Showing papers on "Amyotrophic lateral sclerosis published in 1998"
TL;DR: Analysis of transgenic mice expressing familial amyotrophic lateral sclerosis (ALS)-linked mutations in the enzyme superoxide dismutase (SOD1) have shown that motor neuron death arises from a mutant-mediated toxic property or properties, raising the question of whether toxicity arises from superoxide-mediated oxidative stress.
Abstract: Analysis of transgenic mice expressing familial amyotrophic lateral sclerosis (ALS)-linked mutations in the enzyme superoxide dismutase (SOD1) have shown that motor neuron death arises from a mutant-mediated toxic property or properties. In testing the disease mechanism, both elimination and elevation of wild-type SOD1 were found to have no effect on mutant-mediated disease, which demonstrates that the use of SOD mimetics is unlikely to be an effective therapy and raises the question of whether toxicity arises from superoxide-mediated oxidative stress. Aggregates containing SOD1 were common to disease caused by different mutants, implying that coaggregation of an unidentified essential component or components or aberrant catalysis by misfolded mutants underlies a portion of mutant-mediated toxicity.
1,198 citations
TL;DR: The absence of massive motor neuron death at the early stages of the disease indicates that the majority of motor neurons could be rescued after clinical diagnosis, and indicates that mutant SOD1 toxicity is mediated by damage to mitochondria in motor neurons.
Abstract: Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. Mutations in Cu,Zn superoxide dismutase (SOD1) are one cause of the disease. Mice transgenic for mutated SOD1 develop symptoms and pathology similar to those in human ALS. To understand the disease mechanism, we developed a simple behavioral assay for disease progression in mice. Using this assay, we defined four stages of the disease in mice expressing G93A mutant SOD1. By studying mice with defined disease stages, we tied several pathological features into a coherent sequence of events leading to motor neuron death. We show that onset of the disease involves a sharp decline of muscle strength and a transient explosive increase in vacuoles derived from degenerating mitochondria, but little motor neuron death. Most motor neurons do not die until the terminal stage, approximately 9 weeks after disease onset. These results indicate that mutant SOD1 toxicity is mediated by damage to mitochondria in motor neurons, and this damage triggers the functional decline of motor neurons and the clinical onset of ALS. The absence of massive motor neuron death at the early stages of the disease indicates that the majority of motor neurons could be rescued after clinical diagnosis.
720 citations
TL;DR: It is suggested that the loss of EAAT2 in ALS is due to aberrant mRNA and that these aberrant mRNAs could result from RNA processing errors, and could be important in the pathophysiology of neurodegenerative disease and in excitotoxicity.
680 citations
TL;DR: It is hypothesized that astrocytic activation may exert a trophic influence on the motor neurons that is insufficiently maintained late in the course of the disease, and agents which inhibit microglia may help to limit disease progression.
Abstract: Transgenic mice that highly over-express a mutated human CuZn superoxide dismutase (SOD1) gene [gly93-->ala; TgN(SOD1-G93A)G1H line] found in some patients with familial ALS (FALS) have been shown to develop motor neuron disease that is characterized by motor neuron loss in the lumbar and cervical spinal regions and a progressive loss of motor activity. The mutant Cu,Zn SOD exhibits essentially normal SOD activity but also generates toxic oxygen radicals as a result of an enhancement of a normally minor peroxidase reaction. Consequently, lipid and protein oxidative damage to the spinal motor neurons occurs and is associated with disease onset and progression. In the present study, we investigated the time course of microglial (major histocompatibility-II antigen immunoreactivity) and astrocytic (glial fibrillary acidic protein immunoreactivity) activation in relation to the course of motor neuron disease in the TgN(SOD1-G93A)G1H FALS mice. Four ages were investigated: 30 days (pre-motor neuron pathology and clinical disease); 60 days (after initiation of pathology, but pre-disease); 100 days (approximately 50% loss of motor neurons and function); and 120 days (near complete hindlimb paralysis). Compared to non-transgenic littermates, the TgN(SOD1-G93A)G1H mice showed significantly increased numbers of activated astrocytes (P < 0.01) at 100 days of age in both the cervical and lumbar spinal cord regions. However, at 120 days of age, the activation lost statistical significance. In contrast, microglial activation was significantly increased several-fold at both 100 and 120 days. We hypothesize that astrocytic activation may exert a trophic influence on the motor neurons that is insufficiently maintained late in the course of the disease. On the other hand, the sustained, intense microglial activation may conceivably contribute to the oxidative stress and damage involved in the disease process. If true, then agents which inhibit microglia may help to limit disease progression.
529 citations
TL;DR: Increased modification of proteins by 4‐hydroxynoneal (HNE), a product of membrane lipid peroxidation, in the lumbar spinal cord of sporadic amyotrophic lateral sclerosis patients versus that of neurologically normal controls is reported.
Abstract: We report increased modification of proteins by 4-hydroxynonenal (HNE), a product of membrane lipid peroxidation, in the lumbar spinal cord of sporadic amyotrophic lateral sclerosis (ALS) patients versus that of neurologically normal controls. By immunohistochemistry, HNE-protein modification was detected in ventral horn motor neurons, and immunoprecipitation analysis revealed that one of the proteins modified by HNE was the astrocytic glutamate transporter EAAT2. Given that the function of proteins modified by HNE can be severely compromised as previously demonstrated for glutamate transporters in cortical synaptosome preparations, our findings suggest a scenario in which oxidative stress leads to the production of HNE, impairment of glutamate transport, and excitotoxic motor neuron degeneration in ALS.
374 citations
TL;DR: The results support the viewpoint that an impairment of mitochondria may be of pathophysiological significance in the etiology of amyotrophic lateral sclerosis.
255 citations
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04 Sep 1998
TL;DR: Clinical features and differential diagnosis of classical motor neurone disease, including autoimmune aspects of amyotrophic lateral sclerosis, and the management of the early case.
Abstract: Clinical features and differential diagnosis of classical motor neurone disease. Spinal muscular atrophies. The post-polio motor neurone disease. ALS.PD comples on Guam. Natural history. Neurophysiology. The management of the early case. Coping with the disability of established disease. Respiratory function in motor neurone disease. Nutritional support in motor neurone disease. Terminal care. What part can lay MND/ALS associations play in research. Classical pathology. Molecular patholgy: ubiquitin. Neurofilamentous pathology. Epidemiology. Familial motor neurone disease. Gene expression in motor neurone disease. Environmental/gentic interaction. Excitatory amino acids. Metals and free radicals in motor neurone disease. Autoimmune aspects of amyotrophic lateral sclerosis. Trophic factors. Chemical toxins. Viruses and motor neurone disease - the viral hypothesis lives. Neuropeptides - occurrence in motor nerves and relevance to motor neurone disease. Cell culture of motor neurons. Trials in MND.
254 citations
TL;DR: The classification of amyotrophic lateral sclerosis is reconsidered in the light of developments in the molecular pathogenesis and histopathology of the condition and the possibility is raised that they all represent syndromic manifestations of a similar pathogenetic cascade whose clinical phenotype depends upon the anatomical selectivity of involvement in each individual.
Abstract: The classification of amyotrophic lateral sclerosis (ALS) is reconsidered in the light of developments in the molecular pathogenesis and histopathology of the condition. A current view is encapsulated in the El Escorial World Federation of Neurology criteria for the diagnosis of ALS. While intended for research purposes, use of these criteria for entry into clinical trials may result in the exclusion of some patient groups with related disorders that are likely to share aetiological mechanisms but which are not classified as 'definite ALS' or 'probable ALS'. The relationship between ALS and the more restricted motor disorders of progressive lateral sclerosis and progressive muscular atrophy, together with cerebral degenerations including ALS-dementia and ALS-related frontal lobe dementia, are reviewed. The possibility is raised that they all represent syndromic manifestations of a similar pathogenetic cascade whose clinical phenotype depends upon the anatomical selectivity of involvement in each individual. The new evidence regarding the central role of oxidative stress and abnormal glutamatergic neurotransmission in familial and sporadic ALS seem applicable across these disorders. New evidence regarding the molecular pathology of inclusion bodies in these various syndromes, including ubiquitinated inclusions and hyaline conglomerate inclusions, shows striking similarities between them. Marked differences in the anatomical distribution of lesions determine the predominance and type of motor and cognitive features in each syndrome. This concept of a clinicopathological spectrum is potentially of equal relevance to other late onset neurodegenerative disorders including multisystem atrophies, the Lewy body disorders and various manifestations of Alzheimer's disease. It will gain increasing importance as therapies evolve from the symptomatic to those directed at underlying pathogenetic events.
241 citations
TL;DR: By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced.
Abstract: Mutations in superoxide dismutase 1 (SOD1), the only proven cause of amyotrophic lateral sclerosis (ALS), provoke disease through an unidentified toxic property. Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced. In NF-L-deleted animals, levels of the two remaining neurofilament subunits, NF-M and NF-H, are markedly reduced in axons but are elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments are essential for SOD1-mediated disease, the absence of assembled neurofilaments both diminishes selective vulnerability and slows SOD1G85R mutant-mediated toxicity to motor neurons.
240 citations
TL;DR: It is suggested that oxidative stress and lipid peroxidation are associated with and may promote motor neuron degeneration in sALS and that anti‐oxidants prevented this HNE‐dependent cell death.
Abstract: A marker of lipid peroxidation 4-hydroxynonenal (HNE) was elevated in the cerebrospinal fluid (CSF) of a patient with sporadic amyotrophic lateral sclerosis (sALS) compared with that of most patients with other neurological diseases. Such elevations of HNE were sufficient to kill cyclic adenosine monophosphate (cAMP)-differentiated motor neuron hybrid cells in vitro, and anti-oxidants prevented this HNE-dependent cell death. These data suggest that oxidative stress and lipid peroxidation are associated with and may promote motor neuron degeneration in sALS.
236 citations
TL;DR: Evidence is presented that the enzyme caspase-1 is activated in neurons expressing mutant SOD1 protein, and this activation is enhanced by oxidative challenge (Xanthine/xanthine oxidase), which triggers cleavage and secretion of the interleukin 1beta converting enzyme substrate, pro-interleuk in 1beta, and induces apoptosis.
Abstract: The mechanism by which mutations in the superoxide dismutase (SOD1) gene cause motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS) is unknown. Recent reports that neuronal death in SOD1-familial ALS is apoptotic have not documented activation of cell death genes. We present evidence that the enzyme caspase-1 is activated in neurons expressing mutant SOD1 protein. Proteolytic processing characteristic of caspase-1 activation is seen both in spinal cords of transgenic ALS mice and neurally differentiated neuroblastoma (line N2a) cells with SOD1 mutations. This activation of caspase-1 is enhanced by oxidative challenge (xanthine/xanthine oxidase), which triggers cleavage and secretion of the interleukin 1β converting enzyme substrate, pro-interleukin 1β, and induces apoptosis. This N2a culture system should be an instructive in vitro model for further investigation of the proapoptotic properties of mutant SOD1.
TL;DR: Genetic mapping studies of an 11-generation pedigree with an autosomal dominant, juvenile-onset motor-systems disease detect strong evidence for linkage of the ALS4 locus to markers from chromosome 9q34, and implicate a gene on chromosome 9Q34 as critical for motor-neuron function.
Abstract: Summary We performed genetic mapping studies of an 11-generation pedigree with an autosomal dominant, juvenile-onset motor-systems disease. The disorder is characterized by slow progression, distal limb amyotrophy, and pyramidal tract signs associated with severe loss of motor neurons in the brain stem and spinal cord. The gene for this disorder, classified as a form of juvenile amyotrophic lateral sclerosis (ALS), is designated "ALS4." We performed a genomewide search and detected strong evidence for linkage of the ALS4 locus to markers from chromosome 9q34. The highest LOD score ( Z ) was obtained with D9S1847 ( Z =18.8, recombination fraction of .00). An analysis of recombinant events identified D9S1831 and D9S164 as flanking markers, on chromosome 9q34, that define an ∼5-cM interval that harbors the ALS4 gene. These results extend the degree of heterogeneity within familial ALS syndromes, and they implicate a gene on chromosome 9q34 as critical for motor-neuron function.
TL;DR: A significant difference in the time to transit between the riluzole and the placebo groups in less severely affected cases was showed, ie, state 2 and state A (the milder states) of ALS.
Abstract: Background In an attempt to better understand and define the progression of amyotrophic lateral sclerosis (ALS), we developed a classification of 5 discrete health states that reflect patients' activities of daily living. These health states were used to determine whether patients with ALS who are treated with riluzole differed from those treated with placebo. Setting Clinics for patients with ALS. Design Placebo-controlled trial of riluzole treatment in 959 patients with ALS. Interventions Treatment with riluzole or placebo. Main Dependent Measures A Cox model was used to assess whether, from the initial randomization to the end of an 18-month follow-up, there was a difference in the times of transition into subsequent health states between patients treated with riluzole and those treated with placebo. Results Our analysis showed a significant difference in the time to transit between the riluzole and the placebo groups in less severely affected cases, ie, state 2 and state A (the milder states) of ALS. Conclusion Patients receiving riluzole remained in the milder health states longer ( P
TL;DR: Rec Recapitulation of defects previously observed in ALS subjects and ALS transgenic mice by expression of ALS mtDNA support a pathophysiologic role for mtDNA mutation in some persons with this disease.
TL;DR: In this article, N-acetylaspartate (NAA), a compound that is readily measured in vivo using proton magnetic resonance spectroscopy, can be used as a surrogate marker for neuronal loss or sub-lethal injury.
Abstract: Riluzole, a glutamate antagonist, has been shown to be efficacious in the treatment of patients with amyotrophic lateral sclerosis (ALS), allowing prolonged survival and time to tracheostomy. The efficacy of riluzole in thought to result from reduced glutamate excitotoxicity on motor neurons of patients with ALS, but this has never been demonstrated directly in vivo. N-acetylaspartate (NAA), a compound that is readily measured in vivo using proton magnetic resonance spectroscopy, can be used as a surrogate marker for neuronal loss or sublethal injury. To determine whether riluzole reverses sublethal corticomotoneuron damage in patients with ALS we measured NAA/creatine (Cr) relative intensity ratios in the motor cortex before and after treatment with riluzole 50 mg bid. After 3 weeks of riluzole therapy in 11 patients NAA/Cr increased from 2.14 +/- 0.26 to 2.27 +/- 0.24 (p = 0.044), whereas, in 12 untreated patients NAA/Cr decreased from 2.17 +/- 0.20 to 2.08 +/- 0.20 (p = 0.099). Thus the change in NAA/Cr between the treated and untreated groups was 0.22 +/- 0.095 (p = 0.008). The magnitude of increase in NAA/Cr in those treated was not correlated with age, sex, duration of treatment or disease, the presence of probable or definite upper motor neuron (UMN) signs, bulbar features, or pre-treatment NAA/Cr. We conclude that magnetic resonance spectroscopy can provide a novel surrogate measure of neuronal integrity that demonstrates reversal of sublethal UMN injury in patients with ALS within weeks of initiating riluzole therapy.
TL;DR: Riluzole was tested in a dose-ranging study for preservation of motor function in a transgenic mouse model of familial ALS, suggesting that riluzoles may have benefit for"quality-of-life" measures in ALS.
Abstract: Riluzole was tested in a dose-ranging study for preservation of motor function in a transgenic mouse model of familial ALS. The model is based on expression of mutant human Cu,Zn superoxide dismutase in mouse brain and spinal cord. In contrast with the human ALS trials, in the mouse model, riluzole significantly preserved motor function as assessed by nightly running in a wheel. The effect of riluzole on motor performance was greater earlier in disease than later, suggesting that riluzole may have benefit for "quality-of-life" measures in ALS. Treatment with riluzole was initiated earlier in the transgenic model than in the human ALS trials, which may account for the significantly better outcome.
TL;DR: Findings are consistent with the interpretation that motor axons of the patients with amyotrophic lateral sclerosis have a greater persistent Na+ conductance than normal motor axon, which could contribute to the ectopic activity responsible for fasciculation.
Abstract: In normal subjects, the strength-duration time constant is longer for cutaneous afferents than for motor axons, probably because the former express a greater non-inactivating (persistent) Na+ conductance that is active at threshold Using a threshold-tracking system the strength-duration properties of cutaneous afferents and motor axons were recorded from 23 patients with amyotrophic lateral sclerosis, and compared with those of 32 healthy subjects In control subjects and patients, the strength-duration time constant of sensory fibres declined with age, and there was no difference between the two groups when age was taken into account The motor time constant did not change with age when expressed as a percentage of the time constant for sensory fibres in the same nerve, but was significantly longer for the patients than control subjects In addition, motor rheobase was significantly lower for the patients, when expressed as a percentage of sensory rheobase There was an inverse relationship between the time constant and rheobase for sensory and motor axons, and this was the same for the patients and the control subjects, suggesting that the variations in time constant within and between the groups were related to the expression of a common factor Measurements of refractoriness and supernormality provided no evidence for a difference in resting membrane potential between the patients and control subjects These findings are consistent with the interpretation that motor axons of the patients with amyotrophic lateral sclerosis have a greater persistent Na+ conductance than normal motor axons This could contribute to the ectopic activity responsible for fasciculation
TL;DR: It is suggested that the possibility that the molecular pathology of neuronal inclusions in ALS indicates 2 distinct pathogenetic cascades is higher than previously thought.
Abstract: Molecular pathology has identified 2 distinct forms of neuronal inclusion body in Amyotrophic Lateral Sclerosis (ALS). ALS-type inclusions are skeins or small dense filamentous aggregates which can only be demonstrated by ubiquitin immunocytochemistry (ICC). In contrast hyaline conglomerates (HC) are large multifocal accumulations of neurofilaments. Previous reports have failed to clarify the distinction and relationship between these inclusions. Correlation of molecular pathology with sporadic and familial cases of ALS will detect specific associations between molecular lesions and defined genetic abnormalities; and determine the relevance of molecular events in familial cases to the pathogenesis of sporadic disease. We describe the molecular pathology of 5 ALS cases linked to abnormalities of the SOD1 gene, in comparison with a series of 73 sporadic cases in which SOD1-gene abnormalities were excluded. Hyaline conglomerate inclusions were detected only in the 2 cases with the SOD1 I113T mutation and showed a widespread multisystem distribution. In contrast ALS-type inclusions characterized sporadic cases (70/73) and were restricted to lower motor neurons. Hyaline conglomerates were not seen in sproadic cases. Confocal microscopic analysis and ICC shows that HC contain equally abundant phosphorylated and nonphosphorylated neurofilament epitopes, indicating that phosphorylation is not essential for their formation. In contrast neurofilament immunoreactivity is virtually absent from typical ALS-type inclusions. The SOD1-related cases all had marked corticospinal tract and dorsal column myelin loss. In 4 cases the motor cortex was normal or only minimally affected. This further illustrates the extent to which upper motor neuron damage in ALS is usually a distal axonopathy. Previously reported pathological accounts of SOD1-related familial ALS (FALS) are reviewed. Hyaline conglomerates are so far described in cases with mutations A4V, I113T and H48Q. In only 1 of 12 cases (H48Q) reported were both HC and ALS-type inclusions present in the same case. These findings suggest the possibility that the molecular pathology of neuronal inclusions in ALS indicates 2 distinct pathogenetic cascades.
TL;DR: The elevated IL- 6 in ALS may reflect an ongoing humoral immune response, or IL-6 may be non-specifically expressed in these patients as a putative neurotrophic factor in response to nerve cell degeneration.
TL;DR: The relationship of motor neuron disease to other conditions, including benign fasciculation, paraneoplastic syndromes, lymphoproliferative disease, radiation damage, monomelic amyotrophy, and multisystem disorders of the central nervous system are examined.
TL;DR: It seems likely that unknown factors linked to male sex predispose a proportion of patients to develop the flail arm phenotype, and this syndrome probably represents a variant of ALS.
Abstract: In a retrospective case note study of patients referred to a specialist clinic for motor neuron disorders we identified a subgroup of patients with severe wasting and weakness of the arms without significant functional involvement of other regions. This “flail arm syndrome” was identified in 39/395 (10%) of the subjects studied. Their clinical characteristics were compared with the amyotrophic lateral sclerosis (ALS) group as a whole. The age of onset was similar between the two groups but the male:female ratio was 9:1 in the flail arm group, compared with 1.5:1 in the ALS group (p=0.0015). Although there was a trend towards improved survival in the flail arm group (median survival 57 (95%CI 45–69) months) compared with the ALS group (39 (95%CI 35–43) months), this did not reach significance (p=0.204) and was not an independent prognostic factor. As many patients with flail arm syndrome develop upper motor neuron signs in the lower limbs this syndrome probably represents a variant of ALS. It seems likely that unknown factors linked to male sex predispose a proportion of patients to develop the flail arm phenotype.
Historically, physicians have categorised illnesses according to their clinical characteristics. As a result the adult sporadic motor neuron disease syndromes have been described according to the site of lesion onset. Most patients present with both upper and lower motor neuron signs in the limbs (classic motor neuron disease or ALS). Rarer forms of predominantly upper and lower motor neuron syndromes are also recognised (primary lateral sclerosis and progressive muscular atrophy respectively). We have noted that a subgroup of patients with classic ALS present with progressive wasting and weakness of the arms, with little or no functional impairment of the bulbar muscles …
TL;DR: Spectroscopic changes in the motor cortices of patients with ALS correspond with a reduction in Levels of NAA and an elevation in levels of choline and inositol compounds, so the release of these compounds may be related to membrane disorders.
Abstract: Objectives To determine the motor cortex degeneration in patients with amyotrophic lateral sclerosis (ALS) using proton magnetic resonance spectroscopy, and to prove that proton magnetic resonance spectroscopy is suited to monitor the course of disease with follow-up examinations Materials and Methods We studied 33 patients with ALS whose conditions were diagnosed according to the El Escorial World Federation of Neurology criteria Nine patients with ALS were followed up for up to 2 years The control group included 20 healthy volunteers and 4 patients with multifocal motor neuropathy Proton magnetic resonance spectroscopy determined levels of the brain metabolites N -acetylaspartate (NAA), choline, inositol-containing compounds, glutamate/glutamine, and phosphocreatine Results Patients with ALS showed a significant reduction in the NAA-choline ( P P P P P 1 and T 2 relaxation times were observed Patients with multifocal motor neuropathy showed normal metabolic ratios Progressive alterations in affected metabolite ratios could be documented in the follow-up examinations Conclusions Spectroscopic changes in the motor cortices of patients with ALS correspond with a reduction in levels of NAA and an elevation in levels of choline and inositol compounds Since NAA is exclusively expressed in neurons, the observed decrease of NAA reflects neuronal loss or dysfunction Inositol and choline are associated with plasma membrane metabolism, so the release of these compounds may be related to membrane disorders
TL;DR: Current diagnostic criteria for ALS, requiring clinical evidence for both upper and lower motor neuron involvement, should be modified; ie, the diagnosis should be deemed established when there is evidence of denervation in three or more limbs and a mutation in the gene for SOD1, even without clinical signs of UMN involvement.
Abstract: We examined 11 subjects with inherited amyotrophic lateral sclerosis (familial amyotrophic lateral sclerosis, FALS) associated with the most common copper/zinc superoxide dismutase 1 (SOD1) mutation, an alanine for valine substitution in codon 4 (A4V) Autopsies were performed on 5 subjects The clinical and pathological findings are described and compared with those of 9 sporadic ALS (SALS) subjects There was no clinical evidence of upper motor neuron (UMN) involvement in 10 FALS A4V subjects All subjects had lower motor neuron (LMN) signs and electrophysiological evidence of denervation in at least three limbs All SALS subjects had signs of both UMN and LMN involvement Pathological studies found severe abnormalities of LMNs in all FALS and SALS subjects UMN involvement was either absent or mild in the A4V SOD1 FALS subjects and severe in the SALS subjects Pathological abnormalities in systems other than the motor neurons were more frequent in the FALS A4V subjects This information suggests that current diagnostic criteria for ALS, requiring dinical evidence for both upper and lower motor neuron involvement, should be modified; ie, the diagnosis should be deemed established when there is evidence of denervation in three or more limbs and a mutation in the gene for SOD1, even without dinical signs of UMN involvement
TL;DR: By combining neurochemical and anatomic correlates of vulnerability, an integrated view of vulnerable neurons is emerging in which characteristics of vulnerability neurons appear to transcend both brain region and disease state, suggesting that neurodegenerative disorders share common mechanisms of degeneration.
Abstract: Selective neuronal vulnerability can be defined anatomically by the differential vulnerability of circuits and neurochemically by the vulnerability of neurons that differentially express particular proteins. The anatomic perspective is exemplified by the vulnerability of the nigrostriatal projection in Parkinson's disease (PD), the degeneration of upper and lower motor neurons in amyotrophic lateral sclerosis (ALS), and the preferential loss of long corticocortical projections in Alzheimer's disease (AD). The neurochemical perspective is reflected in the heightened vulnerability of neurons that normally express high somatodendritic levels of neurofilament (eg, entorhinal and association cortices in AD, the spinal cord in a mouse model of ALS, and the retina in a primate model of glaucoma), as well as the reduced vulnerability of neurons that express calcium-binding proteins (eg, neocortex of AD patients, the spinal cord and brainstem of ALS patients, and the spinal cord of a mouse model of ALS). By combining neurochemical and anatomic correlates of vulnerability, an integrated view of vulnerable neurons is emerging in which characteristics of vulnerable neurons appear to transcend both brain region and disease state, suggesting that neurodegenerative disorders share common mechanisms of degeneration.
TL;DR: It is suggested that anterogradely transported mutant SOD1 may act locally to damage motor axons of the sciatic nerve.
TL;DR: Individual electrical occupations were associated more strongly with disease than overall electrical occupations, particularly amyotrophic lateral sclerosis, for which relative risks ranged from 2 to 5 across several job categories.
Abstract: Investigators have hypothesized that occupations involving electric and magnetic field exposure are associated with a variety of health problems, including neurological disease. The authors conducted a case-control study, and they used U.S. death certificates with occupational coding to compare male cases of Alzheimer's disease (n = 256), Parkinson's disease (n = 168), and amyotrophic lateral sclerosis (n = 114) with controls matched for age and calendar time. The authors selected controls in a 3:1 ratio to cases from persons who died of causes other than leukemia, brain cancer, and breast cancer. Overall associations with electrical occupations were modest (i.e., adjusted odds ratios of 1.2, 1.1, and 1.3 for Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, respectively). Individual electrical occupations were associated more strongly with disease than overall electrical occupations, particularly amyotrophic lateral sclerosis, for which relative risks ranged from 2 to 5 across several job categories. The largest associations with all three diseases occurred for power plant operators.
TL;DR: Stable fasciculations, representing part of large, reinnervated motor units, and probably arising from distal axonal sprouts, usually had a higher firing rate than more complex and unstable fasciculation, and were generally more unstable than in other neurogenic disorders.
Abstract: We studied fasciculation potentials in amyotrophic lateral sclerosis (ALS), and in other neurogenic disorders, in strength and single-fiber electromyography-matched muscles. Benign fasciculations were studied in 3 normal subjects. Fasciculations were more stable and easier to recruit voluntarily in the early phase of ALS; later, fasciculations were more unstable, more complex, and less likely to be voluntarily recruited. Stable fasciculations, representing part of large, reinnervated motor units, and probably arising from distal axonal sprouts, usually had a higher firing rate than more complex and unstable fasciculations. In weak muscles in ALS, fasciculations were generally more unstable than in other neurogenic disorders. In normal-strength muscles fasciculations are less complex in ALS than in other disorders. Benign fasciculations have a high firing rate and normal morphologic parameters. In ALS fasciculations arise proximally early in the disease and distally in the later stages. Fasciculation may be important in excitotoxic cell death in ALS.
TL;DR: The identical timing of motor neuron and interneuron degeneration in this model of ALS strongly suggests that degenerationIn the spinal cord of patients with ALS is not specifically directed at motor neurons, but rather more generally at several populations of neurons in the spinal Cord.
Abstract: Transgenic mice with a G86R mutation in the mouse superoxide dismutase (SOD-1) gene, which corresponds to a mutation observed in familial amyotrophic lateral sclerosis (ALS), display progressive motor dysfunction leading to paralysis and premature death. In endstage SOD-1 transgenic mice, there is marked loss of spinal motor neurons and interneurons, accumulation of phosphorylated neurofilament inclusions, and reactive astrocytosis. The present study details the time course and ultrastructural appearance of these pathologic changes and correlates the timing of these events with the behavioral symptoms. There is no significant reduction in the number of total neurons, motor neurons, or interneurons in the ventral spinal cord of presymptomatic mice, as compared to age-matched control mice. In contrast, there is a significant reduction in the number of total neurons (−23.5%), motor neurons (-28.9%), and interneurons (-23.5%) in symptomatic SOD-1 transgenic mice. This neuron loss correlates temporally with the onset of reactive astrocytosis and the appearance of phosphorylated neurofilament inclusions. The identical timing of motor neuron and interneuron degeneration in this model of ALS strongly suggests that degeneration in the spinal cord of patients with ALS is not specifically directed at motor neurons, but rather more generally at several populations of neurons in the spinal cord. In addition, the late onset and rapid progression of neuron loss suggest that a toxic property is accumulating while the SOD-1 transgenic mice are presymptomatic, and that this toxic property must reach a threshold level before the onset of neuronal degeneration. J. Comp. Neurol. 391:64–77, 1998. © 1998 Wiley-Liss, Inc.
TL;DR: The results suggest that LMN loss appears to be the primary cause of progressive weakness in ALS; while UMN impairment in ALS leads to slowing of contraction speed and rapid movements, and modest decreases in central activation.
Abstract: The objective of this study was to examine the contribution of lower motor neuron (LMN) and upper motor neuron (UMN) dysfunction to weakness and impaired motor control in 27 patients with amyotrophic lateral sclerosis (ALS). Isometric strength was measured by dorsiflexor maximum voluntary contraction force (MVC). LMN function was measured by tetanic force, twitch force, and the amplitude of the compound muscle action potential. UMN function was measured by the speed of rapid foot taps, the maximum rate of rise of voluntary force, and the central activation ratio [CAR = MVC/(MVC + superimposed tetanic force)]. The results suggest that (1) LMN loss appears to be the primary cause of progressive weakness in ALS; while (2) UMN impairment in ALS leads to slowing of contraction speed and rapid movements, and modest decreases in central activation; and (3) during 6 months of progression, LMN changes were greater than UMN changes.
TL;DR: The World Federation of Neurology diagnostic criteria for ALS was modified and used for enrollment of ALS patients in a clinical trial and the diagnosis of ALS was believed to be accurate in those patients entered in the trial.
Abstract: We modified the World Federation of Neurology (WFN) diagnostic criteria for ALS to facilitate early diagnosis and used these criteria for enrollment of ALS patients in a clinical trial. The criteria developed required lower motor neuron (LMN) involvement in at least two limbs and upper motor neuron involvement in at least one region (bulbar, cervical, or lumbosacral). The EMG finding of fibrillation potentials was required for evidence of LMN involvement. Electrodiagnostic studies, neuroimaging, and laboratory studies were also used to exclude disorders that might mimic ALS. Using these criteria, the diagnosis of ALS was made at a mean time of 9.7 months from onset of symptoms, which compares favorably with the 12-month period cited in the literature. Using clinical assessment at completion of the trial, the diagnosis of ALS was believed to be accurate in those patients entered in the trial. However, pathologic confirmation of the diagnosis of ALS was not obtained. Based on our preliminary experience, we propose that these ALS diagnostic criteria will facilitate early diagnosis of ALS. Future studies should prospectively compare these criteria with the WFN criteria currently in use.