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Acta Neuropathologica Jan 2020Multiple system atrophy (MSA) is a fatal late-onset neurodegenerative disease. Although presenting with distinct pathological hallmarks, which in MSA consist of glial...
Multiple system atrophy (MSA) is a fatal late-onset neurodegenerative disease. Although presenting with distinct pathological hallmarks, which in MSA consist of glial cytoplasmic inclusions (GCIs) containing fibrillar α-synuclein in oligodendrocytes, both MSA and Parkinson's disease are α-synucleinopathies. Pathologically, MSA can be categorized into striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) or mixed subtypes. Despite extensive research, the regional vulnerability of the brain to MSA pathology remains poorly understood. Genetic, epigenetic and environmental factors have been proposed to explain which brain regions are affected by MSA, and to what extent. Here, we explored for the first time epigenetic changes in post-mortem brain tissue from MSA cases. We conducted a case-control study, and profiled DNA methylation in white mater from three brain regions characterized by severe-to-mild GCIs burden in the MSA mixed subtype (cerebellum, frontal lobe and occipital lobe). Our genome-wide approach using Illumina MethylationEPIC arrays and a powerful cross-region analysis identified 157 CpG sites and 79 genomic regions where DNA methylation was significantly altered in the MSA mixed-subtype cases. HIP1, LMAN2 and MOBP were amongst the most differentially methylated loci. We replicated these findings in an independent cohort and further demonstrated that DNA methylation profiles were perturbed in MSA mixed subtype, and also to variable degrees in the other pathological subtypes (OPCA and SND). Finally, our co-methylation network analysis revealed several molecular signatures (modules) significantly associated with MSA (disease status and pathological subtypes), and with neurodegeneration in the cerebellum. Importantly, the co-methylation module having the strongest association with MSA included a CpG in SNCA, the gene encoding α-synuclein. Altogether, our results provide the first evidence for DNA methylation changes contributing to the molecular processes altered in MSA, some of which are shared with other neurodegenerative diseases, and highlight potential novel routes for diagnosis and therapeutic interventions.
Topics: Aged; Brain; Case-Control Studies; DNA Methylation; DNA-Binding Proteins; Female; Gene Expression Profiling; Humans; Male; Mannose-Binding Lectins; Membrane Transport Proteins; Middle Aged; Multiple System Atrophy; Myelin Proteins; White Matter; alpha-Synuclein
PubMed: 31535203
DOI: 10.1007/s00401-019-02074-0 -
Acta Neuropathologica Communications Jul 2019Multiple system atrophy (MSA) is a devastating neurodegenerative disease characterized by the clinical triad of parkinsonism, cerebellar ataxia and autonomic failure,... (Review)
Review
Multiple system atrophy (MSA) is a devastating neurodegenerative disease characterized by the clinical triad of parkinsonism, cerebellar ataxia and autonomic failure, impacting on striatonigral, olivopontocerebellar and autonomic systems. At early stage of the disease, the clinical symptoms of MSA can overlap with those of Parkinson's disease (PD). The key pathological hallmark of MSA is the presence of glial cytoplasmic inclusions (GCI) in oligodendrocytes. GCI comprise insoluble proteinaceous filaments composed chiefly of α-synuclein aggregates, and therefore MSA is regarded as an α-synucleinopathy along with PD and dementia with Lewy bodies. The etiology of MSA is unknown, and the pathogenesis of MSA is still largely speculative. Much data suggests that MSA is a sporadic disease, although some emerging evidence suggests rare genetic variants increase susceptibility. Currently, there is no general consensus on the susceptibility genes as there have been differences due to geographical distribution or ethnicity. Furthermore, many of the reported studies have been conducted on patients that were only clinically diagnosed without pathological verification. The purpose of this review is to bring together available evidence to cross-examine the susceptibility genes and genetic pathomechanisms implicated in MSA. We explore the possible involvement of the SNCA, COQ2, MAPT, GBA1, LRRK2 and C9orf72 genes in MSA pathogenesis, highlight the under-explored areas of MSA genetics, and discuss future directions of research in MSA.
Topics: Alkyl and Aryl Transferases; Brain; C9orf72 Protein; Genetic Predisposition to Disease; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Multiple System Atrophy; Neurons; alpha-Synuclein; tau Proteins
PubMed: 31340844
DOI: 10.1186/s40478-019-0769-4 -
Movement Disorders : Official Journal... Jul 2019
Topics: Humans; Multiple System Atrophy; Shy-Drager Syndrome
PubMed: 31322774
DOI: 10.1002/mds.27716 -
European Journal of Medical Genetics Jan 2020Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with...
Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with mutations in exosome subunits exhibit a generally lethal phenotype characterized by cerebellar and pontine hypoplasia in association with spinal motor neuropathy and multiple systemic and neurologic features. Recently, two variants in the novel PCH1 associated protein EXOSC9 p.(Leu14Pro) and p.(Arg161*) have been identified in 4 unrelated patients exhibiting a severe phenotype involving cerebellar hypoplasia, axonal motor neuropathy, hypotonia, feeding difficulties, and respiratory insufficiency (PCH1D). We report clinical and molecular characterization of 2 unrelated patients exhibiting a relatively milder phenotype involving hypotonia, brachycephaly, cerebellar atrophy, psychomotor delay, as well as lactic acidosis and aberrant CNS myelination, resulting from the recurring homozygous missense mutation NM_001034194.1: c.41T>C; p.(Leu14Pro) in the EXOSC9 gene. We review the clinical picture of the EXOSC9-related PCH disorder.
Topics: Brain Stem Neoplasms; Cerebellum; Child; Developmental Disabilities; Exosome Multienzyme Ribonuclease Complex; Female; Genetic Association Studies; Genetic Predisposition to Disease; Homozygote; Humans; Male; Mutation; Nervous System Malformations; Neurodegenerative Diseases; Olivopontocerebellar Atrophies; Phenotype; RNA-Binding Proteins; Spinal Nerves
PubMed: 30690203
DOI: 10.1016/j.ejmg.2019.01.012 -
Gait & Posture Mar 2019Analysis of sensorimotor synergies has been greatly advanced by the Uncontrolled Manifold (UCM) approach. The UCM method is based on partitioning inter-trial variance...
BACKGROUND
Analysis of sensorimotor synergies has been greatly advanced by the Uncontrolled Manifold (UCM) approach. The UCM method is based on partitioning inter-trial variance displayed by elemental variables into 'good' (V) and 'bad' (V) variability that, respectively, indicate maintenance or loss of task stability. In clinical populations, these indices can be used to investigate the strength, flexibility, stereotypy and agility of synergistic control.
RESEARCH QUESTION
How are synergies affected by neurological impairment in adults? Specifically, this study aimed to determine i) the impact of pathology on V, V, and their ratio (synergy index); ii) the relationship between synergy indices and functional performance; iii) changes in anticipatory synergy adjustments (ASAs); and iv) the effects of interventions on synergies.
METHODS
Systematic review of UCM studies on adults with neurological impairment.
RESULTS
Most of the 17 studies had moderate to high quality scores in the adapted Critical Review Form and the UCM reporting quality checklist developed for this review. i) Most of the studies found reduced synergy indices for patients with Parkinson's disease (PD), olivo-ponto-cerebellar atrophy, multiple sclerosis and spinocerebellar degeneration, with variable levels of change in V and V. Reduction in synergy indices was not as consistent for stroke, in three out of six studies it was unchanged. ii) Five of seven studies found no significant correlations between scores on motor function scales and UCM indices. iii) Seven studies consistently reported ASAs that are smaller in magnitude, delayed, or both, for patients compared to healthy controls. iv) Two studies reported increased synergy indices, either via increase in V or decrease in V, after dopaminergic drugs for patients with PD. There were similar synergy indices but improved ASAs after deep brain stimulation for patients with PD.
SIGNIFICANCE
UCM can provide reliable and sensitive indicators of altered synergistic control in adults with neurological impairment.
Topics: Deep Brain Stimulation; Dopamine Agents; Humans; Parkinson Disease; Psychomotor Performance
PubMed: 30677709
DOI: 10.1016/j.gaitpost.2019.01.003 -
Journal of Movement Disorders Jan 2019To clarify the specificity of the 'hot cross bun' sign (HCBS) for multiple system atrophy (MSA) in adult cerebellar ataxia or parkinsonism.
OBJECTIVE
To clarify the specificity of the 'hot cross bun' sign (HCBS) for multiple system atrophy (MSA) in adult cerebellar ataxia or parkinsonism.
METHODS
The radiologic information systems at an academic center and affiliated veterans' hospital were queried using the keywords 'hot cross bun,' 'pontocerebellar,' 'cruciate,' 'cruciform,' 'MSA,' 'multiple system atrophy,' and 'multisystem atrophy.' Scans were reviewed by a neurologist and neuroradiologist to identify the HCBS. Subjects with the HCBS were reviewed by 2 neurologists to identify the most likely etiology of the patient's neurologic symptoms.
RESULTS
Eleven cases were identified. Etiologies included MSA (4 probable, 2 possible), hereditary cerebellar ataxia (3/11), probable dementia with Lewy bodies (1/11), and uncertain despite autopsy (1/11).
CONCLUSION
MSA was the most common etiology. However, 5 of the 11 patients did not have MSA. The most common alternate etiology was an undefined hereditary cerebellar ataxia (3/11).
PubMed: 30563313
DOI: 10.14802/jmd.18031 -
World Neurosurgery Mar 2019Hypertrophic olivary degeneration (HOD) is a rare neurological condition of trans-synaptic degeneration caused by disruption of the dentatorubro-olivary pathway. We...
BACKGROUND
Hypertrophic olivary degeneration (HOD) is a rare neurological condition of trans-synaptic degeneration caused by disruption of the dentatorubro-olivary pathway. We present new radiologic findings of HOD in 2 cases of brainstem lymphoma.
CASE DESCRIPTION
A 35-year-old woman (Case 1) and a 69-year-old man (Case 2) presented with remarkably similar clinical courses. The primary lesion was located at the dorsal pons extending to the midbrain. Pathologic diagnosis of diffuse large B-cell lymphoma was obtained after surgical resection. Complete remission of the primary lesion was achieved by treatment with 3 courses of high-dose methotrexate and radiotherapy. Arterial spin-labeling and T-weighted imagings showed high signal intensity in the inferior olive (IO) at some time after the operation. Slight contrast enhancement in the IO was also found in Case 1. These radiologic findings nearly misled us into a diagnosis of recurrence of lymphoma. Signal intensity in the IO on arterial spin-labeling imaging changed with time. Normalized regional cerebral blood flow (rCBF) in the IO was defined as a percentage of rCBF to the global cerebral blood flow calculated using automated software. Chronologic change in normalized rCBF in the IO revealed a large peak in Case 1, but only a mild increase in Case 2. Neurological findings demonstrated severe oculopalatal tremor in Case 1 and mild palatal tremor in Case 2.
CONCLUSIONS
Hyperperfusion and contrast enhancement in the IO were found in 2 patients with HOD. These findings may be confused with recurrence of malignant tumor.
Topics: Adult; Aged; Brain Stem Neoplasms; Female; Humans; Imaging, Three-Dimensional; Lymphoma; Magnetic Resonance Imaging; Male; Olivary Nucleus; Olivopontocerebellar Atrophies; Positron-Emission Tomography; Spin Labels
PubMed: 30496930
DOI: 10.1016/j.wneu.2018.11.161 -
International Review of Neurobiology 2018Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the main instruments for neuroimaging... (Review)
Review
Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the main instruments for neuroimaging investigation of patients with chronic ataxia. MRI has a predominant diagnostic role in the single patient, based on the visual detection of three patterns of atrophy, namely, spinal atrophy, cortical cerebellar atrophy and olivopontocerebellar atrophy, which correlate with the aetiologies of inherited or sporadic ataxia. In fact spinal atrophy is observed in Friedreich ataxia, cortical cerebellar atrophy in Ataxia Telangectasia, gluten ataxia and Sporadic Adult Onset Ataxia and olivopontocerebellar atrophy in Multiple System Atrophy cerebellar type. The 39 types of dominantly inherited spinocerebellar ataxias show either cortical cerebellar atrophy or olivopontocerebellar atrophy. T2 or T2* weighted MR images can contribute to the diagnosis by revealing abnormally increased or decreased signal with a characteristic distribution. These include symmetric T2 hyperintensity of the posterior and lateral columns of the cervical spinal cord in Friedreich ataxia, diffuse and symmetric hyperintensity of the cerebellar cortex in Infantile Neuro-Axonal Dystrophy, symmetric hyperintensity of the peridentate white matter in Cerebrotendineous Xanthomatosis, and symmetric hyperintensity of the middle cerebellar peduncles and peridentate white matter, cerebral white matter and corpus callosum in Fragile X Tremor Ataxia Syndrome. Abnormally decreased T2 or T2* signal can be observed with a multifocal distribution in Ataxia Telangectasia and with a symmetric distribution in the basal ganglia in Multiple System Atrophy. T2 signal hypointensity lining diffusely the outer surfaces of the brainstem, cerebellum and cerebrum enables diagnosis of superficial siderosis of the central nervous system. The diagnostic role of nuclear medicine techniques is smaller. SPECT and PET show decreased uptake of radiotracers investigating the nigrostriatal system in Multiple System Atrophy and in patients with Fragile X Tremor Ataxia Syndrome. Semiquantitative or quantitative MRI, SPECT and PET data describing structural, microstructural and functional changes of the cerebellum, brainstem, and spinal cord have been widely applied to investigate physiopathological changes in patients with chronic ataxias. Moreover they can track diseases progression with a greater sensitivity than clinical scales. So far, a few small-size and single center studies employed neuroimaging techniques as surrogate markers of treatment effects in chronic ataxias.
Topics: Ataxia; Brain Diseases; Humans; Magnetic Resonance Imaging; Neuroimaging; Positron-Emission Tomography; Spinal Cord Diseases; Tomography, Emission-Computed, Single-Photon
PubMed: 30473193
DOI: 10.1016/bs.irn.2018.09.011 -
Singapore Medical Journal Oct 2018A 49-year-old Chinese man was evaluated for progressive uncoordinated movements, dysphagia and urinary symptoms. Magnetic resonance imaging demonstrated a cruciform...
A 49-year-old Chinese man was evaluated for progressive uncoordinated movements, dysphagia and urinary symptoms. Magnetic resonance imaging demonstrated a cruciform pattern of T2-weighted hyperintensity within the pons and selective atrophy of the cerebellar hemispheres and pons. The clinical history and radiological findings were consistent with a diagnosis of multiple system atrophy-cerebellar type. This article discussed the background, proposed mechanisms, diagnosis, radiological characteristics, prognosis and management of multiple system atrophy-cerebellar type.
Topics: Alcoholism; Atrophy; Autonomic Nervous System; Cerebellum; Diagnosis, Differential; Disease Progression; Fatal Outcome; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple System Atrophy; Pneumonia, Aspiration; Prognosis
PubMed: 30386855
DOI: 10.11622/smedj.2018128 -
The Canadian Journal of Neurological... Sep 2018
Topics: Female; Humans; Hypertrophy; Listeria; Magnetic Resonance Imaging; Middle Aged; Olivary Nucleus; Olivopontocerebellar Atrophies; Rhombencephalon
PubMed: 30234466
DOI: 10.1017/cjn.2018.324