Showing papers on "Amyotrophic lateral sclerosis published in 2000"
TL;DR: It is found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls, and stride-to-stride control of gait rhythm is apparently compromised with ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions.
439 citations
TL;DR: Results indicate that 21q linked FALS is not a primary disorder of astrocytes, and that expression of mutant SOD1 restricted to astroCytes is not sufficient to cause motoneuron degeneration in vivo.
Abstract: Evidence garnered from both human autopsy studies and genetic animal models has suggested a potential role for astrocytes in the pathogenesis of amyotrophic lateral sclerosis (ALS). Currently, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) represent the only known cause of motoneuron loss in the disease, producing 21q linked familial ALS (FALS). To determine whether astrocytic dysfunction has a primary role in familial ALS, we have generated multiple lines of transgenic mice expressing G86R mutant SOD1 restricted to astrocytes. In GFAP-m SOD1 mice, astrocytes exhibit significant hypertrophy and increased GFAP reactivity as the animals mature. However, GFAP-mutant SOD1 transgenic mice develop normally and do not experience spontaneous motor deficits with increasing age. Histological examination of spinal cord in aged GFAP-mSOD1 mice reveals normal motoneuron and microglial morphology. These results indicate that 21q linked FALS is not a primary disorder of astrocytes, and that expression of mutant SOD1 restricted to astrocytes is not sufficient to cause motoneuron degeneration in vivo. Expression of mutant SOD1 in other cell types, most likely neurons, is critical for the initiation of disease.
384 citations
TL;DR: The hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons is supported and therapeutic approaches should be directed towards preventing axonal degeneration and/or promoting axonal regeneration.
Abstract: Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of CMT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients with CMT1A typically have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs), distal weakness, sensory loss and decreased reflexes. In order to understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration.
371 citations
TL;DR: In vivo expression of high levels of wild-type hSOD1 is not only harmful to neurons in itself, but also increases or facilitates the deleterious action of a fALS-mutant SOD1.
370 citations
TL;DR: A common toxicity of mutant SOD1 is a sequential activation of at least two caspases, caspase-1 that acts slowly as a chronic initiator and casp enzyme-3 acting as the final effector of cell death.
Abstract: Familial amyotrophic lateral sclerosis-linked mutations in copper-zinc superoxide dismutase cause motor neuron death through one or more acquired toxic properties. An early event in the mechanism of toxicity from such mutants is now demonstrated to be activation of caspase-1. Neuronal death, however, follows only after months of chronic caspase-1 activation concomitantly with activation of the executioner caspase-3 as the final step in the toxic cascade. Thus, a common toxicity of mutant SOD1 is a sequential activation of at least two caspases, caspase-1 that acts slowly as a chronic initiator and caspase-3 acting as the final effector of cell death.
340 citations
TL;DR: It is suggested that 8OH2'dG may provide a useful tool for monitoring therapeutic interventions in this disease and be consistent with the hypothesis that oxidative pathology accompanies the neurodegenerative process in ALS.
307 citations
TL;DR: The results support the viewpoint that an oxygen radical-induced impairment of mtDNA is of pathophysiological significance in the aetiology of at least a subgroup of patients with SALS.
Abstract: Amyotrophic lateral sclerosis is a neurodegenerative disease affecting the anterior horn cells of the spinal cord and cortical motor neurons. Previous findings have suggested a specific impairment of mitochondrial function in skeletal muscle of at least a limited number of patients. Applying flavoprotein/NAD(P)H autofluorescence imaging of mitochondrial function in saponin-permeabilized muscle fibres, we detected a heterogeneous distribution of the respiratory chain defect among individual fibres in muscle biopsies of patients (11 out of 17) with sporadic amyotrophic lateral sclerosis (SALS). These findings correlate with the presence of cytochrome c oxidase (COX)-negative muscle fibres detected histologically. We established the molecular basis for the decreased activities of NADH:CoQ oxidoreductase and COX in SALS muscle. In the skeletal muscle of the investigated patients, diminished levels (13 out of 17) or multiple deletions (one out of 17) of mitochondrial DNA (mtDNA) were observed. These alterations of mtDNA seem to be related to decreased levels of membrane-associated mitochondrial Mn-superoxide dismutase. Our results support the viewpoint that an oxygen radical-induced impairment of mtDNA is of pathophysiological significance in the aetiology of at least a subgroup of patients with SALS.
266 citations
TL;DR: More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.
Abstract: Current research evidence suggests that genetic factors, oxidative stress and glutamatergic toxicity, with damage to critical target proteins and organelles, may be important contributory factors to motor neuron injury in amyotrophic lateral sclerosis (ALS). Various molecular and neurochemical features of human motor neurons may render this cell group differentially vulnerable to such insults. Motor neurons are large cells with long axonal processes which lead to requirements for a high level of mitochondrial activity and a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low expression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor activation. Motor neurons also have a high perisomatic expression of the glutamate transporter protein EAAT2 and a very high expression of the cytosolic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which may render this cell group vulnerable in the face of genetic or post-translational alterations interfering with the function of these proteins. More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.
240 citations
TL;DR: An unusual and remarkable preservation of phasic inspiratory sternomastoid activation during REM was associated with longer REM sleep duration in six of the other patients with diaphragmatic dysfunction.
Abstract: In amyotrophic lateral sclerosis (ALS), the progressive loss of upper and lower motor neurons leads to respiratory failure, often with predominant diaphragm dysfunction, and death. Because the diaphragm is the only active inspiratory muscle during rapid eye movement (REM) sleep, there is a high theoretical risk of respiratory disorders during REM sleep in patients with ALS. To assess this hypothesis, we studied sleep characteristics (polysomnography) in 21 patients with ALS, stratified according to the presence or absence of diaphragmatic dysfunction. Diaphragmatic dysfunction was defined as an absent or delayed diaphragm response to cervical or cortical magnetic stimulation, abdominal paradox, or respiratory pulse (Group 1, 13 patients). These patients did not differ in age, clinical course, or form (bulbar or spinal) from the eight others, who did not have diaphragmatic dysfunction (Group 2). REM sleep was reduced in Group 1 (7 ± 7% of total sleep time; mean ± SD) and normal in Group 2 (18 ± 6%, p = 0.0...
218 citations
TL;DR: Clinical and demographic details of patients included in the Irish ALS Register who were incorrectly diagnosed as having ALS (patients who were ultimately rediagnosed as having an "ALS mimic syndrome") are described.
Abstract: Background The Irish ALS Register is a population-based register of the epidemiological characteristics of amyotrophic lateral sclerosis (ALS) in the republic of Ireland. Objective To describe the clinical and demographic details of those patients included in the Irish ALS Register who were incorrectly diagnosed as having ALS (patients who were ultimately rediagnosed as having an "ALS mimic syndrome"). Methods The medical records of each patient referred to the register are routinely reviewed and, where possible, patients are examined by our group during their illness. Results Between January 1, 1993, and December 31, 1997, 32 patients (representing 7.3% of 437 referrals) were rediagnosed as having a condition other than ALS. The median age at onset for these 32 patients was 56.0 years (range, 19.5-85.8 years) for men and 53.5 years (range, 39.5-70.4 years) for women. Twenty-nine patients (91%) presented with symptoms referable to the limbs, and the remainder presented with symptoms involving the bulbar musculature. Multifocal motor neuropathy was the most common condition mistaken for ALS, accounting for 7 cases (22%), followed closely by Kennedy disease (4 cases [13%]). Factors leading to diagnostic revision included evolution of atypical symptoms, results of specific investigations, and failure of symptoms to progress. Twenty-seven (84%) of the patients with an ALS mimic syndrome fulfilled the El Escorial criteria for either "suspected" or "possible" ALS, 4 (13%) met the criteria for probable ALS, and 1 (3%) had definite ALS. Conclusions The application of the El Escorial diagnostic criteria may facilitate early recognition of non-ALS cases. Misdiagnosis of ALS remains a common clinical problem despite the increased availability of investigations and a greater awareness among neurologists of potential diagnostic pitfalls.
209 citations
TL;DR: An activation of the TNF system in ALS is reported and the role of this activation in the pathogenesis of the disease remains elusive.
01 Jan 2000
TL;DR: The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD.
Abstract: A motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/ motor neurone disease (MND). FTD is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex. The motor neuronopathy comprises bulbar palsy and limb amyotrophy. The major histological change is typically of microvacuolation of the cerebral cortex, with atrophy of the bulbar neurones and anterior horn cells of the spinal cord. Ubiquitinated inclusion bodies occur in large pyramidal cortical neurones and in surviving cranial nerve nuclei and anterior horn cells. Evidence is emerging that some patients with classical MND/ amyotrophic lateral sclerosis (ALS), who are thought not to be demented, develop cognitive deficits in the realm of frontal executive functions. Moreover, frontal lobe abnormalities have been demonstrated by neuroimaging. The findings point to a link between FTD/ MND and cMND/ALS and suggest that a proportion of patients with cMND/ALS go on to develop FTD. Patients with cMND/ALS may not be equally vulnerable. The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD. © 2000 Published by Elsevier Science B.V.
TL;DR: In this article, a motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/motor neurone disease (MND), which is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex.
TL;DR: Based on the immuno-electron microscopical finding that these abnormal granulecoated fibrils are positive for SOD1, the formation (or aggregation) of the abnormal fibril containing S OD1 would be essential evidence in diseases caused by various SOD 1 mutations.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. Approximately 5-10% of ALS is familial. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS (FALS) patients. The neuronal Lewy-body-like hyaline inclusion (LBHI) and astrocytic hyaline inclusion (Ast-HI) are morphological hallmarks of certain SOD1-linked FALS patients with SOD1 gene mutant and transgenic mice expressing human SOD1 with G85R mutation. From the detailed immunohistochemical analyses, the essential common protein of both inclusions is SOD1. Ultrastructurally, both inclusions consist of granule-coated fibrils 15-25 nm in diameter. Based on the immuno-electron microscopical finding that these abnormal granule-coated fibrils are positive for SOD1, the formation (or aggregation) of the abnormal fibrils containing SOD1 would be essential evidence in diseases caused by various SOD1 mutations. The granule-coated fibrils are also modified by advanced glycation end products (AGEs). The AGEs themselves are insoluble molecules with direct toxic effects on cells. AGE formation of SOD1 composing the granule-coated fibrils (probable AGE-modified mutant SOD1) may amplify their aggregation and produce a more marked toxicity.
TL;DR: This paper showed that the stoichiometry of cytoskeletal protein expression in ALS spinal motor neurons is significantly altered in a pattern conducive to the formation of neurofilamentous aggregates.
Abstract: Because transgenic mice expressing an altered stoichiometry of neurofilament proteins develop a motor neuron degeneration associated with neurofilamentous aggregate formation similar to that found in amyotrophic lateral sclerosis (ALS), we studied the expression of intermediate filament proteins in sporadic ALS. Archival cervical spinal cord paraffin-embedded sections from 11 disease and 11 control cases were studied by either in situ hybridization using 35S-labeled riboprobes or immunohistochemically using specific antibodies for the individual neurofilament subunit proteins, α-internexin, nestin, peripherin, vimentin, β-actin, or Tα1-tubulin. Median NFL, α-internexin, and peripherin steady-state mRNA levels were significantly reduced in the lateral motor neuron cell column (p < 0.05) of ALS cases, while neither NFM nor NFH mRNA levels were altered. ALS cases demonstrated an elevation of β-actin mRNA levels (p < 0.01) with no increase in Tα1-tubulin mRNA levels. No motor neuronal expression of nestin or vimentin was observed. Ubiquitin-immunoreactive perikaryal aggregates were immunoreactive for NFH or β-actin, but not for peripherin, α-internexin, vimentin, or nestin. In contrast, neuroaxonal spheroids were strongly immunoreactive for NFH and peripherin, but not for β-actin, α-internexin, vimentin, or nestin. These findings suggest that the stoichiometry of cytoskeletal protein expression in ALS spinal motor neurons is significantly altered in a pattern conducive to the formation of neurofilamentous aggregates.
TL;DR: The 88.3% rate of detection of enterovirus nucleic acids in the neuronal cell bodies within the gray matter of the spinal cord of patients with ALS strongly suggests association between persistent EV RNA and ALS.
Abstract: Objective: To investigate the possible association of persistent enterovirus (EV) infection with the development of ALS. Background: Although ALS is a clinically well-defined motor neuron disease, little is known about the etiology and pathogenesis of the sporadic cases. Among the different causes that have been hypothesized, conflicting results have been reported about the possible role of persistent enteroviral infection. Methods: Reverse transcriptase-PCR (RT-PCR) and direct RT in situ PCR (RT-IS-PCR) were performed in formaldehyde-fixed spinal cord samples of 17 patients with confirmed ALS and 29 control subjects with no history of motor neuron disease. When obtained, PCR products were sequenced subsequently. Results: Using direct RT-IS-PCR, EV nucleic acid sequences were detected in 15 (88.3%) of 17 patients with ALS compared to 1 (3.4%) of 29 control subjects. PCR products were located in neuronal cell bodies of the anterior horns of the spinal cord. The RT-PCR products obtained in 13 of the 17 patients with ALS showed between 94% and 86% homology with echovirus 7 sequences. Conclusion: The 88.3% rate of detection of enterovirus (EV) nucleic acids in the neuronal cell bodies within the gray matter of the spinal cord of patients with ALS strongly suggests association between persistent EV RNA and ALS. Further work is required to confirm that the persisting EV sequences we detected are somehow involved in the development of ALS.
TL;DR: It is demonstrated that caspase activation occurs in this mouse model of ALS during neurodegeneration and suggests that modulation of caspases activity may provide protective benefit in the treatment of ALS, a view that is consistent with the recent demonstration ofcaspase inhibition extending the survival of transgenic mSOD1 mice.
Abstract: Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant copper/zinc superoxide dismutase (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, herein we show that the spinal cord of transgenic mSOD1 mice is the site of the sequential activation of caspase-1 and caspase-3. Activated caspase-3 and its produced beta-actin cleavage fragments are found in apoptotic neurons in the anterior horn of the spinal cord of affected transgenic mSOD1 mice; although such neurons are few, their scarcity should not undermine the potential importance of apoptosis in the overall mSOD1-related neurodegeneration. Overexpression of the anti-apoptotic protein Bcl-2 attenuates neurodegeneration and delays activation of the caspases and fragmentation of beta-actin. These data demonstrate that caspase activation occurs in this mouse model of ALS during neurodegeneration. Our study also suggests that modulation of caspase activity may provide protective benefit in the treatment of ALS, a view that is consistent with our recent demonstration of caspase inhibition extending the survival of transgenic mSOD1 mice.
TL;DR: The results point to two pathophysiological mechanisms that operate to cause dysphagia in amyotrophic lateral sclerosis patients, related mainly to the progressive degeneration of the excitatory and inhibitory corticobulbar pyramidal fibres.
Abstract: We investigated the pathophysiological mechanisms of dysphagia in amyotrophic lateral sclerosis. Forty-three patients with sporadic amyotrophic lateral sclerosis were examined by clinical and electrophysiological methods that objectively measured the oropharyngeal phase of voluntarily initiated swallowing, and these results were compared with those obtained from 50 age-matched control subjects. Laryngeal movements were detected by a piezoelectric sensor and EMG of submental muscles, and needle EMG of the cricopharyngeal muscle of the upper oesophageal sphincter of both the amyotrophic lateral sclerosis and control groups was recorded during swallowing. Amyotrophic lateral sclerosis patients with dysphagia displayed the following abnormal findings. (i) Submental muscle activity of the laryngeal elevators, which produce reflex upward deflection of the larynx during wet swallowing, was significantly prolonged whereas the laryngeal relocation time of the swallowing reflex remained within normal limits. (ii) The cricopharyngeal sphincter muscle EMG demonstrated severe abnormalities during voluntarily initiated swallows. The opening of the sphincter was delayed and/or the closure occurred prematurely, the total duration of opening was shortened and, at times, unexpected motor unit bursts appeared during this period. (iii) During voluntarily initiated swallows there was significant lack of co-ordination between the laryngeal elevator muscles and the cricopharyngeal sphincter muscle. These results point to two pathophysiological mechanisms that operate to cause dysphagia in amyotrophic lateral sclerosis patients. (i) The triggering of the swallowing reflex for the voluntarily initiated swallow is delayed and eventually abolished, whereas the spontaneous reflexive swallows are preserved until the preterminal stage of amyotrophic lateral sclerosis. (ii) The cricopharyngeal sphincter muscle of the upper oesophageal sphincter becomes hyper-reflexic and hypertonic. As a result, the laryngeal protective system and the bolus transport system of deglutition lose their co-ordination during voluntarily initiated swallowing. We conclude that these pathophysiological changes are related mainly to the progressive degeneration of the excitatory and inhibitory corticobulbar pyramidal fibres.
TL;DR: Interest has been shown in the population incidence and prevalence of amyotrophic lateral sclerosis, and in the clinical variants that cause diagnostic confusion, and the requirement to measure quality of life with a new disease-specific instrument.
Abstract: The mechanisms by which mutations of the SOD1 gene cause selective motor neuron death remain uncertain, although interest continues to focus on the role of peroxynitrite, altered peroxidase activity of mutant SOD1, changes in intracellular copper homeostasis, protein aggregation, and changes in the function of glutamate transporters leading to excitotoxicity. Neurofilaments and peripherin appear to play some part in motor neuron degeneration, and amyotrophic lateral sclerosis is occasionally associated with mutations of the neurofilament heavy chain gene. Linkage to several chromosomal loci has been established for other forms of familial amyotrophic lateral sclerosis, but no new genes have been identified. In the clinical field, interest has been shown in the population incidence and prevalence of amyotrophic lateral sclerosis and the clinical variants that cause diagnostic confusion. Transcranial magnetic stimulation has been used to detect upper motor neuron damage and to explore cortical excitability in amyotrophic lateral sclerosis, and magnetic resonance imaging including proton magnetic resonance spectroscopy and diffusion weighted imaging also provide useful information on the upper motor neuron lesion. Aspects of care including assisted ventilation, nutrition, and patient autonomy are addressed, and underlying these themes is the requirement to measure quality of life with a new disease-specific instrument. Progress has been made in developing practice parameters. Riluzole remains the only drug to slow disease progression, although interventions such as non-invasive ventilation and gastrostomy also extend survival.
TL;DR: In this paper, the authors studied 137 ulnar nerve and abductor digiti minimi (ADM) muscles in 70 patients with ALS and correlated the results with ADM strength graded on the Medical Research Council (MRC) scale, to address the potential value of a standardized neurophysiological assessment of this nerve-muscle system.
Abstract: We studied 137 ulnar nerves and abductor digiti minimi (ADM) muscles in 70 patients with amyotrophic lateral sclerosis (ALS), and correlated the results with ADM strength graded on the Medical Research Council (MRC) scale, to address the potential value of a standardized neurophysiological assessment of this nerve-muscle system. The ulnar nerves of 35 normal subjects matched for age, gender, and height served as controls. Reduced compound muscle action potential (CMAP) amplitude and area in the ADM muscle recordings correlated strongly with weakness. Distal motor latency, proximal conduction time, and F-wave frequency were abnormal with minimally detectable weakness. In weaker ADM muscles, conduction velocities and F-wave latencies were also abnormal. Conduction block was never observed and sensory potentials were normal. An "ALS neurophysiological index" was derived from these ulnar nerve studies and consisted of the expression: (CMAP amplitude/DML) x F frequency -, where F frequency was expressed as the number of F responses recorded in 20 trials. This index was strongly correlated with ADM weakness (r = 0.74, P < 0.001). Neurophysiological studies restricted to a single nerve-muscle system, the ulnar nerve/ADM, appear potentially useful in objectively assessing change in ALS.
TL;DR: The first successful transduction and protection of spinal motoneurons by direct gene transfer in a model of progressive motoneuron disease is described, which supports the use of AAVs for the delivery of protective genes to spinal cord moto-neurons as a possible way to enhance mot oneuron survival and repair.
Abstract: Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) underlie some familial cases of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by loss of cortical, brainstem and spinal motoneurons. Transgenic mice over- expressing a mutated form of human SOD1 containing a Gly-->Ala substitution at position 93 (SOD1(G93A)) develop a severe, progressive motoneuron disease. We investigated the potential of recombinant adeno-associated virus (rAAV) to transfer neuroprotective molecules in this animal ALS model. Initial experiments showed that injection of an rAAV vector encoding green fluorescent protein unilaterally into the lumbar spinal cord of wild-type mice leads to expression of the reporter gene in 34.7 +/- 5.2% of the motoneurons surrounding the injection site. Intraspinal injection of an rAAV encoding the anti-apoptotic protein bcl-2 in SOD1 (G93A) mice resulted in sustained bcl-2 expression in motoneurons and significantly increased the number of surviving motoneurons at the end-stage of disease. Moreover, the compound muscle action potential amplitude elicited by nerve stimulation and recorded by electromyographic measurements was higher in the rAAV-bcl-2-treated group than in controls. Local bcl-2 expression in spinal motoneurons delayed the appearance of signs of motor deficiency but was not sufficient to prolong the survival of SOD1 (G93A) mice. To our know-ledge, this study describes the first successful transduction and protection of spinal motoneurons by direct gene transfer in a model of progressive motoneuron disease. Our results support the use of AAVs for the delivery of protective genes to spinal cord moto-neurons as a possible way to enhance motoneuron survival and repair.
TL;DR: Re-examination has revealed ubiquitin-positive but tau-negative inclusions as well as neurites in the frontotemporal cortices and ubiquit inclusions in the granule cells of the dentate fascia, but none were seen in brainstem or spinal cord motor neurons.
Abstract: Three cases are reported with dementia and ubiquitin-positive but tau-negative inclusion bodies. All patients had a semantic dementia and the clinical details of two of these have been published as the first description of a selective semantic memory impairment. The original diagnosis had been of Pick's disease based on frontotemporal atrophy, but re-examination has revealed ubiquitin-positive but tau-negative inclusions as well as neurites in the frontotemporal cortices and ubiquitin-positive, intracytoplasmic inclusions in the granule cells of the dentate fascia. These inclusions are identical to those reported in association with amyotrophic lateral sclerosis (motor neuron disease), but none were seen in brainstem or spinal cord motor neurons.
TL;DR: The effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage, in transgenic mice with a superoxide dismutase (SOD1) mutation (G93A) causes a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC.
Abstract: Increasing evidence implicates oxidative damage as a major mechanism in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage, in transgenic mice with a superoxide dismutase (SOD I) mutation (G93A), used as an animal model of familial ALS. NAC was administered at 1% concentration in the drinking water from 4-5 weeks of age. The treatment caused a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC compared to control mice. These results provide further evidence for the involvement of free radical damage in the G93A mice, and support the possibility that NAC, an over-the-counter antioxidant, could be explored in clinical trials for ALS.
TL;DR: Evidence for oxidative stress is not only found in mutant SOD1-related familial amyotrophic lateral sclerosis, but also in sporadic Amyotrophicateral sclerosis, so it is tempting to speculate that a similar mechanism is at work in both forms of the disease.
Abstract: The pathogenesis of amyotrophic lateral sclerosis is poorly understood. In one or two percentage of patients, mutations in the SOD1 gene are known to underly the disease. Even in these cases, the mechanism of cell death remains unclear. Most researchers agree that damage by reactive oxygen species is involved in this process, but whether the latter plays a primary role or is an epiphenomenon is uncertain. As evidence for oxidative stress is not only found in mutant SOD1-related familial amyotrophic lateral sclerosis, but also in sporadic amyotrophic lateral sclerosis, it is tempting to speculate that a similar mechanism is at work in both forms of the disease.
TL;DR: The findings for Alzheimer’s disease, congenital malformations of the central nervous system, and mental retardation are contradictory and insufficient to draw any conclusions, and studies of cerebral palsy are not conclusive.
Abstract: Existing seasonal birth studies were reviewed for multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), epilepsy, cerebral palsy, congenital malformat
TL;DR: It is concluded that p53 may participate in the mechanisms for motor neuron apoptosis in ALS.
TL;DR: The results indicate that the increase of MMP-9 in serum of ALS patients might be caused by upregulation of M MPs in denervated muscles or in degenerating peripheral nerves following motor neurone loss.
Abstract: Matrix metalloproteinase-9 (MMP-9) and its specific inhibitor, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), were analysed by enzyme-linked immunosorbent assay (ELISA) and by zymography in serum and cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). In contrast to patients with inflammatory diseases, MMP-9 levels were not elevated in CSF of ALS patients. In serum, however, compared to healthy donors, MMP-9 was significantly (p = 0.0003) increased up to levels as high as those of viral meningoencephalitis (VM) or bacterial meningitis (BM) patients. MMP-9 levels remained elevated during long-term observation of ALS patients. In the absence of an inflammatory response, the results indicate that the increase of MMP-9 in serum of ALS patients might be caused by upregulation of MMP-9 in denervated muscles or in degenerating peripheral nerves following motor neurone loss.
TL;DR: The relatively moderate and late involvement of the hypoglossal nucleus indicates that, although the general patterns of neuronal pathology match closely those seen in ALS patients, some differences exist in this transgenic model compared with the progression of the disease in humans.
Abstract: In recent years, several mouse models of amyotrophic lateral sclerosis (ALS) have been developed. One, caused by a G86R mutation in the superoxide dismutase-1 (SOD-1) gene associated with familial ALS, has been subjected to extensive quantitative analyses in the spinal cord. However, the human form of ALS includes pathology elsewhere in the nervous system. In the present study, analyses were extended to three motor nuclei in the brainstem. Mutant mice and control littermates were evaluated daily, and mutants, along with their littermate controls, were killed when they were severely affected. Brains were removed after perfusion and processed for Nissl staining, the samples were randomized, and the investigators were blinded to their genetic status. Stereologic methods were used to estimate the number of neurons, mean neuronal volumes, and nuclear volume in three brainstem motor nuclei known to be differentially involved in the human form of the disease, the oculomotor, facial, and hypoglossal nuclei. In the facial nucleus, neuron number consistently declined (48%), an effect that was correlated with disease severity. The nuclear volume of the facial nucleus was smaller in the SOD-1 mutant mice (45.7% difference from control mice) and correlated significantly with neuron number. The oculomotor and hypoglossal nuclei showed less extreme involvement (<10% neuronal loss overall), with a trend toward fewer neurons in the hypoglossal nucleus of animals with severe facial nucleus involvement. In the oculomotor nucleus, neuronal loss was seen only once in five mice, associated with very severe disease. There was no significant change in the volume of individual neurons in any of these three nuclei in any transgenic mouse. These results suggest that different brainstem motor nuclei are differentially affected in this SOD-1 mutant model of ALS. The relatively moderate and late involvement of the hypoglossal nucleus indicates that, although the general patterns of neuronal pathology match closely those seen in ALS patients, some differences exist in this transgenic model compared with the progression of the disease in humans. However, these patterns of cellular vulnerability may provide clues for understanding the differential susceptibility of neural structures in ALS and other neurodegenerative diseases.
TL;DR: Findings provide evidence that the p53 signaling pathway is activated in SOD1-linked familial ALS and may play a causative role in spinal cord neuron apoptosis by modulating the Bcl-x/Bax ratio.
TL;DR: The COX‐2 inhibitor (SC236) provided significant protection against loss of spinal motor neurons in this system, suggesting that it may be useful in the treatment of ALS.
Abstract: The pathogenesis of motor neuron loss in amyotrophic lateral sclerosis (ALS) is thought to involve both glutamate-mediated excitotoxicity and oxidative damage due to the accumulation of free radicals and other toxic molecules. Cyclooxygenase-2 (COX-2) may play a key role in these processes by producing prostaglandins, which trigger astrocytic glutamate release, and by inducing free radical formation. We tested the effects of COX-2 inhibition in an organotypic spinal cord culture model of ALS. The COX-2 inhibitor (SC236) provided significant protection against loss of spinal motor neurons in this system, suggesting that it may be useful in the treatment of ALS.