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  • 1. Androulidakis, Alexandros G
    et al.
    Kühn, Andrea A
    Chen, Chiung Chu
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Kempf, Florian
    Kupsch, Andreas
    Schneider, Gerd-Helge
    Doyle, Louise
    Dowsey-Limousin, Patricia
    Hariz, Marwan I
    Brown, Peter
    Dopaminergic therapy promotes lateralized motor activity in the subthalamic area in Parkinson's disease2007In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 130, no Pt 2, p. 457-468Article in journal (Other academic)
  • 2. Brenner, David
    et al.
    Mueller, Kathrin
    Wieland, Thomas
    Weydt, Patrick
    Boehm, Sarah
    Lule, Dorothee
    Huebers, Annemarie
    Neuwirth, Christoph
    Weber, Markus
    Borck, Guntram
    Wahlqvist, Magnus
    Danzer, Karin M.
    Volk, Alexander E.
    Meitinger, Thomas
    Strom, Tim M.
    Otto, Markus
    Kassubek, Jan
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Neurology Department, Ulm University, Ulm, Germany.
    Weishaupt, Jochen H.
    NEK1 mutations in familial amyotrophic lateral sclerosis2016In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 139, p. CP14-CP17Article in journal (Refereed)
  • 3.
    Brenner, David
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Yilmaz, Rüstem
    Müller, Kathrin
    Grehl, Torsten
    Petri, Susanne
    Meyer, Thomas
    Grosskreutz, Julian
    Weydt, Patrick
    Ruf, Wolfgang
    Neuwirth, Christoph
    Weber, Markus
    Pinto, Susana
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Department of Neurosciences and Mental Health, Hospital de Santa Maria-CHLN, Lisbon, Portugal.
    Claeys, Kristl G.
    Schrank, Berthold
    Jordan, Berit
    Knehr, Antje
    Günther, Kornelia
    Hübers, Annemarie
    Zeller, Daniel
    Kubisch, Christian
    Jablonka, Sibylle
    Sendtner, Michael
    Klopstock, Thomas
    de Carvalho, Mamede
    Sperfeld, Anne
    Borck, Guntram
    Volk, Alexander E.
    Dorst, Johannes
    Weis, Joachim
    Otto, Markus
    Schuster, Joachim
    Del Tredici, Kelly
    Braak, Heiko
    Danzer, Karin M.
    Freischmidt, Axel
    Meitinger, Thomas
    Strom, Tim M.
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Neurology Department, Ulm University, Ulm, Germany.
    Weishaupt, Jochen H.
    Hot-spot KIF5A mutations cause familial ALS2018In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, p. 688-697Article in journal (Refereed)
    Abstract [en]

    Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.

  • 4. Freischmidt, Axel
    et al.
    Mueller, Kathrin
    Zondler, Lisa
    Weydt, Patrick
    Volk, Alexander E.
    Bozic, Anze Losdorfer
    Walter, Michael
    Bonin, Michael
    Mayer, Benjamin
    von Arnim, Christine A. F.
    Otto, Markus
    Dieterich, Christoph
    Holzmann, Karlheinz
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Ulm University, Ulm, Germany;Virtual Helmholtz Institute RNA dysmetabolism in Amyotrophic Lateral Sclerosis and Fronto-temporal Dementia, Germany .
    Ludolph, Albert C.
    Danzer, Karin M.
    Weishaupt, Jochen H.
    Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers2014In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 137, no 11, p. 2938-2950Article in journal (Refereed)
    Abstract [en]

    Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

  • 5.
    Hariz, Marwan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Unit of Functional Neurosurgery, University College London-Institute of Neurology, Queen Square, London, UK.
    Tabrizi, Sarah
    Patients with Huntington's disease pioneered human stereotactic neurosurgery 70 years ago2017In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 140, p. 2516-2519Article in journal (Other academic)
  • 6.
    Jacobsson, Johan
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
    Jonsson, P. Andreas
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations2001In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 124, no 7, p. 1461-1466Article in journal (Refereed)
    Abstract [en]

    Mutations in CuZn-superoxide dismutase (CuZn-SOD) have been linked to familial amyotrophic lateral sclerosis (ALS), and motor neurone death is caused by the gain of a toxic property of the mutant protein. Here we determined amounts, activity and molecular forms of CuZn-SOD in CSF from ALS patients carrying the D90A and other CuZn-SOD mutations and patients without such mutations. There were no differences in amount of protein and enzymic activities of CuZn-SOD between 37 neurological controls, 54 sporadic and 12 familial ALS cases, and 10 cases homozygous for the D90A mutation. Three cases heterozygous for the A89V, S105L and G114A CuZn-SOD mutations showed low amounts of CuZn-SOD. There was no evidence for accumulation of inactive protein in any of the groups. Immunoblots showed no evidence for the presence of any precipitates or other molecular forms of CuZn-SOD with higher molecular weight in the groups. About 25% of the CuZn-SOD subunits in CSF from controls shows an N-terminal truncation. This truncated portion does not differ between controls and ALS groups not carrying CuZn-SOD mutations, but is 70% larger in samples from D90A homozygous ALS patients. The findings suggest an essentially normal amount and activity of D90A mutant CuZn-SOD in CNS tissues of ALS cases. The increased occurrence of N-terminally truncated mutant subunits may indicate a difference in degradation routes compared with the wild-type enzyme, resistance against subsequent proteolytic steps and/or a compromised downstream proteolytic machinery. Molecular fragments accumulated to a greater extent from the D90A mutant enzyme might contribute to the motor neurone degeneration. We also determined the other SOD isoenzymes: in the controls, CuZn-SOD contributed 75%, extracellular SOD 25% and Mn-SOD <5% of the total SOD activity. There was no difference in the amount of extracellular SOD between any of the groups.

  • 7.
    Jonsson, P Andreas
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Ernhill, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Bergemalm, Daniel
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Gredal, Ole
    Nilsson, Peter
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis.2004In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 127, no Pt 1, p. 73-88Article in journal (Refereed)
    Abstract [en]

    Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.

  • 8.
    Jonsson, P Andreas
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Graffmo, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Lindberg, Mikael
    Oliveberg, Mikael
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models.2006In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 129, no Pt 2, p. 451-644Article in journal (Refereed)
    Abstract [en]

    Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.

  • 9.
    Lind, Johanna
    et al.
    Department of Clinical Neuroscience, MR Research Center, Karolinska Hospital, Stockholm.
    Persson, Jonas
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Ingvar, Martin
    Department of Clinical Neuroscience, MR Research Center, Karolinska Hospital, Stockholm.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Cruts, Marc
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium.
    Van Broeckhoven, Christine
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Bäckman, Lars
    Stockholm Aging Research Center.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University, Stockholm.
    Petersson, Karl Magnus
    Department of Clinical Neuroscience, MR Research Center, Karolinska Hospital.
    Nyberg, Lars
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Reduced functional brain activity response in cognitively intact apolipoprotein E ε4 carriers2006In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 129, no 5, p. 1240-1248Article in journal (Refereed)
    Abstract [en]

    The apolipoprotein E epsilon4 (APOE epsilon4) is the main known genetic risk factor for Alzheimer's disease. Genetic assessments in combination with other diagnostic tools, such as neuroimaging, have the potential to facilitate early diagnosis. In this large-scale functional MRI (fMRI) study, we have contrasted 30 APOE epsilon4 carriers (age range: 49-74 years; 19 females), of which 10 were homozygous for the epsilon4 allele, and 30 non-carriers with regard to brain activity during a semantic categorization task. Test groups were closely matched for sex, age and education. Critically, both groups were cognitively intact and thus symptom-free of Alzheimer's disease. APOE epsilon4 carriers showed reduced task-related responses in the left inferior parietal cortex, and bilaterally in the anterior cingulate region. A dose-related response was observed in the parietal area such that diminution was most pronounced in homozygous compared with heterozygous carriers. In addition, contrasts of processing novel versus familiar items revealed an abnormal response in the right hippocampus in the APOE epsilon4 group, mainly expressed as diminished sensitivity to the relative novelty of stimuli. Collectively, these findings indicate that genetic risk translates into reduced functional brain activity, in regions pertinent to Alzheimer's disease, well before alterations can be detected at the behavioural level.

  • 10. Mahlknecht, Philipp
    et al.
    Georgiev, Dejan
    Akram, Harith
    Brugger, Florian
    Vinke, Saman
    Zrinzo, Ludvic
    Hariz, Marwan
    Bhatia, Kailash P.
    Hariz, Gun-Marie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Sobell Department of Motor Neuroscience, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.
    Willeit, Peter
    Rothwell, John C.
    Foltynie, Thomas
    Limousin, Patricia
    Parkinsonian signs in patients with cervical dystonia treated with pallidal deep brain stimulation2018In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, p. 3023-3034Article in journal (Refereed)
    Abstract [en]

    Pallidal deep brain stimulation is an established treatment in patients with dystonia. However, evidence from case series or uncontrolled studies suggests that it may lead in some patients to specific parkinsonian symptoms such as freezing of gait, micrographia, and bradykinesia. We investigated parkinsonian signs using the Movement Disorder Society Unified Parkinson's Disease Rating Scale motor score by means of observer-blinded video ratings in a group of 29 patients treated with pallidal stimulation and a non-surgical control group of 22 patients, both with predominant cervical dystonia. Additional assessments included MRI-hased models of volume of neural tissue activated to investigate areas of stimulation related to dystonic symptom control and those likely to induce parkinsonian signs as well as an EMG analysis to investigate functional vicinity of stimulation fields to the pyramidal tract. Compared with controls, stimulated patients had significantly higher motor scores (median, 25th-75th percentile: 14.0, 8.0-19.5 versus 3.0, 2.0-8.0; P < 0.0001), as well as bradykinesia (8.0, 6.0-14.0 versus 2.0, 0.0-3.0; P < 0.0001) and axial motor subscores (2.0, 1.0-4.0 versus 0.0, 0.0-1.0; P= 0.0002), while rigidity and tremor subscores were not different between groups. Parkinsonian signs were partially reversible upon switching stimulation off for a median of 90 min in a subset of 19 patients tolerating this condition. Furthermore, the stimulation group reported more features of freezing of gait on a questionnaire basis. Quality of life was better in stimulated patients compared with control patients, but parkinsonian signs were negatively associated with quality of life. In the descriptive imaging analysis maximum efficacy for dystonia improvement projected to the posteroventrolateral internal pallidum with overlapping dusters driving severity of bradykinesia and axial motor symptoms. The severities of parkinsonian signs were not correlated with functional vicinity to the pyramidal tract as assessed by EMG. In conclusion, parkinsonian signs, particularly bradykinesia and axial motor signs, due to pallidal stimulation in dystonic patients are frequent and negatively impact on motor functioning and quality of life. Therefore, patients with pallidal stimulation should be monitored closely for such signs both in clinical routine and future clinical trials. Spread of current outside the internal pallidum is an unlikely explanation for this phenomenon, which seems to be caused by stimulation of neural elements within the stimulation target volume.

  • 11. Marklund, Petter
    et al.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Elgh, Eva
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Riklund Åhlström, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Temporal dynamics of basal ganglia under-recruitment in Parkinson's disease: transient caudate abnormalities during updating of working memory.2009In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 132, no Pt 2, p. 336-346Article in journal (Refereed)
    Abstract [en]

    Using hybrid-blocked/event-related fMRI and the 2-back task we aimed to decompose tonic and phasic temporal dynamics of basal ganglia response abnormalities in working memory associated with early untreated Parkinson's disease. In view of the tonic/phasic dopamine hypothesis, which posits a functional division between phasic D(2)-dependent striatal updating processes and tonic D(1)-dependent prefrontal context-maintenance processes, we predicted that newly diagnosed, drug-naïve Parkinson's disease patients, with selective striatal dopamine deprivation, would demonstrate transient rather than sustained activation changes in the basal ganglia during 2-back performance. Task-related activation patterns within discrete basal ganglia structures were directly compared between patients and healthy elderly controls. The obtained results yielded uniquely transient underactivation foci in caudate nuclei, putamen and globus pallidus in Parkinson's disease patients, which indicates suboptimal phasic implementation of striatal D(2)-dependent gating mechanisms during updating. Sustained underactivation was only seen in the anterior putamen, which may reflect initial signs of tonic control impairment. No significant changes were exhibited in prefrontal cortex. The present findings resonate well with the tonic/phasic dopamine account and suggest that basal ganglia under-recruitment associated with executive dysfunction in early Parkinson's disease might predominantly stem from deficiencies in phasic executive components subserved by striatum.

  • 12. Mueller, Kathrin
    et al.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Ulm University, Ulm, Germany ; Virtual Helmholtz Institute RNA Dysmetabolism in Amyotrophic Lateral Sclerosis and Fronto-Temporal Dementia, Germany .
    Huebers, Annemarie
    Marroquin, Nicolai
    Volk, Alexander E.
    Danzer, Karin M.
    Meitinger, Thomas
    Ludolph, Albert C.
    Strom, Tim M.
    Weishaupt, Jochen H.
    Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease2014In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 137, no 12, p. e309-Article in journal (Refereed)
  • 13. Thomas, Christine K.
    et al.
    Häger-Ross, Charlotte K.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Klein, Cliff S
    Effects of baclofen on motor units paralysed by chronic cervical spinal cord injury.2010In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 133, no Pt 1, p. 117-225Article in journal (Refereed)
    Abstract [en]

    Baclofen, a gamma-aminobutyric acid receptor(B) agonist, is used to reduce symptoms of spasticity (hyperreflexia, increases in muscle tone, involuntary muscle activity), but the long-term effects of sustained baclofen use on skeletal muscle properties are unclear. The aim of our study was to evaluate whether baclofen use and paralysis due to cervical spinal cord injury change the contractile properties of human thenar motor units more than paralysis alone. Evoked electromyographic activity and force were recorded in response to intraneural stimulation of single motor axons to thenar motor units. Data from three groups of motor units were compared: 23 paralysed units from spinal cord injured subjects who take baclofen and have done so for a median of 7 years, 25 paralysed units from spinal cord injured subjects who do not take baclofen (median: 10 years) and 45 units from uninjured control subjects. Paralysed motor unit properties were independent of injury duration and level. With paralysis and baclofen, the median motor unit tetanic forces were significantly weaker, twitch half-relaxation times longer and half maximal forces reached at lower frequencies than for units from uninjured subjects. The median values for these same parameters after paralysis alone were comparable to control data. Axon conduction velocities differed across groups and were slowest for paralysed units from subjects who were not taking baclofen and fastest for units from the uninjured. Greater motor unit weakness with long-term baclofen use and paralysis will make the whole muscle weaker and more fatigable. Significantly more paralysed motor units need to be excited during patterned electrical stimulation to produce any given force over time. The short-term benefits of baclofen on spasticity (e.g. management of muscle spasms that may otherwise hinder movement or social interactions) therefore have to be considered in relation to its possible long-term effects on muscle rehabilitation. Restoring the strength and speed of paralysed muscles to pre-injury levels may require more extensive therapy when baclofen is used chronically.

  • 14. Weber, M.
    et al.
    Eisen, A.
    Stewart, H.G.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
    Andersen, PM
    Preserved slow conducting corticomotoneuronal projections in ALS patients with autosomal recessive D90A CuZn-SOD mutation.2000In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 123, no 7, p. 1505-1515Article in journal (Refereed)
    Abstract [en]

    Recently, a subgroup of the amyotrophic lateral sclerosis (ALS) syndrome associated with mutations in the gene encoding the free radical scavenging enzyme CuZn-superoxide dismutase (CuZn-SOD, SOD1) has been identified. Some 67 different mutations have been reported worldwide to date, comprising about one-fifth of familial ALS cases in the populations studied. The autosomal recessively inherited D90A CuZn-SOD mutation has been associated with a very slowly progressive, clinically distinct phenotype, and is neurophysiologically characterized by very slow central motor conduction. It is not known which physiological and/or biochemical mechanisms are responsible for the different clinical course. To delineate ALS associated with this particular CuZn-SOD mutation from ALS without mutations, we performed a detailed neurophysiological study of the corticomotoneuronal function using peristimulus time histograms (PSTHs) in eight ALS patients homozygous for the D90A CuZn-SOD mutation. The results were compared with those obtained in 12 non-hereditary ALS patients and 11 healthy subjects. PSTHs were constructed from three to seven different, voluntarily recruited motor units of the extensor digitorum communis muscle (EDC) in each patient. The onset latency, number of excess bins, duration and synchrony of the primary peak were analysed. All measurements differed significantly between healthy controls and the D90A patients (P < 0.0007). The mean onset latency of the primary peak in D90A patients was 35.3 ms, compared with 24.2 ms for non-hereditary ALS patients and 19.3 ms for normal subjects (P < 0.0000). Delayed primary peaks in the D90A patients were desynchronized and characteristically preceded by a marked suppression phase. This suppression phase was not seen in non-hereditary ALS patients. We conclude that the mainly slow conducting and/or polysynaptic corticomotoneuronal connections are preserved in the D90A homozygous cases, and that the cortical and possibly spinal inhibitory circuitry is preserved. These events may partially protect the motor neurons, slowing down the degenerative process.

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