Tissue-resident memory CD8 T cells are responsible for local immune surveillance in different tissues, including the brain. They constitute the first line of defense against pathogens and cancer ...cells and play a role in autoimmunity. A recently published study demonstrated that CD8 T cells with markers of residency containing distinct granzymes and interferon-γ infiltrate the parenchyma of the substantia nigra and contact dopaminergic neurons in an early premotor stage of Parkinson’s disease. This infiltration precedes α-synuclein aggregation and neuronal loss in the substantia nigra, suggesting a relevant role for CD8 T cells in the onset of the disease. To date, the nature of the antigen that initiates the adaptive immune response remains unknown. This review will discuss the role of tissue-resident memory CD8 T cells in brain immune homeostasis and in the onset of Parkinson’s disease and other neurological diseases. We also discuss how aging and genetic factors can affect the CD8 T cell immune response and how animal models can be misleading when studying human-related immune response. Finally, we speculate about a possible infectious or autoimmune origin of Parkinson’s disease.
Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3' untranslated regions (3'UTRs). Yet, the post-transcriptional ...mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3' UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3' UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3' UTR-mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.
Multiple system atrophy (MSA) is a rare oligodendroglial synucleinopathy of unknown etiopathogenesis including two major clinical variants with predominant parkinsonism (MSA-P) or cerebellar ...dysfunction (MSA-C).
To identify novel disease mechanisms we performed a blood transcriptomic study investigating differential gene expression changes and biological process alterations in MSA and its clinical subtypes.
We compared the transcriptome from rigorously gender and age-balanced groups of 10 probable MSA-P, 10 probable MSA-C cases, 10 controls from the Catalan MSA Registry (CMSAR), and 10 Parkinson Disease (PD) patients.
Gene set enrichment analyses showed prominent positive enrichment in processes related to immunity and inflammation in all groups, and a negative enrichment in cell differentiation and development of the nervous system in both MSA-P and PD, in contrast to protein translation and processing in MSA-C. Gene set enrichment analysis using expression patterns in different brain regions as a reference also showed distinct results between the different synucleinopathies.
In line with the two major phenotypes described in the clinic, our data suggest that gene expression and biological processes might be differentially affected in MSA-P and MSA-C. Future studies using larger sample sizes are warranted to confirm these results.
Background
Chronic levodopa treatment in Parkinson’s disease (PD) may promote undesirable motor and non-motor fluctuations. Compared to chronic oral levodopa treatment, continuous infusion of ...levodopa/carbidopa intestinal gel (LCIG) in advanced PD reduces motor fluctuations. However, differences in their effect on acute non-motor changes were not formally demonstrated.
Objective
We performed a randomized, double-blind, double-dummy, crossover study to compare acute non-motor changes between intermittent oral immediate-release carbidopa/levodopa (LC-IR) and LCIG.
Methods
After > 12-h OFF, thirteen PD patients chronically treated with LCIG and without history of non-motor swings, were allocated to receive first, LCIG infusion plus three oral doses of placebo, or placebo infusion plus three oral doses of LC-IR. Over-encapsulated oral medication (LC-IR or placebo) was administered every 2 h. We monitored plasmatic levels of levodopa, motor status (UPDRS-III), mood, anxiety, and frontal functions at baseline (0-h) and hourly after each oral challenge.
Results
Repeated-measures ANOVAs showed significant group by treatment interaction indicating more fluctuations of levodopa plasma levels with LC-IR. No significant interactions were seen in the temporal profile of motor status, anxiety, mood and cognition. However, point-to-point parametric and nonparametric tests showed a significant more marked and more sustained improvement in anxiety scores under LCIG. A significant improvement of mood and verbal fluency was seen a + 3-h only under LCIG.
Discussion
Our sample of advanced PD patients exhibited moderate but significant non-motor fluctuations. LCIG was associated with a more favorable profile of acute affective and cognitive fluctuations that was particularly expressed at the first part of the infusion curve.
In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 ...gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC).
A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD.
Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC.
Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Some reports have emerged describing the occurrence of Guillain-Barré syndrome and polyneuropathy related to vitamin B
12
deficiency in some patients with Parkinson’s disease (PD) treated with ...continuous duodenal levodopa infusion. We describe five PD patients who developed axonal polyneuropathy and vitamin B
12
deficiency while on treatment with duodenal levodopa infusion, review other cases reported in the literature, discuss potential etiologic factors, and suggest a possible algorithm for the management and prevention of this complication. One case of Guillain-Barré syndrome and at least 12 cases of polyneuropathy related to vitamin B
12
deficiency have been reported in PD patients treated with duodenal levodopa infusion. Levodopa gel infusion may induce a decrease in vitamin B
12
levels, leading to peripheral neuropathy. Additional pathogenetic mechanisms include alterations related to the metabolism of
l
-dopa, abnormal
l
-dopa absorption, and direct neurotoxicity of
l
-dopa at high doses. Vitamin B
12
supplementation may need to be considered in PD patients on duodenal levodopa infusion therapy. Vitamin B
12
deficiency in patients on duodenal levodopa infusion therapy may be more frequent than the published data suggest. We must be alert.
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