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Pan H, Balbirnie M, Hou K, Sta Maria NS, Sahay S, Denver P, Lepore S, Jones M, Zuo X, Zhu C, Mirbaha H, Shahpasand-Kroner H, Mekkittikul M, Lu J, Hu CJ, Cheng X, Abskharon R, Sawaya MR, Williams CK, Vinters HV, Jacobs RE, Harris NG, Cole GM, Frautschy SA, Eisenberg DS. Liganded magnetic nanoparticles for magnetic resonance imaging of α-synuclein. NPJ Parkinsons Dis 2025; 11:88. [PMID: 40268938 PMCID: PMC12019173 DOI: 10.1038/s41531-025-00918-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/17/2025] [Indexed: 04/25/2025] Open
Abstract
Aggregation of the protein α-synuclein (α-syn) is the histopathological hallmark of neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Currently, patients with synucleinopathies are diagnosed by physical examination and medical history, often at advanced stages of disease. Because synucleinopathies are associated with α-syn aggregates, and α-syn aggregation often precedes onset of symptoms, detecting α-syn aggregates would be a valuable early diagnostic for patients with synucleinopathies. Here, we design a liganded magnetic nanoparticle (LMNP) functionalized with an α-syn-targeting peptide to be used as a magnetic resonance imaging (MRI)-based biomarker for α-syn. Our LMNPs bind to aggregates of α-syn in vitro, cross the blood-brain barrier in mice with mannitol adjuvant, and can be used as an MRI contrast agent to distinguish mice with α-synucleinopathy from age-matched, wild-type control mice in vivo. These results provide evidence for the potential of magnetic nanoparticles that target α-syn for diagnosis of synucleinopathies.
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Affiliation(s)
- Hope Pan
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Melinda Balbirnie
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Ke Hou
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Naomi S Sta Maria
- Department of Research Physiology, Department of Neuroscience, Keck School of Medicine at USC, Los Angeles, CA, USA
| | - Shruti Sahay
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Paul Denver
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Stefano Lepore
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Mychica Jones
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Xiaohong Zuo
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Chunni Zhu
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Brain Research Institute Electron Microscopy Core Facility, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Hilda Mirbaha
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Hedieh Shahpasand-Kroner
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Marisa Mekkittikul
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jiahui Lu
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Carolyn J Hu
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Xinyi Cheng
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Romany Abskharon
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Michael R Sawaya
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Christopher K Williams
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Harry V Vinters
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Russell E Jacobs
- Department of Research Physiology, Department of Neuroscience, Keck School of Medicine at USC, Los Angeles, CA, USA
| | - Neil G Harris
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Gregory M Cole
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Sally A Frautschy
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - David S Eisenberg
- Department of Chemistry and Biochemistry, Department of Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
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Akiyama N, Kanazawa M, Kasuga K, Hatakeyama M, Ikeuchi T, Onodera O. Utility of Cerebrospinal Fluid Transferrin Receptor per Ferritin Ratio in Progressive Supranuclear Palsy. Mov Disord Clin Pract 2025; 12:446-452. [PMID: 39688304 PMCID: PMC11998682 DOI: 10.1002/mdc3.14313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND Progressive supranuclear palsy (PSP) is a major atypical parkinsonism. Because diagnosis based on the cardinal clinical features is often difficult, misdiagnosis with Parkinson's disease (PD) and multiple system atrophy (MSA) is common in PSP patients. Iron metabolism genes are reportedly involved in tau-accumulating neuronal cell death and ferroptosis in PSP, which is more severe than PD and MSA. The validity of transferrin receptor (TfR) expression as a biomarker of ferroptosis was also demonstrated. OBJECTIVE We investigated whether TfR and the TfR to ferritin ratio in the cerebrospinal fluid (CSF) is a diagnostic biomarker of PSP. METHODS This study included 2 independent retrospective CSF cohorts comprising patients, respectively, from Niigata University and a multicenter memory clinic, consisting of patients with PSP, PD, and MSA. All patients were classified as clinically probable or higher based on the Society of Movement Disorders Criteria. TfR and ferritin levels in the CSF were measured using Luminex assay. RESULTS The levels of TfR in patients with PSP were higher than those in patients with PD and MSA in cohort 1 (PSP: N = 16, PD: N = 13, MSA: N = 20). The TfR to ferritin ratio in patients with PSP was significantly higher than that in patients with MSA. Subsequently, we validated these results in cohort 2 (PSP: N = 23, MSA: N = 6). The TfR to ferritin ratio was significantly higher in patients with PSP than in those with MSA. CONCLUSIONS The CSF TfR to transferrin ratio was elevated in patients with PSP. These results should be validated in a larger cohort of patients.
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Affiliation(s)
- Natsuki Akiyama
- Department of Neurology, Brain Research InstituteNiigata UniversityNiigataJapan
| | - Masato Kanazawa
- Department of Neurology, Brain Research InstituteNiigata UniversityNiigataJapan
| | - Kensaku Kasuga
- Department of Molecular Genetics, Brain Research InstituteNiigata UniversityNiigataJapan
| | - Masahiro Hatakeyama
- Department of Neurology, Brain Research InstituteNiigata UniversityNiigataJapan
| | - Takeshi Ikeuchi
- Department of Molecular Genetics, Brain Research InstituteNiigata UniversityNiigataJapan
| | - Osamu Onodera
- Department of Neurology, Brain Research InstituteNiigata UniversityNiigataJapan
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3
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Bauer T, Brendel M, Zaganjori M, Bernhardt AM, Jäck A, Stöcklein S, Scheifele M, Levin J, van Eimeren T, Drzezga A, Sabri O, Barthel H, Perneczky R, Höglinger G, Franzmeier N, Gnörich J. Pragmatic algorithm for visual assessment of 4-Repeat tauopathies in [ 18F]PI-2620 PET Scans. Neuroimage 2025; 306:121001. [PMID: 39798829 DOI: 10.1016/j.neuroimage.2025.121001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 11/11/2024] [Accepted: 01/06/2025] [Indexed: 01/15/2025] Open
Abstract
AIM Standardized evaluation of [18F]PI-2620 tau-PET scans in 4R-tauopathies represents an unmet need in clinical practice. This study aims to investigate the effectiveness of visual evaluation of [18F]PI-2620 images for diagnosing 4R-tauopathies and to develop a straight-forward reading algorithm to improve objectivity and data reproducibility. METHODS A total of 83 individuals with [18F]PI-2620 PET scans were included. Participants were classified as probable 4R-tauopathies (n = 29), Alzheimer's disease (AD) (n = 20), α-synucleinopathies (n = 15), and healthy controls (n = 19) based on clinical criteria. Visual assessment of tau-PET scans (choice: 4R-tauopathy, AD-tauopathy, no-tauopathy) was conducted using either 20-40-minute or 40-60-minute intervals, with raw (common) and cerebellar grey matter scaled standardized reading settings (intensity-scaled). Two readers evaluated scans independently and blinded, with a third reader providing consensus in case of discrepant primary evaluation. A regional analysis was performed using the cortex, basal ganglia, midbrain, and dentate nucleus. Sensitivity, specificity, and interrater agreement were calculated for all settings and compared against the visual reads of parametric images (0-60-minutes, distribution volume ratios, DVR). RESULTS Patients with 4R-tauopathies in contrast to non-4R-tauopathies were detected at higher sensitivity in the 20-40-minute frame (common: 79%, scaled: 76%) compared to the 40-60-minute frame (common: 55%, scaled: 62%), albeit with reduced specificity in the common setting (20-40-min: 78%, 40-60-min: 95%), which was ameliorated in the intensity-scaled setting (20-40-min: 91%, 40-60-min: 96%). Combined assessment of multiple brain regions did not significantly improve diagnostic sensitivity, compared to assessing the basal ganglia alone (76% each). Evaluation of intensity-scaled parametric images resulted in higher sensitivity compared to intensity-scaled static scans (86% vs. 76%) at similar specificity (89% vs. 91%). CONCLUSION Visual reading of [18F]PI-2620 tau-PET scans demonstrated reliable detection of 4R-tauopathies, particularly when standardized processing methods and early imaging windows were employed. Parametric images should be preferred for visual assessment of 4R-tauopathies.
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Affiliation(s)
- Theresa Bauer
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Matthias Brendel
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Mirlind Zaganjori
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Alexander M Bernhardt
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Department of Neurology, University Hospital, LMU Munich, Munich, Germany
| | - Alexander Jäck
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Department of Neurology, University Hospital, LMU Munich, Munich, Germany
| | - Sophia Stöcklein
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Maximilian Scheifele
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Johannes Levin
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Department of Neurology, University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Thilo van Eimeren
- Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn/Cologne, Germany
| | - Alexander Drzezga
- Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn/Cologne, Germany; Institute of Neuroscience and Medicine (INM-2), Molecular Organization of the Brain, Forschungszentrum Jülich, Germany
| | - Osama Sabri
- University Hospital Leipzig, Department of Nuclear Medicine, Leipzig, Germany
| | - Henryk Barthel
- University Hospital Leipzig, Department of Nuclear Medicine, Leipzig, Germany
| | - Robert Perneczky
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK; Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, London, UK
| | - Günter Höglinger
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Department of Neurology, University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Nicolai Franzmeier
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Institute for Stroke and Dementia Research, LMU Munich, Munich, Germany; University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Mölndal and Gothenburg, Sweden
| | - Johannes Gnörich
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
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Ortega-Robles E, de Celis Alonso B, Cantillo-Negrete J, Carino-Escobar RI, Arias-Carrión O. Advanced Magnetic Resonance Imaging for Early Diagnosis and Monitoring of Movement Disorders. Brain Sci 2025; 15:79. [PMID: 39851446 PMCID: PMC11763950 DOI: 10.3390/brainsci15010079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 01/26/2025] Open
Abstract
Advanced magnetic resonance imaging (MRI) techniques are transforming the study of movement disorders by providing valuable insights into disease mechanisms. This narrative review presents a comprehensive overview of their applications in this field, offering an updated perspective on their potential for early diagnosis, disease monitoring, and therapeutic evaluation. Emerging MRI modalities such as neuromelanin-sensitive imaging, diffusion-weighted imaging, magnetization transfer imaging, and relaxometry provide sensitive biomarkers that can detect early microstructural degeneration, iron deposition, and connectivity disruptions in key regions like the substantia nigra. These techniques enable earlier and more accurate differentiation of movement disorders, including Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, Lewy body and frontotemporal dementia, Huntington's disease, and dystonia. Furthermore, MRI provides objective metrics for tracking disease progression and assessing therapeutic efficacy, making it an indispensable tool in clinical trials. Despite these advances, the absence of standardized protocols limits their integration into routine clinical practice. Addressing this gap and incorporating these techniques more systematically could bring the field closer to leveraging advanced MRI for personalized treatment strategies, ultimately improving outcomes for individuals with movement disorders.
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Affiliation(s)
- Emmanuel Ortega-Robles
- Unidad de Trastornos del Movimiento y Sueño, Hospital General Dr. Manuel Gea González, Calzada de Tlalpan 4800, Mexico City 14080, Mexico;
| | - Benito de Celis Alonso
- Facultad de Ciencias Físico Matemáticas, Benemérita Universidad Autónoma de Puebla, Puebla 72570, Mexico;
| | - Jessica Cantillo-Negrete
- Technological Research Subdirection, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico;
| | - Ruben I. Carino-Escobar
- Division of Research in Clinical Neuroscience, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico;
| | - Oscar Arias-Carrión
- Unidad de Trastornos del Movimiento y Sueño, Hospital General Dr. Manuel Gea González, Calzada de Tlalpan 4800, Mexico City 14080, Mexico;
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5
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Lazzeri G, Houot M, Patout M, Londner C, Philippe C, Attard S, Delpy T, Ruggeri J, Degos B, Cormier F, Vidailhet M, Corvol JC, Arnulf I, Grabli D, Dodet P. Immediate Effect of Continuous Positive Airway Pressure Therapy on Sleep and Respiration in Patients with Multiple System Atrophy and Sleep-Disordered Breathing. Mov Disord 2024; 39:2026-2038. [PMID: 39285740 DOI: 10.1002/mds.29993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Sleep-disordered breathing (SDB; including stridor and sleep apnea syndromes) is frequent in multiple system atrophy (MSA), but the immediate effect of continuous positive airway pressure (CPAP) therapy is incompletely determined. OBJECTIVE We sought to evaluate the acute effect and safety of CPAP therapy on SDB and sleep architecture, as well as the clinical characteristics of nonresponders to CPAP therapy. METHODS The measures of 63 consecutive patients with MSA who underwent a video-polysomnography during two consecutive nights (a first night in ambient air, a second night with or without CPAP, depending on the presence of SDB and availability of CPAP) in routine care were retrospectively collected. Linear mixed models assessed the two-night change in sleep and respiratory measures, comparing those with and without the CPAP therapy on the second night. RESULTS SDB was frequent and mainly associated with the cerebellar phenotype. The introduction of CPAP had immediate benefits, including the normalization of the apnea-hypopnea index and a resolution of stridor in more than two-thirds of the cases, decreased arousal index, and increased rapid eye movement sleep. CPAP therapy was well tolerated, and only two patients had emergent central apneas. Nonresponse to CPAP was generally associated with more severe motor disease. CONCLUSIONS CPAP seems a well-tolerated and effective therapy in patients with MSA and SDB in the short term. This treatment shows remarkable immediate benefits by objectively improving both respiratory disturbances and sleep architecture. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Giulia Lazzeri
- Centro Parkinson e Parkinsonismi, ASST G. Pini-CTO, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Marion Houot
- Center of Excellence of Neurodegenerative Disease, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
- Department of Neurology, Institute of Memory and Alzheimer's Disease, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
- Clinical Investigation Centre Neuroscience, Brain Institute, Pitié-Salpêtrière Hospital, Paris, France
| | - Maxime Patout
- Inserm UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Sorbonne Université, Paris, France
- Service des Pathologies du Sommeil, Pitié-Salpêtrière hospital, AP-HP, Paris, France
| | - Cécile Londner
- Service des Pathologies du Sommeil, Pitié-Salpêtrière hospital, AP-HP, Paris, France
| | - Carole Philippe
- Neurology Department, University Hospital of Limoges, Limoges, France
| | - Stephane Attard
- Service des Pathologies du Sommeil, Pitié-Salpêtrière hospital, AP-HP, Paris, France
| | - Teddy Delpy
- Service des Pathologies du Sommeil, Pitié-Salpêtrière hospital, AP-HP, Paris, France
| | - Joanna Ruggeri
- Sorbonne Université, Paris Brain Institute, Inserm, CNRS, Paris, France
- Department of Neurology, Pitié-Salpêtrière Hospital, APHP, Paris, France
| | - Bertrand Degos
- Service de Neurologie, Hôpital Avicenne, Hôpitaux Universitaires de Paris Seine-Saint-Denis, Sorbonne Paris Nord, AP-HP, Bobigny, France
- Dynamics and Pathophysiology of Neuronal Networks Team, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR7241/INSERM U1050, Université PSL, Paris, France
| | - Florence Cormier
- Sorbonne Université, Paris Brain Institute, Inserm, CNRS, Paris, France
- Department of Neurology, Pitié-Salpêtrière Hospital, APHP, Paris, France
| | - Marie Vidailhet
- Sorbonne Université, Paris Brain Institute, Inserm, CNRS, Paris, France
- Department of Neurology, Pitié-Salpêtrière Hospital, APHP, Paris, France
| | - Jean Cristophe Corvol
- Sorbonne Université, Paris Brain Institute, Inserm, CNRS, Paris, France
- Department of Neurology, Pitié-Salpêtrière Hospital, APHP, Paris, France
| | - Isabelle Arnulf
- Service des Pathologies du Sommeil, Pitié-Salpêtrière hospital, AP-HP, Paris, France
- Sorbonne Université, Paris Brain Institute, Inserm, CNRS, Paris, France
| | - David Grabli
- Sorbonne Université, Paris Brain Institute, Inserm, CNRS, Paris, France
- Department of Neurology, Pitié-Salpêtrière Hospital, APHP, Paris, France
| | - Pauline Dodet
- Service des Pathologies du Sommeil, Pitié-Salpêtrière hospital, AP-HP, Paris, France
- Sorbonne Université, Paris Brain Institute, Inserm, CNRS, Paris, France
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Wada T, Shimizu T, Asano Y, Kaneko T, Kawazoe T, Bokuda K, Nakata Y, Naito R, Tobisawa S, Nagaoka U, Sugaya K, Takahashi K. Early-onset dysphagia predicts short survival in multiple system atrophy. J Neurol 2024; 271:6715-6723. [PMID: 39158732 DOI: 10.1007/s00415-024-12623-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/20/2024]
Abstract
BACKGROUND The prognostic impact of dysphagia in multiple system atrophy (MSA) remains controversial. This study aimed to investigate the relationship between dysphagia severity and survival in MSA and to elucidate whether this impact differs between MSA-cerebellar ataxia (MSA-C) and MSA-parkinsonism (MSA-P). METHODS This retrospective study included 297 patients with MSA: 251 met criteria for clinically established MSA and 46 for clinically probable MSA. Among them, 171 had MSA-C and 126 had MSA-P. We evaluated symptomatic dysphagia within 3 years of onset and quantified dysphagia severity using the Hyodo score (0 to 12) through fibreoptic endoscopic evaluation of swallowing (FEES) and clinical features, including autonomic dysfunction and vocal cord paralysis. Patients were followed up until death or tracheostomy, and survival factors were analysed using the log-rank test and multivariate Cox proportional hazards model. RESULTS Ninety patients developed symptomatic dysphagia within 3 years of onset, and 75 were evaluated for dysphagia severity using FEES. Survival from onset was shorter in patients with dysphagia within 3 years compared to those without (median: 4.2 years vs. 7.3 years; p < 0.001). Symptomatic dysphagia within 3 years of onset was an independent predictor of shorter survival in the multivariate Cox analysis. While the Hyodo score was higher in MSA-P than in MSA-C patients (p = 0.048), the Hyodo score was associated with survival in both MSA-C and MSA-P patients (log-rank p < 0.001 and p = 0.046, respectively). CONCLUSION Symptomatic dysphagia within 3 years of onset predicts shorter survival in MSA-C and MSA-P patients.
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Affiliation(s)
- Takahide Wada
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan.
| | - Toshio Shimizu
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan
| | - Yuri Asano
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan
| | - Tetsuji Kaneko
- Department of Clinical Trial, Clinical Research Support Center, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Tomoya Kawazoe
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan
| | - Kota Bokuda
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan
| | | | - Rie Naito
- Department of Neurotology, TMNH, Tokyo, Japan
| | - Shinsuke Tobisawa
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan
| | - Utako Nagaoka
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan
| | - Keizo Sugaya
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan
| | - Kazushi Takahashi
- Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), 2-6-1 Musashidai, Fuchu, Tokyo, 183-0042, Japan
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7
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Zhu S, Shi Y, Chen Z, Long Z, Wan L, Chen D, Yuan X, Fu Y, Deng F, Long X, Du K, Qiu R, Tang B, Wang C, Jiang H. The characteristic and biomarker value of transcranial sonography in cerebellar ataxia. Ann Clin Transl Neurol 2024; 11:2100-2111. [PMID: 38924300 PMCID: PMC11330234 DOI: 10.1002/acn3.52131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 05/18/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
OBJECTIVE Transcranial sonography (TCS) is a noninvasive neuroimaging technique, visualizing deep brain structures and the ventricular system. Although widely employed in diagnosing various movement disorders, such as Parkinson's disease and dystonia, by detecting disease-specific abnormalities, the specific characteristics of the TCS in cerebellar ataxia remain inconclusive. We aimed to assess the potential value of TCS in patients with cerebellar ataxias for disease diagnosis and severity assessment. METHODS TCS on patients with genetic and acquired cerebellar ataxia, including 94 with spinocerebellar ataxias (SCAs) containing 10 asymptomatic carriers, 95 with cerebellar subtype of multiple system atrophy (MSA-C), and 100 healthy controls (HC), was conducted. Assessments included third ventricle width, substantia nigra (SN) and lentiform nucleus (LN) echogenicity, along with comprehensive clinical evaluations and genetic testing. RESULTS The study revealed significant TCS abnormalities in patients with cerebellar ataxia, such as enlarged third ventricle widths and elevated rates of hyperechogenic SN and LN. TCS showed high accuracy in distinguishing patients with SCA or MSA-C from HC, with an AUC of 0.870 and 0.931, respectively. TCS abnormalities aided in identifying asymptomatic SCA carriers, effectively differentiating them from HC, with an AUC of 0.725. Furthermore, third ventricle width was significantly correlated with SARA and ICARS scores in patients with SCA3 and SCOPA-AUT scores in patients with MSA-C. The SN area and SARA or ICARS scores in patients with SCA3 were also positively correlated. INTERPRETATION Our findings illustrate remarkable TCS abnormalities in patients with cerebellar ataxia, serving as potential biomarkers for clinical diagnosis and progression assessment.
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Affiliation(s)
- Sudan Zhu
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Yuting Shi
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
| | - Zhao Chen
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic DiseasesChangshaChina
| | - Zhe Long
- Department of Neurology, The Second Xiangya HospitalCentral South UniversityChangshaChina
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Linlin Wan
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
- Department of Radiology, Xiangya HospitalCentral South UniversityChangshaChina
- National International Collaborative Research Center for Medical MetabolomicsCentral South UniversityChangshaChina
| | - Daji Chen
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Xinrong Yuan
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - You Fu
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Feiyan Deng
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Xiafei Long
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Kefang Du
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Rong Qiu
- School of Computer Science and EngineeringCentral South UniversityChangshaChina
| | - Beisha Tang
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic DiseasesChangshaChina
| | - Chunrong Wang
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- Department of Pathology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Hong Jiang
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic DiseasesChangshaChina
- National International Collaborative Research Center for Medical MetabolomicsCentral South UniversityChangshaChina
- Department of Neurology, The Third Xiangya HospitalCentral South UniversityChangshaChina
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Fanciulli A, Krismer F, Struhal W, Stefanova N. Gregor K. Wenning: a brilliant mind. Clin Auton Res 2024; 34:327-328. [PMID: 38850369 DOI: 10.1007/s10286-024-01043-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/10/2024]
Affiliation(s)
- Alessandra Fanciulli
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
| | - Florian Krismer
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Walter Struhal
- Department of Neurology, Karl Landsteiner University of Health Sciences, University Hospital Tulln, Tulln, Austria
| | - Nadia Stefanova
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
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Leys F, Eschlböck S, Campese N, Mahlknecht P, Peball M, Goebel G, Sidoroff V, Krismer F, Granata R, Kiechl S, Poewe W, Seppi K, Wenning GK, Fanciulli A. Sex-related differences in the clinical presentation of multiple system atrophy. Clin Auton Res 2024; 34:253-268. [PMID: 38630378 PMCID: PMC11127878 DOI: 10.1007/s10286-024-01028-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 03/20/2024] [Indexed: 05/26/2024]
Abstract
PURPOSE To investigate sex-related differences in the clinical presentation of multiple system atrophy (MSA) through a literature review and an analysis of a retrospective cohort. METHODS The PubMed database was searched for articles including sex-related information in MSA. In a retrospective Innsbruck cohort, we investigated the baseline to last available follow-up clinical-demographic differences between men and women with MSA in a univariate fashion, followed by multivariable binary regression analysis. RESULTS The literature search yielded 46 publications with sex-related information in MSA. Most studies found comparable survival rates between the sexes, while some recent reports suggested a potential survival benefit for women, possibly due to initial motor onset and overall less severe autonomic failure compared to men. The retrospective Innsbruck MSA cohort comprised 56 female and 60 male individuals with a comparable median follow-up of 27 months. At baseline, female sex was independently associated with depression (odds ratio [OR] 4.7; p = 0.007) and male sex with severe orthostatic hypotension (OR 5.5; p = 0.016). In addition, at last follow-up, female sex was associated with the intake of central nervous system-active drugs (OR 4.1; p = 0.029), whereas male sex was associated with the presence of supine hypertension (OR 3.0; p = 0.020) and the intake of antihypertensive medications (OR 8.7; p = 0.001). Male sex was also associated with initiation of antihypertensive medications over the observation period (OR 12.4; p = 0.004). CONCLUSION The available literature and findings of the present study indicate sex-related differences in the clinical presentation of MSA and its evolution over time, highlighting the importance of considering sex in symptom exploration, therapeutic decision-making, and future clinical trial design.
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Affiliation(s)
- Fabian Leys
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Sabine Eschlböck
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Hochzirl-Natters Hospital, Zirl, Austria
| | - Nicole Campese
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Philipp Mahlknecht
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Marina Peball
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Goebel
- Institute of Medical Statistics and Informatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Victoria Sidoroff
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Florian Krismer
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Roberta Granata
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Kiechl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Werner Poewe
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Klaus Seppi
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Provincial Hospital of Kufstein, Kufstein, Austria
| | - Gregor K Wenning
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Villena-Salinas J, Ortega-Lozano SJ, Amrani-Raissouni T, Agüera-Morales E, Caballero-Villarraso J. Comparative Study between the Diagnostic Effectiveness of Brain SPECT with [ 123I]Ioflupane and [ 123I]MIBG Scintigraphy in Multiple System Atrophy. Biomedicines 2024; 12:102. [PMID: 38255208 PMCID: PMC10813386 DOI: 10.3390/biomedicines12010102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/23/2023] [Accepted: 12/28/2023] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Multiple system atrophy (MSA) is a neurodegenerative disease. It has a fast progression, so early diagnosis is decisive. Two functional imaging tests can be involved in its diagnosis: [123I]Ioflupane SPECT and [123I]MIBG scintigraphy. Our aim is to comparatively analyze the diagnostic performance of both techniques. METHODS 46 patients (24 males and 22 females) with MSA underwent [123I]Ioflupane SPECT and [123I]MIBG scintigraphy. In each of these techniques, qualitative assessment was compared with quantitative assessment. RESULTS SPECT visual assessment was positive in 93.5% of subjects (S = 95.24%; PPV = 93.02%). A cut-off of 1.363 was established for overall S/O index (S = 85.7%, E = 100%). Visual assessment of scintigraphy was positive in 73.1% (S = 78.57%, PPV = 94.29%). For the delayed heart/medistinum ratio (HMR) a cut-off of 1.43 (S = 85.3, E = 100%) was obtained. For each unit increase in delayed HMR, the suspicion of MSA increased by 1.58 (OR = 1.58, p < 0.05). The quantitative assessment showed an association with the visual assessment for each technique (p < 0.05). CONCLUSIONS Both tests are useful in MSA diagnosis. Comparatively, we did not observe a clear superiority of either. Striatal and myocardial deterioration do not evolve in parallel. Qualitative assessment is crucial in both techniques, together with the support of quantitative analysis. Delayed HMR shows a direct relationship with the risk of MSA.
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Affiliation(s)
- Javier Villena-Salinas
- Nuclear Medicine Service, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.V.-S.); (S.J.O.-L.); (T.A.-R.)
| | - Simeón José Ortega-Lozano
- Nuclear Medicine Service, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.V.-S.); (S.J.O.-L.); (T.A.-R.)
| | - Tomader Amrani-Raissouni
- Nuclear Medicine Service, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.V.-S.); (S.J.O.-L.); (T.A.-R.)
| | - Eduardo Agüera-Morales
- Neurology Service, Reina Sofia University Hospital, 14004 Cordoba, Spain;
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain
| | - Javier Caballero-Villarraso
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain
- Clinical Analyses Service, Reina Sofía University Hospital, 14004 Córdoba, Spain
- Department of Biochemistry and Molecular Biology, Universidad of Córdoba, 14071 Córdoba, Spain
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11
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Krismer F, Péran P, Beliveau V, Seppi K, Arribarat G, Pavy-Le Traon A, Meissner WG, Foubert-Samier A, Fabbri M, Schocke MM, Gordon MF, Wenning GK, Poewe W, Rascol O, Scherfler C. Progressive Brain Atrophy in Multiple System Atrophy: A Longitudinal, Multicenter, Magnetic Resonance Imaging Study. Mov Disord 2024; 39:119-129. [PMID: 37933745 DOI: 10.1002/mds.29633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 08/27/2023] [Accepted: 09/28/2023] [Indexed: 11/08/2023] Open
Abstract
OBJECTIVE To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA). BACKGROUND Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion. METHODS Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion. RESULTS Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively. CONCLUSIONS Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Florian Krismer
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
- Neuroimaging Research Core Facility, Medical University Innsbruck, Innsbruck, Austria
| | - Patrice Péran
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Vincent Beliveau
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
- Neuroimaging Research Core Facility, Medical University Innsbruck, Innsbruck, Austria
| | - Klaus Seppi
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
- Neuroimaging Research Core Facility, Medical University Innsbruck, Innsbruck, Austria
| | - Germain Arribarat
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Anne Pavy-Le Traon
- French Reference Center for MSA, Neurology Department, University Hospital of Toulouse and INSERM-Institute of Cardiovascular and Metabolic Diseases (I2MC) UMR1297, Toulouse, France
| | - Wassilios G Meissner
- CHU Bordeaux, Service de Neurologie des Maladies Neurodégénératives, IMNc, CRMR AMS, Bordeaux, France
- University of Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France
- Department of Medicine, University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand
| | - Alexandra Foubert-Samier
- CHU Bordeaux, Service de Neurologie des Maladies Neurodégénératives, IMNc, CRMR AMS, Bordeaux, France
- University of Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France
- INSERM, UMR1219, Bordeaux Population Health Research Center, University of Bordeaux, ISPED, Bordeaux, France
| | - Margherita Fabbri
- French Reference Center for MSA, Clinical Investigation Center CIC1436, Departments of Clinical Pharmacology and Neurosciences, NS-Park/FCRIN Network and NeuroToul Center of Excellence for Neurodegeneration, INSERM, University Hospital of Toulouse and University of Toulouse, Toulouse, France
| | - Michael M Schocke
- Neuroimaging Research Core Facility, Medical University Innsbruck, Innsbruck, Austria
| | | | - Gregor K Wenning
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
| | - Werner Poewe
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
- Neuroimaging Research Core Facility, Medical University Innsbruck, Innsbruck, Austria
| | - Olivier Rascol
- French Reference Center for MSA, Clinical Investigation Center CIC1436, Departments of Clinical Pharmacology and Neurosciences, NS-Park/FCRIN Network and NeuroToul Center of Excellence for Neurodegeneration, INSERM, University Hospital of Toulouse and University of Toulouse, Toulouse, France
| | - Christoph Scherfler
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
- Neuroimaging Research Core Facility, Medical University Innsbruck, Innsbruck, Austria
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12
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Lenka A, Isonaka R, Holmes C, Goldstein DS. Cardiac 18F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure. Clin Auton Res 2023; 33:737-747. [PMID: 37843677 DOI: 10.1007/s10286-023-00987-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/13/2023] [Indexed: 10/17/2023]
Abstract
PURPOSE Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), no known secondary cause, and lack of a neurodegenerative movement or cognitive disorder. Clinically diagnosed PAF can evolve ("phenoconvert") to a central Lewy body disease [LBD, e.g., Parkinson's disease (PD) or dementia with Lewy bodies (DLB)] or to the non-LBD synucleinopathy multiple system atrophy (MSA). Since cardiac 18F-dopamine-derived radioactivity usually is low in LBDs and usually is normal in MSA, we hypothesized that patients with PAF with low cardiac 18F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA. METHODS We reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 with a clinical diagnosis of PAF and data about 18F-dopamine positron emission tomography (PET). RESULTS Nineteen patients (15 with low 18F-dopamine-derived radioactivity, 4 with normal radioactivity) met the above criteria and had follow-up data. Nine (47%) phenoconverted to a central synucleinopathy over a mean of 6.6 years (range 1.5-18.8 years). All 6 patients with low cardiac 18F-dopamine-derived radioactivity who phenoconverted during follow-up developed a central LBD, whereas none of 4 patients with consistently normal 18F-dopamine PET phenoconverted to a central LBD (p = 0.0048), 3 evolving to probable MSA and 1 upon autopsy having neither a LBD nor MSA. CONCLUSION Cardiac 18F-dopamine PET can predict the type of phenoconversion of PAF. This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs.
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Affiliation(s)
- Abhishek Lenka
- Autonomic Medicine Section, National Institute of Neurological, Disorders and Stroke (NINDS), National Institutes of Health (NIH), CNP/DIR/NINDS/NIH, 9000 Rockville Pike MSC-1620, Building 10 Room 8N260, Bethesda, MD, 20892, USA
- Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA
| | - Risa Isonaka
- Autonomic Medicine Section, National Institute of Neurological, Disorders and Stroke (NINDS), National Institutes of Health (NIH), CNP/DIR/NINDS/NIH, 9000 Rockville Pike MSC-1620, Building 10 Room 8N260, Bethesda, MD, 20892, USA
| | - Courtney Holmes
- Autonomic Medicine Section, National Institute of Neurological, Disorders and Stroke (NINDS), National Institutes of Health (NIH), CNP/DIR/NINDS/NIH, 9000 Rockville Pike MSC-1620, Building 10 Room 8N260, Bethesda, MD, 20892, USA
| | - David S Goldstein
- Autonomic Medicine Section, National Institute of Neurological, Disorders and Stroke (NINDS), National Institutes of Health (NIH), CNP/DIR/NINDS/NIH, 9000 Rockville Pike MSC-1620, Building 10 Room 8N260, Bethesda, MD, 20892, USA.
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13
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Bigi A, Cascella R, Cecchi C. α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies. Neural Regen Res 2023; 18:2332-2342. [PMID: 37282450 PMCID: PMC10360081 DOI: 10.4103/1673-5374.371345] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023] Open
Abstract
The misfolding and aggregation of α-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In such conditions, a range of different misfolded aggregates, including oligomers, protofibrils, and fibrils, are present both in neurons and glial cells. Growing experimental evidence supports the proposition that soluble oligomeric assemblies, formed during the early phases of the aggregation process, are the major culprits of neuronal toxicity; at the same time, fibrillar conformers appear to be the most efficient at propagating among interconnected neurons, thus contributing to the spreading of α-synuclein pathology. Moreover, α-synuclein fibrils have been recently reported to release soluble and highly toxic oligomeric species, responsible for an immediate dysfunction in the recipient neurons. In this review, we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused by α-synuclein oligomers and fibrils, both contributing to neurodegeneration in synucleinopathies.
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Affiliation(s)
- Alessandra Bigi
- Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy
| | - Roberta Cascella
- Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy
| | - Cristina Cecchi
- Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy
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Chen B, Yang W, Luo Y, Tan EK, Wang Q. Non-pharmacological and drug treatment of autonomic dysfunction in multiple system atrophy: current status and future directions. J Neurol 2023; 270:5251-5273. [PMID: 37477834 DOI: 10.1007/s00415-023-11876-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/11/2023] [Accepted: 07/11/2023] [Indexed: 07/22/2023]
Abstract
Multiple system atrophy (MSA) is a sporadic, fatal, and rapidly progressive neurodegenerative disease of unknown etiology that is clinically characterized by autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. Early onset and extensive autonomic dysfunction, including cardiovascular dysfunction characterized by orthostatic hypotension (OH) and supine hypertension, urinary dysfunction characterized by overactive bladder and incomplete bladder emptying, sexual dysfunction characterized by sexual desire deficiency and erectile dysfunction, and gastrointestinal dysfunction characterized by delayed gastric emptying and constipation, are the main features of MSA. Autonomic dysfunction greatly reduces quality of life and increases mortality. Therefore, early diagnosis and intervention are urgently needed to benefit MSA patients. In this review, we aim to discuss the systematic treatment of autonomic dysfunction in MSA, and focus on the current methods, starting from non-pharmacological methods, such as patient education, psychotherapy, diet change, surgery, and neuromodulation, to various drug treatments targeting autonomic nerve and its projection fibers. In addition, we also draw attention to the interactions among various treatments, and introduce novel methods proposed in recent years, such as gene therapy, stem cell therapy, and neural prosthesis implantation. Furthermore, we elaborate on the specific targets and mechanisms of action of various drugs. We would like to call for large-scale research to determine the efficacy of these methods in the future. Finally, we point out that studies on the pathogenesis of MSA and pathophysiological mechanisms of various autonomic dysfunction would also contribute to the development of new promising treatments and concepts.
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Affiliation(s)
- BaoLing Chen
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Gongye Road 253, Guangzhou, 510282, Guangdong, People's Republic of China
| | - Wanlin Yang
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Gongye Road 253, Guangzhou, 510282, Guangdong, People's Republic of China
| | - Yuqi Luo
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Gongye Road 253, Guangzhou, 510282, Guangdong, People's Republic of China
| | - Eng-King Tan
- Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore.
- Duke-NUS Medical School, Singapore, Singapore.
| | - Qing Wang
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Gongye Road 253, Guangzhou, 510282, Guangdong, People's Republic of China.
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15
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Villena-Salinas J, Ortega-Lozano SJ, Amrani-Raissouni T, Agüera E, Caballero-Villarraso J. Follow-Up Findings in Multiple System Atrophy from [ 123I]Ioflupane Single-Photon Emission Computed Tomography (SPECT): A Prospective Study. Biomedicines 2023; 11:2893. [PMID: 38001894 PMCID: PMC10669007 DOI: 10.3390/biomedicines11112893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/12/2023] [Accepted: 10/19/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Multiple system atrophy (MSA) is subdivided into two types: MSA-P (parkinsonian) and MSA-C (cerebellar). Brain SPECT allows for the detection of nigrostriatal involvement, even in the early stages. To date, the scientific literature does not show a consensus on how to follow-up MSA, especially MSA-C. Our aim was to analyze the diagnostic effectiveness of repeat [123I]Ioflupane SPECT for the follow-up of MSA. METHODS A longitudinal observational study on 22 MSA patients (11 males and 11 females). RESULTS Significant changes were obtained in the quantitative SPECT assessments in the three Striatum/Occipital indices. The qualitative SPECT diagnosis did not show differences between the initial and evolving SPECT, but the neurologist's clinical suspicion did. Our results showed a brain deterioration of around 31% at 12 months, this being the optimal cut-off for differentiating a diseased subject (capable of solving diagnostic error rate). Previous imaging tests were inconclusive, as they showed less deterioration in the SPECT and quantitative assessments with respect to the group of confirmed patients. Repeated SPECT increased the diagnostic sensitivity (50% vs. 75%) and positive predictive value (72.73% vs. 77%). In addition, repeated SPECT proved decisive in the diagnosis of initial inconclusive cases. CONCLUSION Repeat SPECT at 12 months proves useful in the diagnosis and follow-up of MSA.
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Affiliation(s)
- Javier Villena-Salinas
- Nuclear Medicine Service, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.V.-S.); (S.J.O.-L.); (T.A.-R.)
| | - Simeón José Ortega-Lozano
- Nuclear Medicine Service, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.V.-S.); (S.J.O.-L.); (T.A.-R.)
| | - Tomader Amrani-Raissouni
- Nuclear Medicine Service, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.V.-S.); (S.J.O.-L.); (T.A.-R.)
| | - Eduardo Agüera
- Neurology Service, Reina Sofia University Hospital, 14004 Córdoba, Spain;
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain
| | - Javier Caballero-Villarraso
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain
- Clinical Analyses Service, Reina Sofía University Hospital, 14004 Córdoba, Spain
- Department of Biochemistry and Molecular Biology, Universidad of Córdoba, 14071 Córdoba, Spain
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Stankovic I, Fanciulli A, Sidoroff V, Wenning GK. A Review on the Clinical Diagnosis of Multiple System Atrophy. CEREBELLUM (LONDON, ENGLAND) 2023; 22:825-839. [PMID: 35986227 PMCID: PMC10485100 DOI: 10.1007/s12311-022-01453-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/30/2022] [Indexed: 06/15/2023]
Abstract
Multiple system atrophy (MSA) is a rare, adult-onset, progressive neurodegenerative disorder with major diagnostic challenges. Aiming for a better diagnostic accuracy particularly at early disease stages, novel Movement Disorder Society criteria for the diagnosis of MSA (MDS MSA criteria) have been recently developed. They introduce a neuropathologically established MSA category and three levels of clinical diagnostic certainty including clinically established MSA, clinically probable MSA, and the research category of possible prodromal MSA. The diagnosis of clinically established and clinically probable MSA is based on the presence of cardiovascular or urological autonomic failure, parkinsonism (poorly L-Dopa-responsive for the diagnosis of clinically established MSA), and cerebellar syndrome. These core clinical features need to be associated with supportive motor and non-motor features (MSA red flags) and absence of any exclusion criteria. Characteristic brain MRI markers are required for a diagnosis of clinically established MSA. A research category of possible prodromal MSA is devised to capture patients manifesting with autonomic failure or REM sleep behavior disorder and only mild motor signs at the earliest disease stage. There is a number of promising laboratory markers for MSA that may help increase the overall clinical diagnostic accuracy. In this review, we will discuss the core and supportive clinical features for a diagnosis of MSA in light of the new MDS MSA criteria, which laboratory tools may assist in the clinical diagnosis and which major differential diagnostic challenges should be borne in mind.
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Affiliation(s)
- Iva Stankovic
- Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | | | - Victoria Sidoroff
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Gregor K Wenning
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Goolla M, Cheshire WP, Ross OA, Kondru N. Diagnosing multiple system atrophy: current clinical guidance and emerging molecular biomarkers. Front Neurol 2023; 14:1210220. [PMID: 37840912 PMCID: PMC10570409 DOI: 10.3389/fneur.2023.1210220] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 09/18/2023] [Indexed: 10/17/2023] Open
Abstract
Multiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder characterized by motor and autonomic dysfunction. Accurate and early diagnosis of MSA is challenging due to its clinical similarity with other neurodegenerative disorders, such as Parkinson's disease and atypical parkinsonian disorders. Currently, MSA diagnosis is based on clinical criteria drawing from the patient's symptoms, lack of response to levodopa therapy, neuroimaging studies, and exclusion of other diseases. However, these methods have limitations in sensitivity and specificity. Recent advances in molecular biomarker research, such as α-synuclein protein amplification assays (RT-QuIC) and other biomarkers in cerebrospinal fluid and blood, have shown promise in improving the diagnosis of MSA. Additionally, these biomarkers could also serve as targets for developing disease-modifying therapies and monitoring treatment response. In this review, we provide an overview of the clinical syndrome of MSA and discuss the current diagnostic criteria, limitations of current diagnostic methods, and emerging molecular biomarkers that offer hope for improving the accuracy and early detection of MSA.
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Affiliation(s)
- Meghana Goolla
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Department of Surgery, University of Illinois, Chicago, IL, United States
| | | | - Owen A. Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, United States
- Department of Biology, University of North Florida, Jacksonville, FL, United States
| | - Naveen Kondru
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
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18
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Eschlboeck S, Goebel G, Eckhardt C, Fanciulli A, Raccagni C, Boesch S, Djamshidian A, Heim B, Mahlknecht P, Mair K, Nachbauer W, Scherfler C, Stockner H, Poewe W, Seppi K, Kiechl S, Wenning G, Krismer F, and the EMSA‐SG NHS Investigators. Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy. Mov Disord Clin Pract 2023; 10:1368-1376. [PMID: 37772304 PMCID: PMC10525072 DOI: 10.1002/mdc3.13822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 06/05/2023] [Accepted: 06/14/2023] [Indexed: 09/30/2023] Open
Abstract
Background Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.
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Affiliation(s)
| | - Georg Goebel
- Department of Medical Statistics Informatics and Health EconomicsInnsbruck Medical UniversityInnsbruckAustria
| | - Christine Eckhardt
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
- Department of AnesthesiaInnsbruck Medical UniversityInnsbruckAustria
| | | | - Cecilia Raccagni
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
- Department of Neurology, Provincial Hospital of BolzanoTeaching hospital of Paracelsus Medical Private UniversityBolzano‐BozenItaly
| | - Sylvia Boesch
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
| | | | - Beatrice Heim
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
| | | | - Katherina Mair
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
| | | | | | - Heike Stockner
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
| | - Werner Poewe
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
| | - Klaus Seppi
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
- Department of NeurologyProvincial Hospital of KufsteinKufsteinAustria
| | - Stefan Kiechl
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
| | - Gregor Wenning
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
| | - Florian Krismer
- Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
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Chompoopong P, Reiter-Campeau S. Recent updates in autonomic research: orthostatic hypotension and cognitive function in Parkinson disease and multiple system atrophy, the skin as a window into synuclein pathology, and RFC1 repeat expansions in hereditary sensory autonomic neuropathies. Clin Auton Res 2023; 33:387-389. [PMID: 37493897 DOI: 10.1007/s10286-023-00968-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 07/15/2023] [Indexed: 07/27/2023]
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Raheel K, Deegan G, Di Giulio I, Cash D, Ilic K, Gnoni V, Chaudhuri KR, Drakatos P, Moran R, Rosenzweig I. Sex differences in alpha-synucleinopathies: a systematic review. Front Neurol 2023; 14:1204104. [PMID: 37545736 PMCID: PMC10398394 DOI: 10.3389/fneur.2023.1204104] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/13/2023] [Indexed: 08/08/2023] Open
Abstract
Background Past research indicates a higher prevalence, incidence, and severe clinical manifestations of alpha-synucleinopathies in men, leading to a suggestion of neuroprotective properties of female sex hormones (especially estrogen). The potential pathomechanisms of any such effect on alpha-synucleinopathies, however, are far from understood. With that aim, we undertook to systematically review, and to critically assess, contemporary evidence on sex and gender differences in alpha-synucleinopathies using a bench-to-bedside approach. Methods In this systematic review, studies investigating sex and gender differences in alpha-synucleinopathies (Rapid Eye Movement (REM) Behavior Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) from 2012 to 2022 were identified using electronic database searches of PubMed, Embase and Ovid. Results One hundred sixty-two studies were included; 5 RBD, 6 MSA, 20 DLB and 131 PD studies. Overall, there is conclusive evidence to suggest sex-and gender-specific manifestation in demographics, biomarkers, genetics, clinical features, interventions, and quality of life in alpha-synucleinopathies. Only limited data exists on the effects of distinct sex hormones, with majority of studies concentrating on estrogen and its speculated neuroprotective effects. Conclusion Future studies disentangling the underlying sex-specific mechanisms of alpha-synucleinopathies are urgently needed in order to enable novel sex-specific therapeutics.
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Affiliation(s)
- Kausar Raheel
- Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
| | - Gemma Deegan
- Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- BRAIN, Imaging Centre, CNS, King’s College London, London, United Kingdom
| | - Irene Di Giulio
- Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- School of Basic and Medical Biosciences, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom
| | - Diana Cash
- Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- BRAIN, Imaging Centre, CNS, King’s College London, London, United Kingdom
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
| | - Katarina Ilic
- Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- BRAIN, Imaging Centre, CNS, King’s College London, London, United Kingdom
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
| | - Valentina Gnoni
- Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- Center for Neurodegenerative Diseases and the Aging Brain, University of Bari Aldo Moro, Lecce, Italy
| | - K. Ray Chaudhuri
- Movement Disorders Unit, King’s College Hospital and Department of Clinical and Basic Neurosciences, Institute of Psychiatry, Psychology and Neuroscience and Parkinson Foundation Centre of Excellence, King’s College London, London, United Kingdom
| | - Panagis Drakatos
- School of Basic and Medical Biosciences, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom
- Sleep Disorders Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
| | - Rosalyn Moran
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
| | - Ivana Rosenzweig
- Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- Sleep Disorders Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
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Lenka A, Isonaka R, Holmes C, Goldstein DS. Cardiac 18F-Dopamine Positron Emission Tomography Predicts the Type of Phenoconversion of Pure Autonomic Failure. RESEARCH SQUARE 2023:rs.3.rs-3157807. [PMID: 37503103 PMCID: PMC10371148 DOI: 10.21203/rs.3.rs-3157807/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Background Pure autonomic failure (PAF) is a rare disease characterized clinically by neurogenic orthostatic hypotension (nOH) and biochemically by peripheral noradrenergic deficiency. Clinically diagnosed PAF can evolve ("phenoconvert") to a central Lewy body disease (LBD, e.g., Parkinson's disease (PD) or dementia with Lewy bodies (DLB)) or to the non-LBD synucleinopathy multiple system atrophy (MSA). We examined whether cardiac 18F-dopamine positron emission tomography (PET) predicts the trajectory of phenoconversion in PAF. Since cardiac 18F-dopamine-derived radioactivity always is decreased in LBDs with nOH and usually is normal in MSA, we hypothesized that PAF patients with low cardiac 18F-dopamine-derived radioactivity may phenoconvert to a central LBD but do not phenoconvert to MSA. Methods We reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 with a clinical diagnosis of PAF and data about serial 18F-dopamine PET. Results Twenty patients met the above criteria. Of 15 with low cardiac 18F-dopamine-derived radioactivity, 6 (40%) phenoconverted to PD or DLB and none to MSA. Of 5 patients with consistently normal 18F-dopamine PET, 4 phenoconverted to MSA, and the other at autopsy had neither a central LBD nor MSA. Conclusion In this case series, 40% of patients with nOH and low cardiac 18F-dopamine-derived radioactivity phenoconverted to PD or DLB during follow-up; none phenoconverted to MSA. Cardiac 18F-DA PET therefore can predict the type of phenoconversion in PAF. This capability could refine eligibility criteria for entry into disease-modification trials aiming to prevent evolution of PAF to symptomatic central LBDs.
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Affiliation(s)
| | - Risa Isonaka
- National Institute of Neurological Disorders and Stroke Intramural Research Program
| | - Courtney Holmes
- National Institute of Neurological Disorders and Stroke Intramural Research Program
| | - David S Goldstein
- National Institute of Neurological Disorders and Stroke Intramural Research Program
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22
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Villena-Salinas J, Ortega-Lozano SJ, Amrani-Raissouni T, Agüera E, Caballero-Villarraso J. Diagnostic Effectiveness of [ 123I]Ioflupane Single Photon Emission Computed Tomography (SPECT) in Multiple System Atrophy. J Clin Med 2023; 12:jcm12103478. [PMID: 37240584 DOI: 10.3390/jcm12103478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/07/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder that has no curative treatment. Diagnosis is based on a set of criteria established by Gilman (1998 and 2008) and recently updated by Wenning (2022). We aim to determine the effectiveness of [123I]Ioflupane SPECT in MSA, especially at the initial clinical suspicion. METHODS A cross-sectional study of patients at the initial clinical suspicion of MSA, referred for [123I]Ioflupane SPECT. RESULTS Overall, 139 patients (68 men, 71 women) were included, 104 being MSA-probable and 35 MSA-possible. MRI was normal in 89.2%, while SPECT was positive in 78.45%. SPECT showed high sensitivity (82.46%) and positive predictive value (86.24), reaching maximum sensitivity in MSA-P (97.26%). Significant differences were found when relating both SPECT assessments in the healthy-sick and inconclusive-sick groups. We also found an association when relating SPECT to the subtype (MSA-C or MSA-P), as well as to the presence of parkinsonian symptoms. Lateralization of striatal involvement was detected (left side). CONCLUSIONS [123I]Ioflupane SPECT is a useful and reliable tool for diagnosing MSA, with good effectiveness and accuracy. Qualitative assessment shows a clear superiority when distinguishing between the healthy-sick categories, as well as between the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes at initial clinical suspicion.
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Affiliation(s)
- Javier Villena-Salinas
- Nuclear Medicine Service, Virgen de la Victoria University Hospital, 29010 Málaga, Spain
| | | | | | - Eduardo Agüera
- Neurology Service, Reina Sofia University Hospital, 14004 Córdoba, Spain
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain
| | - Javier Caballero-Villarraso
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain
- Clinical Analyses Service, Reina Sofía University Hospital, 14004 Córdoba, Spain
- Department of Biochemistry and Molecular Biology, Universidad of Córdoba, 14004 Córdoba, Spain
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23
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Bougea A, Stefanis L. microRNA and circRNA in Parkinson's Disease and atypical parkinsonian syndromes. Adv Clin Chem 2023; 115:83-133. [PMID: 37673523 DOI: 10.1016/bs.acc.2023.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
Abstract
Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are atypical parkinsonian syndromes (APS) with various clinical phenotypes and considerable clinical overlap with idiopathic Parkinson's disease (iPD). This disease heterogeneity makes ante-mortem diagnosis extremely challenging with up to 24% of patients misdiagnosed. Because diagnosis is predominantly clinical, there is great interest in identifying biomarkers for early diagnosis and differentiation of the different types of parkinsonism. Compared to protein biomarkers, microRNAs (miRNAs) and circularRNAs (circRNAs) are stable tissue-specific molecules that can be accurately measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). This chapter critically reviews miRNAs and circRNAs as diagnostic biomarkers and therapeutics to differentiate atypical parkinsonian disorders and their role in disease pathogenesis.
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Affiliation(s)
- Anastasia Bougea
- 1st Department of Neurology, Medical School, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | - Leonidas Stefanis
- 1st Department of Neurology, Medical School, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Goh YY, Saunders E, Pavey S, Rushton E, Quinn N, Houlden H, Chelban V. Multiple system atrophy. Pract Neurol 2023; 23:208-221. [PMID: 36927875 DOI: 10.1136/pn-2020-002797] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2023] [Indexed: 03/18/2023]
Abstract
This is a practical guide to diagnosing and managing multiple system atrophy (MSA). We explain the newly published Movement Disorders Society Consensus Diagnostic Criteria, which include new 'Clinically Established MSA' and 'Possible Prodromal MSA' categories, hopefully reducing time to diagnosis. We then highlight the key clinical features of MSA to aid diagnosis. We include a list of MSA mimics with suggested methods of differentiation from MSA. Lastly, we discuss practical symptom management in people living with MSA, including balancing side effects, with the ultimate aim of improving quality of life.
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Affiliation(s)
- Yee Yen Goh
- Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
| | | | | | | | - Niall Quinn
- Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
| | - Henry Houlden
- Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
| | - Viorica Chelban
- Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK .,Neurobiology and Medical Genetics Laboratory, "Nicolae Testemitanu" State University of Medicine and Pharmacy, Chisinau, Moldova
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Sturchio A, Espay AJ. The theoretical problems of "prodrome" and "phenoconversion" in neurodegeneration. HANDBOOK OF CLINICAL NEUROLOGY 2023; 192:155-167. [PMID: 36796940 DOI: 10.1016/b978-0-323-85538-9.00002-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
The recognition of and approach to prodromal symptoms, those which manifest before a diagnosis can be ascertained at the bedside, are of increasing interest in neurodegenerative research. A prodrome is conceived of as an early window into a disease, a critical time when putative disease-modifying interventions may be best suited for examination. Several challenges affect research in this area. Prodromal symptoms are highly prevalent in the population, can be nonprogressive for years or decades, and exhibit limited specificity in predicting conversion versus nonconversion into a neurodegenerative category within a time window feasible for most longitudinal clinical studies. In addition, there is a large range of biological alterations subsumed within each prodromal syndrome, forced to converge into the unifying nosology of each neurodegenerative disorder. Initial prodromal subtyping efforts have been developed but given the scarcity of prodrome-to-disease longitudinal studies, it is not yet clear whether any prodromal subtype can be predicted to evolve into the corresponding subtype of manifesting disease - a form of construct validity. As current subtypes generated from one clinical population are not faithfully replicated to others, it is likely that, lacking biological or molecular anchors, prodromal subtypes may only be applicable to the cohorts within which they were developed. Furthermore, as clinical subtypes have not aligned with a consistent pattern of pathology or biology, such might also be the fate of prodromal subtypes. Finally, the threshold defining the change from prodrome to disease for most neurodegenerative disorders remains clinical (e.g., a motor change in gait becoming noticeable to a clinician or measurable with portable technologies), not biological. As such, a prodrome can be viewed as a disease state not yet overt to a clinician. Efforts into identifying biological subtypes of disease, regardless of clinical phenotype or disease stage, may best serve future disease-modifying therapeutic strategies deployed not for a prodromal symptom but for a defined biological derangement as soon as it can be determined to lead to clinical changes, prodromal or not.
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Affiliation(s)
- Andrea Sturchio
- James J. and Joan A. Gardner Family Center for Parkinson's disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, United States; Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institutet, Stockholm, Sweden.
| | - Alberto J Espay
- James J. and Joan A. Gardner Family Center for Parkinson's disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, United States.
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Franco I. Anatomy, physiology, and evaluation: Bowel, bladder, and sexual disorders. HANDBOOK OF CLINICAL NEUROLOGY 2023; 196:403-423. [PMID: 37620081 DOI: 10.1016/b978-0-323-98817-9.00009-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
Our present understanding of bowel and bladder control has changed dramatically with the introduction of functional imagining technologies such as PET, SPECT, fMRI scanning, and near-infrared spectroscopy of the brain. Urologists tend to see control of urination and defecation as processes that occurred at or below the level of the pons for the most part. In this chapter, we examine the control of storing and emptying of urine and stool from what will be a more neurocentric perspective, integrating the frontal lobes into the process and moving beyond the pons on which most of the literature has focused in the past. Utilizing this approach gives us a better understanding of why there is an overlapping of neuropsychiatric problems in many patients with voiding dysfunction.
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Affiliation(s)
- Israel Franco
- Yale School of Medicine, Yale-New Haven Children's Bladder and Continence Program, Yale New Haven Children's Hospital, New Haven, CT, United States.
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Younger DS. Autonomic failure: Clinicopathologic, physiologic, and genetic aspects. HANDBOOK OF CLINICAL NEUROLOGY 2023; 195:55-102. [PMID: 37562886 DOI: 10.1016/b978-0-323-98818-6.00020-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Over the past century, generations of neuroscientists, pathologists, and clinicians have elucidated the underlying causes of autonomic failure found in neurodegenerative, inherited, and antibody-mediated autoimmune disorders, each with pathognomonic clinicopathologic features. Autonomic failure affects central autonomic nervous system components in the α-synucleinopathy, multiple system atrophy, characterized clinically by levodopa-unresponsive parkinsonism or cerebellar ataxia, and pathologically by argyrophilic glial cytoplasmic inclusions (GCIs). Two other central neurodegenerative disorders, pure autonomic failure characterized clinically by deficits in norepinephrine synthesis and release from peripheral sympathetic nerve terminals; and Parkinson's disease, with early and widespread autonomic deficits independent of the loss of striatal dopamine terminals, both express Lewy pathology. The rare congenital disorder, hereditary sensory, and autonomic neuropathy type III (or Riley-Day, familial dysautonomia) causes life-threatening autonomic failure due to a genetic mutation that results in loss of functioning baroreceptors, effectively separating afferent mechanosensing neurons from the brain. Autoimmune autonomic ganglionopathy caused by autoantibodies targeting ganglionic α3-acetylcholine receptors instead presents with subacute isolated autonomic failure affecting sympathetic, parasympathetic, and enteric nervous system function in various combinations. This chapter is an overview of these major autonomic disorders with an emphasis on their historical background, neuropathological features, etiopathogenesis, diagnosis, and treatment.
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Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States; Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States.
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Lamotte G, Singer W. Synucleinopathies. HANDBOOK OF CLINICAL NEUROLOGY 2023; 196:175-202. [PMID: 37620069 DOI: 10.1016/b978-0-323-98817-9.00032-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
The α-synucleinopathies include pure autonomic failure, multiple system atrophy, dementia with Lewy bodies, and Parkinson disease. The past two decades have witnessed significant advances in the diagnostic strategies and symptomatic treatment of motor and nonmotor symptoms of the synucleinopathies. This chapter provides an in-depth review of the pathophysiology, pathology, genetic, epidemiology, and clinical and laboratory autonomic features that distinguish the different synucleinopathies with an emphasis on autonomic failure as a common feature. The treatment of the different synucleinopathies is discussed along with the proposal for multidisciplinary, individualized care models that optimally address the various symptoms. There is an urgent need for clinical scientific studies addressing patients at risk of developing synucleinopathies and the investigation of disease mechanisms, biomarkers, potential disease-modifying therapies, and further advancement of symptomatic treatments for motor and nonmotor symptoms.
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Affiliation(s)
- Guillaume Lamotte
- Department of Neurology, University of Utah, Salt Lake City, UT, United States
| | - Wolfgang Singer
- Department of Neurology, Mayo Clinic, Rochester, MN, United States.
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Abstract
Multiple system atrophy (MSA) is a rare neurodegenerative disorder with unclear etiology, currently difficult and delayed diagnosis, and rapid progression, leading to disability and lethality within 6 to 9 years after symptom onset. The neuropathology of MSA classifies the disease in the group of a-synucleinopathies together with Parkinson's disease and other Lewy body disorders, but features specific oligodendroglial inclusions, which are pathognomonic for MSA. MSA has no efficient therapy to date. Development of experimental models is crucial to elucidate the disease mechanisms in progression and to provide a tool for preclinical screening of putative therapies for MSA. In vitro and in vivo models, based on selective neurotoxicity, a-synuclein oligodendroglial overexpression, and strain-specific propagation of a-synuclein fibrils, have been developed, reflecting various facets of MSA pathology. Over the years, the continuous exchange from bench to bedside and backward has been crucial for the advancing of MSA modelling, elucidating MSA pathogenic pathways, and understanding the existing translational gap to successful clinical trials in MSA. The review discusses specifically advantages and limitations of the PLP-a-syn mouse model of MSA, which recapitulates motor and non-motor features of the human disease with underlying striatonigral degeneration, degeneration of autonomic centers, and sensitized olivopontocerebellar system, strikingly mirroring human MSA pathology.
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Affiliation(s)
- Nadia Stefanova
- Laboratory for Translational Neurodegeneration Research, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
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Nasri A, Gharbi A, Sghaier I, Mrabet S, Souissi A, Gargouri A, Djebara MB, Kacem I, Gouider R. Determinants of cognitive impairment in multiple system atrophy: Clinical and genetic study. PLoS One 2022; 17:e0277798. [PMID: 36508411 PMCID: PMC9744291 DOI: 10.1371/journal.pone.0277798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/03/2022] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Classically, cognitive impairment (CI) was not considered as a paramount feature of multiple system atrophy(MSA) in both parkinsonian(MSA-P) and cerebellar(MSA-C) motor-subtypes. Yet, growing evidence indicates currently the commonness of such deficits among MSA patients in different populations. Our aim was to evaluate the cognitive profile of MSA Tunisian patients and to analyze the underlying clinical and genetic determinants. METHODS In a retrospective cross-sectional study, clinically-diagnosed MSA patients were included. All subjects underwent clinical and neuropsychological assessments to characterize their cognitive profile. The associations with their APOE genotype status were analyzed. Determinant of CI were specified. RESULTS We included 71 MSA patients. Female gender(sex-ratio = 0.65) and MSA-P subtype(73%) were predominant. Mean age of disease onset was 59.1years. CI was found in 85.7% of patients(dementia in 12.7% and Mild cognitive impairment(MCI) in 73% of patients mainly of multiple-domain amnestic type(37.3%)). Mean MMSE score was lower among MSA-P compared to MSA-C(23.52 vs. 26.47;p = 0.027). Higher postural instability gait disorder(PIGD) and MDS-UPDRS-III scores were noted in demented MSA patients(p = 0.019;p = 0.015 respectively). The main altered cognitive domain was attention(64.8%). Executive functions and mood disorders were more affected in MSA-P(p = 0.029,p = 0.035 respectively). Clinical and neurophysiological study of dysautonomia revealed no differences across cognitive subtypes. APOE genotyping was performed in 51 MSA patients with available blood samples. Those carrying APOEε4 had 1.32 fold higher risk to develop CI, with lower MMSE score(p = 0.0001). Attention and language were significantly altered by adjusting the p value to APOEɛ4 carriers(p = 0.046 and p = 0.044 respectively). Executive dysfunction was more pronounced among MSA-PAPOEε4 carriers(p = 0.010). CONCLUSION In this study, the main determinants of CI in Tunisian MSA patients were MSA-P motor-subtype, mainly of PIGD-phenotype, disease duration and APOEε4 carrying status, defining a more altered cognitive phenotype. This effect mainly concerned executive, attention and language functions, all found to be more impaired in APOEε4 carriers with variable degrees across MSA motor-subtypes.
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Affiliation(s)
- Amina Nasri
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
| | - Alya Gharbi
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
| | - Ikram Sghaier
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
| | - Saloua Mrabet
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
| | - Amira Souissi
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
| | - Amina Gargouri
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
| | - Mouna Ben Djebara
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
| | - Imen Kacem
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
| | - Riadh Gouider
- Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia
- * E-mail:
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Pedroso JL, Vale TC, França Junior MC, Kauffman MA, Teive H, Barsottini OGP, Munhoz RP. A Diagnostic Approach to Spastic ataxia Syndromes. CEREBELLUM (LONDON, ENGLAND) 2022; 21:1073-1084. [PMID: 34782953 DOI: 10.1007/s12311-021-01345-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/08/2021] [Indexed: 06/13/2023]
Abstract
Spastic ataxia is characterized by the combination of cerebellar ataxia with spasticity and other pyramidal features. It is the hallmark of some hereditary ataxias, but it can also occur in some spastic paraplegias and acquired conditions. It often presents with heterogenous clinical features with other neurologic and non-neurological symptoms, resulting in complex phenotypes. In this review, the differential diagnosis of spastic ataxias are discussed and classified in accordance with inheritance. Establishing an organized classification method based on mode inheritance is fundamental for the approach to patients with these syndromes. For each differential, the clinical features, neuroimaging and genetic aspects are reviewed. A diagnostic approach for spastic ataxias is then proposed.
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Affiliation(s)
- José Luiz Pedroso
- Department of Neurology, Ataxia Unit, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Thiago Cardoso Vale
- Department of Internal Medicine, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil
| | | | - Marcelo A Kauffman
- Laboratorio de Neurogenética, Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, Buenos Aires, Argentina
| | - Helio Teive
- Department of Neurology, Universidade Federal do Paraná, Curitiba, PR, Brazil
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32
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Vichayanrat E, Valerio F, Koay S, De Pablo-Fernandez E, Panicker J, Morris H, Bhatia K, Chelban V, Houlden H, Quinn N, Navarro-Otano J, Miki Y, Holton J, Warner T, Mathias C, Iodice V. Diagnosing Premotor Multiple System Atrophy: Natural History and Autonomic Testing in an Autopsy-Confirmed Cohort. Neurology 2022; 99:e1168-e1177. [PMID: 35790426 PMCID: PMC9536739 DOI: 10.1212/wnl.0000000000200861] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 05/02/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Nonmotor features precede motor symptoms in many patients with multiple system atrophy (MSA). However, little is known about differences between the natural history, progression, and prognostic factors for survival in patients with MSA with nonmotor vs motor presentations. We aimed to compare initial symptoms, disease progression, and clinical features at final evaluation and investigate differences in survival and natural history between patients with MSA with motor and nonmotor presentations. METHODS Medical records of autopsy-confirmed MSA cases at Queen Square Brain Bank who underwent both clinical examination and cardiovascular autonomic testing were identified. Clinical features, age at onset, sex, time from onset to diagnosis, disease duration, autonomic function tests, and plasma noradrenaline levels were evaluated. RESULTS Forty-seven patients with autopsy-confirmed MSA (age 60 ± 8 years; 28 men) were identified. Time from symptom onset to first autonomic evaluation was 4 ± 2 years, and the disease duration was 7.7 ± 2.2 years. Fifteen (32%) patients presented with nonmotor features including genitourinary dysfunction, orthostatic hypotension, or REM sleep behavior disorder before developing motor involvement (median delay 1-6 years). A third (5/15) were initially diagnosed with pure autonomic failure (PAF) before evolving into MSA. All these patients had normal supine plasma noradrenaline levels (332.0 ± 120.3 pg/mL) with no rise on head-up tilt (0.1 ± 0.3 pg/mL). Patients with MSA with early cardiovascular autonomic dysfunction (within 3 years of symptom onset) had shorter survival compared with those with later onset of cardiovascular autonomic impairment (6.8 years [5.6-7.9] vs 8.5 years [7.9-9.2]; p = 0.026). Patients with early urinary catheterization had shorter survival than those requiring catheterization later (6.2 years [4.6-7.8] vs 8.5 years [7.6-9.4]; p = 0.02). The survival of patients with MSA presenting with motor and nonmotor symptoms did not differ (p > 0.05). DISCUSSION Almost one-third of patients with MSA presented with nonmotor features, which could predate motor symptoms by up to 6 years. Cardiovascular autonomic failure and early urinary catheterization were predictors of poorer outcomes. A normal supine plasma noradrenaline level in patients presenting with PAF phenotype is a possible autonomic biomarker indicating later conversion to MSA.
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Affiliation(s)
- Ekawat Vichayanrat
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Fernanda Valerio
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Shiwen Koay
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Eduardo De Pablo-Fernandez
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Jalesh Panicker
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Huw Morris
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Kailash Bhatia
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Viorica Chelban
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Henry Houlden
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Niall Quinn
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Judith Navarro-Otano
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Yasuo Miki
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Janice Holton
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Thomas Warner
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Christopher Mathias
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
| | - Valeria Iodice
- From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom.
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Abstract
Multiple system atrophy (MSA) is a rare neurodegenerative disease that is characterized by neuronal loss and gliosis in multiple areas of the central nervous system including striatonigral, olivopontocerebellar and central autonomic structures. Oligodendroglial cytoplasmic inclusions containing misfolded and aggregated α-synuclein are the histopathological hallmark of MSA. A firm clinical diagnosis requires the presence of autonomic dysfunction in combination with parkinsonism that responds poorly to levodopa and/or cerebellar ataxia. Clinical diagnostic accuracy is suboptimal in early disease because of phenotypic overlaps with Parkinson disease or other types of degenerative parkinsonism as well as with other cerebellar disorders. The symptomatic management of MSA requires a complex multimodal approach to compensate for autonomic failure, alleviate parkinsonism and cerebellar ataxia and associated disabilities. None of the available treatments significantly slows the aggressive course of MSA. Despite several failed trials in the past, a robust pipeline of putative disease-modifying agents, along with progress towards early diagnosis and the development of sensitive diagnostic and progression biomarkers for MSA, offer new hope for patients.
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Sekiya H, Koga S, Otsuka Y, Chihara N, Ueda T, Sekiguchi K, Yoneda Y, Kageyama Y, Matsumoto R, Dickson DW. Clinical and pathological characteristics of later onset multiple system atrophy. J Neurol 2022; 269:4310-4321. [PMID: 35305144 PMCID: PMC10315173 DOI: 10.1007/s00415-022-11067-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND In the current consensus criteria, onset after age 75 is considered as non-supporting for diagnosis of multiples system atrophy (MSA); however, some MSA patients present after age 75. Clinical and pathological characteristics of such later onset MSA (LO-MSA) compared to usual onset MSA (UO-MSA) remain poorly understood. METHODS The clinical cohort included patients from Kobe University Hospital and Amagasaki General Medical Center Hospital, while the autopsy cohort was from the brain bank at Mayo Clinic Florida. We identified 83 patients in the clinical cohort and 193 patients in the autopsy cohort. We divided MSA into two groups according to age at onset: UO-MSA (≤ 75) and LO-MSA (> 75). We compared clinical features and outcomes between the two groups in the clinical cohort and compared the findings to the autopsy cohort. RESULTS LO-MSA accounted for 8% in the clinical cohort and 5% in the autopsy cohort. The median time from onset to death or to life-saving tracheostomy was significantly shorter in LO-MSA than in UO-MSA in both cohorts (4.8 vs 7.9 years in the clinical cohort and 3.9 vs 7.5 years in the autopsy cohort; P = 0.043 and P < 0.0001, respectively). The median time from diagnosis to death was less than 3 years in LO-MSA in the clinical cohort. CONCLUSIONS Some MSA patients have late age of onset and short survival, limiting time for clinical decision making. MSA should be considered in the differential diagnosis of elderly patients with autonomic symptoms and extrapyramidal and/or cerebellar syndromes.
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Affiliation(s)
- Hiroaki Sekiya
- Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
- Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
| | - Shunsuke Koga
- Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Yoshihisa Otsuka
- Department of Neurology, Hyogo Prefectural Amagasaki General Medical Center Hospital, Amagasaki, Hyogo, Japan
| | - Norio Chihara
- Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Takehiro Ueda
- Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Kenji Sekiguchi
- Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Yukihiro Yoneda
- Department of Neurology, Hyogo Prefectural Amagasaki General Medical Center Hospital, Amagasaki, Hyogo, Japan
| | - Yasufumi Kageyama
- Department of Neurology, Hyogo Prefectural Amagasaki General Medical Center Hospital, Amagasaki, Hyogo, Japan
| | - Riki Matsumoto
- Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Dennis W Dickson
- Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
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Chen R, Berardelli A, Bhattacharya A, Bologna M, Chen KHS, Fasano A, Helmich RC, Hutchison WD, Kamble N, Kühn AA, Macerollo A, Neumann WJ, Pal PK, Paparella G, Suppa A, Udupa K. Clinical neurophysiology of Parkinson's disease and parkinsonism. Clin Neurophysiol Pract 2022; 7:201-227. [PMID: 35899019 PMCID: PMC9309229 DOI: 10.1016/j.cnp.2022.06.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 06/11/2022] [Accepted: 06/22/2022] [Indexed: 01/01/2023] Open
Abstract
This review is part of the series on the clinical neurophysiology of movement disorders and focuses on Parkinson’s disease and parkinsonism. The pathophysiology of cardinal parkinsonian motor symptoms and myoclonus are reviewed. The recordings from microelectrode and deep brain stimulation electrodes are reported in detail. This review is part of the series on the clinical neurophysiology of movement disorders. It focuses on Parkinson’s disease and parkinsonism. The topics covered include the pathophysiology of tremor, rigidity and bradykinesia, balance and gait disturbance and myoclonus in Parkinson’s disease. The use of electroencephalography, electromyography, long latency reflexes, cutaneous silent period, studies of cortical excitability with single and paired transcranial magnetic stimulation, studies of plasticity, intraoperative microelectrode recordings and recording of local field potentials from deep brain stimulation, and electrocorticography are also reviewed. In addition to advancing knowledge of pathophysiology, neurophysiological studies can be useful in refining the diagnosis, localization of surgical targets, and help to develop novel therapies for Parkinson’s disease.
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Affiliation(s)
- Robert Chen
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Neurology, Department of Medicine, University of Toronto, Ontario, Canada.,Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
| | - Alfredo Berardelli
- Department of Human Neurosciences, Sapienza University of Rome, Italy.,IRCCS Neuromed Pozzilli (IS), Italy
| | - Amitabh Bhattacharya
- Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India
| | - Matteo Bologna
- Department of Human Neurosciences, Sapienza University of Rome, Italy.,IRCCS Neuromed Pozzilli (IS), Italy
| | - Kai-Hsiang Stanley Chen
- Department of Neurology, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Alfonso Fasano
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Neurology, Department of Medicine, University of Toronto, Ontario, Canada.,Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
| | - Rick C Helmich
- Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology and Centre of Expertise for Parkinson & Movement Disorders, Nijmegen, the Netherlands
| | - William D Hutchison
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Departments of Surgery and Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Nitish Kamble
- Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India
| | - Andrea A Kühn
- Department of Neurology, Movement Disorder and Neuromodulation Unit, Charité - Universitätsmedizin Berlin, Germany
| | - Antonella Macerollo
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, United Kingdom.,The Walton Centre NHS Foundation Trust for Neurology and Neurosurgery, Liverpool, United Kingdom
| | - Wolf-Julian Neumann
- Department of Neurology, Movement Disorder and Neuromodulation Unit, Charité - Universitätsmedizin Berlin, Germany
| | - Pramod Kumar Pal
- Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India
| | | | - Antonio Suppa
- Department of Human Neurosciences, Sapienza University of Rome, Italy.,IRCCS Neuromed Pozzilli (IS), Italy
| | - Kaviraja Udupa
- Department of Neurophysiology National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India
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Lee WW, Kim HJ, Lee HJ, Kim HB, Park KS, Sohn CH, Jeon B. Semiautomated Algorithm for the Diagnosis of Multiple System Atrophy With Predominant Parkinsonism. J Mov Disord 2022; 15:232-240. [PMID: 35880384 PMCID: PMC9536910 DOI: 10.14802/jmd.21178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/10/2022] [Indexed: 11/24/2022] Open
Abstract
Objective Putaminal iron deposition is an important feature that helps differentiate multiple system atrophy with predominant parkinsonism (MSA-p) from Parkinson’s disease (PD). Most previous studies used visual inspection or quantitative methods with manual manipulation to perform this differentiation. We investigated the value of a new semiautomated diagnostic algorithm using 3T-MR susceptibility-weighted imaging for MSA-p. Methods This study included 26 MSA-p, 68 PD, and 41 normal control (NC) subjects. The algorithm was developed in 2 steps: 1) determine the image containing the remarkable putaminal margin and 2) calculate the phase-shift values, which reflect the iron concentration. The next step was to identify the best differentiating conditions among several combinations. The highest phase-shift value of each subject was used to assess the most effective diagnostic set. Results The raw phase-shift values were present along the lateral margin of the putamen in each group. It demonstrates an anterior-to-posterior gradient that was identified most frequently in MSA-p. The average of anterior 5 phase shift values were used for normalization. The highest area under the receiver operating characteristic curve (0.874, 80.8% sensitivity, and 86.7% specificity) of MSA-p versus PD was obtained under the combination of 3 or 4 vertical pixels and one dominant side when the normalization methods were applied. In the subanalysis for the MSA-p patients with a longer disease duration, the performance of the algorithm improved. Conclusion This algorithm detected the putaminal lateral margin well, provided insight into the iron distribution of the putaminal rim of MSA-p, and demonstrated good performance in differentiating MSA-p from PD.
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Affiliation(s)
- Woong-Woo Lee
- Department of Neurology, Nowon Eulji Medical Center, Eulji University, Seoul, Korea.,Department of Neurology, Eulji University College of Medicine, Daejeon, Korea
| | - Han-Joon Kim
- Department of Neurology, Seoul National University Hospital, Seoul, Korea.,Department of Neurology, Seoul National University College of Medicine, Seoul, Korea
| | - Hong Ji Lee
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Korea
| | - Han Byul Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang Suk Park
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Korea
| | - Chul-Ho Sohn
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Beomseok Jeon
- Department of Neurology, Seoul National University Hospital, Seoul, Korea.,Department of Neurology, Seoul National University College of Medicine, Seoul, Korea
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Lin CR, Viswanathan A, Chen TX, Mitsumoto H, Vonsattel JP, Faust PL, Kuo S. Clinicopathological correlates of pyramidal signs in multiple system atrophy. Ann Clin Transl Neurol 2022; 9:988-994. [PMID: 35593123 PMCID: PMC9268870 DOI: 10.1002/acn3.51576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/23/2022] [Accepted: 04/26/2022] [Indexed: 01/03/2023] Open
Abstract
OBJECTIVE Pyramidal signs are common but often under-recognized in multiple system atrophy (MSA). The clinicopathological correlates of pyramidal signs in MSA are not well characterized. The present study aims to understand the role of pyramidal signs in MSA. METHODS We examined 40 autopsy-confirmed MSA cases in New York Brain Bank. The pyramidal signs were quantified by an established rating scale, summarized as the pyramidal score. We assessed whether pyramidal scores are associated with autonomic, parkinsonism, and cerebellar features and survival. We also examined whether the density of glial cytoplasmic inclusions (GCIs) in the motor cortex and its underlying white matter is associated with the pyramidal score. RESULTS MSA parkinsonian type cases have higher pyramidal scores compared to cerebellar type cases (p = 0.017). MSA cases with high pyramidal scores are more likely to have laryngeal stridor (OR = 4.89, p = 0.022), but less likely to have orthostatic hypotension (OR = 0.11, p = 0.006) and erectile dysfunction (OR = 0.05, p = 0.018). MSA cases with high pyramidal scores do not differ from those with low pyramidal scores in terms of bowel dysfunction, dry eyes and mouth, and survival. Finally, MSA cases with more GCIs in the motor cortex have higher pyramidal scores compared to those with few GCIs (p = 0.017). INTERPRETATION Pyramidal signs in MSA are associated with the parkinsonian subtype, laryngeal stridor, and certain autonomic dysfunction.
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Affiliation(s)
- Chi‐Ying R. Lin
- Department of NeurologyParkinson's Disease Center and Movement Disorders Clinic, Baylor College of MedicineHoustonTexasUSA
| | - Anisha Viswanathan
- Department of NeurologyColumbia University Irving Medical Center and the New York Presbyterian HospitalNew YorkNew YorkUSA
- Initiative for Columbia Ataxia and TremorColumbia University Irving Medical CenterNew YorkNew YorkUSA
| | - Tiffany X. Chen
- Department of NeurologyColumbia University Irving Medical Center and the New York Presbyterian HospitalNew YorkNew YorkUSA
- Initiative for Columbia Ataxia and TremorColumbia University Irving Medical CenterNew YorkNew YorkUSA
- Department of Biomedical Engineering, Whiting School of EngineeringJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Hiroshi Mitsumoto
- Department of NeurologyColumbia University Irving Medical Center and the New York Presbyterian HospitalNew YorkNew YorkUSA
- Eleanor and Lou Gehrig ALS CenterColumbia University Irving Medical CenterNew YorkNew YorkUSA
| | - Jean P. Vonsattel
- Department of Pathology and Cell BiologyColumbia University Irving Medical Center and the New York Presbyterian HospitalNew YorkNew YorkUSA
| | - Phyllis L. Faust
- Department of Pathology and Cell BiologyColumbia University Irving Medical Center and the New York Presbyterian HospitalNew YorkNew YorkUSA
| | - Sheng‐Han Kuo
- Department of NeurologyColumbia University Irving Medical Center and the New York Presbyterian HospitalNew YorkNew YorkUSA
- Initiative for Columbia Ataxia and TremorColumbia University Irving Medical CenterNew YorkNew YorkUSA
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Symptomatic Care in Multiple System Atrophy: State of the Art. CEREBELLUM (LONDON, ENGLAND) 2022; 22:433-446. [PMID: 35581488 PMCID: PMC10125958 DOI: 10.1007/s12311-022-01411-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 04/23/2022] [Indexed: 12/14/2022]
Abstract
Without any disease-modifying treatment strategy for multiple system atrophy (MSA), the therapeutic management of MSA patients focuses on a multidisciplinary strategy of symptom control. In the present review, we will focus on state of the art treatment in MSA and additionally give a short overview about ongoing randomized controlled trials in this field.
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Giannini G, Provini F, Cani I, Cecere A, Mignani F, Guaraldi P, Di Mirto CVF, Cortelli P, Calandra-Buonaura G. Tracheostomy is associated with increased survival in multiple system atrophy patients with stridor. Eur J Neurol 2022; 29:2232-2240. [PMID: 35384153 PMCID: PMC9545543 DOI: 10.1111/ene.15347] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/02/2022] [Indexed: 11/29/2022]
Abstract
Background and purpose Stridor treatment in multiple system atrophy (MSA) mainly comprises tracheostomy or continuous positive airway pressure (CPAP), but guidelines for the use of these treatments are lacking. The aim of the study was to evaluate the predictive value of stridor treatment in an MSA cohort. Methods This is a retrospective and prospective monocentric cohort study including MSA patients evaluated at least once a year during the disease course. Stridor was video‐polysomnography confirmed. The time of stridor treatment (CPAP or tracheostomy) and latency from stridor onset were collected. Survival and predictors of survival were calculated. Results A total of 182 (107 males, mean age at disease onset 57.3 ± 8.4 years) MSA patients were included in the study; 141 were deceased at the time of study. Of the total sample, 75 patients were diagnosed with stridor: 22 patients were treated with tracheostomy and 29 with CPAP, whilst 24 patients did not receive treatment. Treatment with tracheostomy showed longer survival compared with both treatment with CPAP or no treatment (incidence rate of death 12 vs. 21 vs. 23 per 100 person‐years, respectively). Tracheostomy remained an independent factor associated with longer survival (hazard ratio 0.38, p = 0.029), also after adjustment for other confounders and latency for stridor treatment. Conclusions This is the largest monocentric and long‐term follow‐up study comparing survival between tracheostomy and CPAP in MSA patients with stridor. Treatment with tracheostomy showed longer survival compared with both treatment with CPAP or no treatment. A careful multidisciplinary approach is required for the management of MSA patients with stridor.
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Affiliation(s)
- Giulia Giannini
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica Rete Metropolitana NEUROMET, Bologna, Italy.,Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Alma Mater Studiorum - University of Bologna, Italy
| | - Federica Provini
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica Rete Metropolitana NEUROMET, Bologna, Italy.,Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Alma Mater Studiorum - University of Bologna, Italy
| | - Ilaria Cani
- Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Alma Mater Studiorum - University of Bologna, Italy
| | - Annagrazia Cecere
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica Rete Metropolitana NEUROMET, Bologna, Italy
| | - Francesco Mignani
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica Rete Metropolitana NEUROMET, Bologna, Italy
| | - Pietro Guaraldi
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica Rete Metropolitana NEUROMET, Bologna, Italy
| | | | - Pietro Cortelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica Rete Metropolitana NEUROMET, Bologna, Italy.,Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Alma Mater Studiorum - University of Bologna, Italy
| | - Giovanna Calandra-Buonaura
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica Rete Metropolitana NEUROMET, Bologna, Italy.,Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Alma Mater Studiorum - University of Bologna, Italy
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40
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Jellinger KA. Heterogeneity of Multiple System Atrophy: An Update. Biomedicines 2022; 10:599. [PMID: 35327402 PMCID: PMC8945102 DOI: 10.3390/biomedicines10030599] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/24/2022] [Accepted: 03/02/2022] [Indexed: 02/04/2023] Open
Abstract
Multiple system atrophy (MSA) is a fatal, rapidly progressing neurodegenerative disease of uncertain etiology, clinically characterized by various combinations of Levodopa unresponsive parkinsonism, cerebellar, autonomic and motor dysfunctions. The morphological hallmark of this α-synucleinopathy is the deposition of aberrant α-synuclein in both glia, mainly oligodendroglia (glial cytoplasmic inclusions /GCIs/) and neurons, associated with glioneuronal degeneration of the striatonigral, olivopontocerebellar and many other neuronal systems. Typical phenotypes are MSA with predominant parkinsonism (MSA-P) and a cerebellar variant (MSA-C) with olivocerebellar atrophy. However, MSA can present with a wider range of clinical and pathological features than previously thought. In addition to rare combined or "mixed" MSA, there is a broad spectrum of atypical MSA variants, such as those with a different age at onset and disease duration, "minimal change" or prodromal forms, MSA variants with Lewy body disease or severe hippocampal pathology, rare forms with an unusual tau pathology or spinal myoclonus, an increasing number of MSA cases with cognitive impairment/dementia, rare familial forms, and questionable conjugal MSA. These variants that do not fit into the current classification of MSA are a major challenge for the diagnosis of this unique proteinopathy. Although the clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers, its distinction from clinically similar extrapyramidal disorders with other pathologies and etiologies may be difficult. These aspects should be taken into consideration when revising the current diagnostic criteria. This appears important given that disease-modifying treatment strategies for this hitherto incurable disorder are under investigation.
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Affiliation(s)
- Kurt A Jellinger
- Institute of Clinical Neurobiology, Alberichgasse 5/13, A-1150 Vienna, Austria
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41
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Todisco M, Cosentino G, Scardina S, Fresia M, Prunetti P, Pisani A, Alfonsi E. Diagnostic and Prognostic Value of External Anal Sphincter
EMG
Patterns in Multiple System Atrophy. Mov Disord 2022; 37:1069-1074. [PMID: 35122320 PMCID: PMC9305564 DOI: 10.1002/mds.28938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/06/2022] [Accepted: 01/09/2022] [Indexed: 11/08/2022] Open
Abstract
Background It is debated whether external anal sphincter (EAS) electromyography can distinguish between multiple system atrophy (MSA) and Parkinson's disease (PD), whereas its usefulness for MSA prognosis is unknown. Objectives We explored the diagnostic and prognostic value and clinical correlations of EAS electromyography patterns in MSA. Methods We collected clinical data and EAS electromyography findings in 72 patients with MSA and 21 with PD. Results We identified four EAS patterns. The normal pattern was frequently observed in PD and associated with prolonged survival when identified in MSA. Abnormal patterns were predominant in MSA. The most severe pattern was associated with the highest likelihood of MSA diagnosis and with the worst prognosis in the MSA cohort. MSA patients with EAS abnormalities often showed urogenital symptoms and fecal incontinence. Conclusions The increasing severity of EAS electromyography patterns paralleled diagnostic accuracy and survival in MSA, and correlated with prevalence of bladder and bowel symptoms. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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Affiliation(s)
- Massimiliano Todisco
- Translational Neurophysiology Research Unit IRCCS Mondino Foundation Pavia Italy
- Movement Disorders Research Center IRCCS Mondino Foundation Pavia Italy
- Department of Brain and Behavioral Sciences University of Pavia Pavia Italy
| | - Giuseppe Cosentino
- Translational Neurophysiology Research Unit IRCCS Mondino Foundation Pavia Italy
- Department of Brain and Behavioral Sciences University of Pavia Pavia Italy
| | - Serena Scardina
- Department of Biomedicine, Neuroscience and advanced Diagnostics (BIND) University of Palermo Palermo Italy
| | - Mauro Fresia
- Translational Neurophysiology Research Unit IRCCS Mondino Foundation Pavia Italy
| | - Paolo Prunetti
- Translational Neurophysiology Research Unit IRCCS Mondino Foundation Pavia Italy
| | - Antonio Pisani
- Movement Disorders Research Center IRCCS Mondino Foundation Pavia Italy
- Department of Brain and Behavioral Sciences University of Pavia Pavia Italy
| | - Enrico Alfonsi
- Translational Neurophysiology Research Unit IRCCS Mondino Foundation Pavia Italy
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Deuschl G, Becktepe JS, Dirkx M, Haubenberger D, Hassan A, Helmich R, Muthuraman M, Panyakaew P, Schwingenschuh P, Zeuner KE, Elble RJ. The clinical and electrophysiological investigation of tremor. Clin Neurophysiol 2022; 136:93-129. [DOI: 10.1016/j.clinph.2022.01.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/05/2022] [Accepted: 01/07/2022] [Indexed: 01/18/2023]
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Marmion DJ, Peelaerts W, Kordower JH. A historical review of multiple system atrophy with a critical appraisal of cellular and animal models. J Neural Transm (Vienna) 2021; 128:1507-1527. [PMID: 34613484 PMCID: PMC8528759 DOI: 10.1007/s00702-021-02419-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/15/2021] [Indexed: 12/31/2022]
Abstract
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.
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Affiliation(s)
- David J Marmion
- Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA
| | - Wouter Peelaerts
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
| | - Jeffrey H Kordower
- ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ, USA.
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Mehra S, Gadhe L, Bera R, Sawner AS, Maji SK. Structural and Functional Insights into α-Synuclein Fibril Polymorphism. Biomolecules 2021; 11:1419. [PMID: 34680054 PMCID: PMC8533119 DOI: 10.3390/biom11101419] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/21/2021] [Accepted: 09/23/2021] [Indexed: 12/21/2022] Open
Abstract
Abnormal accumulation of aggregated α-synuclein (α-Syn) is seen in a variety of neurodegenerative diseases, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), Parkinson's disease dementia (PDD), and even subsets of Alzheimer's disease (AD) showing Lewy-body-like pathology. These synucleinopathies exhibit differences in their clinical and pathological representations, reminiscent of prion disorders. Emerging evidence suggests that α-Syn self-assembles and polymerizes into conformationally diverse polymorphs in vitro and in vivo, similar to prions. These α-Syn polymorphs arising from the same precursor protein may exhibit strain-specific biochemical properties and the ability to induce distinct pathological phenotypes upon their inoculation in animal models. In this review, we discuss clinical and pathological variability in synucleinopathies and several aspects of α-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains. The current review sheds light on the recent advances in delineating the structure-pathogenic relationship of α-Syn and how diverse α-Syn molecular polymorphs contribute to the existing clinical heterogeneity in synucleinopathies.
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Affiliation(s)
- Surabhi Mehra
- Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India; (L.G.); (R.B.); (A.S.S.)
| | | | | | | | - Samir K. Maji
- Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India; (L.G.); (R.B.); (A.S.S.)
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Louis ED, Faust PL. Essential Tremor Within the Broader Context of Other Forms of Cerebellar Degeneration. THE CEREBELLUM 2021; 19:879-896. [PMID: 32666285 DOI: 10.1007/s12311-020-01160-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Essential tremor (ET) has recently been reconceptualized by many as a degenerative disease of the cerebellum. Until now, though, there has been no attempt to frame it within the context of these diseases. Here, we compare the clinical and postmortem features of ET with other cerebellar degenerations, thereby placing it within the broader context of these diseases. Action tremor is the hallmark feature of ET. Although often underreported in the spinocerebellar ataxias (SCAs), action tremors occur, and it is noteworthy that in SCA12 and 15, they are highly prevalent, often severe, and can be the earliest disease manifestation, resulting in an initial diagnosis of ET in many cases. Intention tremor, sometimes referred to as "cerebellar tremor," is a common feature of ET and many SCAs. Other features of cerebellar dysfunction, gait ataxia and eye motion abnormalities, are seen to a mild degree in ET and more markedly in SCAs. Several SCAs (e.g., SCA5, 6, 14, and 15), like ET, follow a milder and more protracted disease course. In ET, numerous postmortem changes have been localized to the cerebellum and are largely confined to the cerebellar cortex, preserving the cerebellar nuclei. Purkinje cell loss is modest. Similarly, in SCA3, 12, and 15, Purkinje cell loss is limited, and in SCA12 and 15, there is preservation of cerebellar nuclei and relative sparing of other central nervous system regions. Both clinically and pathologically, there are numerous similarities and intersection points between ET and other disorders of cerebellar degeneration.
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Affiliation(s)
- Elan D Louis
- Department of Neurology and Therapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Phyllis L Faust
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY, USA
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Marsili L, Giannini G, Cortelli P, Colosimo C. Early recognition and diagnosis of multiple system atrophy: best practice and emerging concepts. Expert Rev Neurother 2021; 21:993-1004. [PMID: 34253122 DOI: 10.1080/14737175.2021.1953984] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Introduction: Multiple system atrophy (MSA) is a progressive degenerative disorder of the central and autonomic nervous systems characterized by parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal signs. The confirmatory diagnosis is pathological, but clinical-diagnostic criteria have been developed to help clinicians. To date, the early diagnosis of MSA is challenging due to the lack of reliable diagnostic biomarkers.Areas covered: The authors reappraised the main clinical, neurophysiological, imaging, genetic, and laboratory evidence to help in the early diagnosis of MSA in the clinical and in the research settings. They also addressed the practical clinical issues in the differential diagnosis between MSA and other parkinsonian and cerebellar syndromes. Finally, the authors summarized the unmet needs in the early diagnosis of MSA and proposed the next steps for future research efforts in this field.Expert opinion: In the last decade, many advances have been achieved to help the correct MSA diagnosis since early stages. In the next future, the early diagnosis and correct classification of MSA, together with a better knowledge of the causative mechanisms of the disease, will hopefully allow the identification of suitable candidates to enroll in clinical trials and select the most appropriate disease-modifying strategies to slow down disease progression.
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Affiliation(s)
- Luca Marsili
- Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA
| | - Giulia Giannini
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica NeuroMet, Ospedale Bellaria, Bologna, Italy.,Dipartimento di Scienze Biomediche e Neuromotorie, Università Bologna, Bologna, Italy
| | - Pietro Cortelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica NeuroMet, Ospedale Bellaria, Bologna, Italy.,Dipartimento di Scienze Biomediche e Neuromotorie, Università Bologna, Bologna, Italy
| | - Carlo Colosimo
- Department of Neurology, Santa Maria University Hospital, Terni, Italy
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Vidhale TA, Gupta HR, Pj R, Gandhi C. Very late-onset Friedreich's ataxia with rapid course mimicking as possible multiple system atrophy cerebellar type. BMJ Case Rep 2021; 14:e242073. [PMID: 34301694 PMCID: PMC8311314 DOI: 10.1136/bcr-2021-242073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2021] [Indexed: 11/04/2022] Open
Abstract
This 55-year-old man was admitted to the hospital with an insidious onset, progressive backward fall (due to severe truncal ataxia), dysarthria, stiffness in extremities, distal dominant muscle wasting along with behavioural changes and urinary incontinence. Clinical assessment indicated mild cognitive decline (Mini-Mental State Examination 22/27) with cerebellar, pyramidal and peripheral nerves involvement. On investigations, nerve conduction studies revealed symmetrical, sensorimotor peripheral neuropathy affecting both lower limbs. Brain and whole spine MRI revealed widespread cerebral and mild cerebellar atrophy, pons and medulla volume loss, and a normal spinal cord. Transthoracic echocardiography revealed concentric left ventricular hypertrophy. His gene analysis revealed eight GAA repeats on allele 1, and 37 GAA repeats on allele 2 in the first intron of the frataxin gene. Considering his clinical profile and genetic analysis, he was diagnosed as a case of very late-onset Friedreich's ataxia with likely compound heterozygous genotype.
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Affiliation(s)
- Tushar Ashok Vidhale
- Department of Medicine, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
| | - Hemant R Gupta
- Department of Medicine, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
| | - Rohan Pj
- Department of Radiology, BGS Global Institute of Medical Sciences, Bangalore, Karnataka, India
| | - Charmi Gandhi
- Department of Medicine, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
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Ganguly J, Chai JR, Jog M. Minipolymyoclonus: A Critical Appraisal. J Mov Disord 2021; 14:114-118. [PMID: 34062647 PMCID: PMC8175814 DOI: 10.14802/jmd.20166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Affiliation(s)
- Jacky Ganguly
- London Movement Disorder Centre, London Health Sciences Centre, The University of Western Ontario, London, Canada
| | - Jia Ren Chai
- Memorial University of Newfoundland, St. John̕s, Canada
| | - Mandar Jog
- London Movement Disorder Centre, London Health Sciences Centre, The University of Western Ontario, London, Canada
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Ryu HS, Kim HJ, You S, Kim MJ, Kim YJ, Kim J, Kim K, Lee SA, Chung SJ. Nocturnal stridor in multiple system atrophy: Video-polysomnography and clinical features. Parkinsonism Relat Disord 2021; 89:48-53. [PMID: 34225134 DOI: 10.1016/j.parkreldis.2021.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/04/2021] [Accepted: 03/15/2021] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Nocturnal stridor, a life-threatening condition linked to respiratory failure and sudden death during sleep, is a serious issue in patients with multiple system atrophy (MSA). However, little is known about polysomnographic findings and clinical features of MSA patients with nocturnal stridor. Hence, we investigated video-polysomnography (VPSG) findings and clinical features associated with nocturnal stridor in patients with MSA. METHODS We retrospectively analyzed the clinical data of patients with MSA (n = 49) who underwent overnight VPSG for the evaluation of sleep-disordered breathing. The presence of nocturnal stridor was confirmed based on overnight VPSG findings. Clinical data, including VPSG findings and clinical features, were compared between MSA patients with and without nocturnal stridor. RESULTS Nocturnal stridor was present in 31 (63.3%) patients with MSA. Patients with stridor showed significantly higher apnea-hypopnea, respiratory disturbance, and oxygen desaturation indices than those without stridor (P = 0.024, P = 0.049, and P = 0.006, respectively). Patients with stridor had more severe axial motor features, more impaired activities of daily living, and longer disease duration than those without stridor (P = 0.012, P = 0.036, and P = 0.003, respectively). However, there were no significant between-group differences in sex, age at disease onset, MSA subtype, parkinsonian features, cerebellar ataxia, residual urine volume, or systolic and diastolic blood pressure change. CONCLUSIONS MSA with nocturnal stridor is related to higher apnea indices in conjunction with higher O2 desaturation index, more severe axial motor features, more impaired activities of daily living, and longer disease duration.
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Affiliation(s)
- Ho-Sung Ryu
- Department of Neurology, Kyungpook National University Hospital, Daegu, South Korea
| | - Hyo Jae Kim
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sooyeoun You
- Department of Neurology, Dongsan Medical Center, Keimyung University, Daegu, South Korea
| | - Mi-Jung Kim
- Department of Neurology, Bobath Memorial Hospital, Seongnam, South Korea
| | - Young Jin Kim
- Department of Neurology, Best Heals Hospital, Ansan, South Korea
| | - Juyeon Kim
- Department of Neurology, Metro Hospital, Anyang, South Korea
| | - Kiju Kim
- Department of Neurology, The Good Light Hospital, Gwangju, South Korea
| | - Sang-Ahm Lee
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sun Ju Chung
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
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50
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Coon EA, Ahlskog JE. My Treatment Approach to Multiple System Atrophy. Mayo Clin Proc 2021; 96:708-719. [PMID: 33673922 DOI: 10.1016/j.mayocp.2020.10.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/07/2020] [Accepted: 10/13/2020] [Indexed: 11/28/2022]
Abstract
Multiple system atrophy (MSA) is a neurodegenerative disorder primarily characterized by autonomic failure plus parkinsonism or cerebellar ataxia. The diagnosis may be challenging and is usually made at a tertiary care center. The long-term management issues are equally challenging and frequently require collaboration with the patient's local care providers. Whereas there is currently no cure for MSA, treatment focuses on the most problematic symptoms experienced by the patient. Autonomic symptoms may include severe orthostatic hypotension with syncope, urinary symptoms culminating in incontinence, constipation, anhidrosis, and erectile dysfunction. Motor symptoms include parkinsonism, cerebellar ataxia, and falls. Although certain motor symptoms may respond partially to medications, some of these medications may exacerbate autonomic problems. In this manuscript, we seek to bridge the gap between tertiary care providers and the patient's local care providers to provide multidisciplinary care to the MSA patient. Patients are often best served by management of their chronic and evolving complex problems with a team approach involving their primary care providers and subspecialists. Treatment guidelines typically list myriad therapeutic options without clarifying the most efficacious and simplest treatment strategies. Herein, we provide a guideline based on what has worked in our MSA clinic, a clinic designed to provide care throughout the disease course with subspecialty integration with the goal of empowering a partnership with the patient's home primary care providers.
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