Systemic hemodynamics during orthostasis in multiple system atrophy.
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ABSTRACT:
SUBMITTER: Goldstein DS
PROVIDER: S-EPMC5126504 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The present study aims to analyze the systemic response to auditory stimulation by means of hemodynamic (cephalic and peripheral) and autonomic responses in a broad range of auditory intensities (70.9, 77.9, 84.5, 89.5, 94.5 dBA). This approach could help to understand the possible influence of the autonomic nervous system on the cephalic blood flow. Twenty-five subjects were exposed to auditory stimulation while electrodermal activity (EDA), photoplethysmography (PPG), electrocardiogram, and functional near-infrared spectroscopy signals were recorded. Seven trials with 20 individual tones, each for the five intensities, were presented. The results showed a differentiated response to the higher intensity (94.5 dBA) with a decrease in some peripheral signals such as the heart rate (HR), the pulse signal, the pulse transit time (PTT), an increase of the LFnu power in PPG, and at the head level a decrease in oxygenated and total hemoglobin concentration. After the regression of the visual channel activity from the auditory channels, a decrease in deoxyhemoglobin in the auditory cortex was obtained, indicating a likely active response at the highest intensity. Nevertheless, other measures, such as EDA (Phasic and Tonic), and heart rate variability (Frequency and time domain) showed no significant differences between intensities. Altogether, these results suggest a systemic and complex response to high-intensity auditory stimuli. The results obtained in the decrease of the PTT and the increase in LFnu power of PPG suggest a possible vasoconstriction reflex by a sympathetic control of vascular tone, which could be related to the decrease in blood oxygenation at the head level.
| S-EPMC9251853 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed α-synucleinopathies, which also include Parkinson's disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal α-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of α-synuclein are oligodendroglial cells . This pathological hallmark, also called glial cytoplasmic inclusions (GCIs) , is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of α-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson's syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies.
| S-EPMC4730554 | biostudies-literature
Project description:Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an ?-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant ?-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded ?-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.
| S-EPMC5870010 | biostudies-other
Project description:Multiple system atrophy (MSA) is a rare, late-onset and fatal neurodegenerative disease including multisystem neurodegeneration and the formation of α-synuclein containing oligodendroglial cytoplasmic inclusions (GCIs), which present the hallmark of the disease. MSA is considered to be a sporadic disease; however certain genetic aspects have been studied during the last years in order to shed light on the largely unknown etiology and pathogenesis of the disease. Epidemiological studies focused on the possible impact of environmental factors on MSA disease development. This article gives an overview on the findings from genetic and epigenetic studies on MSA and discusses the role of genetic or epigenetic factors in disease pathogenesis.
| S-EPMC4276800 | biostudies-literature
Project description:BackgroundDysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA.ObjectiveThis study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and α-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect α-synuclein uptake in a oligodendrocyte cell.MethodsOne hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with α-synuclein and recombinant human apolipoprotein E, with internalized α-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry.ResultsNo significant association with risk of MSA or was observed for either Apolipoprotein E ɛ2 or ɛ4. α-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E ɛ4 significantly reduced α-synuclein uptake in the oligodendrocytic cell line.ConclusionsDespite differential effects of apolipoprotein E isoforms on α-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or α-synuclein pathology. © 2018 International Parkinson and Movement Disorder Society.
| S-EPMC5889322 | biostudies-literature
Project description:BackgroundDespite controversies, epinephrine remains a mainstay of cardiopulmonary resuscitation (CPR). Recent animal studies have suggested that epinephrine may decrease cerebral blood flow (CBF) and cerebral oxygenation, possibly potentiating neurological injury during CPR. We investigated the cerebrovascular effects of intravenous epinephrine in a swine model of pediatric in-hospital cardiac arrest. The primary objectives of this study were to determine if (1) epinephrine doses have a significant acute effect on CBF and cerebral tissue oxygenation during CPR and (2) if the effect of each subsequent dose of epinephrine differs significantly from that of the first.MethodsOne-month-old piglets (n = 20) underwent asphyxia for 7 min, ventricular fibrillation, and CPR for 10-20 min. Epinephrine (20 mcg/kg) was administered at 2, 6, 10, 14, and 18 min of CPR. Invasive (laser Doppler, brain tissue oxygen tension [PbtO2]) and noninvasive (diffuse correlation spectroscopy and diffuse optical spectroscopy) measurements of CBF and cerebral tissue oxygenation were simultaneously recorded. Effects of subsequent epinephrine doses were compared to the first.ResultsWith the first epinephrine dose during CPR, CBF and cerebral tissue oxygenation increased by > 10%, as measured by each of the invasive and noninvasive measures (p < 0.001). The effects of epinephrine on CBF and cerebral tissue oxygenation decreased with subsequent doses. By the fifth dose of epinephrine, there were no demonstrable increases in CBF of cerebral tissue oxygenation. Invasive and noninvasive CBF measurements were highly correlated during asphyxia (slope effect 1.3, p < 0.001) and CPR (slope effect 0.20, p < 0.001).ConclusionsThis model suggests that epinephrine increases CBF and cerebral tissue oxygenation, but that effects wane following the third dose. Noninvasive measurements of neurological health parameters hold promise for developing and directing resuscitation strategies.
| S-EPMC7522922 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of ?-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic ?-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of ?-synuclein in a prion-like manner, ?-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of ?-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit ?-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchymal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review.
| S-EPMC4265580 | biostudies-other
Project description:We performed RNA-seq on total RNA from tissue samples from putamen of the brain from Multiple system atrophy patients.
2020-02-01 | GSE134472 | GEO
Project description:Genome-wide methylation profiling of DNA extracted from the prefrontal cortex of post-mortem MSA patients (n=41) or normal, healthy controls (CTRLs; n=37). The Illumina Infinium MethylationEPIC BeadChip was used, investigating app. 850,000 CpG sites throughout the genome
2020-03-10 | GSE143157 | GEO
Project description:Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiopathogenesis manifesting with autonomic failure, parkinsonism, and ataxia in any combination. The underlying neuropathology affects central autonomic, striatonigral and olivopontocerebellar pathways and it is associated with distinctive glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) that contain aggregates of α-synuclein. Current treatment options are very limited and mainly focused on symptomatic relief, whereas disease modifying options are lacking. Despite extensive testing, no neuroprotective drug treatment has been identified up to now; however, a neurorestorative approach utilizing autologous mesenchymal stem cells has shown remarkable beneficial effects in the cerebellar variant of MSA. Here, we review the progress made over the last decade in defining pathogenic targets in MSA and summarize insights gained from candidate disease-modifying interventions that have utilized a variety of well-established preclinical MSA models. We also discuss the current limitations that our field faces and suggest solutions for possible approaches in cause-directed therapies of MSA.
| S-EPMC4068324 | biostudies-literature