Pathological synchronization in large‐scale motor networks constitutes a pathophysiological hallmark of Parkinson’s disease (PD). Corticomuscular synchronization in PD is pronounced in lower ...frequency bands (< 10 Hz), whereas efficient cortical motor integration in healthy persons is driven in the beta frequency range. Electroencephalogram and electromyogram recordings at rest and during an isometric precision grip task were performed in four perioperative sessions in 10 patients with PD undergoing subthalamic nucleus deep‐brain stimulation: (i) 1 day before (D0); (ii) 1 day after (D1); (iii) 8 days after implantation of macroelectrodes with stimulation off (D8StimOff); and (iv) on (D8StimOn). Analyses of coherence and phase delays were performed in order to challenge the effects of microlesion and stimulation on corticomuscular coherence (CMC). Additionally, local field potentials recorded from the subthalamic nucleus on D1 allowed comprehensive mapping of motor‐related synchronization in subthalamocortical and cerebromuscular networks. Motor performance improved at D8StimOn compared with D0 and D8StimOff paralleled by a reduction of muscular activity and CMC in the theta band (3.9–7.8 Hz) and by an increase of CMC in the low‐beta band (13.7–19.5 Hz). Efferent motor cortical drives to muscle presented mainly below 10 Hz on D8StimOff that were suppressed on D8StimOn and occurred on higher frequencies from 13 to 45 Hz. On D1, coherence of the high‐beta band (20.5–30.2 Hz) increased during movement compared with rest in subthalamomuscular and corticomuscular projections, whereas it was attenuated in subcorticocortical projections. The present findings lend further support to the concept of pathological network synchronization in PD that is beneficially modulated by stimulation.
Pathological synchronization in large‐scale motor networks constitutes a pathophysiological hallmark of Parkinson’s disease (PD). Corticomuscular synchronization in PD is pronounced in lower frequency bands (< 10 Hz), whereas efficient cortical motor integration in healthy persons is driven in the beta frequency range.
Heterozygous variants in the glucocerebrosidase GBA1 gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the GBAP1 pseudogene, which shares 96% sequence homology with ...the GBA1 coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA1-associated PD. We analyzed 660 patients with PD, 100 patients with Parkinsonism and 808 healthy controls from the Luxembourg Parkinson's study, sequenced using amplicon-based long-read DNA sequencing technology. We found that 12.1% (77/637) of PD patients carried GBA1 variants, with 10.5% (67/637) of them carrying known pathogenic variants (including severe, mild, risk variants). In comparison, 5% (34/675) of the healthy controls carried GBA1 variants, and among them, 4.3% (29/675) were identified as pathogenic variant carriers. We found four GBA1 variants in patients with atypical parkinsonism. Pathogenic GBA1 variants were 2.6-fold more frequently observed in PD patients compared to controls (OR = 2.6; CI = 1.6,4.1). Three novel variants of unknown significance (VUS) were identified. Using a structure-based approach, we defined a potential risk prediction method for VUS. This study describes the full landscape of GBA1-related parkinsonism in Luxembourg, showing a high prevalence of GBA1 variants as the major genetic risk for PD. Although the long-read DNA sequencing technique used in our study may be limited in its effectiveness to detect potential structural variants, our approach provides an important advancement for highly accurate GBA1 variant calling, which is essential for providing access to emerging causative therapies for GBA1 carriers.
Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, ...particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations.
Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings.
We identified potentially disease-causing variants in the established dystonia genes (
; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (
; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis.
Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.
To determine whether single nucleotide polymorphisms (SNPs) of the cholinergic system and quantitative parameters of postural control are associated in healthy older adults. This is a cross-sectional ...analysis from the TREND study.
All participants performed a static postural control task for 30 s on a foam pad in semitandem stance and eyes closed. We analyzed mean power frequency (MPF), area, acceleration, jerk, and velocity from a mobile sensor worn at the lower back using a validated algorithm. Genotypes of four SNPs in genes involved in the cholinergic system (
) were extracted from the NeuroX chip. All participants present a normal neurological examination and a Minimental state examination score >24.
Four hundred and seventy seven participants were included. Mean age was 69 years, 41% were female. One SNP of the cholinergic pathway was significantly associated with a quantitative postural control parameter. The minor allele of rs6542746 in
was associated with lower MPF (4.04 vs. 4.22 Hz;
= 3.91 × 10
). Moreover, the following associations showed trends toward significance: minor allele of rs6542746 in
with higher anteroposterior acceleration (318 vs. 287 mG;
= 0.005), and minor allele of rs3810950 in
with higher mediolateral acceleration 1.77 vs. 1.65 log(mG);
= 0.03 and velocity 1.83 vs. 1.74 log(mm/s);
= 0.019. Intraindividual occurrence of rs6542746 and rs3810950 minor alleles was dose-dependently related with lower MPF (
= 0.004).
This observational study suggests an influence of SNPs of the cholinergic pathway on postural control in older adults.
BACKGROUNDPLA2G6-associated neurodegeneration (PLAN) is a recessive neurodegenerative disorder characterized by three distinct phenotypes: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal ...dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. METHODSA consanguineous index case from Turkey was diagnosed with early-onset Parkinsonism at the Istanbul Faculty of Medicine. She and her unaffected brother were subjected to whole-genome sequencing. RESULTSIn this report, we describe a 33-year-old index case with parental consanguinity and early-onset Parkinsonism. Whole-genome sequencing of this individual revealed that a homozygous p.R747W mutation in PLA2G6 segregates with the disease in this family. DISCUSSIONThis result supports the importance of prioritizing this gene in mutational analysis of autosomal recessive Parkinsonism, and confirms the clinical heterogeneity of PLAN.
Introduction. Parkinson’s disease patients carrying a heterozygous mutation in the gene glucocerebrosidase (GBA-PD) show faster motor and cognitive decline than idiopathic Parkinson’s disease (iPD) ...patients, but the mechanisms behind this observation are not well understood. Successful dual tasking (DT) requires a smooth integration of motor and nonmotor operations. This study compared the DT performances between GBA-PD and iPD patients. Methods. Eleven GBA-PD patients (p.N370S, p.L444P) and eleven matched iPD patients were included. Clinical characterization included a motor score (Unified PD Rating Scale-III, UPDRS-III) and nonmotor scores (Montreal Cognitive Assessment, MoCA, and Beck’s Depression Inventory). Quantitative gait analysis during the single-task (ST) and DT assessments was performed using a wearable sensor unit. These parameters corrected for UPDRS and MoCA were then compared between the groups. Results. Under the DT condition “walking while checking boxes,” GBA-PD patients showed slower gait and box-checking speeds than iPD patients. GBA-PD and iPD patients did not show significant differences regarding dual-task costs. Conclusion. This pilot study suggests that DT performance with a secondary motor task is worse in GBA-PD than in iPD patients. This finding may be associated with the known enhanced motor and cognitive deficits in GBA-PD compared to iPD and should motivate further studies.
OBJECTIVE:To evaluate whether genetic variants in β-amyloid (Aβ) clearance proteins are associated with CSF levels of Aβ1-42 on a biological level and the onset of dementia on a clinical level in ...Parkinson disease (PD).
METHODS:We analyzed genetic variants known to be involved in Aβ clearance in a PD group comprising 456 patients, 103 of them with dementia. Single nucleotide polymorphisms in the genes APOE, cystatin C (CST), and membrane metalloendopeptidase (MME) were evaluated in relation to demographic variables, clinical phenotypes, and CSF Aβ1-42 levels using a cross-sectional approach.
RESULTS:Risk variants in the genes APOE and CST were associated with lower CSF Aβ1-42 levels. Clinically, patients with 2 risk alleles in CST tended to show a shorter interval from age at onset of PD to age at onset of dementia.
CONCLUSIONS:This study suggests that genetic variants associated with Aβ clearance are involved in the pathogenesis of dementia in PD and possibly influence the onset of dementia.
Abstract Background Parkinson's disease (PD) patients show a large phenotypic variability probably reflecting inter-individual pathologic heterogeneity. Next to typical Lewy-body pathology, β-amyloid ...(Aβ) and tau pathology have been found at autopsy and several studies have reported altered CSF levels of Aβ1-42, total-Tau (t-Tau) and phosphorylated-Tau (p-Tau). Objectives To evaluate whether CSF levels of neurodegenerative markers are influenced by genetics and whether specific subgroups of PD are more prone to a concomitant pathology possibly reflecting aspects of disease progression. Methods In an explorative study we assessed CSF profiles of Aβ1-42, t-Tau, and p-Tau longitudinally in PD patients carrying LRRK2 (n = 5) or GBA mutations (n = 12), sporadic PD patients (n = 30) and healthy controls (n = 16). Results Compared to healthy controls, all three PD cohorts showed lower levels of Aβ1-42. Moreover, sporadic PD and GBA -PD patients presented with lower levels of t-Tau and p-Tau whereas this phenomenon was not seen in LRRK2 -PD patients. Regression analyses revealed an association between higher levels of Baseline p-Tau with more accelerated cognitive deterioration over time in LRRK2 -PD and GBA -PD patients, but not in sporadic PD. Conclusion PD patients present with disease-specific CSF profiles of Aβ1-42, t-Tau and p-Tau arguing in favor of an involvement of these proteins in PD pathogenesis in both sporadic and genetic forms. Moreover, we found first hints for differences in these CSF profiles between genetically determined PD cohorts but that CSF constellations which tend to predict aspects of disease progression such as cognitive decline seem similar across subgroups of PD.
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