Abnormalities of white and grey matter in early multiple system atrophy: comparison of parkinsonian and cerebellar variants

Dash, Santosh Kumar; Stezin, Albert; Takalkar, Tejashree; George, Lija; Kamble, Nitish; Netravathi, M; Yadav, Ravi; Kumar, Keshav; Ingalhalikar, Madhura; Saini, Jitender; Pal, Pramod Kumar

doi:10.1007/s00330-018-5594-9

Cited by 34 publications

(42 citation statements)

References 38 publications

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“…Of note, the ratio of MSA-P:MSA-C was 2.6:1 therefore the decreased number of DEGs noted in the combined MSA analysis is likely due to the higher number of MSA-P patients in our study. These results agree with the larger involvement of CWM alterations in MSA-C compared to MSA-P during the early stages of the disease[18,46]. It is possible that due to the early involvement of CWM in MSA-C there is a longer time for the disease-related transcriptional changes to develop in the CWM in these patients [46].…”

supporting

confidence: 84%

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Piras

Bleul

Schrauwen

et al. 2020

Preprint

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Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC; n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis of MSA-C showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and an enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for βamyloid related functional classes, including the known Alzheimer's disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and ADrelated genes despite the clinical and neuropathological distinctions between the two diseases.3

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confidence: 84%

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Piras

Bleul

Schrauwen

et al. 2020

Preprint

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“…Atrophy of the cerebellum and brainstem are common features of MSA‐C and SAOA . In addition, microstructural alterations of the white matter have been reported in previous studies in MSA‐C patients .…”

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confidence: 62%

“…Previous volumetric and VBM studies in MSA‐C have consistently shown cerebellar and brainstem volume loss . In SAOA, volume loss has been reported as being most prominent in the cerebellum, although some studies also detected involvement of the cerebellar peduncles and brainstem.…”

Section: Discussionmentioning

confidence: 92%

“…A strength of our study is the multimodal approach that thoroughly assessed the structural integrity of brain gray and white matter tissue with different state‐of‐the‐art MRI methods. This approach provides a more comprehensive view of brain morphology than that of previous studies focusing on either structural volume or DTI changes alone …”

Section: Discussionmentioning

confidence: 99%

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Prominent White Matter Involvement in Multiple System Atrophy of Cerebellar Type

et al. 2020

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A BS TRACT: Background: Sporadic degenerative ataxia patients fall into 2 major groups: multiple system atrophy with predominant cerebellar ataxia (MSA-C) and sporadic adultonset ataxia (SAOA). Both groups have cerebellar volume loss, but little is known about the differential involvement of gray and white matter in MSA-C when compared with SAOA. Objectives: The objective of this study was to identify structural differences of brain gray and white matter between both patient groups. Methods: We used magnetic resonance imaging to acquire T1-weighted images and diffusion tensor images from 12 MSA-C patients, 31 SAOA patients, and 55 healthy controls. Magnetic resonance imaging data were analyzed with voxel-based-morphometry, tract-based spatial statistics, and tractography-based regional diffusion tensor images analysis. Results: Whole-brain and cerebellar-focused voxel-basedmorphometry analysis showed gray matter volume loss in both patient groups when compared with healthy controls, specifically in the cerebellar areas subserving sensorimotor functions. When compared with controls, the SAOA and MSA-C patients showed white matter loss in the cerebellum, whereas brainstem white matter was reduced only in the MSA-C patients. The tract-based spatial statistics revealed reduced fractional anisotropy within the pons and cerebellum in the MSA-C patients both in comparison with the SAOA patients and healthy controls. In addition, tractographybased regional analysis showed reduced fractional anisotropy along the corticospinal tracts in MSA-C, but not SAOA. Conclusion: Although in our cohort extent and distribution of gray and white matter loss were similar between the MSA-C and SAOA patients, magnetic resonance imaging data showed prominent microstructural white matter involvement in the MSA-C patients that was not present in the SAOA patients. Our findings highlight the significance of microstructural white matter changes in the differentiation between both conditions.

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“…In India, large‐scale studies on epidemiology of MSA are lacking. Studies that have reported imaging features have enrolled small numbers of patients, with varying proportions of MSA‐P and MSA‐C …”

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confidence: 99%

Is There a Difference in Autonomic Dysfunction Between Multiple System Atrophy Subtypes?

Garg

Srivastava

Jaryal

et al. 2020

Movement Disord Clin Pract

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Background Autonomic dysfunction forms the diagnostic cornerstone in MSA. Data are limited on autonomic dysfunction differences between the two subtypes, MSA‐C and MSA‐P. Objectives To assess autonomic dysfunction in MSA subtypes and Parkinson's disease (PD) and compare it to healthy controls. Methods We conducted a cross‐sectional study. A validated questionnaire (Scales for Outcomes in Parkinson's Disease–Autonomic Dysfunction; SCOPA‐AUT) was used for symptom screening. Cardiovascular autonomic testing included deep breathing (change in heart rate, E: I ratio), Valsalva ratio, diastolic blood pressure (BP) rise (hand grip, cold pressor), and postural (tilt, 30:15 ratio) tests. Disease severity was assessed by the Unified MSA Rating Scale (UMSARS), H & Y stage, and International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating scale part III. Results MSA‐P (48 subjects; age, 63.6 ± 9.7 years; UMSARS, 45.0 ± 16.5), MSA‐C (52 subjects; age, 58.0 ± 8.1 years; UMSARS, 44.0 ± 12.8), PD (50 subjects; age, 57.6 ± 6.7 years), and healthy controls (50 subjects; age, 58.0 ± 8.0 years) were enrolled. MSA patients had higher SCOPA‐AUT scores in gastrointestinal, urinary, cardiovascular, and sexual domains than controls and in gastrointestinal, urinary, and cardiovascular domains compared to PD. The two MSA subtypes did not differ in autonomic dysfunction. Heart‐rate change on tilt and deep breathing, and diastolic BP rise on cold pressor test, differed significantly between MSA and PD patients. Conclusions Autonomic dysfunction symptomatology and cardiovascular autonomic tests were similar between MSA‐P and MSA‐C patients. Autonomic symptoms were more prominent in MSA than PD. Emphasis on these domains may improve likelihood of accurate clinical diagnosis of MSA at earlier stages.

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Abnormalities of white and grey matter in early multiple system atrophy: comparison of parkinsonian and cerebellar variants

Abstract: • Structural changes in early multiple system atrophy were evaluated using multi-modal neuroimaging. • White matter was more affected than grey matter in early MSA. • Clinical variables did not correlate with early structural changes.

Cited by 34 publications

References 38 publications

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Prominent White Matter Involvement in Multiple System Atrophy of Cerebellar Type

Is There a Difference in Autonomic Dysfunction Between Multiple System Atrophy Subtypes?

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