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
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.
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.
Objectives
To present our experience with ammonium tetrathiomolybdate (ATTM) in the decoppering phase treatment of Wilson's disease (WD) with neurological symptoms.
Methods
An uncontrolled ...longitudinal study was carried out to describe a case series of five patients diagnosed of WD with neurological symptoms in our hospital over the last 5 years and receiving ATTM for 8 (or 16) weeks. Unified Wilson's Disease Rating Scale (UWDRS), Global Assessment Scale (GAS) for WD and the Brewer‐adapted Unified Huntington's Disease Rating Scale (UHDRS) for WD, magnetic resonance imaging, and monitoring for potential adverse effects were carried out in all patients before starting ATTM and 3 months later when ATTM was stopped and zinc treatment was initiated.
Results
All five patients presented neurological clinical improvement in UWDRS, GAS, and Brewer‐adapted UHDRS for WD. Neuroimaging improvement was present in 2/5 patients with brain edema reduction. Mild anemia, leukopenia, and elevation of transaminases were detected in 1 patient, with complete remission after stopping ATTM for 1 week and then restarting at a half dose.
Conclusion
ATTM could be a good treatment for the initial treatment of WD with neurological symptoms due to its high efficacy, with a lower rate of neurological deterioration than the drugs currently available, despite the potential adverse effects.
Effectiveness and safety of ammonium tetrathiomolybdate in decoppering therapy for Wilson's disease with neurological symptoms, a pilot study in routine care.
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.
Introduction
Continuous delivery of levodopa–carbidopa intestinal gel (LCIG) by percutaneous endoscopic gastrojejunostomy (PEG-J) in advanced Parkinson’s disease (PD) patients reduces variability in ...plasma levels, providing better control of motor fluctuations (“on” and “off” states). The MONOTREAT study assessed the effect of LCIG on activities of daily living, motor and non-motor symptoms, and quality of life in advanced PD patients.
Methods
This prospective, observational study included patients with advanced, levodopa-responsive PD with either 2–4 h of “off” time or 2 h of dyskinesia daily. Patients received LCIG via PEG-J for 16 h continuously. Effectiveness was assessed using Unified PD Rating Scale parts II and III, the Non-Motor Symptom Scale, and the PD Questionnaire-8.
Results
The mean (SD) treatment duration was 275 (157) days. Patients experienced significant improvement from baseline in activities of daily living at final visit (
p
< 0.05) as well as at months 3 and 6 (
p
< 0.0001). Patients also experienced significant improvements from baseline in quality of life and non-motor symptoms at all time points (
p
< 0.001 for all). Specifically, patients manifested significant improvements in mean change from baseline at every study visit in five of nine non-motor symptom score domains: sleep/fatigue, mood/cognition, gastrointestinal tract, urinary, and miscellaneous. One-third of patients (32.8%) experienced an adverse event; 21.9% experienced a serious adverse event; 11.1% discontinued because of an adverse event.
Conclusion
This study demonstrated significant and clinically relevant improvements in measures of activities of daily living, quality of life, and a specific subset of non-motor symptoms after treatment with LCIG.
Funding
AbbVie Inc.
Introduction
Levodopa‐carbidopa intestinal gel (LCIG) infusion has demonstrated to improve motor fluctuations. The aim of this study is to assess the long‐term safety and effectiveness of LCIG ...infusion in advanced Parkinson's disease (PD) patients with motor fluctuations and its effect in nonmotor symptoms.
Methods
Adverse events (AE) and their management, clinical motor, and nonmotor aspects were assessed up to 10 years. Thirty‐seven patients were treated with LGIC; in three subsets of patients, specific batteries of tests were used to assess cognitive and behavior assessment for 6 months, quality of sleep for 6 months, and quality of life and caregiver burden for 1 year.
Results
There was a high number of AE, but manageable, most of mild and moderate severity. All patients experienced significant improvement in motor fluctuations with a reduction in mean daily off time of 4.87 hr after 3 months (n = 37) to 6.25 hr after 9 years (n = 2). Diskynesias remained stables in 28 patients (75.7%) and improved in 5 patients (13.5%). There was no neuropsychological deterioration, but an improvement in attentional functions, voluntary motor control, and semantic fluency. Quality of sleep did not worsen, and there was an improvement in the subjective parameters, although overnight polysomnography did not change. There was a significant sustained improvement of 37% in PD‐Q39 after 3 months and to 1 year, and a significant reduction in caregiver burden of 10% after 3 months.
Conclusion
LCIG infusion is a safe and efficacious treatment for the control of motor fluctuations, and for improvement or nonworsening of nonmotor aspects, long‐term sustained, and feasible for use in routine care.
This long‐term safety and effectiveness study of levodopa‐carbidopa intestinal gel (LCIG) infusion in advanced Parkinson's disease patients with motor fluctuations and its effect in nonmotor symptoms concludes that LCIG infusion is a safe and efficacious treatment for the control of motor fluctuations, and for improvement or nonworsening of cognition and behavior, quality of sleep and improvement of quality of life and caregiver burden, long‐term sustained, and feasible for use in routine care.
Background. Sleep problems in patients with advanced Parkinson’s disease (PD) have a deleterious impact on quality of life. Objective. To assess the effect of levodopa-carbidopa intestinal gel (LCIG) ...infusion on sleep quality in advanced PD patients. Methods. Seven patients participated in a prospective pilot study. Before and after 6 months of LCIG infusion, an overnight polysomnography was performed and the Epworth Sleepiness Scale, fatigue scale, Pittsburgh Sleep Quality Index, Beck Depression Inventory, and the Hamilton Anxiety Rating Scale were administered. Results. PSG showed low sleep efficiency. REM sleep without atony was found in 5 patients. After 6 months of LCIG infusion, the percentage of REM sleep decreased as well as the number of arousals especially due to reduction of spontaneous arousals and periodic leg movements during REM sleep, but differences were not statistically significant. Also, scores of all study questionnaires showed a tendency to improve. Conclusion. The results show a trend toward an improvement of sleep quality after 6 months of LCIG infusion, although differences as compared to pretreatment values were not statistically significant. The sleep architecture was not modified by LCIG. Further studies with larger study samples are needed to confirm these preliminary findings.
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.
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