Frequent globular neuronal cytoplasmic inclusions in the medial temporal region as a possible characteristic feature in multiple system atrophy with dementia

2016 ◽  
Vol 36 (5) ◽  
pp. 421-431 ◽  
Author(s):  
Taku Homma ◽  
Yoko Mochizuki ◽  
Takashi Komori ◽  
Eiji Isozaki
Keyword(s):  
Characteristic Feature ◽  
Multiple System Atrophy ◽  
Temporal Region ◽  
Cytoplasmic Inclusions ◽  
Neuronal Cytoplasmic Inclusions

scholarly journals Hippocampal α-synuclein pathology correlates with memory impairment in multiple system atrophy

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1798-1810 ◽  
Author(s):  
Yasuo Miki ◽  
Sandrine C Foti ◽  
Daniela Hansen ◽  
Kate M Strand ◽  
Yasmine T Asi ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Multiple System Atrophy ◽  
Dentate Gyrus ◽  
Memory Impairment ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Cornu Ammonis ◽  
Neuronal Cytoplasmic Inclusions ◽  
With Memory ◽  
Normal Cognition

Abstract Recent post-mortem studies reported 22–37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79.7%) were reported to have had normal cognition in life, whereas the remaining 30 (20.3%) developed cognitive impairment. Twelve of them had pure frontal-subcortical dysfunction, defined as the presence of executive dysfunction, impaired processing speed, personality change, disinhibition or stereotypy; six had pure memory impairment; and 12 had both types of impairment. Semi-quantitative analysis of neuronal cytoplasmic inclusions in the hippocampus and parahippocampus revealed a disease duration-related increase in neuronal cytoplasmic inclusions in the dentate gyrus and cornu ammonis regions 1 and 2 of patients with normal cognition. In contrast, such a correlation with disease duration was not found in patients with cognitive impairment. Compared to the patients with normal cognition, patients with memory impairment (pure memory impairment: n = 6; memory impairment + frontal-subcortical dysfunction: n = 12) had more neuronal cytoplasmic inclusions in the dentate gyrus, cornu ammonis regions 1–4 and entorhinal cortex. In the multiple system atrophy mixed pathological subgroup, which equally affects the striatonigral and olivopontocerebellar systems, patients with the same combination of memory impairment developed more neuronal inclusions in the dentate gyrus, cornu ammonis regions 1, 2 and 4, and the subiculum compared to patients with normal cognition. Using patients with normal cognition (n = 18), frontal-subcortical dysfunction (n = 12) and memory impairment + frontal-subcortical dysfunction (n = 18), we further investigated whether neuronal or glial cytoplasmic inclusions in the prefrontal, temporal and cingulate cortices or the underlying white matter might affect cognitive impairment in patients with multiple system atrophy. We also examined topographic correlates of frontal-subcortical dysfunction with other clinical symptoms. Although no differences in neuronal or glial cytoplasmic inclusions were identified between the groups in the regions examined, frontal release signs were found more commonly when patients developed frontal-subcortical dysfunction, indicating the involvement of the frontal–subcortical circuit in the pathogenesis of frontal-subcortical dysfunction. Here, investigating cognitive impairment in the largest number of pathologically proven multiple system atrophy cases described to date, we provide evidence that neuronal cytoplasmic inclusion burden in the hippocampus and parahippocampus is associated with the occurrence of memory impairment in multiple system atrophy. Further investigation is necessary to identify the underlying pathological basis of frontal-subcortical dysfunction in multiple system atrophy.

XIAP immunoreactivity in glial and neuronal cytoplasmic inclusions in multiple system atrophy

2014 ◽  
Vol 33 (01) ◽  
pp. 76-83 ◽  
Author(s):  
Yasuhiro Kawamoto ◽  
Hidefumi Ito ◽  
Masafumi Ihara ◽  
Ryosuke Takahashi
Keyword(s):  
Multiple System Atrophy ◽  
Cytoplasmic Inclusions ◽  
Neuronal Cytoplasmic Inclusions

Activated caspase-9 immunoreactivity in glial and neuronal cytoplasmic inclusions in multiple system atrophy

2016 ◽  
Vol 628 ◽  
pp. 207-212 ◽  
Author(s):  
Yasuhiro Kawamoto ◽  
Takashi Ayaki ◽  
Makoto Urushitani ◽  
Hidefumi Ito ◽  
Ryosuke Takahashi
Keyword(s):  
Multiple System Atrophy ◽  
Caspase 9 ◽  
Cytoplasmic Inclusions ◽  
Neuronal Cytoplasmic Inclusions

Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy

2017 ◽  
Vol 89 (2) ◽  
pp. 175-184 ◽  
Author(s):  
Shunsuke Koga ◽  
Dennis W Dickson
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Cytoplasmic Inclusion ◽  
Olivopontocerebellar Atrophy ◽  
Cytoplasmic Inclusions ◽  
Cellular Origin ◽  
Recent Advances ◽  
Neuronal Cytoplasmic Inclusions ◽  
Variable Combination

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterised by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal symptoms. The pathological hallmark is the oligodendrocytic glial cytoplasmic inclusion (GCI) consisting of α-synuclein; therefore, MSA is included in the category of α-synucleinopathies. MSA has been divided into two clinicopathological subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia, which generally correlate with striatonigral degeneration and olivopontocerebellar atrophy, respectively. It is increasingly recognised, however, that clinical and pathological features of MSA are broader than previously considered.In this review, we aim to describe recent advances in neuropathology of MSA from a review of the literature and from information derived from review of nearly 200 definite MSA cases in the Mayo Clinic Brain Bank. In light of these new neuropathological findings, GCIs and neuronal cytoplasmic inclusions play an important role in clinicopathological correlates of MSA. We also focus on clinical diagnostic accuracy and differential diagnosis of MSA as well as candidate biomarkers. We also review some controversial topics in MSA. Cognitive impairment, which has been a non-supporting feature of MSA, is considered from both clinical and pathological perspectives. The cellular origin of α-synuclein in GCI and a ‘prion hypothesis’ are discussed. Finally, completed and ongoing clinical trials targeting disease modification, including immunotherapy, are summarised.

scholarly journals Comparison of Neuropathological Characteristics between Multiple System Atrophy Cerebellar Type and Parkinsonian Type

2020 ◽  
Vol 38 (3) ◽  
pp. 194-203
Author(s):  
Eun-Joo Kim ◽  
Sukmin Lee ◽  
Sung-Hwan Jang ◽  
Myung Jun Lee ◽  
Jae-Hyeok Lee ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
University Hospital ◽  
Cytoplasmic Inclusions ◽  
Age Related ◽  
National University ◽  
Neuronal Cytoplasmic Inclusions ◽  
Cerebellar Type

Background: Multiple system atrophy (MSA) is a sporadic neurodegenerative disease characterized by various combinations of parkinsonism, cerebellar ataxia, autonomic dysfunction and pyramidal signs. Two clinical subtypes are recognized: MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). The aim of this study was to compare pathological features between MSA-C and MSA-P.Methods: Two autopsy confirmed cases with MSA were included from the Pusan National University Hospital Brain Bank. Case 1 had been clinically diagnosed as MSA-C and case 2 as MSA-P. The severity of neuronal loss and gliosis as well as the glial and neuronal cytoplasmic inclusions were semiquantitatively assessed in both striatonigral and olivopontocerebellar regions. Based on the grading system, pathological phenotypes of MSA were classified as striatonigral degeneration (SND) predominant (SND type), olivopontocerebellar degeneration (OPC) predominant (OPC type), or equivalent SND and OPC pathology (SND=OPC type).Results: Both cases showed widespread and abundant α-synuclein positive glial cytoplasmic inclusions in association with neurodegenerative changes in striatonigral or olivopontocerebellar structures, leading to the primary pathological diagnosis of MSA. Primary age-related tauopathy was incidentally found but Lewy bodies were not in both cases. The pathological phenotypes of MSA were MSA-OPC type in case 1 and MSA-SND=OPC type in case 2.Conclusions: Our data suggest that clinical phenotypes of MSA reflect the pathological characteristics.

Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy

2004 ◽  
Vol 100 (3) ◽  
pp. 553-556 ◽  
Author(s):  
Kelvin L. Chou ◽  
Mark S. Forman ◽  
John Q. Trojanowski ◽  
Howard I. Hurtig ◽  
Gordon H. Baltuch
Keyword(s):  
Deep Brain Stimulation ◽  
Multiple System Atrophy ◽  
Subthalamic Nucleus ◽  
Brain Stimulation ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Content Type ◽  
Clinicopathological Findings ◽  
Diagnostic Modalities ◽  
Deep Brain

✓ The authors report the clinicopathological findings in a patient in whom levodopa-responsive parkinsonism developed at 45 years of age. The patient experienced asymmetrical onset of symptoms, sustained benefit from levodopa, and motor fluctuations and dyskinesias, but there were no prominent autonomic, cerebellar, or pyramidal signs. He was diagnosed clinically with Parkinson disease (PD) and underwent bilateral subthalamic nucleus deep brain stimulation (DBS) surgery 9 years after symptom onset. He did not respond to stimulation or medication postoperatively, however, and died 12 weeks after surgery of repeated aspiration pneumonias. Postmortem examination revealed neuron loss in the substantia nigra and basal ganglia, and numerous α-synuclein—positive glial cytoplasmic inclusions in the subcortical nuclei, cerebellum, and brainstem, findings that established a neuropathological diagnosis of multiple system atrophy (MSA). Furthermore, there was an atypical and robust inflammatory reaction, as well as numerous glial cytoplasmic inclusions surrounding both DBS electrode termination sites. The authors speculate that the presence of α-synuclein in the striatum, combined with the inflammation surrounding the electrodes, contributed to the ineffectiveness of stimulation and dopaminergic medications postoperatively. This case demonstrates the ineffectiveness of DBS in MSA, even when the patient is responsive to levodopa, and emphasizes the need for diagnostic modalities that can be used to distinguish PD from MSA and other parkinsonian syndromes in which the levodopa response pattern is typical of PD.

scholarly journals Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ethan W. Hass ◽  
Zachary A. Sorrentino ◽  
Grace M. Lloyd ◽  
Nikolaus R. McFarland ◽  
Stefan Prokop ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Biochemical Properties ◽  
Detection Methods ◽  
Inferior Olivary Nucleus ◽  
Cytoplasmic Inclusions ◽  
Neuronal Populations ◽  
Carboxy Terminal Region ◽  
High Level ◽  
Carboxy Terminal

AbstractMultiple system atrophy (MSA) is an insidious middle age-onset neurodegenerative disease that clinically presents with variable degrees of parkinsonism and cerebellar ataxia. The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes that are comprised of α-synuclein (αSyn) aberrantly polymerized into fibrils. Experimentally, MSA brain samples display a high level of seeding activity to induce further αSyn aggregation by a prion-like conformational mechanism. Paradoxically, αSyn is predominantly a neuronal brain protein, with only marginal levels expressed in normal or diseased oligodendrocytes, and αSyn inclusions in other neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies, are primarily found in neurons. Although GCIs are the hallmark of MSA, using a series of new monoclonal antibodies targeting the carboxy-terminal region of αSyn, we demonstrate that neuronal αSyn pathology in MSA patient brains is remarkably abundant in the pontine nuclei and medullary inferior olivary nucleus. This neuronal αSyn pathology has distinct histological properties compared to GCIs, which allows it to remain concealed to many routine detection methods associated with altered biochemical properties of the carboxy-terminal domain of αSyn. We propose that these previously underappreciated sources of aberrant αSyn could serve as a pool of αSyn prion seeds that can initiate and continue to drive the pathogenesis of MSA.

scholarly journals Multiple system atrophy: genetic risks and alpha-synuclein mutations

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2072 ◽  
Author(s):  
Heather T Whittaker ◽  
Yichen Qui ◽  
Conceição Bettencourt ◽  
Henry Houlden
Keyword(s):  
Multiple System Atrophy ◽  
Protein Misfolding ◽  
Research Collaboration ◽  
Late Onset ◽  
Alpha Synuclein ◽  
Common Mechanism ◽  
International Research Collaboration ◽  
Cytoplasmic Inclusions ◽  
Genetic Risks

Multiple system atrophy (MSA) is one of the few neurodegenerative disorders where we have a significant understanding of the clinical and pathological manifestations but where the aetiology remains almost completely unknown. Research to overcome this hurdle is gaining momentum through international research collaboration and a series of genetic and molecular discoveries in the last few years, which have advanced our knowledge of this rare synucleinopathy. In MSA, the discovery of α-synuclein pathology and glial cytoplasmic inclusions remain the most significant findings. Families with certain types of α-synuclein mutations develop diseases that mimic MSA, and the spectrum of clinical and pathological features in these families suggests a spectrum of severity, from late-onset Parkinson’s disease to MSA. Nonetheless, controversies persist, such as the role of common α-synuclein variants in MSA and whether this disorder shares a common mechanism of spreading pathology with other protein misfolding neurodegenerative diseases. Here, we review these issues, specifically focusing on α-synuclein mutations.

scholarly journals Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Lisa Mészáros ◽  
Markus J. Riemenschneider ◽  
Heiko Gassner ◽  
Franz Marxreiter ◽  
Stephan von Hörsten ◽  
...  
Keyword(s):  
Mouse Model ◽  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Purkinje Cells ◽  
Alpha Synuclein ◽  
Significant Loss ◽  
Disease Stage ◽  
Cytoplasmic Inclusions ◽  
Unsteady Gait ◽  
Advanced Disease Stage

AbstractMultiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.

Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia

2008 ◽  
Vol 116 (2) ◽  
pp. 193-203 ◽  
Author(s):  
Fumiaki Mori ◽  
Kunikazu Tanji ◽  
Hai-Xin Zhang ◽  
Yasushi Nishihira ◽  
Chun-Feng Tan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Maturation Process ◽  
Cytoplasmic Inclusions ◽  
Neuronal Cytoplasmic Inclusions ◽  
Lateral Sclerosis
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