Showing papers on "Amyotrophic lateral sclerosis published in 1995"

Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis.

Abstract: The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but defects in synaptosomal high-affinity glutamate transport have been observed. In experimental models, chronic loss of glutamate transport can produce a loss of motor neurons and, therefore, could contribute to the disease. With the recent cloning of three glutamate transporters, i.e., EAAC1, GLT-1, and GLAST, it has become possible to determine if the loss of glutamate transport in ALS is subtype specific. We developed C-terminal, antioligopeptide antibodies that were specific for each glutamate transporter. EAAC1 is selective for neurons, while GLT-1 and GLAST are selective for astroglia. Tissue from various brain regions of ALS patients and controls were examined by immunoblot or immunocytochemical methods for each transporter subtype. All tissue was matched for age and postmortem delay. GLT-1 immunoreactive protein was severely decreased in ALS, both in motor cortex (71% decrease compared with control) and in spinal cord. In approximately a quarter of the ALS motor cortex specimens, the loss of GLT-1 protein (90% decrease from control) was dramatic. By contrast, there was only a modest loss (20% decrease from control) of immunoreactive protein EAAC1 in ALS motor cortex, and there was no appreciable change in GLAST. The minor loss of EAAC1 could be secondary to loss of cortical motor neurons. As a comparison, glial fibrillary acidic protein, which is selectively localized to astroglia, was not changed in ALS motor cortex. Because there is no loss of astroglia in ALS, the dramatic abnormalities in GLT-1 could reflect a primary defect in GLT-1 protein, a secondary loss due to down regulation, or other toxic processes.

Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder primarily involving motoneurons. A subset of individuals with familial autosomal dominant forms of the disease have mutations of the copper/zinc superoxide dismutase (Cu/Zn SOD, SOD-1) gene, which encodes a ubiquitously expressed enzyme that plays a key role in oxygen free radical scavenging. This observation suggests that altered or reduced SOD-1 activity may play a role in the neurodegenerative process. To explore this possibility further, we have introduced a mutation into the mouse SOD-1 gene that corresponds to one of the changes found in the human gene in familial amyotrophic lateral sclerosis. Integration and expression of this mouse gene in transgenic mice was identified by the presence of a unique restriction enzyme site in the transgene coding sequence generated by introduction of the mutation. We report here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex. These findings indicate a causative relationship between altered SOD activity and motoneuron degeneration. Moreover, biochemical studies indicate normal levels of total SOD activity in transgenic mouse tissues, results that indicate that the neurodegenerative disorder does not result from a diminution of activity and, as such, represents a dominant "gain of function" mutation.

Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction.

Abstract: Over 1200 patients with motor neuron disease have been carefully diagnosed, followed, and included in a detailed database delineating characteristics of the disease. Of these patients, 831 were identified as exhibiting typical, sporadic amyotrophic lateral sclerosis (ALS). The progression of the disease in these patients has been followed with our scoring system, and the ALS score was verified as a significant covariate of survival. Age at first symptom, delay from first symptom to entering ALS clinic, and rate of change of respiratory function were also identified as significant covariates of survival. These measures, applied to the Cox proportional hazards model, were used to develop a mathematical model for prediction of survival time in ALS, which proved highly accurate for the 80% of patients at intermediate risk. For those patients, a second model was developed which accurately predicts, after an initial period of observation, the time over which ALS patients will decline a set number of points in total ALS score. Such validation permits initial trials for drug therapies in ALS by comparison of relatively small groups of treated patients to this historical control group, based on the model of predicted time to a particular decrement in total ALS score.

Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons, characterized by depositions of neurofilaments in the perikarya and proximal axons. The pathogenesis of ALS remains poorly understood, but two lines of evidence suggest that neurofilament accumulation may play a causal role. First, transgenic mice that overexpress neurofilament proteins show motor neuron degeneration and, second, variant alleles of the neurofilament heavy-subunit gene (NF-H) have been found in some human ALS patients. To investigate how disorganized neurofilaments might cause neurodegeneration, we examined axonal transport of newly synthesized proteins in mice that overexpress the human NF-H gene. We observed dramatic defects of axonal transport, not only of neurofilament proteins but also of other proteins, including tubulin and actin. Ultrastructural analysis revealed a paucity of cytoskeletal elements, smooth endoplasmic reticulum and especially mitochondria in the degenerating axons. We therefore propose that the neurofilament accumulations observed in these mice cause axonal degeneration by impeding the transport of components required for axonal maintenance, and that a similar mechanism may account for the pathogenesis of ALS in human patients.

Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons

Abstract: Mutation in superoxide dismutase 1 (SOD1), a Cu/Zn enzyme that removes oxygen radicals and protects against oxidative injury, has been implicated in some cases of familial amyotrophic lateral sclerosis (FALS). As a first approach to examining the mechanism(s) through which these mutations cause specific degeneration of motor neurons, we have used immunocytochemistry to identify the distribution of SOD1 in populations of cells in the peripheral and central nervous systems. In the spinal cord, intense SOD1 immunoreactivity was present in motor neurons, interneurons, and substantia gelatinosa. In motor neurons, SOD1 immunoreactivity was abundant in perikarya, dendrites, and axons; most of this activity appeared to be free in the cytoplasm, although a portion was associated with membranous vesicles, presumably peroxisomes. Since a variety of central nervous system neurons, including pyramidal cells in cerebral cortex and neurons of the CA3 and CA4 sectors of the hippocampus, showed high immunoreactivity but are unaffected in ALS, the apparent abundance of SOD1 does not predict vulnerability of neurons to mutations in SOD1. Rather, SOD1 accumulates in many neuronal populations but is particularly abundant in motor neurons. Consistent with recent studies of FALS-linked SOD1 mutations in vitro and in transgenic mice, our findings offer further support for the view that the mutations confer a gain of adverse function. In this view, high, rather than limiting, levels of SOD1 may place motor neurons selectively at risk in FALS.

Percutaneous endoscopic gastrostomy and enteral nutrition in amyotrophic lateral sclerosis

Abstract: Bulbar involvement in amyotrophic lateral sclerosis (ALS) is often related to a worse prognosis on account of the higher risk of pulmonary aspiration and undernutrition due to dysphagia. The aim of our study was to assess the effects of enteral feeding by percutaneous endoscopic gastrostomy (PEG) in a long-term follow-up of ALS patients. We report the results of PEG in 31 ALS patients with bulbar involvement. The patients were observed at 3-monthly intervals over a period of 2 years after PEG. All the data were compared with those obtained from a control group of 35 ALS patients who refused PEG. Mortality did not differ significantly between the two groups of patients during the first 6 months of observation, whereas after this period it was lower in the PEG group. In the patients who had had PEG, the body mass index showed a mild but statistically significant improvement after tube insertion while in the control group it decreased significantly. The findings of this study demonstrate that PEG can improve survival in elderly and young ALS patients with bulbar involvement; it enhances their quality of life and helps their integration in their social and family surroundings. We think that PEG should be included symptomatic treatment of all ALS patients with bulbar involvement from the onset of symptoms.

Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.

Abstract: Recent reports have shown heterozygosity for some twenty different mutations in the CuZn–superoxide dismutase (CuZn–SOD) gene in familial amyotrophic lateral sclerosis (FALS), and analysed samples from patients have shown decreased enzymic activity. Here we report homozygosity for an exon 4 mutation, Asp90Ala in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland. The erythrocyte CuZn–SOD activity is essentially normal. Our findings suggest that this CuZn–SOD mutation causes ALS by a gain of function rather than by loss, and that the Asp90Ala mutation is less detrimental than previously reported mutations.

Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis.

Abstract: A large number of studies have documented abnormalities of glutamate metabolism in ALS patients or in postmortem ALS tissue. These abnormalities include altered synthetic enzymes, tissue glutamate levels, transporter proteins, and postsynaptic receptors, as well as the presence of potentially toxic agonists. As yet, there is no hypothesis effectively linking all the observations to one central defect. Furthermore, it is not clear if the various abnormalities in glutamate systems represent a primary defect or a secondary response. For example, defects of glutamate transport subtypes could reflect the primary loss of the proteins or the secondary effect of another toxic insult. Nevertheless, experimental paradigms suggest that, even if secondary, glutamate could contribute to the death of motor neurons. Therefore, interventions to minimize the toxicity of glutamate (e.g., receptor antagonists, release inhibitors, or antioxidants) could partially ameliorate the degeneration of motor neurons. This has been observed experimentally in cultured motor neurons. More importantly, a small study with riluzole suggests that glutamate-acting drugs could alter the progression of the disease. Future studies with riluzole and other glutamate-acting agents will evaluate this possibility.

Axonal ion channel dysfunction in amyotrophic lateral sclerosis

Abstract: Summary In amyotrophic lateral sclerosis (ALS) it is not known how or why the motor neurons die, but a clue is provided by observations that the dying cells discharge spontaneously, producing muscle fasciculations The fasciculations can arise either proximally or distally in the motor unit, suggesting a widespread disturbance of membrane excitability To test for this, we applied the technique of threshold electrotonus to ulnar motor axons at the wrist, comparing the responses to 100 ms polarizing currents in 11 ALS patients with those from 15 normal controls, six patients with benign fasciculations, 19 with lower motor neuron disorders and six with upper motor neuron disorders We found that the motor axons of ALS patients, unlike those in the neurological control groups, responded abnormally to subthreshold depolarizing currents, becoming either more (seven cases) or much less excitable (four cases) than normal Both types of abnormality could be reproduced in rat nerves in vitro, and in a computer model of human motor axons, by reducing voltage dependent potassium conductances When sufficient potassium channels were blocked, the model axon became unstable and depolarized regeneratively, resulting in an abrupt fall in excitability We conclude that the fasciculations in ALS are caused by an imbalance between functional sodium and potassium channels, and we propose that this ion channel dysfunction could also be responsible for the motor neuron degeneration in this disease

Epidemiology of ALS.

Abstract: Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is the most common motor neuron disease. ALS is a late-onset rapidly deteriorating neurological disorder characterized by the selective death of motor neurons in the brain and spinal cord that innervate skeletal muscles, with clinical symptoms of progressive weakness, muscle wasting, and spasticity (1). The median survival with ALS is usually three years and the cause of death is respiratory failure, pneumonia, or cardiac arrhythmias. Scientific advancements have been made over the past several years to understand the Mendelian forms of ALS and other diseases of the motor neuron. The most significant advancement has been the identification of genes causing some forms of familial ALS (2,3), the spinal muscular atrophies (4,5), and frontotemporal dementia (6). The epidemiologic observation of specific patterns of familial aggregation in some individuals with motor neuron disease started the chain of events that led to the identification of the underlying genes. Despite exciting advances into understanding the molecular genetic basis of some Mendelian forms of the disease, however, the causes of sporadic (non-familial) ALS are still unknown, and the apparent selectivity for motor neurons remains unexplained.

Excitotoxicity and neurodegeneration in amyotrophic lateral sclerosis.

Abstract: The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but several observations suggest that glutamate could participate in selective motor neuron degeneration. Extracellular levels of glutamate are elevated in ALS. Synaptic concentrations of glutamate are regulated by high-affinity glutamate transport, and defects in glutamate transport have also been observed in ALS tissue. Three sodium-dependent glutamate transporters have now been identified: a neuronal transporter EAAC1, and two astroglial transporters GLT-1 and GLAST. The defect in glutamate transport in ALS appears to be relatively specific for the GLT-1 subtype. The role of chronic excess glutamate and glutamate transporter loss has been investigated in experimental paradigms, where it was found that excitotoxicity could account for selective motor neuron degeneration. These culture paradigms have demonstrated that motor neurons are sensitive to glutamate toxicity via non-NMDA receptors and that various agents (e.g., antioxidants, glutamate release inhibitors, non-NMDA receptor antagonists) can be neuroprotective. These experimental studies will provide a basis for understanding the primary and secondary role of glutamate in motor neuron death and will provide important insight into possible therapeutic interventions.

Image analyser-assisted morphometry of the locus coeruleus in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

Abstract: Summary Several observations suggest that neuronal shrinkage rather than cell death is the major phenomenon in neurodegenerative diseases In order to make this distinction, smaller cells should also be included in cell counts Also, morphometric determination of total cell numbers of brain structures is required Morphometry was performed on the locus coeruleus using a newly developed method to delineate this nucleus from five patients who had died with Alzheimer's disease, five with Parkinson's disease, five with amyotrophic lateral sclerosis and from five control subjects who had died from causes that would not have affected the locus coeruleus The length and volume of the locus coeruleus and its total number of large pigmented neurons, small unpigmented neurons and glial cells were determined Since reliable delineation of the boundaries of the locus coeruleus is a requirement for the determination of total cell numbers, an image analyser-assisted procedure was developed In Alzheimer's disease we found an 82% decrease in the number of large pigmented neurons and a 39% decrease of small unpigmented neurons In Parkinson's disease, we found a 39% decrease of large pigmented neurons but also a 44% (though not significant) increase of small unpigmented neurons, which is indicative of a shift from large pigmented neurons to small unpigmented neurons in Parkinson's disease The large pigmented/small unpigmented neuron number ratio was greatly and significantly reduced in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis These findings support the hypothesis that the decrease of large pigmented neurons of the locus coeruleus in some neurodegenerative diseases is not entirely due to cell death, but rather to cell shrinkage and a loss of phenotype This hypothesis may have consequences for the development of therapeutic strategies since atrophied cells can be activated On the other hand our data confirm that, at least in Alzheimer's disease, large pigmented neurons do also undergo cell death

Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis.

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons Although most cases of ALS are sporadic, approximately 10% are inherited as an autosomal dominant trait Mutations in the Cu/Zn superoxide dismutase gene (SOD 1) are responsible for a fraction of familial ALS (FALS) Screening our FALS kindreds by SSCP, we have identified mutations in 15 families, of which 9 have not been previously reported Two of the new mutations alter amino acids that have never been implicated in FALS One of them affects a highly conserved amino acid involved in dimer contact, and the other one affects the active-site loop of the enzyme These two mutations reduce significantly SOD 1 enzyme activity in lymphoblasts Our results suggest that SOD 1 mutations are responsible for > or = 13% of FALS cases

Apoptosis in the Nervous System: Morphological Features, Methods, Pathology, and Prevention.

Abstract: For nearly 70 years apoptosis has been known to be a form of cell death distinct from necrosis as well as an important regressive event during the normal development of the nervous system. For example, in the chick, mouse, rat and human approxiamately 50% of postmitotic neurons die naturally during embryonic or fetal development. It is generally accepted that neurons die during this period by apoptosis. After the period of naturally occurring cell death, the surviving neurons may undergo degeneration and death due to injury or disease later either during development or in adulthood. Recently, apoptosis has been suggested to be involved in the abnormal neuronal death that occurs following axonal injury or in neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's. Although little is known about the etiology of these diseases, progress is steadilly being made toward understanding their underlying mechanisms. For diseases of spinal motoneurons, during the past two years gene mutations have been identified in patients with familial amyotrophic lateral sclerosis or spinal muscular atrophy. Furthermore, a number of in vitro, in vivo, and mutant animal models have been developed in order to study the factors which control motoneuron survival and/or death. Here, we review the morphological differences between necrotic and apoptotic cell death and some of the methods used to differentiate the two pathways. We also discuss motoneuron cell death during development, following injury and in disease, and its prevention by different agents, including neurotrophic factors.

Parvalbumin is a marker of ALS-resistant motor neurons.

Abstract: The selective vulnerability of limb and bulbar motor neurons is a hallmark of degenerative human motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Currently, there are no known molecular characteristics to distinguish between motor neuron pools which are highly susceptible to degeneration in ALS and those populations which are resistant. Using in situ hybridization on adult rat tissue, we demonstrated that ALS-resistant motor pools robustly express mRNA for the calcium binding protein parvalbumin, while no measurable parvalbumin expression is found in ALS-sensitive motor neuron populations. In contrast, mRNA expression for each of several other calcium binding proteins such as calbindin-D28K, calretinin and calmodulin appears similar in the various motor pools. Thus, parvalbumin represents a biochemical marker of ALS-resistant motor neurons, and may provide insight into the mechanisms of resistance of certain motor neurons to disease.

Physiology of fatigue in amyotrophic lateral sclerosis

Abstract: We investigated the mechanisms of muscle fatigue in ALS. In the muscles of ALS patients and healthy control subjects, we examined (1) fatigue using measurements of muscle force, (2) energy metabolism using phosphorus-31 magnetic resonance spectroscopy, and (3) activation using neurophysiologic measures and MRI. During 25 minutes of intermittent isometric exercise of the tibialis anterior muscle, both maximum voluntary and tetanic force declined more in patients than in controls, indicating greater fatigability in ALS. There was a similar decline of voluntary and tetanic force, suggesting that much of the fatigue was not central. Evoked compound muscle action potential amplitudes were preserved during exercise in both groups, indicating no failure of neuromuscular transmission; this result suggests that the source of fatigue was not at the neuromuscular junction or within the muscle membrane. In spite of greater fatigability, changes during exercise in energy metabolites and proton signal intensity tended to be less in ALS patients compared with controls, suggesting impaired muscular activation. We conclude that the greater muscle fatigue in ALS patients results from activation impairment, due in part to alterations distal to the muscle membrane.

Superoxide dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients.

Abstract: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are responsible for some cases of familial amyotrophic lateral sclerosis (ALS). We have shown that SOD1 mutations can also occur in apparently sporadic ALS. To establish how often this happens we have undertaken a study of the prevalence of SOD1 mutations in an unselected cohort of Scottish ALS patients, with both sporadic (n = 57) and familial (n = 10) disease. Single strand conformation polymorphism analysis was used to scan for new mutations, and selective restriction enzyme digestion to screen for 11 of the 20 SOD1 mutations published to date. We detected mutations in five (50%) of the familial ALS patients and also in four (7%) of the sporadic patients. One mutation, ile113thr, seems to be particularly prevalent in the Scottish population since it was detected in a total of 6/67 (9%) unrelated cases.

Familial amyotrophic lateral sclerosis with a point mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles.

Abstract: Mutations of SOD-1 have recently been associated with autosomal dominant familial amyotrophic lateral sclerosis (ALS) A patient is described with a 20 year duration of motor neuron disease, with clinical features of ALS, who was heterozygous for a point mutation ATT to ACT leading to substitution of isoleucine for threonine at codon 113 in exon 4 of SOD-1 This mutation has previously been described in two families with ALS and three apparently sporadic cases of ALS The patient described here had a family history suggestive of autosomal dominant inheritance of this genetic mutation; other members of the family having a more typical disease duration Unusual pathological features included neurofibrillary tangles in neurons of the globus pallidus, substantia nigra, locus coeruleus, and inferior olivary nuclei, and absence of ubiquitin immunoreactive inclusions in motor neurons This may reflect the slow progression of the neurodegeneration associated with the SOD-1 mutation in this patient The prolonged survival, of over 20 years, with other family members having a more typical survival of two to three years, has important implications for genetic counselling in families with ALS in addition to the fundamental biological questions concerning the influence of these mutations on disease expression

Apoptosis in amyotrophic lateral sclerosis is not restricted to motor neurons. Bcl‐2 expression is increased in unaffected post‐central gyrus

Abstract: We searched for the presence of apoptotic cell death and studied the distribution of bcl-2, an oncoprotein that counteracts apoptosis, in amyotrophic lateral sclerosis (ALS). Brain and spinal cord specimens from 12 ALS patients were compared with those from six non-neurological controls. ALS brain tissue was pre-selected by the presence of reactive cortical damage. Apoptosis was demonstrated by in situ end-labelling of fragmented DNA, a method that is suitable for formalin-fixed, paraffin-embedded tissue. All ALS patients exhibited some apoptosis, eight of them did so in each of the three central nervous system (CNS)-levels studied. Apoptosis was not restricted to the motor system, but also affected other neuronal and non-neuronal CNS elements. Apoptosis corresponded with cell shrinkage, and neuronophagia in Nissl stains and with small Nissl-positive bodies. None of the non-neurological controls showed as much apoptosis as any of the ALS cases. Immunocyto-chemically, the overall distribution of Bcl-2 did not differ between ALS and non-neurological controls. In ALS. however, we found variable degrees of increased Bcl-2 expressed in the nuclei and in the cytoplasm. We found no inverse relationship between apoptosis and bcl-2 expression.

Regional changes of ciliary neurotrophic factor and nerve growth factor levels in post mortem spinal cord and cerebral cortex from patients with motor disease

Abstract: Ciliary neurotrophic factor (CNTF) rescues motor neurons in animal models of injury and neurodegeneration, and disruption of the mouse CNTF gene results in motor neuron degeneration in mature adults. Glial cells increase nerve growth factor (NGF) expression in neuropathological conditions, and the sensory system can be affected in the amyotrophic lateral sclerosis (ALS) type of motor neuronic disease. We therefore studied CNTF and NGF levels in post mortem spinal cord and cerebral cortex from patients with ALS and matched controls. We report a marked decrease of CNTF in the ventral horn of spinal cord in ALS, with no change in cerebral motor cortex. In contrast, NGF levels were decreased in ALS cerebral motor cortex, where the corticospinal tract originates, but increased in the lateral column of spinal cord, which includes the region of corticospinal tract degeneration in ALS. Both CNTF and NGF levels were decreased in ALS dorsal spinal cord.

Amyotrophic lateral sclerosis immunoglobulins increase Ca2+ currents in a motoneuron cell line

Abstract: The sporadic form of amyotrophic lateral sclerosis (ALS) is an idiopathic and eventually lethal disorder causing progressive degeneration of cortical and spinal motoneurons. Recent studies have shown that the majority of patients with sporadic ALS have serum antibodies that bind to purified L-type voltage-gated calcium channels and that antibody titer correlates with the rate of disease progression. Furthermore, antibodies purified from ALS patient sera have been found to alter the physiologic function of voltage-gated calcium channels in nonmotoneuron cell types. Using whole-cell patch-clamp techniques, immunoglobulins purified from sera of 5 of 6 patients with sporadic ALS are now shown to increase calcium currents in a hybrid motoneuron cell line, VSC4.1. These calcium currents are blocked by the polyamine funnel-web spider toxin FTX, which has previously been shown to block Ca2+ currents and evoked transmitter release at mammalian motoneuron terminals. These data provide additional evidence linking ALS to an autoimmune process and suggest that antibody-induced increases in calcium entry through voltage-gated calcium channels may occur in motoneurons in this disease, with possible deleterious effects in susceptible neurons.

Abnormal excitability of the corticospinal pathway in patients with amyotrophic lateral sclerosis: a single motor unit study using transcranial magnetic stimulation.

Abstract: The pathophysiology of corticospinal tract degeneration in amyotrophic lateral sclerosis (ALS) was investigated by studying the effect of transcranial magnetic stimulation on discharge characteristics of single motor units during voluntary activation. The motor units were recorded from the first dorsal interosseus muscles of 12 patients with ALS, 14 healthy subjects, 12 patients with upper motor neuron lesions and 9 with pure lower motor neuron diseases. More than 100 magnetic stimuli were delivered over the scalp during minimal muscle contraction. The occurrence of motor unit discharges was plotted in a peristimulus time histogram. An increase in discharge probability at latencies of 20-30 msec, that represents monosynaptic activation (primary peak) was found in normal units. Motor units from ALS patients with short disease durations had significantly increased discharge probabilities in the primary peak (P < 0.001). Motor units from 4 ALS patients with upper motor neuron signs showed double primary peaks: an initial synchronized peak followed by a dispersed peak. The latter was ascribed to a slow corticospinal pathway, which remains undetected or is functionally insignificant in healthy subjects. We conclude that the excitabilities of the surviving corticospinal tract pathways are abnormally increased in ALS, especially in the early stage.