Multiple-system atrophy.
About: This article is published in The New England Journal of Medicine.The article was published on 2015-01-15. It has received 544 citations till now. The article focuses on the topics: Atrophy.
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TL;DR: The prion concept appears to apply to all human neurodegenerative diseases with abnormal protein assemblies, including AD and PD, which implies that the same molecular events occur independently in a large number of cells in an otherwise healthy brain.
Abstract: The pathological assembly of Aβ, tau, and α-synuclein is at the heart of Alzheimer's and Parkinson's diseases. Extracellular deposits of Aβ and intraneuronal tau inclusions define Alzheimer's disease, whereas intracellular inclusions of α-synuclein make up the Lewy pathology of Parkinson's disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Aβ, tau, and α-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer's and Parkinson's diseases, from where it spreads to other areas.
724 citations
TL;DR: Emerging themes in understanding of disease pathogenesis in synucleinopathies are discussed, including the contributions of aging, selective vulnerability and non-cell-autonomous factors such as α-synuclein cell-to-cell propagation and neuroinflammation.
Abstract: Alterations in α-synuclein dosage lead to familial Parkinson's disease (PD), and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Furthermore, α-synuclein contributes to the fibrilization of amyloid-b and tau, two key proteins in Alzheimer's disease, which suggests a central role for α-synuclein toxicity in neurodegeneration. Recent studies of factors contributing to α-synuclein toxicity and its disruption of downstream cellular pathways have expanded our understanding of disease pathogenesis in synucleinopathies. In this Review, we discuss these emerging themes, including the contributions of aging, selective vulnerability and non-cell-autonomous factors such as α-synuclein cell-to-cell propagation and neuroinflammation. Finally, we summarize recent efforts toward the development of targeted therapies for PD and related synucleinopathies.
581 citations
TL;DR: This document was approved by the American College of Cardiology Cli American Heart Association Science Advisory and Coordinating Committe Rhythm Society Board of Trustees in January 2017.
464 citations
TL;DR: It is found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting the fact that distinct α- synuclein strains are generated by different intracellular milieus, andGCI-α-Syn maintains its high seeding activity when propagated in neurons.
Abstract: In Lewy body diseases-including Parkinson's disease, without or with dementia, dementia with Lewy bodies, and Alzheimer's disease with Lewy body co-pathology 1 -α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites 2 . By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) 3 . Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) is conformationally and biologically distinct. GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-α-Syn and LB-α-Syn show no cell-type preference in seeding α-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting the fact that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.
412 citations
TL;DR: This work critically assess the potential of experimental therapies targeting α-synuclein, and discusses steps that need to be taken for target validation and drug development.
Abstract: Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.
377 citations
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University of Michigan1, Innsbruck Medical University2, Hammersmith Hospital3, Imperial College London4, University of Pennsylvania5, Sapienza University of Rome6, University of Paris7, New York University8, University of Bonn9, Vanderbilt University10, French Institute of Health and Medical Research11
TL;DR: New criteria for diagnosis of multiple system atrophy have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.
Abstract: Background: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here.Methods: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology.Results: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality.Conclusions: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.
2,491 citations
TL;DR: The objective of this work was to update previous EBM reviews on treatments for PD with a focus on non‐motor symptoms and found that most of the other interventions there is insufficient evidence to make adequate conclusions on their efficacy.
Abstract: The Movement Disorder Society (MDS) Task Force on Evidence-Based Medicine (EBM) Review of Treatments for Parkinson's Disease (PD) was first published in 2002 and was updated in 2005 to cover clinical trial data up to January 2004 with the focus on motor symptoms of PD. In this revised version the MDS task force decided it was necessary to extend the review to non-motor symptoms. The objective of this work was to update previous EBM reviews on treat- ments for PD with a focus on non-motor symptoms. Level-I (randomized controlled trial, RCT) reports of pharmacological and nonpharmacological interventions for the non-motor symptoms of PD, published as full
1,061 citations
TL;DR: The central autonomic network (CAN) is an integral component of an internal regulation system through which the brain controls viscerosensory inputs relayed on the nucleus of the tractus solitarius and humoral inputs relayed through the circumventricular organs.
1,042 citations
01 Jan 1993
TL;DR: The central autonomic network (CAN) as discussed by the authors is an integral component of an internal regulation system through which the brain controls visceromotor, neuroendocrine, pain, and behavioral responses essential for survival.
Abstract: The central autonomic network (CAN) is an integral component of an internal regulation system through which the brain controls visceromotor, neuroendocrine, pain, and behavioral responses essential for survival. It includes the insular cortex, amygdala, hypothalamus, periaqueductal gray matter, parabrachial complex, nucleus of the tractus solitarius, and ventrolateral medulla. Inputs to the CAN are multiple, including viscerosensory inputs relayed on the nucleus of the tractus solitarius and humoral inputs relayed through the circumventricular organs. The CAN controls preganglionic sympathetic and parasympathetic, neuroendocrine, respiratory, and sphincter motoneurons. The CAN is characterized by reciprocal interconnections, parallel organization, state-dependent activity, and neurochemical complexity. The insular cortex and amygdala mediate high-order autonomic control, and their involvement in seizures or stroke may produce severe cardiac arrhythmias and other autonomic manifestations. The paraventricular and other hypothalamic nuclei contain mixed neuro nal populations that control specific subsets of preganglionic sympathetic and parasympathetic neu rons. Hypothalamic autonomic disorders commonly producehypothermia or hyperthermia. Hyperthermia and autonomic hyperactivity occur in patients with head trauma, hydrocephalus, neuroleptic malignant syndrome, and fatal familial insomnia. In the medulla, the nucleus of the tractus solitarius and ventrolateral medulla contain a network of respiratory, cardiovagal, and vasomotor neurons. Medullary autonomic disorders may cause orthostatic hypotension, paroxysmal hyperten sion, and sleep apnea. Neurologic catastrophes, such as subarachnoid hemorrhage, may produce cardiac arrhythmias, myocardial injury, hypertension, and pulmonary edema. Multiple system atrophy affects preganglionic autonomic, respiratory, and neuroendocrine outputs. The CAN may be critically involved in panic disorders, essential hypertension, obesity, and other medical conditions.
986 citations
TL;DR: These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that α-synucleinopathies constitute a major class of human neurodegenerative disorder.
891 citations