a loss of serotonergic immunoreactivity in the raphe obscurus (P < 0.001) and pallidus (P < 0.01). There was a negative correlation between α‐synuclein burden and raphe pallidus cell counts (P < 0.05). There was no significant neuronal loss in the pre‐Botzinger complex. The PLP‐αSYN mouse model replicates the breathing variability and part of the neuronal depletion in pontomedullary respiratory nuclei observed in patients with MSA. Our findings support the use of this model for future candidate drugs in the breathing disorders observed in MSA. © 2014 International Parkinson and Movement Disorder Society 相似文献
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Hirohisa Watanabe MD Mizuki Ito MD Hiroshi Fukatsu MD Jo Senda MD Naoki Atsuta MD Tomotsugu Kaga MD Shigetaka Kato MD Masahisa Katsuno MD Fumiaki Tanaka MD Masaaki Hirayama MD Shinji Naganawa MD Gen Sobue MD 《Movement disorders》2010,25(12):1916-1923
We delineated the effects of magnetic field strength on signal intensities to facilitate the specific findings of multiple system atrophy (MSA). Fifteen patients with probable MSA were imaged by 0.35T fast spin‐echo (FSE), 1.5T FSE, and 3.0T FSE using a consistent protocol, testing all field strengths on the same day. Sixty patients with probable Parkinson's disease (PD) also underwent imaging. Moderate or marked hyperintensity at the dorsolateral outer putaminal margin, hyperintensity of the putaminal body, hypointensity relative to the globus pallidus at the dorsolateral putaminal margin, and infratentorial signal changes were evaluated as specific findings for MSA. As the field strength increased, the occurrence of hyperintensity both at the dorsolateral outer putaminal margin and of the putaminal body decreased, while the occurrence of hypointensity at the dorsolateral putaminal margin increased in MSA. The occurrence of uniform mild hyperintensity of the outer putaminal margin was evident in 7% at 0.35T, 40% at 1.5T, and 47% at 3.0T in MSA and in 5% at 0.35T, 60% at 1.5T, and 75% at 3.0T in PD. However, no PD patients showed hyperintensity at the dorsolateral outer putaminal margin and that of the putaminal body. Putaminal magnetic resonance imaging (MRI) findings in MSA were altered considerably by magnetic field strength. The severity and distribution of signal changes are important for assessing putaminal MRI findings in MSA. © 2010 Movement Disorders Society 相似文献
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Maria Teresa Pellecchia MD PhD Paolo Barone MD PhD Caterina Vicidomini PhD Carmine Mollica MD PhD Elena Salvatore MD PhD Marta Ianniciello MD Raffaele Liuzzi PhD Katia Longo MD Marina Picillo MD Giuseppe De Michele MD Alessandro Filla MD Arturo Brunetti MD Marco Salvatore MD Sabina Pappatà MD 《Movement disorders》2011,26(7):1303-1309
Diffusion‐weighted imaging has been largely used to detect and quantify early degenerative changes in patients with multiple system atrophy, but progression of neurodegeneration has been poorly investigated. We performed a serial diffusion‐weighted imaging study in a population of multiple system atrophy patients and analyzed the evolution of diffusion properties in striatal and extrastriatal brain regions. Diffusion‐weighted imaging was obtained in 11 multiple system atrophy patients at baseline and after a follow‐up of 11.7 ± 1.2 months, and Trace (D) changes in different brain regions were correlated with disease duration and severity. A significant increase in Trace (D) was observed at follow‐up in the putamen (P < .001), pons (P = .003), cerebellar white matter (P = .03), thalamus (P = .013), and frontal white matter (P = .021). Both Unified Multiple System Atrophy Rating Scale Part II and Unified Parkinson's Disease Rating Scale Part III scores significantly increased at follow‐up (P = .003), but percent changes of Unified Parkinson's Disease Rating Scale Part III and Unified Multiple System Atrophy Rating Scale Part II did not correlate with percent changes of Trace (D) values in any brain region. This longitudinal study provides new insights into the progression of neurodegeneration in different brain regions in multiple system atrophy. Our results confirm that abnormal diffusivity in the putamen is sensitive to change over time in multiple system atrophy patients and show for the first time a progression of Trace (D) alterations in specific extrastriatal regions. Diffusivity changes in these regions may be useful for monitoring disease progression even after a short follow‐up period. © 2011 Movement Disorder Society 相似文献
20.
Tibor Kovács Mátyás I Papp Nigel J Cairns M Nadeem Khan Peter L Lantos 《Movement disorders》2003,18(8):938-942
Olfactory dysfunction is a characteristic clinical sign in Parkinson's disease (PD); it is also present in multiple system atrophy (MSA). The pathological basis of hyposmia or anosmia in PD is well known: the olfactory bulb (OB) contains numerous Lewy bodies and severe neuronal loss is present in the anterior olfactory nucleus (AON). We established that glial cytoplasmic inclusions (GCIs) are present in all the OBs from MSA cases. Their presence in the OB is diagnostic for MSA. Additionally, neuronal loss is present in the AON in MSA. These pathological changes might be responsible for the olfactory dysfunction seen in MSA. 相似文献