Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS

Turner, Martin R; Osei-Lah, Abena; Hammers, Alexander; Al‐Chalabi, Ammar; Shaw, Christopher E.; Andersen, Peter M.; Brooks, David J.; Leigh, P. Nigel; Mills, Kerry

doi:10.1136/jnnp.2004.054429

Cited by 71 publications

(57 citation statements)

References 46 publications

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“…Transcranial magnetic stimulation (TMS) studies have supported the notion that the cortical lesion in PLS behaves differently to ALS, with reduced excitability [15]. Similar observations were made in TMS studies of homD90A patients [7,8]. In both cases this might reflect relative preservation of certain inhibitory GABA-ergic neuronal circuits.…”

Section: Discussionmentioning

confidence: 62%

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Cortical involvement in four cases of primary lateral sclerosis using [11C]-flumazenil PET

et al. 2007

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Four PLS patients underwent cerebral [(11)C]-flumazenil PET. They were compared firstly with a group of controls, then later directly with a group of sporadic ALS patients and a familial ALS group homozygous for the 'D90A' SOD1 gene mutation. There was a similar pattern of decreased binding in PLS patients when compared to controls as that seen in a previous study of sporadic ALS patients, supporting the concept that PLS is part of the same overall spectrum of MND. However, in direct group comparisons, both sporadic and homD90A ALS patients demonstrated relative decreases in anterior and orbito-frontal binding compared to PLS patients, suggesting that there may be differences in cortical vulnerability between phenotypic groups.

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Section: Discussionmentioning

confidence: 62%

“…This was postulated to reflect the distinct phenotype of homD90A, which is also associated with delayed progression of disease and a mean survival of 14 years from diagnosis [6]. This group has a distinct upper motor neuron (UMN) pathology demonstrated both clinically and electrophysiologically [7,8].…”

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confidence: 97%

Cortical involvement in four cases of primary lateral sclerosis using [11C]-flumazenil PET

et al. 2007

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“…75,76 Positron emission tomography (PET) studies showed that binding of the benzodiazepine GABA(A) ligand flumazenil was reduced in the motor cortex of ALS patients. 77,78 In situ hybridization histochemistry studies also indicated that GABA(A)-receptor mRNA expression was reduced in postmortem cortical samples of ALS patients, 79,80 but unchanged in spinal cord of G93A-SOD1 mice. 81 Our results are consistent with the observation that GABAergic innervations of lower motoneurons were unchanged.…”

Section: Discussionmentioning

confidence: 99%

Glycinergic Innervation of Motoneurons Is Deficient in Amyotrophic Lateral Sclerosis Mice

Chang

Martin

2009

The American Journal of Pathology

110

138

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Altered motoneuron excitability is involved in amyotrophic lateral sclerosis pathobiology. To test the hypothesis that inhibitory interneuron innervation of spinal motoneurons is abnormal in an amyotrophic lateral sclerosis mouse model, we measured GABAergic, glycinergic, and cholinergic immunoreactive terminals on spinal motoneurons in mice expressing a mutant form of human superoxide dismutase-1 with a Gly933 Ala substitution (G93A-SOD1) and in controls at different ages. Glutamic acid decarboxylase, glycine transporter-2, and choline acetyltransferase were used as markers for GABAergic, glycinergic, and cholinergic terminals, respectively. Triple immunofluorescent labeling of boutons contacting motoneurons was visualized by confocal microscopy and analyzed quantitatively. Glycine transporter-2-bouton density on lateral motoneurons was decreased significantly in G93A-SOD1 mice compared with controls. This reduction was absent at 6 weeks of age but present in asymptomatic 8-week-old mice and worsened with disease progression from 12 to 14 weeks of age. Motoneurons lost most glycinergic innervation by 16 weeks of age (end-stage) when there was a significant decrease in the numbers of motoneurons and choline acetyltransferase-positive boutons. No significant differences in glutamic acid decarboxylase-bouton densities were found in G93A-SOD1 mice. Reduction of glycinergic innervation preceded mitochondrial swelling and vacuolization. Calbindin-positive Renshaw cell number was decreased significantly at 12 weeks of age in G93A-SOD1 mice. Thus, either the selective loss of inhibitory glycinergic regulation of motoneuron function or glycinergic interneuron degeneration contributes to motoneuron degeneration in amyotrophic lateral sclerosis. (Am J

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“…Abnormalities of CMCT correlated with upper motor neuron signs, and may deteriorate over the course of ALS [116]. The degree of CMCT prolongation is not uniform in different ALS phenotypes, being particularly prominent in the D90A-SOD1-related familial ALS [117]. Importantly, CMCT is especially prolonged when recording from clinically affected regions, such as upper or lower limb muscles in spinal-onset disease (limb-onset), or from cranial muscles in bulbar-onset ALS [9,118].…”

Section: Alsmentioning

confidence: 99%

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Vucic

Kiernan

2017

Neurotherapeutics

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Transcranial magnetic stimulation (TMS) is a noninvasive technique that has provided important information about cortical function across an array of neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and related extrapyramidal disorders. Application of TMS techniques in neurodegenerative diseases has provided important pathophysiological insights, leading to the development of pathogenic and diagnostic biomarkers that could be used in the clinical setting and therapeutic trials. Abnormalities of TMS outcome measures heralding cortical hyperexcitability, as evidenced by a reduction of short-interval intracortical inhibition and increased in motorevoked potential amplitude, have been consistently identified as early and intrinsic features of amyotrophic lateral sclerosis (ALS), preceding and correlating with the ensuing neurodegeneration. Cortical hyperexcitability appears to form the pathogenic basis of ALS, mediated by trans-synaptic glutamate-mediated excitotoxic mechanisms. As a consequence of these research findings, TMS has been developed as a potential diagnostic biomarker, capable of identifying upper motor neuronal pathology, at earlier stages of the disease process, and thereby aiding in ALS diagnosis. Of further relevance, marked TMS abnormalities have been reported in other neurodegenerative diseases, which have varied from findings in ALS. With time and greater utilization by clinicians, TMS outcome measures may prove to be of utility in future therapeutic trial settings across the neurodegenerative disease spectrum, including the monitoring of neuroprotective, stem-cell, and genetic-based strategies, thereby enabling assessment of biological effectiveness at early stages of drug development.

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Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS

Cited by 71 publications

References 46 publications

Cortical involvement in four cases of primary lateral sclerosis using [11C]-flumazenil PET

Cortical involvement in four cases of primary lateral sclerosis using [11C]-flumazenil PET

Glycinergic Innervation of Motoneurons Is Deficient in Amyotrophic Lateral Sclerosis Mice

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

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