Marcus Beck

University of Wuerzburg, Würzburg, Bavaria, Germany

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Publications (33)115.63 Total impact

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    ABSTRACT: While some cases of familial ALS can be entirely attributed to known inherited variation, the majority (∼ 90%) are sporadic, where the cause(s) are not entirely understood. Both genetic and environmental factors may contribute to susceptibility. Mitochondrial damage, a common feature of neurodegenerative disease, is observed in most patients and inherited polymorphism in the mitochondrial genome has been suggested as a contributing factor. We used an economic and efficient method to test whether such involvement is probable. We genotyped 22 mtDNA coding region SNPs and sequenced the mtDNA hypervariable region 1 to determine the position of each mitochondrial genome within the genealogy of mitochondrial haplotypes in samples of ALS patients (n = 700) and controls (n = 462) from two European populations. We compared haplotype and haplogroup distribution in cases and controls drawn from the same populations. No statistical difference was observed between cases and controls at either the haplogroup or haplotype level (p = ≥  0.2). In conclusion, it is unlikely that common, shared genetic variants in the mitochondrial genome contribute substantially to ALS. Combining the data with other studies will allow meta-analysis to look for variants with modest effect sizes. The sequencing of complete mitochondrial genomes will be required to assess the role of rare mutations.
    Amyotrophic Lateral Sclerosis 03/2012; 13(4):341-6. DOI:10.3109/17482968.2012.654394 · 2.37 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with variable involvement of other systems. A pathogenetic role of immune-mediated mechanisms has been suggested. We retrospectively analyzed sural nerve pathology and the clinical course in 18 patients with ALS. These patients had undergone sural nerve biopsy because of clinical or neurophysiological signs indicating sensory involvement (ALS+). Eleven of the 18 ALS+ patients had inflammatory cell infiltrates (ALSvasc) resembling infiltrates seen in patients with vasculitic neuropathy. Data were compared with the 7 patients without vasculitic infiltrates (ALSnonvasc) and with those of 16 patients with isolated peripheral nerve vasculitis (NPvasc). Biopsy specimens were processed with standard histological stains and with immunohistochemistry for a panel of inflammatory markers, with the hypothesis that the composition of infiltrates should differ between ALSvasc and NPvasc. Immunoreactive cells were quantified in a blinded manner. Unlike patients with NPvasc, those with ALSvasc had only minor neurophysiological abnormalities in the sural nerve and, except for the infiltrates, almost normal nerve morphology on semithin sections. The difference in epineurial T cell count was significant between ALSvasc and ALSnonvasc (p=0.031). Surprisingly, the cellular composition of epineurial infiltrates in sural nerve biopsies was indistinguishable between ALSvasc and NPvasc despite a significant difference in fiber pathology (p<0.0001). Standard immunosuppressive treatment did not prevent clinical progression of the motor neuron disease in any of the patients with ALSvasc. ALSvasc appears as a neuropathological subtype in ALS+ suggesting immune-mediated disease components but without response to standard immunosuppressive treatment. KeywordsAmyotrophic lateral sclerosis (ALS)–Sural nerve biopsy–Nonsystemic vasculitic neuropathy
    Acta Neuropathologica 09/2011; 122(3):343-352. DOI:10.1007/s00401-011-0837-8 · 10.76 Impact Factor
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    ABSTRACT: In focal hand dystonia, long-term potentiation (LTP) and depression (LTD)-like neuronal plasticity, as assessed by paired associative stimulation (PAS) targeting the hand-associated motor cortex, is enhanced and the topographic organization of plasticity is lost. However, if any of these abnormalities alone is sufficient to cause focal dystonia (FD) remains unknown. Ten patients with cervical dystonia (CD), 9 with blepharospasm (BS) and 16 age- and sex-matched controls were examined. PAS was performed by combining repetitively electric stimulation of the median nerve with subsequent transcranial magnetic stimulation of the contralateral motor cortex at 21.5ms (PAS21.5) and 10ms (PAS10). Corticospinal excitability was indexed by the magnitude of motor evoked potentials (MEPs) recorded from abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. In controls, MEP size of the homotopically conditioned APB increased after PAS21.5 whereas the MEP size of the heterotopically conditioned ADM remained stable. PAS10 led to a decrease of MEP size of the APB and to an increase of the heterotopic ADM. In contrast, after PAS21.5 and PAS10 in CD and BS MEP size increased and decreased, respectively, in both muscles. The magnitude of excitability changes, however, did not differ between dystonic patients and healthy controls. In FD the topographic organization of PAS21.5 and PAS10-induced plasticity is deranged in cortical areas not involved in the control of the dystonic body part. Somatotopical disorganization of plasticity may represent an endophenotypic trait in FD but may not be sufficient to generate a dystonic phenotype. Development of a dystonic phenotype may require that the gain of plasticity is additionally enhanced. This article is part of a Special Issue entitled "Advances in dystonia".
    Neurobiology of Disease 11/2010; 42(2):171-6. DOI:10.1016/j.nbd.2010.11.009 · 5.08 Impact Factor
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    P Kraft · M Beck · A Grimm · C Wessig · K Reiners · K.V. Toyka ·
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    ABSTRACT: Symptomatic treatment of amyotrophic lateral sclerosis (ALS) is relevant in preventing complications and improving quality of life as long as curative therapies are still out of sight. About one third of ALS patients show disabling problems associated with dysarthria, dysphagia, sialorrhea, and a pseudobulbar affective disorder already in the early stages of ALS. A multidisciplinary approach is the cornerstone of symptomatic treatment of bulbar and pseudobulbar ALS features. Except for riluzole randomized controlled trials are lacking. Here, we review the current views with regard to epidemiology, pathophysiology, diagnosis, and practical aspects of treating bulbar and pseudobulbar symptoms.
    Der Nervenarzt 10/2010; 81(10):1218-25. DOI:10.1007/s00115-010-3008-6 · 0.79 Impact Factor
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    ABSTRACT: Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.
    Brain 09/2010; 133(11):3166-80. DOI:10.1093/brain/awq253 · 9.20 Impact Factor
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    P. Kraft · M. Beck · A. Grimm · C. Wessig · K. Reiners · K.V. Toyka ·
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    ABSTRACT: Die Symptome der amyotrophen Lateralsklerose (ALS) werden überwiegend verursacht durch die erkrankungstypische Degeneration des 1. und 2. motorischen Neurons. Weitere Systeme des zentralen Nervensystems (ZNS) sind ebenfalls betroffen, wie das autonome, sensorische und sensible System. Bei der ALS existiert bislang kein kurativer Therapieansatz. Daher kommt der symptomatischen Therapie für die Verbesserung der Lebensqualität, zur Prävention von Komplikationen und damit auch zur Prognoseverbesserung eine besondere Bedeutung zu. Etwa ein Drittel der ALS-Patienten klagen schon zu Beginn der Erkrankung über Veränderung des Sprech- und Schluckvermögens, verbunden mit Sialorrhö. Gelegentlich treten pathologisches Lachen und Weinen auf, die ohne entsprechende innere Regung ablaufen und als pseudobulbäre Symptome gelten. Die pathophysiologischen Zusammenhänge, die zu dieser pseudobulbären Affektstörung führen, sind bislang nicht ausreichend geklärt. In der Regel wird heute für die bulbären und pseudobulbären Symptome eine interdisziplinäre Betreuung angeraten. Für die bulbären ALS-Symptome kann eine leichte Verlangsamung der Progredienz durch Riluzol erreicht werden. Die Übersicht fasst die wesentlichen Erkenntnisse zur Epidemiologie und Pathophysiologie der die Lebensqualität und Prognose von ALS-Patienten stark beeinträchtigenden bulbären und der pseudobulbären Symptome zusammen. Die dargestellten symptomatischen Behandlungsmöglichkeiten berücksichtigen speziell pragmatische Aspekte in der ambulanten Therapie.
    Der Nervenarzt 01/2010; 81(10). · 0.79 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS), the major form of motor neuron disease in the adult occurs as a sporadic disease in more than 95% of all cases. Analysis of familial forms is considered as a key to understand the pathophysiology of the disease. It is expected that mutations responsible for familial forms are also found in sporadic ALS. During the past years, several loci and genes have been identified in which disease associated mutations have been discovered. We report here on the screening of 596 sporadic ALS patients, 41 familial ALS cases and other motor neuron disease patients from Germany for mutations in the FUS/TLS gene. Sequencing of the last two exons in all patients revealed the C1561T transversion, which leads to the amino acid substitution at R521C, in one familial and one sporadic ALS patient. In addition three patients with a synonymous mutation at codon 522 were identified. None of these variants were present in the control population. Our results indicate that mutations in FUS/TLS are not a major cause of sporadic ALS in the German population.
    Neurobiology of aging 12/2009; 32(3):548.e1-4. DOI:10.1016/j.neurobiolaging.2009.11.017 · 5.01 Impact Factor
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    ABSTRACT: Autoantibodies to the synaptic protein amphiphysin play a crucial pathogenic role in paraneoplastic stiff-person syndrome. Impairment of GABAergic inhibition is the presumed pathophysiological mechanism by which these autoantibodies become pathogenic. Here we used calcium imaging on rat embryonic motor neurons to investigate whether antibodies to amphiphysin directly hinder GABAergic signaling. We found that the immunoglobulin G fraction from a patient with stiff-person syndrome, containing high titer antibodies to amphiphysin and inducing stiffness in rats upon passive transfer, reduced GABA-induced calcium influx in embryonic motor neurons. Depletion of the anti-amphiphysin fraction from the patient's IgG by selective affinity chromatography abolished this effect, showing its specificity for amphiphysin. Quantification of the surface expression of the Na(+)/K(+)/2Cl(2-) cotransporter revealed a reduction after incubation with anti-amphiphysin IgG, which is concordant with a lower intracellular chloride concentration and thus impairment of GABA mediated calcium influx. Thus, anti-amphiphysin antibodies exert a direct effect on GABA signaling, which is likely to contribute to the pathogenesis of SPS.
    Neurobiology of Disease 08/2009; 36(1):191-9. DOI:10.1016/j.nbd.2009.07.011 · 5.08 Impact Factor
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    ABSTRACT: The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.
    Human Molecular Genetics 03/2009; 18(8):1524-32. DOI:10.1093/hmg/ddp059 · 6.39 Impact Factor
  • D. Weise · A. Schramm · M. Beck · K. Reiners · J. Classen ·

    Brain Stimulation 07/2008; 1(3):261-261. DOI:10.1016/j.brs.2008.06.046 · 4.40 Impact Factor
  • JC Ulzheimer · A Schramm · K Reiners · M Beck ·

    Klinische Neurophysiologie 12/2007; 38(04). DOI:10.1055/s-2007-1032255 · 0.12 Impact Factor
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    ABSTRACT: Proximal spinal muscular atrophy (SMA) is a motoneuron disease for which there is currently no effective treatment. In animal models of SMA, spinal motoneurons exhibit reduced axon elongation and growth cone size. These defects correlate with reduced beta-actin messenger RNA and protein levels in distal axons. We show that survival motoneuron gene (Smn)-deficient motoneurons exhibit severe defects in clustering Cav2.2 channels in axonal growth cones. These defects also correlate with a reduced frequency of local Ca2+ transients. In contrast, global spontaneous excitability measured in cell bodies and proximal axons is not reduced. Stimulation of Smn production from the transgenic SMN2 gene by cyclic adenosine monophosphate restores Cav2.2 accumulation and excitability. This may lead to the development of new therapies for SMA that are not focused on enhancing motoneuron survival but instead investigate restoration of growth cone excitability and function.
    The Journal of Cell Biology 11/2007; 179(1):139-49. DOI:10.1083/jcb.200703187 · 9.83 Impact Factor
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    ABSTRACT: Sporadic amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, most likely results from complex genetic and environmental interactions. Although a number of association studies have been performed in an effort to find genetic components of sporadic ALS, most of them resulted in inconsistent findings due to a small number of genes investigated in relatively small sample sizes, while the replication of results was rarely attempted. Defects in retrograde axonal transport, vesicle trafficking and xenobiotic metabolism have been implicated in neurodegeneration and motor neuron death both in human disease and animal models. To assess the role of common genetic variation in these pathways in susceptibility to sporadic ALS, we performed a pathway-based candidate gene case-control association study with replication. Furthermore, we determined reliability of whole genome amplified DNA in a large-scale association study. In the first stage of the study, 1277 putative functional and tagging SNPs in 134 genes spanning 8.7 Mb were genotyped in 822 British sporadic ALS patients and 872 controls using whole genome amplified DNA. To detect variants with modest effect size and discriminate among false positive findings 19 SNPs showing a trend of association in the initial screen were genotyped in a replication sample of 580 German sporadic ALS patients and 361 controls. We did not detect strong evidence of association with any of the genes investigated in the discovery sample (lowest uncorrected P-value 0.00037, lowest permutation corrected P-value 0.353). None of the suggestive associations was replicated in a second sample, further excluding variants with moderate effect size. We conclude that common variation in the investigated pathways is unlikely to have a major effect on susceptibility to sporadic ALS. The genotyping efficiency was only slightly decreased ( approximately 1%) and genotyping quality was not affected using whole genome amplified DNA. It is reliable for large scale genotyping studies of diseases such as ALS, where DNA sample collections are limited because of low disease prevalence and short survival time.
    Brain 10/2007; 130(Pt 9):2292-301. DOI:10.1093/brain/awm055 · 9.20 Impact Factor
  • Marcus Beck · Michael Sendtner · Klaus V Toyka ·
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    ABSTRACT: Familial amyotrophic lateral sclerosis (ALS) is frequently associated with mutations in the SOD1 gene. We identified a rapidly progressive disease in a patient with an inherited ALS. The identified heterozygous T>A exchange in position 1067 in the SOD1 gene results in an amino acid substitution of lysine for asparagine at position 86 (N86K) of the SOD1 protein. The family history suggested that this autosomal dominantly inherited mutation may be associated with rapidly progressive disease. Muscle Nerve, 2007
    Muscle & Nerve 07/2007; 36(1):111-4. DOI:10.1002/mus.20756 · 2.28 Impact Factor
  • A Schramm · D Weise · M Beck · K Reiners · J Claßen ·

    Klinische Neurophysiologie 03/2007; 38(01). DOI:10.1055/s-2007-976426 · 0.12 Impact Factor
  • P Kraft · M Beck · K Reiners ·

    Aktuelle Neurologie 01/2007; 34. DOI:10.1055/s-2007-987970 · 0.32 Impact Factor
  • A. Schramm · M. Naumann · K. Reiners · M. Beck · J. Classen ·

    Aktuelle Neurologie 01/2006; 33. DOI:10.1055/s-2006-953005 · 0.32 Impact Factor

  • Aktuelle Neurologie 01/2006; 33. DOI:10.1055/s-2006-953015 · 0.32 Impact Factor
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    ABSTRACT: This pilot study aimed at exploring the effects of intrathecally administered brain derived neurotrophic factor (BDNF) on autonomic functions in patients with ALS. A battery of autonomic sympathetic and parasympathetic tests was performed at baseline and after nine months of treatment in 10 ALS patients participating in a double-blind placebo-controlled phase II/III study of intrathecally administered BDNF. Results of patients treated with BDNF (25 or 150 microg/day) were compared to those receiving placebo. Sudomotor function and blood pressure response to handgrip significantly worsened during the treatment period (55.4+/-26.1 vs. 38.9+/-23.9 g/m(2)h, p<0.05; 20+/-6 vs. 13+/-4 microHg, p<0.05) whereas other sympathetic and all parasympathetic function tests only tended to be more abnormal at follow-up. Serum norepinephrine levels increased significantly during the nine-months observation period. The results of autonomic function tests were not different between patients treated with BDNF and placebo, but norepinephrine levels were higher in the BDNF group. We conclude that autonomic nervous system function deteriorates along with poorer motor performance independently from treatment with BDNF. The elevation of norepinephrine levels might reflect a non-specific up-regulation, and its association with BDNF an autocrine effect.
    Amyotrophic Lateral Sclerosis 06/2005; 6(2):100-3. DOI:10.1080/14660820510028412
  • S Wiese · M Beck · C Karch · M Sendtner ·
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    ABSTRACT: Mechanisms controlling neuronal survival play an important role both during development and after birth, in particular when the nervous system is lesioned. Isolated embryonic motoneurons and other types of primary neurons have been a useful tool for studying basic mechanisms underlying neuronal cell death during development and under pathophysiological conditions after neurotrauma. These studies have led to the identification of neurotrophic factors which under physiological conditions regulate survival and functional properties, and after neurotrauma promote regeneration and plasticity. Functional analysis of these molecules, in particular by generation of gene knockout mice, has led to a more detailed understanding of complex requirements of individual types of neurons for their survival and also paved the way for a better understanding of the signalling pathways in lesioned neurons which decide on cell death or survival after axotomy and other pathophysiological conditions. These findings could ultimately lead to a rational basis for therapeutic approaches aiming at improving neuronal survival and regeneration after neurotrauma.
    Acta neurochirurgica. Supplement 02/2004; 89(89):21-35. DOI:10.1007/978-3-7091-0603-7_4