| 1. |
- van der Lee, S. J., et al.
(författare)
-
A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
- 2019
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 237-250
-
Tidskriftsartikel (refereegranskat)abstract
- The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
|
|
| 2. |
|
|
| 3. |
- Blanken, M. A. J. T., et al.
(författare)
-
Sex-specifics of ECT outcome
- 2023
-
Ingår i: Journal of Affective Disorders. - : ELSEVIER. - 0165-0327 .- 1573-2517. ; 326, s. 243-248
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. Methods: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). Results: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. Conclusion: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex-specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.
|
|
| 4. |
|
|
| 5. |
- Huybrighs, H. L. F., et al.
(författare)
-
Energetic Proton Losses Reveal Io's Extended and Longitudinally Asymmetrical Atmosphere
- 2024
-
Ingår i: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 129:7
-
Tidskriftsartikel (refereegranskat)abstract
- Along the I24, I27, and I31 flybys of Io (1999-2001), the Energetic Particle Detector (EPD) onboard the Galileo spacecraft observed localized regions of energetic protons losses (155-1,250 keV). Using back-tracking particle simulations combined with a prescribed atmospheric distribution and a magnetohydrodynamics (MHD) model of the plasma/atmosphere interaction, we investigate the possible causes of these depletions. We focus on a limited region within two Io radii, which is dominated by Io's SO2 atmosphere. Our results show that charge exchange of protons with the SO2 atmosphere, absorption by the surface and the configuration of the electromagnetic field contribute to the observed proton depletion along the Galileo flybys. In the 155-240 keV energy range, charge exchange is either a major or the dominant loss process, depending on the flyby altitude. In the 540-1,250 keV range, as the charge exchange cross sections are small, the observed decrease of the proton flux is attributed to absorption by the surface and the perturbed electromagnetic fields, which divert the protons away from the detector. From a comparison between the modeled losses and the data we find indications of an extended atmosphere on the day/downstream side of Io, a lack of atmospheric collapse on the night/upstream side as well as a more global extended atmospheric component (>1 Io radius). Our results demonstrate that observations and modeling of proton depletion around the moon constitute an important tool to constrain the electromagnetic field configuration around Io and the radial and longitudinal atmospheric distribution, which is still poorly understood.
|
|
| 6. |
- Manzoni, Claudia, et al.
(författare)
-
Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
- 2024
-
Ingår i: American Journal of Human Genetics. - 0002-9297. ; 111:7, s. 1316-1329
-
Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
|
|
| 7. |
- Mulders, Peter C.R., et al.
(författare)
-
Structural changes induced by electroconvulsive therapy are associated with clinical outcome
- 2020
-
Ingår i: Brain Stimulation. - : Elsevier BV. - 1935-861X. ; 13:3, s. 696-704
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Electroconvulsive therapy (ECT) is the most effective treatment option for major depressive disorder, so understanding whether its clinical effect relates to structural brain changes is vital for current and future antidepressant research. Objective: To determine whether clinical response to ECT is related to structural volumetric changes in the brain as measured by structural magnetic resonance imaging (MRI) and, if so, which regions are related to this clinical effect. We also determine whether a similar model can be used to identify regions associated with electrode placement (unilateral versus bilateral ECT). Methods: Longitudinal MRI and clinical data (Hamilton Depression Rating Scale) was collected from 10 sites as part of the Global ECT-MRI research collaboration (GEMRIC). From 192 subjects, relative changes in 80 (sub)cortical areas were used as potential features for classifying treatment response. We used recursive feature elimination to extract relevant features, which were subsequently used to train a linear classifier. As a validation, the same was done for electrode placement. We report accuracy as well as the structural coefficients of regions included in the discriminative spatial patterns obtained. Results: A pattern of structural changes in cortical midline, striatal and lateral prefrontal areas discriminates responders from non-responders (75% accuracy, p < 0.001) while left-sided mediotemporal changes discriminate unilateral from bilateral electrode placement (81% accuracy, p < 0.001). Conclusions: The identification of a multivariate discriminative pattern shows that structural change is relevant for clinical response to ECT, but this pattern does not include mediotemporal regions that have been the focus of electroconvulsive therapy research so far.
|
|
| 8. |
|
|
| 9. |
- Bratic, A., et al.
(författare)
-
Complementation between polymerase- and exonuclease-deficient mitochondrial DNA polymerase mutants in genomically engineered flies
- 2015
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Replication errors are the main cause of mitochondrial DNA (mtDNA) mutations and a compelling approach to decrease mutation levels would therefore be to increase the fidelity of the catalytic subunit (POLγA) of the mtDNA polymerase. Here we genomically engineer the tamas locus, encoding fly POLγA, and introduce alleles expressing exonuclease- (exo-) and polymerase-deficient (pol-) POLγA versions. The exo- mutant leads to accumulation of point mutations and linear deletions of mtDNA, whereas pol- mutants cause mtDNA depletion. The mutant tamas alleles are developmentally lethal but can complement each other in trans resulting in viable flies with clonally expanded mtDNA mutations. Reconstitution of human mtDNA replication in vitro confirms that replication is a highly dynamic process where POLγA goes on and off the template to allow complementation during proofreading and elongation. The created fly models are valuable tools to study germ line transmission of mtDNA and the pathophysiology of POLγA mutation disease. © 2015 Macmillan Publishers Limited. All rights reserved.
|
|
| 10. |
- Dols, Juan F.
(författare)
-
Towards a safer fitness to drive and driving ability assessment procedure with joystick
- 2016
-
Konferensbidrag (refereegranskat)abstract
- This paper presents a new fitness to drive and driving ability assessment procedure developed by theUniversity Polytechnic of Valencia (Spain) for evaluating severely drivers with impairments whocannot drive a motor vehicle with standard car control adaptations. The objective of this newassessment approach was based on performing a series of practical tests divided into two main phases.The first phase of the assessment utilize a simulator that allows a safe measurement of all thenecessary parameters needed to determine the residual capacities (e.g. forces, torques, displacements,reaction time, etc.) of the driver that can be used for driving a joystick controlled vehicle. Furthermore,driving maneuvers are performed in a controlled way to determine required movement coordination,response times, etc. The SERCO simulator was designed and developed for this purpose as a modular,portable and adaptive experimental tool that allows assessing driver candidates with or without leavingtheir wheelchair using all types of technical aids including joystick controls. The result of this firstassessment phase determines the more appropriate joystick device and space location as a function ofthe driver needs.The second phase of the assessment procedure includes a series of driving ability tests on a closedcircuit. From the information obtained during the assessment in the simulator, the most suitable typeof joystick device is determined for driving safely and the restraint system needed both by the user andthe wheelchair. At this stage it will also be possible to assess the accessibility requirements needed forthe adapted vehicle. Moreover, at this stage a battery of practical tests is performed in a closed circuitwith the vehicle in motion, which follows the recommendations and requirements defined by the EUcurrent legislation for obtaining a driving license (EC, 2006), reproducing vehicle maneuvers as closeto reality as possible.As a result of the described procedure it is possible to ensure that the driver is able to fulfill theminimum requirements for obtaining a driving license. Furthermore, it is possible to determinerequired driving restrictions or limitations, corrective conditions and coding of adaptations accordingto EU legislation.
|
|
