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

MSA is a sporadic degenerative disease that occurs in striatonigral degeneration (SND), SDS and most cases of sporadic OPCA. Oligodendroglial inclusion is a hallmark of MSA. Recently there have been a small number of reports of neuronal argyrophilic inclusions. To clarify the distribution and dynamic process of neuronal cytoplasmic inclusions (NCI), 31 cases of MSA were studied using histology, immunohistochemistry, and electron microscopy. The inclusions were exclusively found in the pontine nucleus and there was a correlation between the incidence of NCI and the severity of OPCA, but not of SND. NCI were increased to some extent in the cases with moderate OPCA and decreased in number in proportion to devastation of the pontine nuclei. Immunohistochemical and ultrastructural features of NCI were virtually identical to those of glial cytoplasmic inclusions (GCI), which gives some clues to the pathogenesis of MSA. It is tempting to interpret this as NCI playing a significant role in the degenerative changes of the neurons at least in the pons. Further systematic studies on NCI in the other brain regions are necessary to elucidate the pathogenesis of neuronal degeneration in MSA.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmarks are α-synuclein (AS) positive glial cytoplasmic inclusions (GCIs) in oligodendroglias. AS aggregation is also found in glial nuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurties. Reviewing the pathological features of 102 MSA cases, OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases, which suggested different phenotypic pattern of MSA might exist between races, compared to the relatively high frequency of SND-type in western countries. In early stage of MSA, NNIs, NCIs and diffuse homogenous stain of AS in neuronal nuclei and cytoplasm were observed in various vulnerable lesions including the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic cord, lower motor neurons and cortical pyramidal neurons, in additions to GCIs. These findings indicated that the primary nonfibrillar and fibrillar AS aggregation also occurred in neurons. Therefore both the direct involvement of neurons themselves and the oligodendroglia-myelin-axon mechanism may synergistically accelerate the degenerative process of MSA.

Neuronal cytoplasmic inclusions (NCIs) were demonstrated by means of silver staining (Gallyas staining) in the central nervous systems of 18 deceased patients with multiple system atrophy (MSA) - 6 with olivopontocerebellar atrophy (OPCA), 6 with striatonigral degeneration (SND) and 6 with Shy-Drager syndrome (SDS). We observed NCIs in the cerebral cortex, putamen, pons, medulla oblongata and spinal cord, and especially in the putamen and pons of all cases with MSA. No NCIs were observed in the cerebellum and midbrain. The findings were common to all 3 subtypes of MSA. NCIs were not present in patients with other neurodegenerative disorders and non-neurological disorders. Our findings indicate that NCIs represent a special neuronal alteration characteristic of MSA and support the theory that OPCA, SND and SDS represent manifestations of a single condition i.e. MSA.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease clinically marked by autonomic failure and variable degrees of parkinsonism and cerebellar ataxias. The average age of onset is in the sixth decade of life with a five-year survival, although fulminant and more benign courses have been described (1). The pathologic hallmark of MSA is abundant α-synuclein-positive protein aggregates within oligodendrocytes (glial cytoplasmic inclusions, GCI) and neurons (neuronal cytoplasmic inclusions, NCI, and neuronal nuclear inclusions, NNI). The density of GCIs has been correlated with disease duration and severity of neuronal loss (2). Here, we present an unusual case of MSA clinically characterized by rapid decline followed by a 20-year disease duration in a severely affected state. At autopsy, the brain showed severe gliosis and neuronal loss in a pattern characteristic of MSA. Additionally, there were atypical Pick body-like and ring-shaped α-synuclein inclusions, most prominent in limbic regions, consistent with a recently described subtype of MSA designated "atypical MSA" (3). Four different α-synuclein antibodies highlighted only scant α-synuclein-positive pathology; however, Gallyas and Campbell-Switzer silver stains identified additional GCIs most prominent in subcortical white matter. Interestingly, many of the α-synuclein-positive limbic inclusions were Gallyas-negative, while many of the Gallyas-positive inclusions were α-synuclein-negative (4). This observation of markedly disparate α-synuclein immunohistochemical versus Gallyas reactivity of MSA inclusions is unusual and could support the possibility that MSA inclusions have variable compositions, something which has been recently suggested (5).

Multiple system atrophy (MSA) is divided into two clinical subtypes: MSA with predominant parkinsonian features (MSA-P) and MSA with predominant cerebellar dysfunction (MSA-C). We report a 71-year-old Japanese man without clinical signs of MSA, in whom post mortem examination revealed only slight gliosis in the pontine base and widespread occurrence of glial cytoplasmic inclusions in the central nervous system, with the greatest abundance in the pontine base and cerebellar white matter. Neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) were almost restricted to the pontine and inferior olivary nuclei. It was noteworthy that most NCIs were located in the perinuclear area, and the majority of NNIs were observed adjacent to the inner surface of the nuclear membrane. To our knowledge, only four autopsy cases of preclinical MSA have been reported previously, in which neuronal loss was almost entirely restricted to the substantia nigra and/or putamen. Therefore, the present autopsy case of preclinical MSA-C is considered to be the first of its kind to have been reported. The histopathological features observed in preclinical MSA may represent the early pattern of MSA pathology.

Choroid plexus alterations correlate with cognitive impairment in multiple system atrophy.

A variety of neurodegenerative disorders are classified as synucleinopathies based on the presence of prominent α-synuclein pathology. These diseases include Parkinson disease (PD), dementia with Lewy bodies (with neuronal Lewy body formation) and multiple system atrophy (with glial cytoplasmic inclusions). The normal function of α-synuclein includes regulation of presynaptic vesicles. Autosomal dominant PD can be due to coding mutations or multiplications of the α-synuclein gene ( SNCA ). The coding mutations are thought to lead to a gain of function, in particular acceleration of the formation of protofibrils. Duplications and triplications of SNCA lead to autosomal dominant PD with a gene dosage effect on age of onset and clinical severity. Variants in the SNCA promoter, which lead to an upregulation of SNCA expression, are associated with an increased risk of sporadic PD. α-Synuclein is now recognised as the key component of Lewy bodies and as an important target for therapeutic intervention. A number of α-synuclein antibody therapy treatments are in development and have entered early-phase clinical development. Key Concepts α-Synuclein is deposited in the common neurodegenerative conditions, Parkinson disease (PD) and dementia with Lewy bodies, as neuronal cytoplasmic inclusions (Lewy bodies). The normal function of α-synuclein is incompletely understood but is likely to involve interaction with and regulation of synaptic vesicles. There is some evidence that α-synuclein may have a role as a cellular chaperone and in interacting with the proteasome. Mendelian coding mutations in the α-synuclein gene ( SNCA ) can lead to autosomal dominant PD and dementia with Lewy bodies (DLB). SNCA mutations lead to an enhancement of protofibril formation as well as affecting normal α-synuclein function. SNCA duplications and triplications lead to autosomal dominant PD: an increase in the transcription of normal sequence SNCA can lead to disease. Promoter variation at the SNCA is associated with PD; in vitro evidence suggests that protective promoter alleles lead to a downregulation of SNCA expression. There is now substantial evidence for cell-to-cell 'prion-like' spread of synuclein pathology in the brain. This spreading pathology represents a therapeutic target, and a number of anti-α-synuclein antibody therapies are in early-stage clinical trial development.

Multiple system atrophy is characterized pathologically by the accumulation of alpha-synuclein (aSyn) into glial cytoplasmic inclusions (GCIs). The mechanism underlying the formation of GCIs is not well understood.In this study, correlative light and electron microscopy was employed to investigate aSyn pathology in the substantia nigra and putamen of post-mortem multiple system atrophy brain donors.Three distinct types of aSyn immuno-positive inclusions were identified in oligodendrocytes, neurons and dark cells presumed to be dark microglia. Oligodendrocytes contained fibrillar GCIs that were consistently enriched with lysosomes and peroxisomes, supporting the involvement of the autophagy pathway in aSyn aggregation in multiple system atrophy. Neuronal cytoplasmic inclusions exhibited ultrastructural heterogeneity resembling both fibrillar and membranous inclusions, linking multiple systems atrophy and Parkinson’s disease. The novel aSyn pathology identified in the dark cells, displayed GCI-like fibrils or non-GCI-like ultrastructures suggesting various stages of aSyn accumulation in these cells.The observation of GCI-like fibrils within dark cells suggests these cells may be an important contributor to the origin or spread of pathological aSyn in multiple system atrophy. Our results suggest a complex interplay between multiple cell types that may underlie the formation of aSyn pathology in multiple system atrophy brain and highlight the need for further investigation into cell-specific disease pathologies in multiple system atrophy.

Introduction: This study aimed to use a novel MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, to assess damage of the white matter and gray matter in multiple system atrophy (MSA). Furthermore, this study investigated whether the sT1w/T2w ratio was associated with cognitive impairment in MSA. Methods: The white matter and gray matter sT1w/T2w ratio of 37 MSA patients and 19 healthy controls were measured. Correlation analyses were used to evaluate the relationship between sT1w/T2w ratio values and clinical variables, and a multivariate analysis was used to identify independent factors associated with cognitive impairment in MSA. Results: MSA patients showed a higher white matter sT1w/T2w ratio value than controls (p < 0.001), and the white matter sT1w/T2w ratio value was significantly correlated with the International Cooperative Ataxia Rating Scale score (r = 0.377, p = 0.021) and the Addenbrooke’s cognitive examination III score (r = −0.438, p = 0.007). Cognitively impaired MSA patients had a significantly higher white matter sT1w/T2w ratio value than cognitively preserved MSA patients (p = 0.010), and the multiple logistic regression analysis revealed that the median white matter sT1w/T2w ratio value was independently associated with cognitive impairment in MSA. Conclusion: The sT1w/T2w ratio is sensitive to degenerative changes in the white matter that is associated with cognitive ability in MSA patients.

Many efforts have been tried to evaluate multiple system atrophy (MSA)-related cognitive impairment, however, there is still lacking of effective approach. In this study, for the first time, we developed the individual metabolic radiomics networks (IMRN) using [18F]FDG PET imaging to investigate brain metabolic connectivity patterns of MSA and validated the usefulness of IMRN-based predictive model for MSA-related cognitive impairment. In this retrospective study, we recruited 115 MSA patients with [18F]FDG PET/CT scans. IMRN was constructed by extracting non-redundant radiomics features from each brain region and computing pairwise Pearson correlation coefficients among these features. The validation of IMRN included assessments of small-world properties, test-retest reliability, and metabolic-genetic correlations. Connectome-based predictive modeling (CPM) was implemented to predict Mini Mental State Examination (MMSE) scores, while network-based statistics (NBS) were compared between MSA patients with cognitive impairment (MSA-CI, n = 58; MMSE < 27) and those with normal cognition (MSA-NC, n = 57; MMSE ≥ 27). A support vector machine (SVM) classifier for detecting MSA-CI was developed using discriminative IMRN edges. IMRN showed small-world properties (σ > 1), high reliability (average edge ICC = 0.754), and a significant correlation with gene expression (r = 0.44, P < 0.001). CPM significantly predicted cognitive scores through IMRN edges (positive network: r = 0.27, P = 0.03; negative network: r = 0.28, P = 0.02). NBS revealed decreased cerebellar-cortical connectivity (73 edges) and increased intra-cerebellar/limbic connectivity (24 edges) in MSA-CI compared to MSA-NC. The IMRN-based SVM outperformed SUVR-based SVM in classifying MSA-CI (accuracy: 73.91% vs 62.61%; AUC: 0.80 vs 0.69). This study established a novel approach of IMRN for assessing whole brain metabolic connectivity, uncovering distinct cerebellar connectivity patterns in MSA-CI, which held promise for facilitating personalized cognitive evaluations in MSA.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that usually manifests in the early sixth decade of life and progresses relentlessly with a mean survival of 9 years. Clinically, MSA is dominated by autonomic/urogenital failure, which may be associated with either levodopa (L-dopa) -unresponsive parkinsonism in 80% of cases (MSA-P subtype) or with cerebellar ataxia in 20% of cases (MSA-C subtype). Pathologically, MSA is characterized by a neuronal multisystem degeneration and abnormal glial cytoplasmic inclusions containing alpha-synuclein aggregates. Pharmacological treatment of motor features is disappointing except for a transient L-dopa response in a minority of MSA-P patients. In contrast, autonomic and urogenital features of MSA should be identified early on, because they can be treated effectively in many instances. Neuroprotective strategies are presently unavailable, however, two multicentre European trials have been launched to evaluate the effects of riluzole and human recombinant growth hormone on disease progression in MSA. Clearly, further randomised, controlled trials are required to identify effective symptomatic or neuroprotective agents in MSA. Several in vivo models have become available to allow a careful preselection of candidate agents. Several research groups have been formed in Europe (EMSA-SG, NNIPPS) and United States (NAMSA-SG), providing a framework for coordinated trial activity in MSA.

Frontotemporal lobar degeneration with TDP-43 immunoreactive (TDP-ir) inclusions (FTLD-TDP) is sub-classified based on the pattern of neocortical pathology, with each subtype showing clinical and genetic correlations. Recent studies indicate that accurate subtyping of cases may be important to help identify genetic risk factors and develop biomarkers. Although most FTLD-TDP cases are easily classified, some do not match well to one of the existing subtypes. In particular, cases with the C9orf72 repeat expansion (C9+) have been reported to show FTLD-TDP type A, type B or a combination of A and B pathology (A + B). In our series of FTLD-TDP cases, we found that those lacking the C9orf72 mutation (non-C9) were all readily classified as type A (n = 29), B (n = 16) or C (n = 18), using current criteria and standard observational methods. This classification was validated using non-biased hierarchical cluster analysis (HCA) of neocortical pathology data. In contrast, only 14/28 (50%) of the C9+ cases were classified as either pure type A or pure type B, with the remainder showing A + B features. HCA confirmed separation of the C9+ cases into three groups. We then investigated whether patterns of subcortical TDP-ir pathology helped to classify the difficult cases. For the non-C9 cases, each subtype showed a consistent pattern of subcortical involvement with significant differences among the groups. The most distinguishing features included white matter threads, neuronal intranuclear inclusions in hippocampus and striatum, and delicate threads in CA1 in type A; glial cytoplasmic inclusions in white matter and neuronal cytoplasmic inclusions (NCI) in lower motor neurons in type B; compact NCI in striatum in type C. HCA of the C9+ cases based on subcortical features increased the number that clustered with the non-C9 type A (46%) or non-C9 type B (36%); however, there remained a C9+ group with A + B features (18%). These findings suggest that most FTLD-TDP cases can be classified using existing criteria and that each group also shows characteristic subcortical TDP-ir pathology. However, C9+ cases may be unique in the degree to which their pathology overlaps between FTLD-TDP types A and B.

Multiple system atrophy (MSA) is characterized by a variable combination of cerebellar ataxia, parkinsonism and pyramidal signs associated with autonomic failure. Classically, cognitive impairment was not considered a clinical feature of MSA and dementia was pointed out as an exclusion diagnostic criteria. Based on comprehensive neuropsychological assessment, cognitive impairment was found to be a frequent feature in MSA, and clinically-defined dementia is now reported in 14-16% of cases. This article reviews the current data on cognitive impairment in MSA along with its neuropsychological profile and pathophysiology.

Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed α-synucleinopathies, which also include Parkinson's disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal α-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of α-synuclein are oligodendroglial cells . This pathological hallmark, also called glial cytoplasmic inclusions (GCIs) , is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of α-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson's syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies.

Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of α-syn accumulation in GCIs is unclear, in particular whether abnormal α-syn aggregates result from the abnormal elevation of endogenous α-syn expression in MSA or ingested from the neuronal source. Tubulin polymerization promoting protein (TPPP) has been reported to play a crucial role in developing GCI pathology. Here, the total cell body, nucleus, and cytoplasmic area density of SNCA and TPPP transcripts in neurons and oligodendrocytes with and without various α-syn pathologies in the pontine base in autopsy cases of MSA (n = 4) and controls (n = 2) were evaluated using RNAscope with immunofluorescence. Single-nucleus RNA-sequencing data for TPPP was evaluated using control frontal cortex (n = 3). SNCA and TPPP transcripts were present in the nucleus and cytoplasm of oligodendrocytes in both controls and diseased, with higher area density in GCIs and glial nuclear inclusions in MSA. Area densities of SNCA and TPPP transcripts were lower in neurons showing cytoplasmic inclusions in MSA. Indeed, TPPP transcripts were unexpectedly found in neurons, while the anti-TPPP antibody failed to detect immunoreactivity. Single-nucleus RNA-sequencing revealed significant TPPP transcript expression predominantly in oligodendrocytes, but also in excitatory and inhibitory neurons. This study addressed the unclear origin of accumulated α-syn in GCIs, proposing that the elevation of SNCA transcripts may supply templates for misfolded α-syn. In addition, the parallel behavior of TPPP and SNCA transcripts in GCI development highlights their potential synergistic contribution to inclusion formation. In conclusion, this study advances our understanding of MSA pathogenesis, offers insights into the dynamics of SNCA and TPPP transcripts in inclusion formation, and proposes regulating their transcripts for future molecular therapy to MSA.