Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy

Campese, Nicole; Fanciulli, Alessandra; Stefanova, Nadia; Haybaeck, Johannes; Kiechl, Stefan; Wenning, Gregor K.

doi:10.1007/s00702-021-02383-3

Cited by 15 publications

(3 citation statements)

References 121 publications

(179 reference statements)

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“…For example, pathological hallmark of MSA was glial cytoplasmic inclusions (GCIs) predominantly in striatum, midbrain, pons, medulla, and cerebellum whereas for DLB, pathological hallmark was widespread of Lewy bodies or Lewy neurites in cerebral cortex and limbic system. [39][40][41] Due to different pathological seeding locations of alpha synuclein, clinical manifestations, criteria diagnosis, and prognosis of disease also different and that's explained why cut off value of blood alpha synuclein in our study different diagnosis of patient from previous studies, show different results. Second, our recruiting population was in an earlier stage and less severe than others with respect to the UPDRS score.…”

Section: Discussionmentioning

confidence: 58%

Plasma Alpha Synuclein as a Potent Biomarker of Diseases with Synucleinopathies

Dumrikarnlert,

Wachirutmangur,

Udomphanthurak

et al. 2023

Siriraj Med J

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Objective: We explored whether plasma α-syn be used as a potential biomarker for synucleinopathies. Materials and Methods: α-syn levels in plasma from 54 Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) patents, 31 Alzheimer’s disease dementia (AD), and 29 controls were measured by enzymelinked immunosorbent assay (ELISA). Results: The mean age of the synucleinopathies group, the AD group, and the normal controls was 72.70, 74.26, and 62 years old. The median plasma α-syn levels in the synucleinopathies group, AD group and controls were 9.72 (4.41-25.30), 16.78 (7.68-51.41) and 16.65 (10.37-32.72) ng/ml, respectively (Independent-Samples Kruskal-Wallis test, p = 0.026). The α-syn levels in the synucleinopathies group were lower than those of AD and controls. There was a fair correlation between plasma α-syn levels and the sum of the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 (spearman correlation coefficient r = -0.261, p = 0.021) but not with cognition measured by Thai Mental Status Examination (TMSE). The area under the receiver operating characteristic curve (ROC) was 0.710 between the PDD and DLB vs non synucleinopathies group (AD and normal controls) (SE = 0.052, p ≤ 0.001). At the cut-off levels of 11.4 ng/ml indicated a sensitivity of 58% (95% CI 43.21-71.81%), specificity of 84.78% (95% CI 71.13-93.66%), positive predictive value (PPV) of 80.56%, a negative predictive value (NPV) of 65% and a precision of 70.83%. Conclusion: The present results suggest that plasma α-syn could be a potential biomarker to differentiate synucleinopathies from Alzheimer’s disease and the elderly with normal cognition.

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Section: Discussionmentioning

confidence: 58%

Plasma Alpha Synuclein as a Potent Biomarker of Diseases with Synucleinopathies

Dumrikarnlert,

Wachirutmangur,

Udomphanthurak

et al. 2023

Siriraj Med J

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“…This group includes PD, DLB, PDD and multiple system atrophy (MSA). Notably, PD, DLB and PDD also affect the tau protein to a large degree [178][179][180][181], while in MSA, tau pathology is exceptionally rare [182][183][184]. Importantly, synucleinopathies may present with the same triad of parkinsonism (bradykinesia, rigidity and tremor), and as with most neurodegenerative conditions, the definitive diagnosis of a synucleinopathy can only be confirmed through a neuropathological exam [2,[185][186][187][188].…”

Section: Evaluation Of α-Synuclein Using Seed Amplification Assays Fo...mentioning

confidence: 99%

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

Taha

2024

Preprint

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Accurate differential diagnosis of dementia disorders including Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and vascular cognitive impairment and dementia (VCID), along with conditions like prodromal mild cognitive impairment (MCI) or negative controls (NCs), continues to challenge neurologists. The nuanced and sometimes shared pathophysiological features underscore the need for precision in developing disease-modifying therapies. In the pursuit of reliable antemortem biomarkers, extracellular vesicles (EVs) have emerged as a popular tool for their capacity to encapsulate disease-specific signatures, particularly in neurodegenerative and neurological disorders. To this end, we have performed a comprehensive, PRISMA-guided systematic review and meta-analysis, utilizing sophisticated statistical modeling to determine the diagnostic accuracy, explore between-study variance and heterogeneity (I2), and investigate potential publication bias using various statistical tests.Biomarkers derived from general EVs demonstrated superior diagnostic accuracy, less between-study variance, heterogeneity, and publication bias than those from speculative CNS-enriched EVs. The trim-and-fill method suggested a potential overestimation of diagnostic effectiveness for biomarkers derived from CNS-enriched EVs due to four hypothesized missing studies with low diagnostic results, but none for general EVs. Meta-regressions revealed that studies using cerebrospinal fluid or serum, involving non-fasting individuals, sampling in the afternoon, employing citrate instead of EDTA for blood collection, using thrombin for coagulation factor depletion, isolating EVs with purer methods such as combined ultracentrifugation and size-exclusion chromatography, not freezing EVs post-isolation, and quantifying miRNA biomarkers, achieved better diagnostic accuracy and less heterogeneity. The diagnostic accuracy was low in differentiating among different dementia disorders. However, the analysis for diagnosing persons with AD vs. VCID achieved the highest diagnostic accuracy, suggesting that further studies may focus on this comparison. Additionally, we highlight several limitations in the included studies and recommend the following: Implement the use of appropriate negative controls, thorough documentation of preanalytical factors, inclusion of more dementia groups beyond AD, comprehensive reporting on pharmacological treatments, consideration of racial and ethnic minority groups, adherence to ISEV guidelines, application of the A-T-N framework, detailed documentation of dementia stages, extension of studies beyond differential diagnosis, reanalysis when postmortem definitive diagnostics become available, evaluation of prodromal conversion rates, and commitment to accurate statistical modeling and data transparency. We hope that lessons learned from this comprehensive meta-analysis can be beneficial for those attempting to discover biomarkers for AD and related dementias through EVs or alternative approaches.

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“…In MSA, aSyn accumulates inside the myelinating glial cells of brain, the oligodendrocytes, which then forms two different types of lesions (1) glial cytoplasmic inclusions (GCI) and (2) glial nuclear inclusions (GNI) [23][24][25]. When this occurs, neuronal demyelination occurs along with a loss of trophic factors required to support neurons, ultimately impairing function [26][27][28]. MSA can manifest as two different forms, (1) a condition that primarily affects the basal ganglia, thus producing Parkinsonian symptoms (MSA-P) or (2) primarily as cerebellar dysfunction and ataxia (MSA-C) [27].…”

Section: Introductionmentioning

confidence: 99%

Preclinical Validation of FTY720 and FTY720-Mitoxy in Mouse Models of Parkinsons Disease and Multiple System Atrophy (MSA): Evidence for Treating Lewy Body Disease Synucleinopathies Including MSA

Vidal-Martinez,

Lou,

G. Perez

2024

Rare Neurodegenerative Disorders - New Insights [Working Title]

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We assessed FTY720 and our patented-mitochondria-localizing-FTY720-derivative, FTY720-Mitoxy, in mouse models of Parkinson’s disease (PD) and MSA. FTY720 and FTY720-Mitoxy were given by gavage, injection, or osmotic pump. We used symptomatic transgenic alpha-Synuclein (aSyn) PD mice (A53T aSyn) and MSA mice (CNP-aSyn), as well as transgenic GM2 +/− PD mice. We also tested toxin PD and MSA models. We measured movement, constipation, gut motility, sweat ability, and bladder function. We counted blood lymphocytes 24 h after FTY720 or FTY720-Mitoxy. We measured Brain Derived Neurotrophic Factor (BDNF), Glial Cell Line Derived Neurotrophic Factor (GDNF), and Nerve Growth Factor (NGF) mRNA and protein. We assessed aSyn insolubility in gut, brain, and spinal cord by sequential protein extraction and immunoblot. We assessed fecal genomic DNA using 16S rRNA sequencing. In PD mice FTY720 normalized body and gut movement, urinary bladder function while increasing trophic factors and eliminating synucleinopathy. In MSA mice FTY720-Mitoxy normalized body and gut movement, sweat ability, mitochondrial function, improved microbiota while increasing trophic factors and eliminating synucleinopathy. FTY720 and FTY720-Mitoxy improve function and counteract synucleinopathy. As FTY720-Mitoxy is not immunosuppressive, it may be safer for treating PD and/or MSA.

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Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy

Cited by 15 publications

References 121 publications

Plasma Alpha Synuclein as a Potent Biomarker of Diseases with Synucleinopathies

Plasma Alpha Synuclein as a Potent Biomarker of Diseases with Synucleinopathies

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

Preclinical Validation of FTY720 and FTY720-Mitoxy in Mouse Models of Parkinsons Disease and Multiple System Atrophy (MSA): Evidence for Treating Lewy Body Disease Synucleinopathies Including MSA

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