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Results for “Multiple system atrophy”

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At least 19 recordsLinked to original sources
PubMed2025

Distinct spatial transcriptomic patterns of substantia Nigra in Parkinson disease and Parkinsonian subtype of multiple system atrophy.

To investigate transcriptomic signatures of Parkinson's disease (PD) and the Parkinsonian subtype of Multiple System Atrophy (MSA-P) in substantia nigra pars compacta (SNpc), we conducted transcriptome analysis using in-situ hybridization on paraffin-embedded SNpc tissues from post-mortem brains. The study included 2 MSA-P patients, 2 PD patients, and 2 healthy controls (HC), with 12 regions of interest (ROIs) selected from the dorsal to ventral and medial to lateral aspects of the SNpc. A total of 72 ROIs from 6 participants were analyzed, and differentially expressed genes (DEGs) were identified by comparing MSA-P, PD and HC groups. The MSA-P group showed 88 upregulated DEGs and 326 downregulated DEGs (adjusted &#x1d45d;<0.05) compared to HC. The downregulated DEGs were significantly enriched in pathways related to ribosomal translation, immune processes, mitochondrial function, and autophagy. Notably, the dorsomedial quadrant was uniquely linked to antigen presentation, while other quadrants showed downregulation of protein synthesis. The PD group exhibited 165 upregulated DEGs and 350 downregulated DEGs (adjusted &#x1d45d;<0.05) compared to HC, with downregulated DEGs associated with ribosomal translation, mitochondrial function, and the ubiquitin-proteasome system. In both MSA-P and PD, the upregulated DEGs were not associated with any pathways or biological process in gene enrichment analysis. In network propagation analysis, amyloid precursor protein was the most significant network hub among DEGs in both MSA-P and PD. Comparing the transcriptomic signatures of SNpc between MSA-P and PD, we found immune/inflammation, mitochondrial function and neural signaling related genes were significantly downregulated in MSA-P compared to PD. Overall, the transcriptomic signature of the SNpc in MSA-P and PD revealed overlapping but distinct features, including alterations in protein synthesis, immune processes, mitochondrial function, and protein degradation systems. Future studies with larger cohorts and functional validation are needed to further elucidate these findings.

Humans↗
PubMed2026

Plasma cfDNA hypermethylation at SNCA intron 1 as a potential blood-based epigenetic signal in Parkinson's disease and multiple system atrophy.

BACKGROUND: The accumulation of &#x3b1;-synuclein (SNCA) in the central nervous system is a hallmark of Parkinson's disease (PD) and multiple system atrophy (MSA). SNCA intron 1 methylation is implicated in SNCA transcriptional regulation and may serve as a peripheral epigenetic signal in synucleinopathies. However, studies of SNCA methylation in leukocyte-derived DNA have yielded inconsistent results. We aimed to evaluate whether cell-free DNA (cfDNA)-based SNCA intron 1 methylation differs in PD or MSA compared with normal controls (NC). METHODS: Plasma cfDNA was collected from 105 patients with PD, 50 with MSA, and 114 NC. DNA methylation at CpG sites 10-17 was quantified by bisulfite pyrosequencing. Multivariable linear and logistic regression models, adjusted for age, sex, and education, were used to compare methylation levels and estimate odds ratios (ORs). RESULTS: Patients with PD exhibited hypermethylation at CpG site 14 and higher mean methylation across CpG sites 10-17 compared with NC. Patients with MSA showed hypermethylation at CpG sites 10, 12, 13, and 17 and elevated mean methylation. Elevated mean methylation was also observed in drug-na&#xef;ve de novo PD and early-stage PD patients. Compared with the lowest tertile, the highest mean methylation tertile was associated with increased odds of PD (OR, 2.49; 95% CI, 1.08-5.92) and MSA (OR, 5.02; 95% CI, 1.58-18.00). CONCLUSION: Plasma cfDNA SNCA intron 1 hypermethylation is associated with PD and MSA and detectable in drug-na&#xef;ve and early-stage PD. It may represent a peripheral epigenetic alteration and warrants evaluation as an adjunctive signal for early screening.

Humans↗
PubMed1976

[Multiple systemic atrophies, mental retardation, neurogenic amyotrophy and congenital bone fragility. A new neuro-generative disorder].

Five cases of a congenital neurological disorder are reported. Four patients, born after a breech delivery, belong to one sibship while the fifth patient is the only child in another family. The clinical features include quadriplegia, amyotrophy, a peripheral neuropathy, severe mental retardation and a subluxation of the hips. X-rays reveal diffuse osteoporosis and multiple spontaneous fractures. Autopsies in 3 patients showed multiple system atrophies involving the spinal cord and the cerebellum, coarse cerebral gyri and a marked reduction in volume of the white matter. These various pathological features are compared with the lesions found in a few other cases reported in the literature, none of which can be considered to be identical to the ones described. It is therefore felt that the condition under discussion represents a new syndrome to be classified, at least temporarily, within the group of multiple system atrophies.

Atrophy↗
PubMed2026

Chromosome X-wide association study in multiple system atrophy identifies sex-differential risk loci.

The human X chromosome accounts for &#x223c;5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40-2.03, P-value = 2.43 &#xd7; 10&#x207b;&#x2078;], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26-1.73, P-value = 9.92 &#xd7; 10&#x207b;&#x2077;). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Humans↗
PubMed1979

Multiple system atrophy with autonomic failure: clinical, histological and neurochemical observations on four cases.

Four cases of progressive autonomic failure are described, in all of which there were additional non-autonomic neurological abnormalities, including pyramidal, extra-pyramidal and cerebellar features. Histological examination revealed cell degeneration in the substantia nigra, putamen and intermediolateral columns of the spinal cord as a common pathological finding. In addition, 3 cases showed loss of Purkinje cells in the cerebellum and degeneration of pontine nuclei and inferior olivary nuclei. In one case there was cell loss from the locus coeruleus, caudate nucleus, vestibular nuclei and dorsal vagal nuclei. These were, therefore, cases of multiple system atrophy. Neurochemically, a common feature was a profound depletion in dopamine and noradrenaline from brain regions which are normally rich in these catecholamines. Central cholinergic systems appeared to be involved also, but to a variable degree.

Aged↗
PubMed1976

Dysautonomia in Parkinsonism: a clinicopathological study.

Necropsy studies were done on six patients with idiopathic paralysis agitans, one with multiple system atrophy including features of Parkinsonism, and one control. Autonomic functions had been evaluated during life to a varying degree. Intra-arterial blood pressure studies were carried out on two patients with paralysis agitans (cases 4 and 6) and the one with multiple system atrophy (case 7). Lewy bodies with or without cell loss were seen in the sympathetic ganglia of five cases of paralysis agitans. Three of these had orthostatic hypotension and the severity of the lesion approximately correlated with the degree of hypotension. It is concluded that the lesions of the sympathetic ganglia may play a major role in the production of orthostatic hypotension in idiopathic paralysis agitans.

Aged↗
PubMed2026

Synaptic vesicle glycoprotein 2A PET imaging in parkinsonian &#x3b1;-synucleinopathies: a systematic review.

Synaptic dysfunction is increasingly recognized as an early and biologically relevant component of &#x3b1;-synucleinopathies. However, conventional imaging biomarkers mainly assess dopaminergic dysfunction, glucose metabolism, or structural damage rather than presynaptic density itself. Synaptic vesicle glycoprotein 2A (SV2A) PET enables in vivo assessment of presynaptic terminal integrity and may provide complementary information in Parkinson's disease (PD), Parkinson's disease dementia/dementia with Lewy bodies (PDD/DLB), and multiple system atrophy (MSA). This systematic review synthesized the available evidence on SV2A-targeted PET in parkinsonian &#x3b1;-synucleinopathies, focusing on regional imaging patterns, clinical associations, longitudinal findings, and methodological determinants of interpretation. Seventeen reports were included. In PD, the most recurrent finding was reduced SV2A binding in the substantia nigra, although additional involvement of brainstem, caudate, striatal, thalamic, raphe, or cortical regions was reported in selected cohorts. In PDD/DLB, abnormalities appeared broader and more cortical, with evidence of association between cortical SV2A binding and cognitive performance. In MSA, one study suggested a distinct infratentorial and cerebellar pattern with potential relevance for phenotypic stratification. SV2A PET is a promising research biomarker for biological characterization of synucleinopathies. However, the field remains limited by small cohorts, methodological heterogeneity, variable quantification strategies, limited longitudinal evidence, and potential cohort overlap. Multicentre validation and harmonized protocols are required before clinical translation.

Humans↗
PubMed1978

Basiparallel cut by pneumoencephalotomography and cerebellar atrophy.

The basiparallel cut is a nearly horizontal slice of the posterior fossa used in air study and the structures are observed on a plane parallel to the clivus. Total shrinkage of the cerebellum, with or without fourth ventricle dilatation, was found in cases of olivopontocerebellar atrophy, some intoxications, and a few senile subjects. Some atrophy of paleocerebellar portions was seen in Holmes-type degeneration. Another pattern was symmetric shrinkage of neocerebellar lobules and relatively specific for the cases of 'multiple system atrophy' such as progressive supranuclear palsy, striatonigral degeneration, Marie's ataxia, etc. Loss of the superior cerebellar peduncle was clearly demonstrated in this view.

Adult↗
PubMed2026

Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.

The SNCA gene on chromosome 4 encodes the alpha-synuclein (&#x3b1;Syn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While &#x3b1;Syn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence &#x3b1;Syn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Molecular mechanisms↗
PubMed2026

Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.

Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (&#x3c7;), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA&#xa0;=&#xa0;5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated &#x3c7; in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific &#x3c7; alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.

Humans↗
PubMed1979

Defective cardiovascular reflexes and supersensitivity to sympathomimetic drugs in autonomic failure.

In 10 patients with chronic autonomic failure the clinical features and cardiovascular reflexes were correlated with the pressor responses to intravenous noradrenaline and tyramine. In all patients there was an exaggerated response to noradrenaline but a normal or only mildly exaggerated response to tyramine. Patients with lack of sinus arrhythmia and by implication baroreceptor reflex loss had greater responsiveness to pressor drugs than patients with preservation of this reflex. The responses to tyramine infusions imply that there must be sufficient noradrenaline released at defective sympathetic endings for a pressor response to occur. However, the lack of rise of plasma noradrenaline following tyramine, except in the patients with pure autonomic failure, clearly separates these responses from those of normal subjects. These results can be explained by the presence of lesions of both central and peripheral sympathetic pathways in patients with chronic autonomic failure and multiple system atrophy or Parkinsonism. The peripheral lesion, which is incomplete, may consist of replication of the receptors so causing supersensitivity with a duration of response that is little prolonged. The peripheral defect in the two patients with pure autonomic failure was found to be more complex and the prolonged response in one of these patients suggests the possibility of defective re-uptake or metabolism of noradrenaline. Clearly further study of the defects of sympathetic endings is required, including the use of other techniques such as catecholamine fluorescence. The extreme supersensitive responses underline the need for blood pressure monitoring during pressor drug studies prior to treatment, if the hazards of recumbent hypertension are to be avoided.

Adult↗
PubMedDate not supplied

Cerebral hemodynamics in Shy-Drager syndrome: variability of cerebral blood flow dysautoregulation and the compensatory role of chemical control in dysautoregulation.

Cerebrovascular autoregulation and CO2 reactivity were measured repeatedly in 3 patients with the multiple system atrophy type of autonomic insufficiency (Shy-Drager syndrome) by means of the 133Xe injection method. The degree of cerebral blood flow (CBF) dysautoregulation showed day-to-day variations in 2 of the 3 patients. The CO2 reactivity was normal or supernormal in the supine position in patients with impaired autoregulation. In the head-up position the response to CO2 was slightly suppressed in 2 of the patients, suggesting that chemical control may have tended to compensate for CBF dysautoregulation. It is concluded that the mechanism of chemical control of the cerebrovasculature is different from that which controls autoregulation and may have partially compensated for CBF dysautoregulation.

Carbon Dioxide↗
PubMed1979

Paroxysmal dysesthesia in multiple sclerosis.

Seven cases of multiple sclerosis with paroxysmal dysesthesias of an upper extremity were reported. This seizure characteristically is a purely sensory one induced by movements and is not accompanied by convulsions or a disorder of voluntary movements. In other ways it shares some features with other paroxysmal manifestations seen in MS. Clinical observations with subsequent neurophysiologic considerations have led to the hypothesis that paroxysmal dysesthesias are segmental symptoms with their foci lying in or about the spinal cord.

Adult↗
PubMed1977

Histocompatibility antigens (HLA): associations with immunopathic diseases and with responses to microbial antigens.

Described is the experience from a single histocompatibility typing laboratory sampling, firstly, Australian patients with various immunopathic diseases and, secondly, subjects previously classified as "responders" or "non-responders" to various microbial antigens. The diseases considered included chronic active hepatitis (CAH) and various cirrhoses, "thyrogastric" autoimmune diseases, systemic lupus erythematosus (SLE), rheumatoid arthritis, dermatitis herpetiformis (DH) with intestinal villous atrophy, and multiple sclerosis (MS). The immune responses considered included those to flagellin, candidin, mumps, trichophyton, tuberculin and streptococcal enzymes. The HLA specificities particularly associated with disease included B8 (CAH, thyrotoxicosis SLE, DH, and miscellaneous immunopathic diseases) and B7 (thyrotoxicosis, SLE, DH, and MS). The same specificities were present in excess, although not impressively so, among responders to certain of the microbial antigens, i.e. B7 with high responders to flagellin and B8 (and A1) with responders to trichophyton.

Adult↗
PubMed1979

[Threedimensional reconstruction of odontogenic cysts and their relationship to teeth and bone (author's transl)].

This study reports on the first time three-dimensional presentation of odontogenic cysts demonstrated by means of a simple histological method. Histological sections of biopsy material having been embedded in paraffin were projected on cardboard. After the projections had been cut out, the single parts were arranged in a way to form a three-dimensional model. Radicular cysts are monolocular and exhibit a smooth surface. The individual cyst is surrounded unilaterally by epithelial cell remnants of Malassez opposite to the adhering tooth. The bone shows a reactive-inflammatory transformation. Keratocysts occur in connection with the Gorlin-Goltz-syndrome and reveal a primary multiple structure. Smaller cysts have a round and smooth appearance, whereas the larger ones show an irregular surface. Satellite cysts of various sizes which develop in the adjacent areas are connected with the primary cyst. We are therefore dealing with two different types of cysts: with monolocular cysts which show a complex network and are connected with satellite cysts on the one hand, and, on the other, with additional multiple cast systems including monolocular and multilocular cysts of various sizes. The surrounding bone shows the characteristics of compression atrophy rather than signs of an inflammation.

Adult↗