•RNA-sequencing and microarray studies assess coding and non-coding transcripts that may be involved in MSA pathogenesis.•Reports indicate dysfunctions related to inflammation, protein modification, ...mitochondrial, and autophagy-related processes.•Links have been found with prion disease and Alzheimer's disease-associated pathways.•Several differential diagnostic biomarker candidates have been proposed.•Cross-validation between studies is low; thus, clinical applicability and data reliability are challenging.
Multiple system atrophy (MSA) is an atypical parkinsonism that rapidly affects motor ability and autonomic function, leaving patients wheelchair-bound and dependent for daily activities in 3–5 years. Differential diagnosis is challenging as cases may resemble Parkinson's disease or other ataxic syndromes depending on the clinical variant (MSA-P or MSA-C), especially in early stages. There are limited symptomatic treatments and no disease-modifying therapies. Pathologically, alpha-synuclein aggregates are found in glial cytoplasmic inclusions, among other proteins, as well as in neurons. The molecular pathogenesis of the disease, however, is widely unknown. Transcriptomic studies in MSA have tried to unravel the pathological mechanisms involved in the disease. Several biological and molecular processes have been described in the literature that associate disease pathogenesis with inflammation, mitochondrial, and autophagy related dysfunctions, as well as prion disease and Alzheimer disease associated pathways. These reports have also registered several differential diagnostic biomarker candidates. However, cross-validation between studies, in general, is poor, making clinical applicability and data reliability very challenging. This review will go over the main transcriptomic studies done in MSA, reporting on the most significant transcriptive and post-transcriptive changes described, and focusing on the main consensual findings.
Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according ...to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
Mitochondrial dysfunction happens in both idiopathic (iPD) and LRRK2-related Parkinson's disease (LRRK2-PD). Nonetheless, previous studies suggested that a different type of mitochondrial pathology ...underlies the neurodegeneration in these two disorders. To further explore this hypothesis, we developed a novel multiplex digital PCR assay that allows the absolute quantification of cell-free mitochondrial DNA (cf-mtDNA) copy number and deletion ratio directly in cerebrospinal fluid (CSF) by simultaneously measuring two opposed regions of the mtDNA circular molecule, one of them in the commonly deleted major arc. The results confirmed that the content of cf-mtDNA in CSF was statistically significantly different between iPD and LRRK2-PD patients. Moreover, we found high cf-mtDNA deletion levels in CSF from patients with iPD, but not LRRK2-PD. The high cf-mtDNA deletion frequency in iPD was validated in an independent cohort. These results indicated that the content and deletion ratio of cf-mtDNA may differentiate iPD from LRRK2-PD, and provides further evidence of the different mitochondrial pathophysiology between these two forms of the disease.
•Quantification of cell-free mitochondrial DNA deletions in cerebrospinal fluid.•High content of integral cell-free mitochondrial DNA in LRRK2 Parkinson's disease.•High cell-free mitochondrial DNA deletions in idiopathic Parkinson's disease.
Tau imaging in progressive supranuclear palsy Perez‐Soriano, Alexandra; Stoessl, A. Jon
Movement disorders,
January 2017, 2017-01-00, 20170101, Letnik:
32, Številka:
1
Journal Article
Neuroinflammation is a potential player in neurodegenerative conditions, particularly the aggressive ones, such as multiple system atrophy (MSA). Previous reports on cytokine levels in MSA using ...serum or cerebrospinal fluid (CSF) have been inconsistent, including small samples and a limited number of cytokines, often without comparison to Parkinson's disease (PD), a main MSA differential diagnosis.
Cross-sectional study of CSF levels of 38 cytokines using a multiplex assay in 73 participants: 39 MSA patients (19 with parkinsonian type MSAp, 20 with cerebellar type MSAc; 31 probable, 8 possible), 19 PD patients and 15 neurologically unimpaired controls. None of the participants was under non-steroidal anti-inflammatory drugs at the time of the lumbar puncture.
There were not significant differences in sex and age among participants. In global non-parametric comparisons FDR-corrected for multiple comparisons, CSF levels of 5 cytokines (FGF-2, IL-10, MCP-3, IL-12p40, MDC) differed among the three groups. In pair-wise FDR-corrected non-parametric comparisons 12 cytokines (FGF-2, eotaxin, fractalkine, IFN-α2, IL-10, MCP-3, IL-12p40, MDC, IL-17, IL-7, MIP-1β, TNF-α) were significantly higher in MSA vs. non-MSA cases (PD + controls pooled together). Of these, MCP-3 and MDC were the most significant ones, also differed in MSA vs. PD, and were significant MSA-predictors in binary logistic regression models and ROC curves adjusted for age. CSF levels of fractalkine and MIP-1α showed a strong and significant positive correlation with UMSARS-2 scores.
Increased CSF levels of cytokines such as MCP-3, MDC, fractalkine and MIP-1α deserve consideration as potential diagnostic or severity biomarkers of MSA.
•CSF levels of 12 cytokines were higher in MSA (n = 39) vs. PD + controls (n = 19 & 15).•Younger age and increasing CSF levels of MCP-3 and MDC were MSA predictors in adjusted models.•CSF levels of fractalkine and MIP-1α correlated with UMSARS-2 scores.•CSF levels of these cytokines might be diagnostic or severity MSA biomarkers.
Background and Purpose
Multiple system atrophy(MSA) is a rare adult‐onset synucleinopathy that can be divided in two subtypes depending on whether the prevalence of its symptoms is more parkinsonian ...or cerebellar (MSA‐P and MSA‐C, respectively). The aim of this work is to investigate the structural MRI changes able to discriminate MSA phenotypes.
Methods
The sample includes 31 MSA patients (15 MSA‐C and 16 MSA‐P) and 39 healthy controls. Participants underwent a comprehensive motor and neuropsychological battery. MRI data were acquired with a 3T scanner (MAGNETOM Trio, Siemens, Germany). FreeSurfer was used to obtain volumetric and cortical thickness measures. A Support Vector Machine (SVM) algorithm was used to assess the classification between patients’ group using cortical and subcortical structural data.
Results
After correction for multiple comparisons, MSA‐C patients had greater atrophy than MSA‐P in the left cerebellum, whereas MSA‐P showed reduced volume bilaterally in the pallidum and putamen. Using deep gray matter volume ratios and mean cortical thickness as features, the SVM algorithm provided a consistent classification between MSA‐C and MSA‐P patients (balanced accuracy 74.2%, specificity 75.0%, and sensitivity 73.3%). The cerebellum, putamen, thalamus, ventral diencephalon, pallidum, and caudate were the most contributing features to the classification decision (z > 3.28; p < .05 false discovery rate).
Conclusions
MSA‐C and MSA‐P with similar disease severity and duration have a differential distribution of gray matter atrophy. Although cerebellar atrophy is a clear differentiator between groups, thalamic and basal ganglia structures are also relevant contributors to distinguishing MSA subtypes.
Parkinson's disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of
CPBB3 (a ...ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson's disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent
CPBB3 PET. A subset of the PD subjects also underwent PET imaging with
C(+)DTBZ to assess dopaminergic denervation and
CPBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher
CPBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between
CPBB3 and
CPBR28 binding in nigrostriatal regions.
CPBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and
CPBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.
PDF
