Database : MEDLINE
Search on : Multiple and System and Atrophy [Words]
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[PMID]: 29508455
[Au] Autor:Palma JA; Kaufmann H
[Ad] Address:Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA.
[Ti] Title:Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies.
[So] Source:Mov Disord;33(3):372-390, 2018 Mar.
[Is] ISSN:1531-8257
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully. Discontinuation of potentially causative/aggravating drugs, patient education, and nonpharmacological approaches are useful and should be tried first. Pathophysiology-based pharmacological treatments that have shown efficacy in controlled trials of patients with synucleinopathies have been approved in many countries and are key to an effective management. Here, we review the treatment of autonomic dysfunction in patients with Parkinson disease and other synucleinopathies, summarize the nonpharmacological and current pharmacological therapeutic strategies including recently approved drugs, and provide practical advice and management algorithms for clinicians, with focus on neurogenic orthostatic hypotension, supine hypertension, dysphagia, sialorrhea, gastroparesis, constipation, neurogenic overactive bladder, underactive bladder, and sexual dysfunction. © 2018 International Parkinson and Movement Disorder Society.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1803
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1002/mds.27344

  2 / 6330 MEDLINE  
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[PMID]: 29405350
[Au] Autor:Norcliffe-Kaufmann L; Kaufmann H; Palma JA; Shibao CA; Biaggioni I; Peltier AC; Singer W; Low PA; Goldstein DS; Gibbons CH; Freeman R; Robertson D; Autonomic Disorders Consortium
[Ad] Address:Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, NY.
[Ti] Title:Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies.
[So] Source:Ann Neurol;, 2018 Feb 05.
[Is] ISSN:1531-8249
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE: Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. METHODS: Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. RESULTS: We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; -44 ± 25 vs -21 ± 14 mmHg [mean ± standard deviation], p < 0.0001) but only one-third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute [bpm], p < 0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. INTERPRETATION: A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher
[do] DOI:10.1002/ana.25170

  3 / 6330 MEDLINE  
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[PMID]: 29397790
[Au] Autor:Pitteri M; Magliozzi R; Bajrami A; Camera V; Calabrese M
[Ad] Address:a Neurology Section, Department of Neurosciences, Biomedicine and Movement Sciences , University of Verona , Verona , Italy.
[Ti] Title:Potential neuroprotective effect of Fingolimod in multiple sclerosis and its association with clinical variables.
[So] Source:Expert Opin Pharmacother;19(4):387-395, 2018 Mar.
[Is] ISSN:1744-7666
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system affecting both white matter and grey matter in the earliest phases of its course. The crucial role of neurodegeneration in disability progression in MS, regardless of white matter damage, has been confirmed by several imaging and neuropathological studies. Fingolimod is an effective immunomodulator of the sphingosine 1-phosphate receptor, approved in relapsing remitting MS and able to cross the blood-brain barrier and to slow disability progression and brain volume loss. However, it remains unclear whether this neuroprotective action is due to a peripheral anti-inflammatory effect and/or to a direct effect on neuronal cells. Areas covered: In this review, the authors summarize the published preclinical and clinical studies on the effect of Fingolimod in limiting the focal and diffuse grey matter damage in MS. Expert opinion: Fingolimod might have a significant neuroprotective effect on relapsing remitting MS based on its modulatory effect on oligodendroglial cells and astrocytes, and on its direct effect on cortical neurons. Future clinical studies including measures of grey matter damage are required to confirm in vivo such neuroprotective effect.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Process
[do] DOI:10.1080/14656566.2018.1434143

  4 / 6330 MEDLINE  
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[PMID]: 29337114
[Au] Autor:Kaji S; Maki T; Kinoshita H; Uemura N; Ayaki T; Kawamoto Y; Furuta T; Urushitani M; Hasegawa M; Kinoshita Y; Ono Y; Mao X; Quach TH; Iwai K; Dawson VL; Dawson TM; Takahashi R
[Ad] Address:Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8397 Kyoto, Japan.
[Ti] Title:Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy.
[So] Source:Stem Cell Reports;10(2):356-365, 2018 Feb 13.
[Is] ISSN:2213-6711
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenous α-syn expression in oligodendrocyte lineage cells, oligodendrocyte precursor cells (OPCs), and mature oligodendrocytes (OLGs). Here, based on in vitro analysis using primary rat cell cultures, we elucidated that preformed fibrils (PFFs) generated from recombinant human α-syn trigger multimerization and an upsurge of endogenous α-syn in OPCs, which is attributable to insufficient autophagic proteolysis. RNA-seq analysis of OPCs revealed that α-syn PFFs interfered with the expression of proteins associated with neuromodulation and myelination. Furthermore, we detected cytoplasmic α-syn inclusions in OLGs through differentiation of OPCs pre-incubated with PFFs. Overall, our findings suggest the possibility of endogenous α-syn accumulation in OPCs that contributes to GCI formation and perturbation of neuronal/glial support in multiple system atrophy brains.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Data-Review

  5 / 6330 MEDLINE  
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[PMID]: 29514678
[Au] Autor:Dietrich M; Helling N; Hilla A; Heskamp A; Issberner A; Hildebrandt T; Kohne Z; Küry P; Berndt C; Aktas O; Fischer D; Hartung HP; Albrecht P
[Ad] Address:Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
[Ti] Title:Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model.
[So] Source:J Neuroinflammation;15(1):71, 2018 Mar 07.
[Is] ISSN:1742-2094
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: In multiple sclerosis (MS), neurodegeneration is the main reason for chronic disability. Alpha-lipoic acid (LA) is a naturally occurring antioxidant which has recently been demonstrated to reduce the rate of brain atrophy in progressive MS. However, it remains uncertain if it is also beneficial in the early, more inflammatory-driven phases. As clinical studies are costly and time consuming, optic neuritis (ON) is often used for investigating neuroprotective or regenerative therapeutics. We aimed to investigate the prospect for success of a clinical ON trial using an experimental autoimmune encephalomyelitis-optic neuritis (EAE-ON) model with visual system readouts adaptable to a clinical ON trial. METHODS: Using an in vitro cell culture model for endogenous oxidative stress, we compared the neuroprotective capacity of racemic LA with the R/S-enantiomers and its reduced form. In vivo, we analyzed retinal neurodegeneration using optical coherence tomography (OCT) and the visual function by optokinetic response (OKR) in MOG -induced EAE-ON in C57BL/6J mice. Ganglion cell counts, inflammation, and demyelination were assessed by immunohistological staining of retinae and optic nerves. RESULTS: All forms of LA provided equal neuroprotective capacities in vitro. In EAE-ON, prophylactic LA therapy attenuated the clinical EAE score and prevented the thinning of the inner retinal layer while therapeutic treatment was not protective on visual outcomes. CONCLUSIONS: A prophylactic LA treatment is necessary to protect from visual loss and retinal thinning in EAE-ON, suggesting that a clinical ON trial starting therapy after the onset of symptoms may not be successful.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:In-Data-Review
[do] DOI:10.1186/s12974-018-1111-y

  6 / 6330 MEDLINE  
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[PMID]: 29497168
[Au] Autor:Zhou X; Wang C; Ding D; Chen Z; Peng Y; Peng H; Hou X; Wang P; Hou X; Ye W; Li T; Yang H; Qiu R; Xia K; Sequeiros J; Tang B; Jiang H
[Ad] Address:Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.
[Ti] Title:Analysis of (CAG) expansion in ATXN1, ATXN2 and ATXN3 in Chinese patients with multiple system atrophy.
[So] Source:Sci Rep;8(1):3889, 2018 Mar 01.
[Is] ISSN:2045-2322
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Multiple system atrophy (MSA) is a complex and multifactorial neurodegenerative disease, and its pathogenesis remains uncertain. Patients with MSA or spinocerebellar ataxia (SCA) show overlapping clinical phenotypes. Previous studies have reported that intermediate or long CAG expansions in SCA genes have been associated with other neurodegenerative disease. In this study, we screened for the number of CAG repeats in ATXN1, 2 and 3 in 200 patients with MSA and 314 healthy controls to evaluate possible associations between (CAG) in these three polyQ-related genes and MSA. Our findings indicated that longer repeat lengths in ATXN2 were associated with increased risk for MSA in Chinese individuals. No relationship was observed between CAG repeat length in the three examined genes and age at onset (AO) of MSA.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:In-Data-Review
[do] DOI:10.1038/s41598-018-22290-0

  7 / 6330 MEDLINE  
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[PMID]: 29298733
[Au] Autor:Refolo V; Bez F; Polissidis A; Kuzdas-Wood D; Sturm E; Kamaratou M; Poewe W; Stefanis L; Angela Cenci M; Romero-Ramos M; Wenning GK; Stefanova N
[Ad] Address:Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innrain 66 / G2, 6020, Innsbruck, Austria.
[Ti] Title:Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies.
[So] Source:Acta Neuropathol Commun;6(1):2, 2018 01 03.
[Is] ISSN:2051-5960
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1801
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:In-Process
[do] DOI:10.1186/s40478-017-0504-y

  8 / 6330 MEDLINE  
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[PMID]: 29505813
[Au] Autor:Puska G; Lutz MI; Molnar K; Regelsberger G; Ricken G; Pirker W; Laszlo L; Kovacs GG
[Ad] Address:Department of Anatomy, Cell and Developmental Biology, Eötvös Lorand University, Budapest, Hungary.
[Ti] Title:Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy.
[So] Source:Neurobiol Dis;, 2018 Mar 02.
[Is] ISSN:1095-953X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Intracellular deposition of pathologically altered α-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic α-synuclein has been suggested to play a role in the pathogenesis of PD and MSA. This implicates a role of protein processing systems, including lysosomes, supported also by genetic studies in PD. However, particularly for MSA, the mechanism of cell-to-cell propagation of α-synuclein is yet not fully understood. To evaluate the significance of lysosomal response, we systematically compared differently affected neuronal populations in PD, MSA, and non-diseased brains using morphometric immunohistochemistry (cathepsin D), double immunolabelling (cathepsin D/α-synuclein) laser confocal microscopy, and immunogold electron microscopy for the disease associated α-synuclein. We found that i) irrespective of the presence of neuronal inclusions, the volume density of cathepsin D immunoreactivity significantly increases in affected neurons of the pontine base in MSA brains; ii) volume density of cathepsin D immunoreactivity increases in nigral neurons in PD without inclusions and with non-ubiquitinated pre-aggregates of α-synuclein, but not in neurons with Lewy bodies; iii) cathepsin D immunoreactivity frequently colocalises with α-synuclein pre-aggregates in nigral neurons in PD; iv) ultrastructural observations confirm disease-associated α-synuclein in neuronal and astrocytic lysosomes in PD; v) lysosome-associated α-synuclein is observed in astroglia and rarely in oligodendroglia and in neurons in MSA. Our observations support a crucial role for the neuronal endosomal-lysosomal system in the processing of α-synuclein in PD. We suggest a distinct contribution of lysosomes to the pathogenesis of MSA, including the possibility of oligodendroglial and eventually neuronal uptake of exogenous α-synuclein in MSA.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[St] Status:Publisher

  9 / 6330 MEDLINE  
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[PMID]: 29297596
[Au] Autor:Coon EA; Cutsforth-Gregory JK; Benarroch EE
[Ad] Address:Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
[Ti] Title:Neuropathology of autonomic dysfunction in synucleinopathies.
[So] Source:Mov Disord;33(3):349-358, 2018 Mar.
[Is] ISSN:1531-8257
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The synucleinopathies-Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure-result from distinct patterns of abnormal α-synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinson's disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy-related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction. © 2018 International Parkinson and Movement Disorder Society.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1801
[Cu] Class update date: 180306
[Lr] Last revision date:180306
[St] Status:In-Data-Review
[do] DOI:10.1002/mds.27186

  10 / 6330 MEDLINE  
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[PMID]: 29502349
[Au] Autor:Abati E; Di Fonzo A; Corti S
[Ad] Address:Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, Neuroscience Section, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
[Ti] Title:In vitro models of multiple system atrophy from primary cells to induced pluripotent stem cells.
[So] Source:J Cell Mol Med;, 2018 Mar 04.
[Is] ISSN:1582-4934
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Multiple system atrophy (MSA) is a rare neurodegenerative disease with a fatal outcome. Nowadays, only symptomatic treatment is available for MSA patients. The hallmarks of the disease are glial cytoplasmic inclusions (GCIs), proteinaceous aggregates mainly composed of alpha-synuclein, which accumulate in oligodendrocytes. However, despite the extensive research efforts, little is known about the pathogenesis of MSA. Early myelin dysfunction and alpha-synuclein deposition are thought to play a major role, but the origin of the aggregates and the causes of misfolding are obscure. One of the reasons for this is the lack of a reliable model of the disease. Recently, the development of induced pluripotent stem cell (iPSC) technology opened up the possibility of elucidating disease mechanisms in neurodegenerative diseases including MSA. Patient specific iPSC can be differentiated in glia and neurons, the cells involved in MSA, providing a useful human disease model. Here, we firstly review the progress made in MSA modelling with primary cell cultures. Subsequently, we focus on the first iPSC-based model of MSA, which showed that alpha-synuclein is expressed in oligodendrocyte progenitors, whereas its production decreases in mature oligodendrocytes. We then highlight the opportunities offered by iPSC in studying disease mechanisms and providing innovative models for testing therapeutic strategies, and we discuss the challenges connected with this technique.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1803
[Cu] Class update date: 180304
[Lr] Last revision date:180304
[St] Status:Publisher
[do] DOI:10.1111/jcmm.13563


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