Leuven Research Institute for Neuroscience and Disease LIND

Leuven, Belgium

Leuven Research Institute for Neuroscience and Disease LIND

Leuven, Belgium

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McArdle P.F.,University of Maryland Baltimore County | Kittner S.J.,University of Rochester | Ay H.,Harvard University | Brown R.D.,Jr. | And 48 more authors.
Neurology | Year: 2014

Objective: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. Methods: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; k = 0.59, 95%confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (k = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (k = 0.56, 95% CI 0.54-0.58). Conclusion: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner. © 2014 American Academy of Neurology.

PubMed | Hebrew University of Jerusalem, Albert Ludwigs University of Freiburg, Hasselt University, Leuven Research Institute for Neuroscience and Disease LIND and 2 more.
Type: Journal Article | Journal: Stem cell reports | Year: 2015

Tools for rapid and efficient transgenesis in safe harbor loci in an isogenic context remain important to exploit the possibilities of human pluripotent stem cells (hPSCs). We created hPSC master cell lines suitable for FLPe recombinase-mediated cassette exchange (RMCE) in the AAVS1 locus that allow generation of transgenic lines within 15days with 100% efficiency and without random integrations. Using RMCE, we successfully incorporated several transgenes useful for lineage identification, cell toxicity studies, and gene overexpression to study the hepatocyte lineage. However, we observed unexpected and variable transgene expression inhibition invitro, due to DNA methylation and other unknown mechanisms, both in undifferentiated hESC and differentiating hepatocytes. Therefore, the AAVS1 locus cannot be considered a universally safe harbor locus for reliable transgene expression invitro, and using it for transgenesis in hPSC will require careful assessment of the function of individual transgenes.

Leunissen I.,Movement Control and Neuroplasticity Research Group | Coxon J.P.,University of Auckland | Caeyenberghs K.,Movement Control and Neuroplasticity Research Group | Caeyenberghs K.,Ghent University | And 4 more authors.
Cortex | Year: 2014

Traumatic brain injury (TBI) is associated with neuronal loss, diffuse axonal injury and executive dysfunction. Whereas executive dysfunction has traditionally been associated with prefrontal lesions, ample evidence suggests that those functions requiring behavioral flexibility critically depend on the interaction between frontal cortex, basal ganglia and thalamus.To test whether structural integrity of this fronto-striato-thalamic circuit can account for executive impairments in TBI we automatically segmented the thalamus, putamen and caudate of 25 patients and 21 healthy controls and obtained diffusion weighted images. We assessed components of executive function using the local-global task, which requires inhibition, updating and switching between actions.Shape analysis revealed localized atrophy of the limbic, executive and rostral-motor zones of the basal ganglia, whereas atrophy of the thalami was more global in TBI. This subcortical atrophy was related to white matter microstructural organization in TBI, suggesting that axonal injuries possibly contribute to subcortical volume loss. Global volume of the nuclei showed no clear relationship with task performance. However, the shape analysis revealed that participants with smaller volume of those subregions that have connections with the prefrontal cortex and rostral motor areas showed higher switch costs and mixing costs, and made more errors while switching. These results support the idea that flexible cognitive control over action depends on interactions within the fronto-striato-thalamic circuit. © 2013 Elsevier Ltd.

Law B.M.H.,University College London | Law B.M.H.,University of Bath | Spain V.A.,University College London | Leinster V.H.L.,University College London | And 15 more authors.
Journal of Biological Chemistry | Year: 2014

Background: Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) cause Parkinson disease. Results: LRRK2 binds directly to three -tubulin isoforms at the luminal face of microtubules and suppresses α-tubulin acetylation. Interaction is weakened by the R1441G LRRK2 GTPase domain mutant. Conclusion: LRRK2 modulates microtubule stability. Significance: Deregulation of microtubule-dependent processes likely contribute to neurodegeneration in Parkinson disease. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Drijkoningen D.,Catholic University of Leuven | Caeyenberghs K.,Australian Catholic University | Caeyenberghs K.,Ghent University | Vander Linden C.,Pulderbos Rehabilitation Center | And 3 more authors.
Journal of Neurotrauma | Year: 2015

Traumatic brain injury (TBI) can lead to deficits in gait and posture, which are often asymmetric. A possible factor mediating these deficits may be asymmetry in strength of the leg muscles. However, muscle strength in the lower extremities has rarely been investigated in (young) TBI patients. Here, we investigated associations between lower-extremity muscle weakness, strength asymmetry, and impairments in gait and posture in young TBI patients. A group of young patients with moderate-to-severe TBI (n=19; age, 14 years 11 months ±2 years) and a group of typically developing subjects (n=31; age, 14 years 1 month±3 years) participated in this study. A force platform was used to measure postural sway to quantify balance control during normal standing and during conditions of compromised visual and/or somatosensory feedback. Spatiotemporal gait parameters were assessed during comfortable and fast-speed walking, using an electronic walkway. Muscle strength in four lower-extremity muscle groups was measured bilaterally using a handheld dynamometer. Findings revealed that TBI patients had poorer postural balance scores across all sensory conditions, as compared to typically developing subjects. During comfortable and fast gait, TBI patients demonstrated a lower gait velocity, longer double-support phase, and increased step-length asymmetry. Further, TBI patients had a reduced strength of leg muscles and an increased strength asymmetry. Correlation analyses revealed that asymmetry in muscle strength was predictive of a poorer balance control and a more variable and asymmetric gait. To the best of our knowledge, this is the first study to measure strength asymmetry in leg muscles of a sample of TBI patients and illustrate the importance of muscular asymmetry as a potential marker and possible risk factor of impairments in control of posture and gait. © Copyright 2015, Mary Ann Liebert, Inc. 2015.

Billiet T.,Catholic University of Leuven | Billiet T.,University Hospitals Leuven | Billiet T.,Medical Imaging Research Center | Billiet T.,Leuven Research Institute for Neuroscience and Disease LIND | And 27 more authors.
NeuroImage: Clinical | Year: 2014

Introduction The histopathological basis of "unidentified bright objects" (UBOs) (hyperintense regions seen on T2-weighted magnetic resonance (MR) brain scans in neurofibromatosis-1 (NF1)) remains unclear. New in vivo MRI-based techniques (multi-exponential T2 relaxation (MET2) and diffusion MR imaging (dMRI)) provide measures relating to microstructural change. We combined these methods and present previously unreported data on in vivo UBO microstructure in NF1. Methods 3-Tesla dMRI data were acquired on 17 NF1 patients, covering 30 white matter UBOs. Diffusion tensor, kurtosis and neurite orientation and dispersion density imaging parameters were calculated within UBO sites and in contralateral normal appearing white matter (cNAWM). Analysis of MET2 parameters was performed on 24 UBO-cNAWM pairs. Results No significant alterations in the myelin water fraction and intra- and extracellular (IE) water fraction were found. Mean T2 time of IE water was significantly higher in UBOs. UBOs furthermore showed increased axial, radial and mean diffusivity, and decreased fractional anisotropy, mean kurtosis and neurite density index compared to cNAWM. Neurite orientation dispersion and isotropic fluid fraction were unaltered. Conclusion Our results suggest that demyelination and axonal degeneration are unlikely to be present in UBOs, which appear to be mainly caused by a shift towards a higher T2-value of the intra- and extracellular water pool. This may arise from altered microstructural compartmentalization, and an increase in 'extracellular-like', intracellular water, possibly due to intramyelinic edema. These findings confirm the added value of combining dMRI and MET2 to characterize the microstructural basis of T2 hyperintensities in vivo. © 2014 The Authors.

Gooijers J.,Catholic University of Leuven | Chalavi S.,Catholic University of Leuven | Beeckmans K.,Center for Epilepsy and Acquired Brain Injury | Michiels K.,University Hospital Leuven Campus Pellenberg | And 4 more authors.
Neurorehabilitation and Neural Repair | Year: 2016

Background. Traumatic brain injury (TBI) has been associated with altered microstructural organization of white matter (WM) and reduced gray matter (GM). Although disrupted WM organization has been linked to poorer motor performance, the predictive value of GM atrophy for motor impairments in TBI remains unclear. Objective. Here, we investigated TBI-induced GM volumetric abnormalities and uniquely examined their relationship with bimanual motor impairments. Methods. 22 moderate to severe TBI patients (mean age = 25.9 years, standard deviation [SD] = 4.9 years; time since injury = 4.7 years, SD = 3.7 years) and 27 age- and gender-matched controls (mean age = 23.4 years; SD = 3.8 years) completed bimanual tasks and a structural magnetic resonance imaging scan. Cortical and subcortical GM volumes were extracted and compared between groups using FreeSurfer. The association between bimanual performance and GM volumetric measures was investigated using partial correlations. Results. Relative to controls, patients performed significantly poorer on the bimanual tasks and demonstrated significantly smaller total GM as well as overall and regional subcortical GM. However, the groups did not show significant differences in regional cortical GM volume. The majority of the results remained significant even after excluding TBI patients with focal lesions, suggesting that TBI-induced volume reductions were predominantly caused by diffuse injury. Importantly, atrophy of the thalamus, putamen, and pallidum correlated significantly with poorer bimanual performance within the TBI group. Conclusions. Our results reveal that GM atrophy is associated with motor impairments in TBI, providing new insights into the etiology of motor control impairments following brain trauma. © American Society of Neurorehabilitation.

Shen S.,University of Illinois at Chicago | Benoy V.,Leuven Research Institute for Neuroscience and Disease LIND | Bergman J.A.,University of Illinois at Chicago | Kalin J.H.,University of Illinois at Chicago | And 5 more authors.
ACS Chemical Neuroscience | Year: 2016

Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A. © 2015 American Chemical Society.

Boisgontier M.P.,Catholic University of Leuven | Wittenberg G.F.,Catholic University of Leuven | Wittenberg G.F.,Geriatric Research | Wittenberg G.F.,University of Maryland Baltimore County | And 4 more authors.
PLoS ONE | Year: 2014

The default mode of the motor system is a coupling between limbs. However, in some movements, a decoupling is required and thus calls for selection and facilitation/inhibition processes. Here, we investigate the relative contribution of recruitment versus selection processes to the overall processing complexity. To this aim we proposed a new multilimb reaction-time task (MUL-RT). Simple, choice and normalized (choice minus simple) RT were analysed together with error rates in thirty-six young adults for 15 coordination modes including all possible configuration of limb recruitment. Simple and normalized RTs were respectively assumed to be indicative of the recruitment and selection processes. Results supported a model of coupling/decoupling interactions respectively reporting weak, intermediate and strong interaction for selecting diagonal, ipsilateral and homologous limbs. Movement laterality (left vs. right) had no effect on selection complexity, whereas selecting upper limbs was less challenging than selecting lower limbs. Results in the different coordination modes suggested that recruitment complexity decreased as follows: 3 limbs = 4 limbs>2 limbs (homologous, ipsilateral and diagonal).1 limb, and selection complexity as follows: 2 diagonal limbs>3 limbs>2 ipsilateral limbs>1 limb = 2 homologous limbs.4 limbs. Based on these ordinal scales of recruitment and selection complexity, we extrapolated the overall processing complexity of the simple and choice MUL-RT. This method was efficient in reproducing the absolute results we obtained on a ratio scale (ms) and demonstrated that processing complexity in simple RT was mainly governed by the 'recruitment principle' (the more limbs recruited the lower the performance), whereas contributions of recruitment and 'selection principle' (nature of the coordination determines performance) to overall processing complexity were similar in choice RT. © 2014 Boisgontier et al.

PubMed | Leuven Research Institute for Neuroscience and Disease LIND and Movement Control and Neuroplasticity Research Group
Type: | Journal: Frontiers in aging neuroscience | Year: 2015

The cognitive load associated with joint position sense increases with age but does not necessarily result in impaired performance in a joint position matching task. It is still unclear which factors interact with age to predict matching performance. To test whether movement amplitude and direction are part of such predictors, young and older adults performed a bimanual wrist joint position matching task. Results revealed an age-related deficit when the target limb was positioned far from (25) the neutral position, but not when close to (15, 5) the neutral joint position, irrespective of the direction. These results suggest that the difficulty associated with the comparison of two musculoskeletal states increases towards extreme joint amplitude and that older adults are more vulnerable to this increased difficulty.

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