Presence Of Glial Cytoplasmic Inclusions Research Articles

The potential of phosphorylated α-synuclein as a biomarker for the diagnosis and monitoring of multiple system atrophy.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by the presence of glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-Syn). Accurate diagnosis and monitoring of MSA present significant challenges, which can lead to potential misdiagnosis and inappropriate treatment. Biomarkers play a crucial role in improving the accuracy of MSA diagnosis, and phosphorylated α-synuclein (p-syn) has emerged as a promising biomarker for aiding in diagnosis and disease monitoring. A literature search was conducted on PubMed, Scopus, and Google Scholar using specific keywords and MeSH terms without imposing a time limit. Inclusion criteria comprised various study designs including experimental studies, case-control studies, and cohort studies published only in English, while conference abstracts and unpublished sources were excluded. Increased levels of p-syn have been observed in various samples from MSA patients, such as red blood cells, cerebrospinal fluid, oral mucosal cells, skin, and colon biopsies, highlighting their diagnostic potential. The α-Syn RT-QuIC assay has shown sensitivity in diagnosing MSA and tracking its progression. Meta-analyses and multicenter investigations have confirmed the diagnostic value of p-syn in cerebrospinal fluid, demonstrating high specificity and sensitivity in distinguishing MSA from other neurodegenerative diseases. Moreover, combining p-syn with other biomarkers has further improved the diagnostic accuracy of MSA. The p-syn stands out as a promising biomarker for MSA. It is found in oligodendrocytes and shows a correlation with disease severity and progression. However, further research and validation studies are necessary to establish p-syn as a reliable biomarker for MSA. If proven, p-syn could significantly contribute to early diagnosis, disease monitoring, and assessing treatment response.

Phosphorylation of Tau at Threonine 231 in Patients With Multiple System Atrophy and in a Mouse Model.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder pathologically characterized by the presence of glial cytoplasmic inclusions (GCIs). Some MSA patients exhibit motor deficits with accompanying cognitive impairment. Of note, some patients suffering from MSA with longer disease duration have AT8-positive signals, which correspond to phosphorylated tau (P-tau) at 202/205 (P-tau202/205). However, P-tau sites other than the AT8 antibody epitope antibody are less well studied. Here, we focused on the effect of α-synuclein (Syn) expression on the phosphorylation of tau in MSA model mice. Among the 6 kinds of antibodies against P-tau, we confirmed that antibodies against P-tau at 231 (P-tau231) were phospho-specific and found that P-tau231 level was increased in parallel with disease progression in MSA model mice. Additional studies of human brains revealed that P-tau231 was mainly expressed in the temporal cortex in MSA brains and that its expression level was significantly higher in MSA patients than in controls. Immunohistochemical analysis showed that anti-P-tau231-, but not AT8, antibodies mainly immunolabeled hippocampal CA2/3 pyramidal neurons, and some GCIs in MSA. These data suggest that P-tau231 occurs in MSA differently from P-tau202/205.

Abnormal aggregation of NLRP3 in microglia cells in multiple system atrophy disease

Background: Multiple system atrophy (MSA) is a sporadic, adult-onset neurodegenerative disorder. It is characterized by a combination of autonomic failure, parkinsonism, cerebellar ataxia, and corticospinal dysfunction with varying severity, causing progressive disability and death, usually within 7-9 years. Patients with MSA are clinically classified into one of two subtypes (parkinsonian or cerebellar) based on their predominant motor presentation. Neuropathological features include multiple system degeneration with the presence of glial cytoplasmic inclusions (GCI), gliosis and microglia infiltlation in the affected area. However the precise mechanism of propagation of GCI and relationship between GCI and neuroinflammation remain unknown.

Mouse models contribute to develop a therapeutic strategy for multiple system atrophy

Background: Multiple system atrophy (MSA) is a neurodegenerative disease caused by α-synuclein accumulation in oligodendrocytes and neurons. Pathological hallmark of MSA is the presence of glial cytoplasmic inclusions, which are found in oligodendrocytes and are composed of α-synuclein. Understanding of the complexity of degeneration in two types of CNS cells, oligodendrocytes and neurons, may be directly relevant to the exploration of therapeutic targets in MSA.

Advance in genetic research on multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. Widespread presence of glial cytoplasmic inclusions is the neuropathologic hallmark of MSA. The disease has long been considered as a sporadic disorder. However, in recent years, a few familial cases of MSA have been reported, and researches have verified certain genetic variants could increase the risk of MSA. These indicated genetic factors may play an imported role in the pathogenesis of MSA. In this review, the emerging evidence in favor of genetic players in MSA is discussed.

Selective Nuclear Shrinkage of Oligodendrocytes Lacking Glial Cytoplasmic Inclusions in Multiple System Atrophy: A 3-Dimensional Volumetric Study

Glial cytoplasmic inclusions (GCIs) are a pathologic hallmark of multiple system atrophy (MSA), but their pathogenetic roles need to be clarified. To determine possible roles of GCIs in individual cells, serial optical sections obtained by confocal microscopy were reconstructed to yield 3-dimensional (3D) images of the nuclei to quantify nuclear volume. Oligodendroglial nuclear volumes were determined in the pons of 6 MSA and 7 control patients. The nuclear volumes were significantly smaller in the MSA group as a whole (135.81 +/- 60.83 microm, mean +/- SD; n = 404) than in the control group (188.05 +/- 55.71 microm; n = 308; p < 0.001). This difference was due to a significantly smaller nuclear volume of oligodendrocytes without GCIs (GCI group, 91.26 +/- 23.77 microm; n = 210) compared with the control group (p < 0.001) and compared with the oligodendrocytes with GCIs (GCI group, 184.03 +/- 51.18 microm; n = 194; p < 0.001); the difference between the latter GCI and control groups was not significant (p > 0.05). This selective decrease in nuclear volume restricted to the GCI group cannot be explained if nuclear shrinkage was accelerated in the presence of GCIs. Conversely, GCI formation might be linked, either directly or indirectly, to a mechanism that counteracts rather than accelerates nuclear shrinkage. This novel 3-dimensional strategy provides pivotal data that link GCI formation and degeneration in MSA.

Depletion of putative chemosensitive respiratory neurons in the ventral medullary surface in multiple system atrophy

Multiple system atrophy (MSA) is a disorder that may manifest with reduced respiratory chemosensitivity and central sleep apnoea. Chemosensitive glutamatergic and serotonergic neurons located just beneath the ventral medullary surface, corresponding to the human arcuate nucleus (ArcN), have recently been implicated in control of automatic breathing in response to hypercapnia and hypoxia. We sought to determine whether these neurons were affected in MSA. Medullae were obtained at post-mortem from 11 patients (8 men, 3 women, age 64 +/- 3 years) with neuropathologically confirmed MSA and 11 control subjects (6 men and 5 women, age 66 +/- 4 years). Fifty micrometre sections obtained throughout the medulla were processed for vesicular glutamate transporter-2 (VGLUT-2), tryptophan-hydroxylase (TrOH), glial fibrillary acid protein (GFAP) and alpha-synuclein immunoreactivity. Cell counts, GFAP immunoreactivity and presence of glial cytoplasmic inclusions (GCIs) were assessed in the ArcN. In MSA, compared with controls, there was a marked depletion of ArcN neurons immunoreactive for either VGLUT-2 (74 +/- 21 versus 342 +/- 84 cells/section, P < 0.004) or TrOH (5 +/- 1 versus 16 +/- 2 cells/section, P < 0.001). There was also marked astrocytic gliosis and accumulation of alpha-synuclein immunoreactive GCIs in the ventral medullary surface in all cases. Our results indicate that there is severe loss of putative chemosensitive glutamatergic and serotonergic neurons as well as marked astrocytic gliosis in the ventral medullary surface in MSA. This may provide a possible morphological basis for impaired respiratory chemosensitivity and central sleep apnoea in this disorder.

Alpha-synuclein overexpression in oligodendrocytic cells results in impaired adhesion to fibronectin and cell death

The cardinal pathological features of multiple system atrophy (MSA) are the presence of glial cytoplasmic inclusions (GCIs) in oligodendrocytes and loss of oligodendrocytes. To understand the mechanisms underlying MSA, we examined the effects of overexpression of human α-synuclein (hα-syn) in CG-4 oligodendrocytic progenitor cells. CG-4 cells overexpressing hα-syn (hα-syn CG-4) demonstrated severely impaired adhesion and increased cell death when plated on fibronectin compared to laminin. The expression of the αv integrin subunit in whole cell lysates was also significantly downregulated in hα-syn CG-4. These results demonstrate a cytotoxic consequence of hα-syn overexpression in CG-4. This cytotoxicity appears to be the result of alterations in cell–extracellular matrix interactions, where impaired adhesion to fibronectin is associated with downregulation of the αv integrin subunit and increased cell death. It may, therefore, be one of the mechanisms underlying the loss of oligodendrocytes in MSA.

Primary involvement of the motor area in association with the nigrostriatal pathway in multiple system atrophy: neuropathological and morphometric evaluations

To evaluate the changes that occur in the motor and supplementary motor cortices in cases of multiple system atrophy (MSA), we carried out morphological and morphometric studies in 7 cases of MSA and 11 age-matched controls. Neuropathological study revealed presence of glial cytoplasmic inclusions (GCIs) in the cortex and subcortical white matter of the motor and supplementary motor areas, loss of small to medium-sized pyramidal neurons, and astrocytosis in the motor cortex in all cases of MSA, showing a definite predilection in the cortical layers V and VI. The severity of neuronal loss in the motor cortex was highly correlated with the incidence of GCIs and the involvement of the nigrostriatal pathway. Morphometrically, significant reductions of both the thickness of motor cortical layers V and VI and the number of neurons were observed. In addition, a reduction in the number of neurons in the supplementary motor cortex was detected in three out of the seven MSA cases. The results of this study suggest that the motor area is a cardinal target in MSA, and that in association with the nigrostriatal pathway it forms a motor loop degeneration in this disease.

Constant involvement of the Betz cells and pyramidal tract in multiple system atrophy: a clinicopathological study of seven autopsy cases.

We investigated clinicopathologically the pyramidal signs, including spasticity, hyperreflexia, and Babinski's sign, and the involvement of the pyramidal tract and primary motor cortex, in seven Japanese autopsy cases of multiple system atrophy (MSA). Pyramidal signs were observed in six (86%) of the seven autopsy cases. Hyperreflexia and Babinski's sign were each evident in five patients, but spasticity was observed in only one patient. Loss of Betz cells and presence of glial cytoplasmic inclusions in the primary motor cortex were noticed in all seven cases. Astrocytosis in the fifth layer of the primary motor cortex was noticed in five cases, but its presence was not related to the duration of the disease. Involvement of the pyramidal tract in the spinal cord, particularly of the small myelinated fibers, was observed in all seven cases, but no involvement of the pyramidal tract in the midbrain was evident in any of the six cases in which this structure was examined. In MSA, pyramidal signs were shown to be present more frequently than believed before, and the clinicopathological correlation between pyramidal signs and involvement of the pyramidal tract was obvious. Constant involvement of Betz cells in MSA has not been reported. Our clinicopathological findings may also make a contribution to the understanding of the clinicopathological hallmarks of MSA.

The relationship of multiple system atrophy to sporadic olivopontocerebellar atrophy and other forms of idiopathic late-onset cerebellar atrophy.

Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disease of undetermined cause characterized clinically by combinations of cerebellar, pyramidal, extrapyramidal, and autonomic disorders. 1,2 Many patients with MSA initially develop extrapyramidal symptoms and later experience autonomic disturbance or cerebellar features, or both; others start with autonomic disturbance, and some first manifest cerebellar symptoms and later develop autonomic or extrapyramidal features. Many patients develop only extrapyramidal and autonomic symptoms, but in most of these cases, subsequent neuropathologic studies also demonstrate degenerative changes in the cerebellum and brainstem. 3,4 The term MSA encompasses striatonigral degeneration (SND), the Shy-Drager syndrome (SDS), and many cases of sporadic olivopontocerebellar atrophy (sOPCA). Autopsy examination discloses neuronal loss and gliosis within some or all of the following structures: inferior olives, pons, cerebellum, substantia nigra, locus ceruleus, striatum (mainly putamen), and the intermediolateral columns and Onufs nucleus of the spinal cord. 5 Recently there have been descriptions of distinctive neuropathologic features of MSA consisting of oligodendroglial 6–11 and neuronal 12–14 intracytoplasmic and intranuclear argyrophilic inclusions containing accumulations of tubular structures. The glial cytoplasmic inclusions (GCIs) are present in all MSA brains, regardless of whether the patients were diagnosed in life as having SND, SDS, or sOPCA-type MSA. 6,14,15 In contrast, GCIs were not initially 6 found in a large number of neurologic controls, including patients with Parkinson's disease, progressive supranuclear palsy (PSP), and Machado-Joseph disease. However, a recent report 16 indicates that, although characteristic of MSA, the presence of GCIs is not …