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Treatment of multiple system atrophy using intravenous immunoglobulin.

ABSTRACT: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA.This was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen®, dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment.Nine subjects were enrolled, and seven (2 women and 5 men, age range 55-64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p<0.05). Two participants dropped out from the study because of a non-threatening skin rash. The UMSARS-I (activities of daily living) and USMARS-II (motor functions) improved significantly post-treatment. UMSARS-I improved in all subjects (pre-treatment 23.9 ± 6.0 vs. post-treatment 19.0±5.9 (p=0.01). UMSARS-II improved in 5 subjects, was unchanged in 1 and worsened in 1 (pre-treatment 26.1±7.5 vs. post-treatment 23.3±7.3 (p=0.025). The MR imaging results were not different comparing pre- to post-treatment.Treatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed.

SUBMITTER: Novak P

PROVIDER: S-EPMC3551813 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Treatment of multiple system atrophy using intravenous immunoglobulin.

Novak Peter P Williams Arlene A Ravin Paula P Zurkiya Omar O Abduljalil Amir A Novak Vera V

BMC neurology 20121101

<h4>Background</h4>Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA.<h4>Methods</h4>This was a single-arm in ...[more]

PMID: 23116538

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Project description:See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of ?-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between ?-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric ?-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide-1 agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial.

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.

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Treatment of multiple system atrophy using intravenous immunoglobulin.

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Treatment of multiple system atrophy using intravenous immunoglobulin.

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