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Nature Reviews. Disease Primers Aug 2022Multiple system atrophy (MSA) is a rare neurodegenerative disease that is characterized by neuronal loss and gliosis in multiple areas of the central nervous system... (Review)
Review
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.
Topics: Biomarkers; Cerebellar Ataxia; Humans; Multiple System Atrophy; Parkinsonian Disorders
PubMed: 36008429
DOI: 10.1038/s41572-022-00382-6 -
Nature Reviews. Neuroscience Jun 2023Multiple system atrophy (MSA) is a rare oligodendroglial α-synucleinopathy characterized by neurodegeneration in striatonigral and olivopontocerebellar regions and... (Review)
Review
Multiple system atrophy (MSA) is a rare oligodendroglial α-synucleinopathy characterized by neurodegeneration in striatonigral and olivopontocerebellar regions and autonomic brain centres. It causes complex cumulative motor and non-motor disability with fast progression and effective therapy is currently lacking. The difficulties in the diagnosis and treatment of MSA are largely related to the incomplete understanding of the pathogenesis of the disease. The MSA pathogenic landscape is complex, and converging findings from genetic and neuropathological studies as well as studies in experimental models of MSA have indicated the involvement of genetic and epigenetic changes; α-synuclein misfolding, aggregation and spreading; and α-synuclein strain specificity. These studies also indicate the involvement of myelin and iron dyshomeostasis, neuroinflammation, mitochondrial dysfunction and other cell-specific aspects that are relevant to the fast progression of MSA. In this Review, we discuss these findings and emphasize the implications of the complexity of the multifactorial pathogenic cascade for future translational research and its impact on biomarker discovery and treatment target definitions.
Topics: Humans; Multiple System Atrophy; alpha-Synuclein; Brain; Oligodendroglia; Myelin Sheath
PubMed: 37085728
DOI: 10.1038/s41583-023-00697-7 -
International Journal of Molecular... Feb 2020A variety of Magnetic Resonance (MR) and nuclear medicine (NM) techniques have been used in symptomatic and presymptomatic SCA2 gene carriers to explore,in vivo, the... (Review)
Review
A variety of Magnetic Resonance (MR) and nuclear medicine (NM) techniques have been used in symptomatic and presymptomatic SCA2 gene carriers to explore,in vivo, the physiopathological biomarkers of the neurological dysfunctions characterizing the associated progressive disease that presents with a cerebellar syndrome, or less frequently, with a levodopa-responsive parkinsonian syndrome. Morphometry performed on T1-weighted images and diffusion MR imaging enable structural and microstructural evaluation of the brain in presymptomatic and symptomatic SCA2 gene carriers, in whom they show the typical pattern of olivopontocerebellar atrophy observed at neuropathological examination. Proton MR spectroscopy reveals, in the pons and cerebellum of SCA2 gene carriers,a more pronounced degree of abnormal neurochemical profile compared to other spinocerebellar ataxias with decreased NAA/Cr and Cho/Cr, increased mi/Cr ratios, and decreased NAA and increased mI concentrations. These neurochemical abnormalities are detectable also in presymtomatic gene carriers. Resting state functional MRI (rsfMRI) demonstrates decreased functional connectivity within the cerebellum and of the cerebellum with fronto-parietal cortices and basal ganglia in symptomatic SCA2 subjects. F-fluorodeoxyglucose Positron Emission Tomography (PET) shows a symmetric decrease of the glucose uptake in the cerebellar cortex, the dentate nucleus, the brainstem and the parahippocampal cortex. Single photon emission tomography and PET using several radiotracers have revealed almost symmetric nigrostriatal dopaminergic dysfunction irrespective of clinical signs of parkinsonism which are already present in presymtomatic gene carriers. Longitudinal small size studies have proven that morphometry and diffusion MR imaging can track neurodegeneration in SCA2, and hence serve as progression biomarkers. So far, such a capability has not been reported for proton MR spectroscopy, rsfMRI and NM techniques. A search for the best surrogate marker for future clinical trials represents the current challenge for the neuroimaging community.
Topics: Ataxin-2; Biomarkers; Brain; Disease Progression; Heterozygote; Humans; Nervous System Diseases; Neuroimaging
PubMed: 32033120
DOI: 10.3390/ijms21031020 -
Parkinsonism & Related Disorders Apr 2020Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is... (Review)
Review
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is mainly characterized by the abnormal accumulation of misfolded α-synuclein in the cytoplasm of oligodendrocytes, which plays a major role in the pathogenesis of the disease. Striatonigral degeneration and olivopontecerebellar atrophy underlie the motor syndrome, while degeneration of autonomic centers defines the autonomic failure in MSA. At present, there is no treatment that can halt or reverse its progression. However, over the last decade several studies in preclinical models and patients have helped to better understand the pathophysiological events underlying MSA. The etiology of this fatal disorder remains unclear and may be multifactorial, caused by a combination of factors which may serve as targets for novel therapeutic approaches. In this review, we summarize the current knowledge about the etiopathogenesis and neuropathology of MSA, its different preclinical models, and the main disease modifying therapies that have been used so far or that are planned for future clinical trials.
Topics: Animals; Humans; Multiple System Atrophy; Olivopontocerebellar Atrophies; Striatonigral Degeneration
PubMed: 32005598
DOI: 10.1016/j.parkreldis.2020.01.010 -
Movement Disorders : Official Journal... Oct 2022Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either...
BACKGROUND
Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease.
OBJECTIVE
Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases.
METHODS
We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898).
RESULTS
The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4).
INTERPRETATION
Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Autoantibodies; Autopsy; Genome-Wide Association Study; Humans; Multiple System Atrophy; Nerve Tissue Proteins; Olivopontocerebellar Atrophies; Striatonigral Degeneration; Transcription Factors; alpha-Synuclein
PubMed: 35997131
DOI: 10.1002/mds.29164 -
Tomography (Ann Arbor, Mich.) Feb 2022MRI shows the three archetypal patterns of CNS volume loss underlying progressive ataxias in vivo, namely spinal atrophy (SA), cortical cerebellar atrophy (CCA) and... (Review)
Review
MRI shows the three archetypal patterns of CNS volume loss underlying progressive ataxias in vivo, namely spinal atrophy (SA), cortical cerebellar atrophy (CCA) and olivopontocerebellar atrophy (OPCA). The MRI-based CNS atrophy pattern was reviewed in 128 progressive ataxias. A CNS atrophy pattern was identified in 91 conditions: SA in Friedreich's ataxia, CCA in 5 acquired and 72 (24 dominant, 47 recessive,1 X-linked) inherited ataxias, OPCA in Multi-System Atrophy and 12 (9 dominant, 2 recessive,1 X-linked) inherited ataxias. The MRI-based CNS atrophy pattern may be useful for genetic assessment, identification of shared cellular targets, repurposing therapies or the enlargement of drug indications in progressive ataxias.
Topics: Ataxia; Atrophy; Cerebellar Ataxia; Humans; Magnetic Resonance Imaging; Spinocerebellar Degenerations
PubMed: 35202200
DOI: 10.3390/tomography8010035 -
Biomedicines Mar 2022Multiple system atrophy (MSA) is a fatal, rapidly progressing neurodegenerative disease of uncertain etiology, clinically characterized by various combinations of... (Review)
Review
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.
PubMed: 35327402
DOI: 10.3390/biomedicines10030599 -
Tremor and Other Hyperkinetic Movements... 2019The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery,... (Review)
Review
BACKGROUND
The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery, specific features of the SCAs - clinical, laboratorial, and neuroradiological (NR) - can facilitate establishing the diagnosis. The purpose of this study was to review the particular NR abnormalities in the main SCAs.
METHODS
We conducted a literature search on this topic.
RESULTS
The main NR characteristics of brain imaging (magnetic resonance imaging or computerized tomography) in SCAs were: (1) pure cerebellar atrophy; (2) cerebellar atrophy with other findings (e.g., pontine, olivopontocerebellar, spinal, cortical, or subcortical atrophy; "hot cross bun sign", and demyelinating lesions); (3) selective cerebellar atrophy; (4) no cerebellar atrophy.
DISCUSSION
The main NR abnormalities in the commonest SCAs, are not pathognomonic of any specific genotype, but can be helpful in limiting the diagnostic options. We are progressing to a better understanding of the SCAs, not only genetically, but also pathologically; NR is helpful in the challenge of diagnosing the specific genotype of SCA.
Topics: Brain; Humans; Neuroimaging; Spinocerebellar Ataxias
PubMed: 31632837
DOI: 10.7916/tohm.v0.682 -
Journal of Neural Transmission (Vienna,... Oct 2021Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no... (Review)
Review
Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are α-synuclein rich glial cytoplasmic inclusions (GCIs). Neuropathologically, various degrees of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) can be observed. Since the original descriptions of this multifaceted disorder, several steps forward have been made to clarify its neuropathological hallmarks and key pathophysiological mechanisms. The Austrian neuropathologist Kurt Jellinger substantially contributed to the understanding of the underlying neuropathology of this disease, to its standardized assessment and to a broad systematical clinic-pathological correlation. On the occasion of his 90th birthday, we reviewed the current state of the art in the field of MSA neuropathology, highlighting Prof. Jellinger's substantial contribution.
Topics: Austria; Humans; Inclusion Bodies; Multiple System Atrophy; Neuropathology; alpha-Synuclein
PubMed: 34319460
DOI: 10.1007/s00702-021-02383-3