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Biomedical subjects

Wim Robberecht

Publications and source records attributed to Wim Robberecht.

At least 19 recordsLinked to original sources
PubMed2006

Quantitative diffusion tensor imaging in amyotrophic lateral sclerosis.

OBJECTIVE: Aim of present study was to evaluate changes in diffusion tensor imaging (DTI) parameters in the whole brain of 28 patients with amyotrophic lateral sclerosis (ALS) compared to 26 healthy controls. METHODS: In both fibertracking and voxel-based analysis, quantitative comparisons of the diffusion parameters between ALS patients and controls were performed. Correlation analyses of diffusion parameters and disease duration and disease severity were performed. A second DTI examination was acquired, allowing the evaluation of the effect of disease progression on the diffusion parameters. RESULTS: Fibertracking analysis revealed that especially the precentral part of the corticospinal tract (CST) was impaired. In the voxel-based analysis, it was shown that changes of diffusion parameters occurred throughout the brain, including frontal, temporal and parietal lobes. Disease severity was inversely correlated with the fractional anisotropy (FA). In the follow-up examination, a further decline of FA over time could be demonstrated in the CST as well as in the whole brain white matter. INTERPRETATION: This study provides support for the view of ALS as being a multisystem degenerative disease, in which abnormalities of extra-motor areas play an important role in the in vivo physiopathology.

Adult↗
PubMed2006

Ivermectin inhibits AMPA receptor-mediated excitotoxicity in cultured motor neurons and extends the life span of a transgenic mouse model of amyotrophic lateral sclerosis.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated excitotoxicity contributes to the selective motor neuron death in amyotrophic lateral sclerosis (ALS). In this study, we investigated the effect of P2 receptor-influencing substances on kainate-induced motor neuron death in an in vitro model for AMPA receptor-mediated excitotoxicity. Complete protection was found after preincubation of the motor neurons with ivermectin or Cibacron Blue 3G-A. Preincubation with both P2X4 modulators did not influence the number or Ca2+ permeability of the AMPA receptors and addition during kainate stimulation alone had no effect. Preincubation with a low concentration of ATP, the natural agonist of the P2X4 receptor, also protected the motor neurons against a subsequent excitotoxic stimulation, while high concentrations of ATP were toxic. Moreover, ivermectin increased the toxicity of low ATP concentrations, indicating that ivermectin can potentiate the effect of ATP on its receptor. Ivermectin and ATP also protected against hypoxia/hypoglycemia. To further investigate the relevance of these findings for ALS, we treated SOD1(G93A)-mice, a transgenic animal model for familial ALS, with ivermectin. This resulted in an extension of the life span of these mice with almost 10%. We conclude that ivermectin induces a mechanism in motor neurons, in vivo and in vitro, that protects against subsequent excitotoxic insults. Our in vitro data indicate that this protective mechanism is due to the potentiation by ivermectin of an effect of ATP mediated by the P2X4 receptor.

Adenosine Triphosphate↗
PubMed2006

MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.

Adolescent↗
PubMed2006

Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.

Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.

Amino Acid Sequence↗
PubMed2006

The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis.

BACKGROUND: Twenty percent of familial amyotrophic lateral sclerosis (ALS) is caused by mutations in the superoxide dismutase 1 gene (SOD1). Few data exist on their clinicopathologic phenotypes. OBJECTIVES: To determine the clinical and pathologic phenotype associated with the G93C mutation in SOD1 and to compare survival in familial ALS related to this mutation with survival in other ALS subgroups. DESIGN: Retrospective study. SETTING: Tertiary referral center for neuromuscular disorders. PATIENTS: Twenty patients with the G93C mutation for whom clinical data were available and 1 patient with pathologic data. MAIN OUTCOME MEASURES: Characteristics and survival compared with other ALS subgroups, adjusting for known prognostic factors. RESULTS: The G93C mutation was associated with a purely lower motor neuron phenotype without bulbar involvement. Presence of the mutation independently predicted longer survival compared with other ALS subgroups. Pathologic examination showed degeneration of the anterior horn, spinocerebellar tracts, and posterior funiculi, with minimal involvement of corticospinal tracts and no degeneration of brainstem motor nuclei. Survival motor neuron gene copy number had no significant influence on age at onset or survival in patients with the G93C mutation. CONCLUSIONS: These findings add to the knowledge of SOD1-related familial ALS and demonstrate further clinicopathologic variability between different SOD1 mutations. Finally, they demonstrate the independent prognostic value of the G93C mutation.

Adult↗
PubMed2006

Vascular endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative diseases.

The angiogenic activity of vascular endothelial growth factor (VEGF) is well known. Recently, it has become evident that VEGF is involved in central nervous system physiology and may play a role in the pathogenesis of neurological diseases. In particular, it may be involved in the mechanism of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), and has been hypothesized to be implicated in the pathogenesis of peripheral neuropathies such as occur in the so-called POEMS syndrome and diabetes. VEGF is also being studied as a possible treatment option in some of these disorders. In this review we critically analyze the data supporting the notion that VEGF is a factor involved in motor neuron degeneration and review the studies linking VEGF to other diseases of the peripheral and central nervous systems.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Manofluorographic evaluation of swallowing in amyotrophic lateral sclerosis and its relationship with clinical evaluation of swallowing.

The aim of this cross-sectional study was, first, to identify swallowing dysfunctions in an ALS population of 40 consecutive patients through combined videofluoroscopy and manometry. Secondly, these objective swallowing data were correlated with the functional feeding status as reported by the patient or family member. Videofluoroscopic evaluation showed dysfunctions in the oral phase of swallowing, pharyngeal initiation and pharyngeal transport. In addition, manometric data revealed low tongue driving forces and pharyngeal contraction amplitudes but normal relaxation of the upper oesophageal sphincter (UES). Aspiration was noted in a not negligible number of 9/40 patients. These objective data were then correlated with the clinical swallowing and feeding status, assessed by means of the ALS Swallowing Severity Scale. Patients receiving scores of 6 or lower on the ALSSSS, report dietary consistency changes but are considered 'safe oral feeders'. Nevertheless, our data revealed that these patients showed significant aspiration during videofluoroscopy. Although not every patient with ALS should be referred routinely for radiographic evaluation of swallowing, our findings suggest referral for a radiological examination as soon as the ALSSSS drops to a score of 6 or lower, to evaluate the presence of (silent) aspiration.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Synaptopodin and 4 novel genes identified in primary sensory neurons.

We performed differential gene expression profiling in the peripheral nervous system by comparing the transcriptome of sensory neurons with the transcriptome of lower motor neurons. Using suppression subtractive cDNA hybridization, we identified 5 anonymous transcripts with a predominant expression in sensory neurons. We determined the gene structures and predicted the functional protein domains. The 4930579P15Rik gene encodes for a novel inhibitor of protein phosphatase-1 and 9030217H17Rik was found to be the mouse gene synaptopodin. We performed in situ hybridization for all genes in mouse embryos, and found expression predominantly in the primary class of sensory neurons. Expression of 4930579P15Rik and synaptopodin was restricted to craniospinal sensory ganglia. Neither synaptopodin, nor any known family member of 4930579P15Rik, has ever been described in sensory neurons. The identification of protein domains and expression patterns allows further functional analysis of these novel genes in relation to the development and biology of sensory neurons.

Animals↗
PubMed2005

Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease.

The prior diagnosis of fatal astrocytoma in a 60-year-old man with Crohn's disease treated with natalizumab, a monoclonal antibody against alpha4 integrins, was reclassified as JC virus-related progressive multifocal leukoencephalopathy (PML). Analysis of frozen serum samples showed that JC virus DNA had appeared in the serum three months after the initiation of open-label natalizumab monotherapy and two months before the appearance of symptomatic PML. There was staining of the brain lesion for polyomavirus. This case report, along with two others, suggests that anti-alpha4-integrin therapy can result in JC virus-induced PML.

Antibodies, Monoclonal↗
PubMed2005

Role of matrix metalloproteinase-9 in a mouse model for amyotrophic lateral sclerosis.

The pathogenesis of amyotrophic lateral sclerosis remains poorly understood, but microglial and astroglial activation are thought to contribute to motor neuron death. Evidence suggests that matrix metalloproteinase-9 (MMP-9) is a mediator of this deleterious effect. In this study, we evaluated the effect of MMP-9 on the pathogenesis of amyotrophic lateral sclerosis. Although marked microglial and astroglial proliferation was seen in the spinal cord and in-vitro studies proved MMP-9 to be produced by these cells, deletion of the MMP-9 gene in SOD1(G93A) mice accelerated rather than delayed the motor neuron disease and significantly reduced survival. Our results suggest that the effect of MMP-9 on mutant superoxide dismutase-1 (SOD1)-induced motor neuron disease is protective rather than hazardous. Therefore, the effect of pharmacological inhibition of MMP-9 activity is unlikely to be of therapeutical benefit in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed2005

GluR2 deficiency accelerates motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis.

AMPA receptor-mediated excitotoxicity has been implicated in the selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). Motor neurons in vitro are particularly vulnerable to excessive AMPA receptor stimulation and one of the factors underlying this selective vulnerability is the presence of a large proportion of Ca2+ -permeable (i.e. GluR2-lacking) AMPA receptors. However, the precise role of GluR2-lacking AMPA receptors in motor neuron degeneration remains to be defined. We therefore studied the impact of GluR2 deficiency on motor neuron death in vitro and in vivo. Cultured motor neurons from GluR2-deficient embryos displayed an increased Ca2+ influx through AMPA receptors and an increased vulnerability to AMPA receptor-mediated excitotoxicity. We deleted the GluR2 gene in mutant SOD1G93A mice by crossbreeding them with GluR2 knockout mice. GluR2 deficiency clearly accelerated the motor neuron degeneration and shortened the life span of mutant SOD1G93A mice. These findings indicate that GluR2 plays a pivotal role in the vulnerability of motor neurons in vitro and in vivo, and that therapies that limit Ca2+ entry through AMPA receptors might be beneficial in ALS patients.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS.

Neurotrophin treatment has so far failed to prolong the survival of individuals affected with amyotrophic lateral sclerosis (ALS), an incurable motoneuron degenerative disorder. Here we show that intracerebroventricular (i.c.v.) delivery of recombinant vascular endothelial growth factor (Vegf) in a SOD1(G93A) rat model of ALS delays onset of paralysis by 17 d, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery. By protecting cervical motoneurons, i.c.v. delivery of Vegf is particularly effective in rats with the most severe form of ALS with forelimb onset. Vegf has direct neuroprotective effects on motoneurons in vivo, because neuronal expression of a transgene expressing the Vegf receptor prolongs the survival of SOD1(G93A) mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1(G93A) rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Long-lasting changes in GABA responsiveness in cultured neurons.

In neuronal cells, GABA evokes an increase in chloride conductance by activating GABA(A) and GABA(C) receptors. In mature neurons, this increase in conductance generally has a hyperpolarizing and inhibitory action. Using gramicidin-based perforated patch recordings, we show that in cultured motor neurons GABA-induced currents are significantly altered following activation of GABA receptors coinciding with changes in membrane potential. Changes in intracellular chloride concentration constituted the mechanism for this modulation. Because of low resting chloride conductance and low activity of chloride transporters, changes in intracellular chloride concentration and hence GABA response were long-lasting (time constant of recovery was about 2.5 min). Cultured dorsal horn and hippocampal neurons exhibited a similar response pattern, suggesting a general property of cultured neuronal cells. These long-lasting changes in GABA responsiveness may have major implications on neuronal excitability.

Animals↗
PubMed2004

Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.

Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles. In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22). We found a second mutation (K141E) in two smaller families. Both mutations target the same amino acid, which is essential to the structural and functional integrity of the small heat-shock protein alphaA-crystallin. This positively charged residue, when mutated in other small heat-shock proteins, results in various human disorders. Coimmunoprecipitation experiments showed greater binding of both HSPB8 mutants to the interacting partner HSPB1. Expression of mutant HSPB8 in cultured cells promoted formation of intracellular aggregates. Our findings provide further evidence that mutations in heat-shock proteins have an important role in neurodegenerative disorders.

Amino Acid Sequence↗
PubMed2004

Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity. We previously reported a Russian family with autosomal dominant axonal CMT and assigned the locus underlying the disease (CMT2F; OMIM 606595) to chromosome 7q11-q21 (ref. 2). Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F. Screening for mutations in HSPB1 in 301 individuals with CMT and 115 individuals with distal hereditary motor neuropathies (distal HMNs) confirmed the previously observed mutation and identified four additional missense mutations. We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy. Four mutations are located in the Hsp20-alpha-crystallin domain, and one mutation is in the C-terminal part of the HSP27 protein. Neuronal cells transfected with mutated HSPB1 were less viable than cells expressing the wild-type protein. Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments.

Amino Acid Sequence↗
PubMed2004

Effects of vascular endothelial growth factor (VEGF) on motor neuron degeneration.

Both in mice and humans, low expression levels of vascular endothelial growth factor (VEGF) are linked to adult-onset motor neuron disease or amyotrophic lateral sclerosis (ALS). The mechanism through which reduced VEGF levels result in this phenotype is unknown. We therefore examined the direct effects of VEGF on motor neurons and found VEGF to have a direct neurotrophic effect on motor neurons in vitro. Survival and vulnerability to excitotoxicity of motor neurons from VEGF(delta/delta) mice was however similar to that of motor neurons from non-transgenic littermates. The VEGF concentration in the spinal cord of mutant (G93A) SOD1 mice was not different from that found in wild-type SOD1 overexpressing mice. Upregulation of VEGF in the spinal cord, by housing mutant (G93A) SOD1 mice in hypoxic conditions, did not affect their life span. Our results show that VEGF is a neurotrophic factor for motor neurons in vitro, and shortage of this neurotrophic factor may contribute to the motor neuron death observed in humans and animals with low VEGF expression levels.

Animals↗