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Showing papers on "Amyotrophic lateral sclerosis published in 1996"


Journal ArticleDOI
TL;DR: The creation and characterization of mice completely deficient for SOD1 indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.
Abstract: The discovery that some cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) has focused much attention on the function of SOD1 as related to motor neuron survival. Here we describe the creation and characterization of mice completely deficient for this enzyme. These animals develop normally and show no overt motor deficits by 6 months in age. Histological examination of the spinal cord reveals no signs of pathology in animals 4 months in age. However Cu/Zn SOD-deficient mice exhibit marked vulnerability to motor neuron loss after axonal injury. These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.

1,305 citations


Journal ArticleDOI
TL;DR: A double-blind, placebo-controlled, multicentre study to confirm that riluzole is well tolerated and lengthens survival of patients with ALS and suggests that the 100 mg dose of rILuzole has the best benefit-to-risk ratio.

1,178 citations


Journal ArticleDOI
TL;DR: The hypothesis that oxidative damage produced by the expression of mutant Cu,Zn SOD causes slow or weak excitotoxicity that can be inhibited in part by altering glutamate release or biosynthesis presynaptically is suggested.
Abstract: Familial amyotrophic lateral sclerosis (FALS) has been linked in some families to dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase (Cu,ZnSOD). We have used a transgenic model of FALS based on expression of mutant human Cu,ZnSOD to explore the etiology and therapy of the genetic disease. Expression of mutant, but not wild-type, human Cu,ZnSOD in mice places the brain and spinal cord under oxidative stress. This causes depletion of vitamin E, rather than the typical age-dependent increase in vitamin E content as occurs in nontransgenic mice and in mice expressing wild-type human Cu,ZnSOD. Dietary supplementation with vitamin E delays onset of clinical disease and slows progression in the transgenic model but does not prolong survival. In contrast, two putative inhibitors of the glutamatergic system, riluzole and gabapentin, prolong survival. However, riluzole did not delay disease onset. Thus, there was clear separation of effects on onset, progression, and survival by the three therapeutics tested. This suggests the hypothesis that oxidative damage produced by the expression of mutant Cu,ZnSOD causes slow or weak excitotoxicity that can be inhibited in part by alerting glutamate release or biosynthesis presynaptically.

684 citations


Journal ArticleDOI
01 Dec 1996-Brain
TL;DR: This study demonstrates that progressive cerebral atrophy can be detected in individual patients with multiple sclerosis, correlates with worsening disability and gives additional information to that obtained with conventional MRI.
Abstract: Recent studies of the spinal cord and cerebellum have highlighted the importance of atrophy in the development of neurological impairment in multiple sclerosis. We have therefore developed a technique to quantify the volume of another area commonly involved pathologically in multiple sclerosis: the cerebral white matter. The technique we describe extracts the brain from the skull on four contiguous 5 mm periventricular slices using an algorithm integrated in an image analysis package, and quantifies their volume. Intra-observer scan-rescan reproducibility was 0.56%. We have applied this technique serially to 29 patients with multiple sclerosis selected for an 18-month treatment trial with a monoclonal antibody against CD4+ lymphocytes (deemed clinically ineffective). A decrease in volume beyond the 95% confidence limits for measurement variation was seen in 16 patients by the end of the 18-month period. The rate of development of atrophy was significantly higher in those who had a sustained deterioration in their Kurtzke expanded disability status scale (EDSS) score compared with those who did not (respective means: -6.4 ml year-1 and -1.8 ml year-1, P < 0.05) but in both groups these changes differed significantly from baseline (P < 0.05). Baseline T2 lesion load, change in T2 lesion load over 18 months and the volume of new gadolinium enhancing lesions on monthly scans for the first 10 months showed no correlation with the development of atrophy. This study demonstrates that progressive cerebral atrophy can be detected in individual patients with multiple sclerosis, correlates with worsening disability and gives additional information to that obtained with conventional MRI. The effect of putative therapies aimed at preventing disability could be objectively assessed by this measure.

481 citations


Journal ArticleDOI
TL;DR: Comparison studies revealed a striking similarity between the cytoskeletal pathology in the G1H transgenic mice and in patients with amyotrophic lateral sclerosis, linking a specific SOD1 mutation with alterations in the neuronal cytoskeleton of patients with Amyotrophicateral sclerosis.
Abstract: Mutations in the human Cu,Zn superoxide dismutase gene (SOD1) are found in 20% of kindreds with familial amyotrophic lateral sclerosis. Transgenic mice (line G1H) expressing a human SOD1 containing a mutation of Gly-93 --> Ala (G93A) develop a motor neuron disease similar to familial amyotrophic lateral sclerosis, but transgenic mice (line N1029) expressing a wild-type human SOD1 transgene do not. Because neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of amyotrophic lateral sclerosis, we asked whether mutant G1H and/or N1029 mice develop similar NF lesions. NF inclusions (i.e., spheroids, Lewy body-like inclusions) were first detected in spinal cord motor neurons of the G1H mice at 82 days of age about the time these mice first showed clinical evidence of disease. Other neuronal intermediate filament proteins (alpha-internexin, peripherin) also accumulated in these spheroids. The onset of accumulations of ubiquitin immunoreactivity in the G1H mice paralleled the emergence of vacuoles and NF-rich spheroids in neurons, but they did not colocalize exclusively with spheroids. In contrast, NF inclusions were not seen in the N1029 mice until they were 132 days old, and ubiquitin immunoreactivity was not increased in the N1029 mice even at 199 days of age. Astrocytosis in spinal cord was associated with a marked increase in glial fibrillary acidic protein immunoreactivity in the G1H mice, but not in the N1029 mice. Finally, comparative studies revealed a striking similarity between the cytoskeletal pathology in the G1H transgenic mice and in patients with amyotrophic lateral sclerosis. These findings link a specific SOD1 mutation with alterations in the neuronal cytoskeleton of patients with amyotrophic lateral sclerosis. Thus, neuronal cytoskeletal abnormalities may be implicated in the pathogenesis of human familial amyotrophic lateral sclerosis.

399 citations


Journal ArticleDOI
TL;DR: Results provide the first demonstration that neuronal calcium is, in fact, increased in amyotrophic lateral sclerosis in vivo, without exhibiting excess Schwann envelopment specific to denervating terminals.
Abstract: Numerous studies of amyotrophic lateral sclerosis have suggested that increased intracellular calcium is a common denominator in motoneuron injury. In experimental models, IgG from patients with amyotrophic lateral sclerosis enhanced calcium entry and induced apoptotic cell death in vitro as well as increased intracellular calcium and induced ultrastructural alterations of the motor nerve terminals in mice in vivo. To determine whether similar increases in intracellular calcium and altered morphology are present in motor nerve terminals of amyotrophic lateral sclerosis patients in vivo, muscle biopsy specimens from 7 patients with amyotrophic lateral sclerosis, 10 nondenervating disease control subjects, and 5 patients with denervating neuropathies were analyzed with ultrastructural techniques, employing oxalate-pyroantimonate fixation to preserve in situ calcium distribution. Motor nerve terminals from amyotrophic lateral sclerosis specimens contained significantly increased calcium, increased mitochondrial volume, and increased numbers of synaptic vesicles compared to any of the disease control groups, without exhibiting excess Schwann envelopment specific to denervating terminals. These results parallel the effect of amyotrophic lateral sclerosis IgG passively transferred to mice, and provide the first demonstration that neuronal calcium is, in fact, increased in amyotrophic lateral sclerosis in vivo.

317 citations


Journal ArticleDOI
TL;DR: It is concluded that ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake rather than the consumption of high-protein nutritional supplements.

274 citations


Journal ArticleDOI
01 Aug 1996-Brain
TL;DR: Electrophysiological studies confirmed the slow progression and spatial distribution of clinical symptoms in the peripheral motor system and marked slowing of transmission in central motor pathways in ALS patients homozygous for an Asp90Ala mutation.
Abstract: We describe 36 patients (six were apparently sporadic cases and 30 were cases from nine families) with amyotrophic lateral sclerosis (ALS) characterized by a distinct phenotype associated with homozygosity for an Asp90Ala mutation in the CuZn-superoxide dismutase gene. The presenting motor manifestation in all patients was paresis in the legs, with slow progression to the upper extremities and finally to the bulbar muscles. The age of ALS onset varied from 20 to 94 years, with a mean of 44 years. Mean survival time was 13 years for the 11 deceased patients. However, this is probably biased and untypical (low) when compared with the disease duration in the surviving patients, and when considering other medical complications in the deceased patients. The rate of progression was highly variable, even within families. All patients showed signs of involvement of both upper and lower motor neurons. Other neurological features included painful muscle spasms and paraesthesiae in the lower extremities. Two-thirds of patients experienced difficulty with micturition. Electrophysiological studies confirmed the slow progression and spatial distribution of clinical symptoms in the peripheral motor system. Furthermore, [corrected] potentials evoked by transcranial magnetic stimulation (MEP) were compared with those evoked by cervical or lumbosacral electrical stimulation and often revealed marked slowing of transmission in central motor pathways. In Sweden and Finland ALS patients homozygous for the Asp90Ala mutation constitute a phenotypically characteristic subset of motor neuron disease.

267 citations


Journal ArticleDOI
TL;DR: Neither the conventional wisdom that cognition is intact in nearly all patients with amyotrophic lateral sclerosis, nor more recent suggestions that Cognition is often at least mildly impaired seems to be correct.
Abstract: OBJECTIVE: To determine the prevalence and correlates of neuropsychological impairment in a large cohort (n = 146) of patients with typical, sporadic (non-familial) amyotrophic lateral sclerosis. METHODS: A battery of neuropsychological tests was administered to patients with amyotrophic lateral sclerosis who were attending a monthly outpatient clinic or who were in hospital undergoing diagnostic tests. RESULTS: Comparing individual patient's scores with relevant normative data, 35.6% of the patients displayed evidence of clinically significant impairment, performing at or below the 5th percentile on at least two of the eight neuropsychological measures. Deficits were most common in the areas of problem solving, attention/mental control, continuous visual recognition memory, word generation, and verbal free recall. Impairment was most prevalent in patients with dysarthria (48.5%), but 27.4% of non-dysarthric patients were also impaired. Impaired patients had more severe or widespread symptoms of amyotrophic lateral sclerosis than non-impaired patients, and had fewer years of education. CONCLUSION: Neither the conventional wisdom that cognition is intact in nearly all patients with amyotrophic lateral sclerosis, nor more recent suggestions that cognition is often at least mildly impaired seems to be correct. A minority of patients with amyotrophic lateral sclerosis displayed evidence of significant impairment. Dysarthria, low education, and greater severity of motor symptoms were risk factors for impairment.

257 citations


Journal ArticleDOI
TL;DR: It is shown that spinal cord motor neurons of transgenic mice for an SOD1 mutation display a lesion of the Golgi apparatus identical to that found in humans with sporadic ALS.
Abstract: Dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase have been found in members of certain families with familial amyotrophic lateral sclerosis (ALS). To better understand the contribution of SOD1 mutations in the pathogenesis of familial ALS, we developed transgenic mice expressing one of the mutations found in familial ALS. These animals display clinical and pathological features closely resembling human ALS. Early changes observed in these animals were intra-axonal and dendritic vacuoles due to dilatation of the endoplasmic reticulum and vacuolar degeneration of mitochondria. We have reported that the Golgi apparatus of spinal cord motor neurons in patients with sporadic ALS is fragmented and atrophic. In this study we show that spinal cord motor neurons of transgenic mice for an SOD1 mutation display a lesion of the Golgi apparatus identical to that found in humans with sporadic ALS. In these mice, the stacks of the cisternae of the fragmented Golgi apparatus are shorter than in the normal organelle, and there is a reduction in Golgi-associated vesicles and adjacent cisternae of the rough endoplasmic reticulum. Furthermore, the fragmentation of the Golgi apparatus occurs in an early, presymptomatic stage and usually precedes the development of the vacuolar changes. Transgenic mice overexpressing the wild-type human superoxide dismutase are normal. In familial ALS, an early lesion of the Golgi apparatus of motor neurons may have adverse functional effects, because newly synthesized proteins destined for fast axoplasmic transport pass through the Golgi apparatus.

243 citations


Journal ArticleDOI
TL;DR: These studies suggest that the dramatic abnormalities in EAAT2 may be due to translational or post‐ translational processes.
Abstract: Glutamate transport is critical for synaptic inactivation of glutamate and prevention of excitotoxicity The following four glutamate transporters have been identified in human brain: EAAT1, EAAT2, EAAT3, and EAAT4 Deficient glutamate transport has been identified in the motor cortex and the spinal cord of tissue from amyotrophic lateral sclerosis (ALS) patients The defect appears to be due to a selective loss of the astroglial specific glutamate transporter protein EAAT2 In these studies we sought to extend our understanding of glutamate transporters in ALS by examining the mRNA for each transporter subtype in ALS motor cortex All tissue was matched for age and postmortem delay There was no quantitative change in mRNA for EAAT1, EAAT2, or EAAT3 in ALS motor cortex, even in patients with a large loss of EAAT2 protein (95% decrease compared with control) and decreased tissue glutamate transport (73% decrease compared with control) These studies suggest that the dramatic abnormalities in EAAT2 may be due to translational or post-translational processes

Journal ArticleDOI
TL;DR: It is reported that the coexistence of an Ile113 → Thr substitution in exon 4 of the SOD1 gene and marked neurofilamentous pathology in the same FALS patient suggest that two mechanisms, SOD 1‐induced toxicity and neurofilaments disruption, are acting together.
Abstract: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are found in 15 to 20% of patients with familial amyotrophic lateral sclerosis (FALS). Increased levels of neurofilament subunits in transgenic mouse models of ALS also suggests a key role for these proteins in the pathogenesis of the disease. We report the coexistence of an Ile113-->Thr substitution in exon 4 of the SOD1 gene and marked neurofilamentous pathology in the same FALS patient. These observations suggest that two mechanisms, SOD1-induced toxicity and neurofilament disruption, are acting together.

Book ChapterDOI
TL;DR: The nosological status of FLD-MND remains enigmatic in the absence of defined pathological and molecular markers, whereas others suggest it represents an interface between FLD and "classic" (non-dementing) motor neuron disease (CMND).
Abstract: Frontal lobe dementia (FLD) (syn frontotemporal dementia and dementia of frontal type) is a generic term that describes a clinical syndrome in which patients manifest a profound breakdown in personality and social conduct, together with adynamic spontaneous speech, culminating in mutism This pattern of cognitive impairment implicates bilateral frontal lobe dysfunction, an assumption supported by functional neuroimaging findings of anterior cerebral abnormality Patients with FLD can go on to develop motor neuron disease (FLD-MND), although the clinical features of MND may accompany or occasionally precede the onset of dementia The emergence of MND is responsible for death within 3 years of onset Frontotemporal lobar pathology in FLD-MND is characterized by loss of large cortical neurons, spongiform change and mild astrocytic gliosis Ubiquitinated (but not tau-positive) inclusions are present within the frontal cortex There is severe nigral cell loss (without Lewy bodies), and marked hypoglossal and spinal motor neuron degeneration, together with ubiquitinated (but not tau-positive) inclusions within the spinal neurons Some authors suggest that FLD-MND is a separate disease entity, whereas others suggest it represents an interface between FLD and "classic" (non-dementing) motor neuron disease (CMND) An association with CMND is supported by findings in these patients of failure in tasks sensitive to "frontal lobe" dysfunction, and patterns of functional neuroimaging abnormality which are identical in distribution, but less severe than those encountered in FLD-MND However, the nosological status of FLD-MND remains enigmatic in the absence of defined pathological and molecular markers

Journal ArticleDOI
TL;DR: The finding of intraneuronal ubiquitin-immunoreactive inclusions characteristic of motor neurone disease in patients with frontotemporal dementia, without clinical or pathological evidence of motor system degeneration, extends the clinical spectrum of diseases associated with such inclusions.

Journal ArticleDOI
TL;DR: Peristimulus time histograms of discharging single motor units, recorded from the extensor digitorum communis during randomly applied cortical magnetic stimulation, were obtained in 42 normal subjects and 42 patients with amyotrophic lateral sclerosis, finding an early period of increased firing probability occurring at about 20 msec poststimulus.
Abstract: Peristimulus time histograms (PSTHs) of discharging single motor units, recorded from the extensor digitorum communis (EDC) during randomly applied cortical magnetic stimulation, were obtained in 42 normal subjects aged 24 to 83 years and 42 patients with amyotrophic lateral sclerosis (ALS) aged 37 to 84 years. Normal subjects had an early period of increased firing probability occurring at about 20 msec poststimulus, reflecting an underlying compound excitatory postsynaptic potential (EPSP) induced by fast-conducting, descending volleys of the corticomotoneuronal core facilitating the single spinal motoneuron. There was an age-dependent, linear decline in the amplitude of the EPSP (r = 0.673). We estimated that by age 50 years about 35% of corticomotoneurons are lost or nonfunctioning in normal controls. Compared with age-matched controls, the EPSP in most patients with ALS was reduced, and it was unmeasurable in six. We postulate this reflects a loss of corticomotoneurons. Seven (16.7%) patients phenotypically the same as the others had EPSPs that were larger than age-predicted values. This may reflect glutamate-induced excitotoxicity in a subset of ALS. In a single patient with chronic spinal muscular atrophy the EPSP was normal.

Journal ArticleDOI
TL;DR: Investigations suggest that mutant SOD1 acts through a toxic gain of function which may involve generation of free radicals and to the pathogenesis of ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by degeneration of motor neurons in the brain and spinal cord. Identification of mutations in the gene for Cu,Zn superoxide dismutase (SOD1) in a subset of ALS families made it possible to develop a transgenic mouse model of ALS and to investigate its pathogenesis. These investigations suggest that mutant SOD1 acts through a toxic gain of function which may involve generation of free radicals. Conformational change in the mutant SOD1 protein, especially the distortion of the 'rim' of the electrostatic guidance channel may be central to this toxic gain of function and to the pathogenesis of ALS.

Journal ArticleDOI
01 Oct 1996-Drugs
TL;DR: Riluzole, a benzothiazole, affects neurons by three mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitator amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels as mentioned in this paper.
Abstract: Riluzole, a benzothiazole, affects neurons by 3 mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitatory amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels. It has demonstrated neuroprotective activity in vivo and in vitro. Results from 2 randomised double-blind placebo-controlled trials in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) have demonstrated that riluzole can extend survival and/or time to tracheostomy. After 18 months, the relative risk of death or tracheostomy with riluzole 100 mg/day was reduced by 21%. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second, larger trial. Riluzole had no effect on any other functional or secondary variable. Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. Elevated alanine aminotransferase levels were observed in 10.6 versus 3.8% of patients treated with riluzole 100 mg/day versus placebo, leading to treatment withdrawal in 3.8 versus 2.1% of patients. In conclusion, riluzole is the first drug that has been shown to have an effect on survival in patients with ALS. Although the effect of riluzole was modest, it has allowed some insight into the pathogenesis of ALS from which future gains may be made.

Journal ArticleDOI
TL;DR: The present findings favor a scenario in which this mode of cell death would contribute to spinal cord motor neuron degeneration in ALS.
Abstract: One of the primary neurodegenerative events occurring in amyotrophic lateral sclerosis (ALS) is the selective loss of spinal cord α motor neurons. To study the potential role of apoptosis in the degeneration of these motor neurons, in situ hybridization was used to measure the expression of two apoptotic cell death genes, bcl-2 and bax, in control and ALS lumbar spinal cord sections. The strongest hybridization signal for bcl-2 mRNA in neurological and nonneurological control spinal cords was found primarily in lamina IX α motor neurons, while a weaker hybridization signal was found in neurons of Clarke's nucleus and the proper sensory nucleus of the dorsal horn. Surviving lamina IX motor neurons in ALS spinal cord sections also expressed bcl-2 mRNA, but at levels that were significantly and selectively decreased (4.7-fold) compared with controls. bax mRNA hybridization signal was detected in several cells throughout the gray matter in control and ALS lumbar spinal cord, but was significantly and selectively increased (2.8-fold) in ALS motor neurons. Given the proposed interactive roles of these genes in apoptosis, the present findings favor a scenario in which this mode of cell death would contribute to spinal cord motor neuron degeneration in ALS.

Journal ArticleDOI
TL;DR: These findings suggest a direct link between oxidative stress and the development of a neurodegenerative disease.

Journal ArticleDOI
01 Sep 1996-Chest
TL;DR: Sleep-disordered breathing occurs in patients with ALS and is similar to patients without ALS with respiratory muscle weakness, and one potential reason for its absence might be the inability of patients with respiratory Muscle weakness to generate an inspiratory pressure greater than the upper airway closing pressure.

Journal ArticleDOI
TL;DR: Almost all patients showed upper limbs weakness and diaphragm involvement; few patients had bulbar dysfunction; the prognosis of these patients is not always in permanent ventilator dependence.

Journal ArticleDOI
TL;DR: It is shown that FALSG93A mice suffer from motoneurone dysfunction similar to that observed in ALS patients and fulfill Lambert's criteria for ALS, and a massive loss of functional motor units starting at 47 days of age.
Abstract: Dominant mutations of human Cu/Zn superoxide dismutase (SOD1) are found in about 20% of patients with familial amyotrophic lateral sclerosis (FALS). A transgenic mouse model of FALS (FALSG93A mice) has been generated by overexpression of a mutated form of SOD1. Using electromyography we first show that FALSG93A mice suffer from motoneurone dysfunction similar to that observed in ALS patients and fulfill Lambert's criteria for ALS. We also showed that FALSG93A mice demonstrate a massive loss of functional motor units starting at 47 days of age. Impairment of motor neurone function preceeds by 6 weeks the onset of apparent clinical signs (shaking, tremor) and the beginning of motor neurone loss. Neuromuscular deficits in FALS mice do not result from motoneuronal cell death but rather from loss of axonal integrity.

Journal ArticleDOI
TL;DR: The results suggest that reactive oxygen species may attack the mitochondrial respiratory chain, leading eventually to the degeneration of vulnerable motor neurons in the spinal cord, even though no obvious changes in the activity of antioxidant enzymes are detectable.
Abstract: The cause of selective degeneration of motor neurons in the ventral horn of the spinal cord associated with amyotrophic lateral sclerosis (ALS) has still not been elucidated. Recently, so-called oxidative stress has been suggested to be a significant factor in the pathogenesis of this disease. We measured the antioxidant actions of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and cytochrome c oxidase (CO) of the human spinal cord in patients with ALS in comparison with those in control patients. Total SOD activity in spinal cord transections from patients with sporadic ALS was not significantly different from the controls in ventral, lateral, or dorsal regions, although enzymic activity was relatively higher in the ventral compared with the dorsal region. GSH-Px activity in the spinal cord of ALS patients was not very different from that in the control tissue. In contrast, CO activity was significantly reduced in all three regions of the spinal cord in patients with ALS, although the reduction was more marked in the ventral region. These results suggest that reactive oxygen species may attack the mitochondrial respiratory chain, leading eventually to the degeneration of vulnerable motor neurons in the spinal cord, even though no obvious changes in the activity of antioxidant enzymes are detectable. © 1996 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: Two families with ALS and one apparently sporadic ALS patient who are heterozygous for the D90A mutation are described, and one patient had the unusual phenotype of focal nonprogressing motor neuron disease.
Abstract: All mutations in the SOD1 gene associated with familial ALS behave as dominant traits. One mutation, however, giving rise to an aspartic acid to alanine substitution in codon 90 (D90A), was reported only to induce motor neuron disease in homozygous individuals in the Scandinavian population. We describe two families with ALS and one apparently sporadic ALS patient who are heterozygous for the D90A mutation. One patient had the unusual phenotype of focal nonprogressing motor neuron disease.

Journal ArticleDOI
TL;DR: Critical analysis of the findings indicates a truly multisystem disorder in which ascending sensory pathways and components of the efferent cerebellar pathways are at least as severely affected as the motor system.
Abstract: Detailed molecular pathology studies and clinicopathological phenotyping of familial amyotrophic lateral sclerosis (FALS) with characterised mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) will yield important insights into the pathogenesis of motor neuron degeneration. An autopsy case is described with the mutation E100G (exon 4) of the SOD1 gene in which full neuropathological examination including immunocytochemistry of ubiquitin and neurofilament epitopes was performed. The case falls into the category of "amyotrophic lateral sclerosis (ALS) with posterior column involvement." Critical analysis of the findings indicates a truly multisystem disorder in which ascending sensory pathways and components of the efferent cerebellar pathways are at least as severely affected as the motor system. Abnormal neurofilament phosphorylation was not a prominent feature. Ubiquitinated neuronal inclusions were infrequent except in the hippocampal denate granule cells where they were indistinguishable from sporadic cases of ALS-dementia. The motor cortex was preserved despite severe distal axonal loss in the corticospinal tract. These findings suggest a primary failure of axonal maintainance affecting several neuronal groups with long projecting axons. The differences and similarities compared to previously reported case with I113T (exon 4) and A4T (exon 1) mutations are discussed. Findings related to inflammatory cell infiltration, ubiquitination and neurofilament phosphorylation are discussed with reference to the pathogenesis of sporadic ALS.

Journal ArticleDOI
TL;DR: Results indicate that S OD1 may be involved in the formative process of LBHIs especially in familial ALS but not always in that of SIs or BBs, and imply that SOD2 may have no connection with any of these ALS-related abnormal structures.
Abstract: A role mutations in the superoxide dismutase (SOD)-1 gene in the pathogenesis of amyotrophic lateral sclerosis (ALS) has been discussed. To investigate immunohistochemical alterations of SOD in the spinal cord affected with the disease, we examined 3 patients with SOD1 mutation-associated family with ALS, 20 patients with sporadic ALS and 10 control individuals. Lewy body-like hyaline inclusions (LBHIs) were seen in the anterior horn cells of all the familial patients and 10 of the 20 sporadic patients, while skein-like inclusions (SIs) and Bunina bodies (BBs) were present in the 20 sporadic patients but not in the familial patients. The primary antibodies used for immunostaining were rabbit antisera raised against human SOD1 and SOD2. The anti-SOD1 antibody reacted strongly with all LBHIs of each familial patient and with some LBHIs of each sporadic patient. The cytoplasm of morphologically intact and degenerated spinal cord neurons as well as spheroids seen in the cases examined was only weakly stained by the antibody to SOD1 or not at all. The reactive astrocytes displayed weak to moderate staining for SOD1. The anti-SOD2 antibody strongly immunolabeled the reactive astrocytes and microglia. LBHIs of both familial and sporadic ALS were negatively stained for SOD2. Spinal cord neurons and spheroids of each case exhibited no significant SOD2 immunoreactivity. Neither antibodies reacted with SIs nor BBs. These results indicate that SOD1 may be involved in the formative process of LBHIs especially in familial ALS but not always in that of SIs or BBs, and imply that SOD2 may have no connection with any of these ALS-related abnormal structures.


Journal ArticleDOI
TL;DR: The findings suggest that FALS due to an SOD1 gene mutation is potentially a multisystem degenerative disorder, affecting not only neurons, but also astrocytes.
Abstract: We performed a comparative neuropathological study on two siblings with familial amyotrophic lateral sclerosis (FALS). The clinical course of the sister who died at age 46 was 18 months, and that of the brother who died at age 65, 11 years. The neuropathological findings of the female were compatible with FALS with posterior column involvement. Her brother had multisystem degeneration in addition to the motor neuron disturbance; Lewy body-like hyaline inclusions (LBHIs) were present in the affected neurons of the degenerative lesions. Eosinophilic inclusions were seen in many astrocytes of the affected areas of the male FALS patient. Immunohistochemical assays revealed that most astrocytic inclusions reacted with the antibodies against Cu/Zn-superoxide dismutase 1 (SOD1) and ubiquitin; immunoreactivity was essentially the same as that of the neuronal LBHIs. Ultrastructurally the astrocytic inclusions were composed mainly of 15- to 25-nm granule-coated fibrils and granular material, resembling LBHIs of the neurons. Despite the dissimilar neuropathological features, both patients had the same two base pair deletion in exon 5 of the SOD1 gene. These findings suggest that FALS due to an SOD1 gene mutation is potentially a multisystem degenerative disorder, affecting not only neurons, but also astrocytes.

Journal ArticleDOI
TL;DR: The intracortical inhibitory mechanism may be impaired in patients with amyotrophic lateral sclerosis and responses to test stimuli were markedly attenuated by a subthreshold conditioning stimulus.
Abstract: OBJECTIVE: Transcranial double magnetic stimulation on the motor cortex was used to investigate central motor tract function in 16 patients with amyotrophic lateral sclerosis, five with spinal muscular atrophy, and 16 age matched normal controls. METHODS: Surface EMG responses were recorded from the relaxed abductor pollicis brevis (APB) muscle. RESULTS: Responses to test stimuli were markedly attenuated by a subthreshold conditioning stimulus given at a condition-test (C-T) interval of 1-4 ms in normal controls and patients with spinal muscular atrophy, but attenuation was mild in patients with amyotrophic lateral sclerosis. In the normal controls this suppression was caused by activation of the intracortical inhibitory mechanism because responses to electrical test stimuli and the H wave were not suppressed by the same magnetic subthreshold conditioning stimulus. In amyotrophic lateral sclerosis the effect of the conditioning cortical stimulus on the H wave was also in the normal range. CONCLUSION: The intracortical inhibitory mechanism may be impaired in patients with amyotrophic lateral sclerosis.

Journal ArticleDOI
TL;DR: The observed changes in motor axons resemble changes described in the spinal cord of ALS patients, consistent with the proposal that motor neuron degeneration in ALS may be mediated by an excitotoxic process involving hyperactivation of non-NMDA glutamate receptors.
Abstract: A superoxide dismutase 1 (SOD-1) genetic defect has been identified in familial amyotrophic lateral sclerosis (ALS) and motor neuron degeneration has been described in SOD-1 transgenic mice. Because an excitotoxic mechanism has been implicated in ALS, we undertook studies to provide a description of excitotoxic degeneration of spinal motor neurons for comparison with the degenerative process observed in SOD-1 transgenic mice. Excitotoxin agonists selective for each of the three major types of ionotropic glutamate receptors were applied directly onto the lumbar spinal cord of 21-day-old rats following posterior laminectomy. N-methyl-D-aspartate (NMDA) preferentially affected dorsal horn neurons, whereas the non-NMDA agonist, kainic acid, preferentially affected motor neurons. Cytopathological changes in motor neurons closely resembled those described in SOD-1 mice. These changes consist of massively swollen dendritic processes in the presence of well-preserved presynaptic axon terminals; cell bodies of motor neurons filled with vacuoles that originate both from endoplasmic reticulum and mitochondria; pleomorphic changes in mitochondria; axons of motor neurons becoming swollen proximally with accumulation of vacuoles, organelles, filaments, and degeneration products in the swollen segment. The observed changes in motor axons resemble changes described in the spinal cord of ALS patients. These findings are consistent with the proposal that motor neuron degeneration in ALS may be mediated by an excitotoxic process involving hyperactivation of non-NMDA glutamate receptors.