Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis

The mutation gly93-->ala of Cu,Zn superoxide dismutase (SOD) is found in patients with familial amyotrophic lateral sclerosis and causes motor neuron disease when expressed in transgenic mice. The progression of clinical and pathological disease was studied in a line of mice designated G1H. Clinical disease started at 91 +/- 14 days of age with fine shaking of the limbs, followed by paralysis and death by 136 +/- 7 days of age. Pathological changes begin by 37 days of age with vacuoles derived from swollen mitochondria accumulating in motor neurons. At the onset of clinical disease (90 days), significant death of somatic motor neurons innervating limb muscles has occurred; mice at end-stage disease (136 days) show up to 50% loss of cervical and lumbar motor neurons. However, neither thoracic nor cranial motor neurons show appreciable loss despite vacuolar changes. Autonomic motor neurons also are not affected. Mice that express wild-type human Cu,Zn SOD remain free of disease, indicating that mutations cause neuron loss by a gain-of-function. Thus, the age-dependent penetrance of motor neuron disease in this transgenic model is due to the gradual accumulation of pathological damage in select populations of cholinergic neurons.     

Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis

Equatorial regions of chicken intrafusal fibres were examined with a panel of monoclonal antibodies against intracellular proteins and components of extracellular matrix to identify structural associations at points of contact between sensory terminals and intrafusal fibres, and at points which lacked them. One aspect of this study was to establish whether the known morphological differences between myosensory and neuromuscular junctions also extended to the molecular level. As viewed in cross-sections, myosensory junctions at the equator are restricted to approximately one-half of the intrafusal fibre circumference, a region referred to as the sensory sector. The diametrically opposite region which lacks sensory terminals is referred to as the non-sensory sector. The basal lamina over the sensory sector was positive for chondroitin sulphate, while that part which covered the non-sensory sector was negative. Staining for collagen type IV was very faint at the sensory sector and stronger at the non-sensory sector, but immunoreactivity for heparan sulphate proteoglycan and laminin was moderate to strong in all parts of the basal lamina. Within intrafusal fibres, filamin and alpha-actinin were largely limited to the sensory sector. The major feature of the non-sensory sector was a sharply delineated, narrow intrafibre crescent of vinculin, and colocalized with it, a crescent of talin. The plasmalemma of intrafusal fibres at the non-sensory sector reacted positively for the beta 1 subunit of the integrin family of receptors. Immunolocalization of these receptors was not observed to any significant extent in the sensory sector. Towards the end of the equator and the initial portion of the juxtaequator, chondroitin sulphate, vinculin and the other proteins came gradually to be distributed equally all the way round the intrafusal fibres. This changeover in distribution of connective tissue proteins and structural intracellular proteins parallels the decreasing number of contacts made by sensory terminals.     

Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis

The pathogenesis of neuronal degeneration in both sporadic and familial amyotrophic lateral sclerosis (ALS) associated with mutations in superoxide dismutase may involve oxidative stress. A leading candidate as a mediator of oxidative stress is peroxynitrite, which is formed by the reaction of superoxide with nitric oxide. 3-Nitrotyrosine is a relatively specific marker for oxidative damage mediated by peroxynitrite. In the present study, biochemical measurements showed increased concentrations of 3-nitrotyrosine and 3-nitro-4-hydroxyphenylacetic acid in the lumbar and thoracic spinal cord of ALS patients. Increased 3-nitrotyrosine immunoreactivity was observed in motor neurons of both sporadic and familial ALS patients. Neurologic control patients with cerebral ischemia also showed increased 3-nitrotyrosine immunoreactivity. These findings suggest that peroxynitrite-mediated oxidative damage may play a role in the pathogenesis of both sporadic and familial ALS.     

Transgenic mouse models of Alzheimer's disease and amyotrophic lateral sclerosis

Over the past several years, there has been enormous progress in generating transgenic mice that model aspects of human neurodegenerative diseases. These studies build upon the efforts of molecular geneticists who have identified a number of genes that, when mutated, cause familial forms of these diseases. In this review, we focus on the mutations that cause familial forms of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), and transgenic mouse models that develop clinical and pathological abnormalities resembling those occurring in the human diseases.     

Cricopharyngeal myotomy in amyotrophic lateral sclerosis

Reported herein is the experience of the authors with 38 amyotrophic lateral sclerosis (ALS) patients for whom cricopharyngeal myotomy was performed. The major surgical objectives were facilitation of swallowing and amelioration of the tendency of these patients to aspirate ingestants and secretions. In the group of these patients in which the follow-up information has been adequate, 64% were improved and 36% experienced no significant benefits. The authors' surgical indications, methods of anesthesia, surgical technique, and postoperative care are described.     

Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis

The X-ray crystal structure of a human copper/zinc superoxide dismutase mutant (G37R CuZnSOD) found in some patients with the inherited form of Lou Gehrig's disease (FALS) has been determined to 1.9 angstroms resolution. The two SOD subunits have distinct environments in the crystal and are different in structure at their copper binding sites. One subunit (subunit[intact]) shows a four-coordinate ligand geometry of the copper ion, whereas the other subunit (subunit[broken]) shows a three-coordinate geometry of the copper ion. Also, subunit(intact) displays higher atomic displacement parameters for backbone atoms ((B) = 30 +/- 10 angstroms2) than subunit(broken) ((B) = 24 +/- 11 angstroms2). This structure is the first CuZnSOD to show large differences between the two subunits. Factors that may contribute to these differences are discussed and a possible link of a looser structure to FALS is suggested.     

Prognostic factors in amyotrophic lateral sclerosis

Survival in patients with amyotrophic lateral sclerosis is highly variable. In a prospective study of 71 patients, we analyzed the influence of several clinical factors on survival: age of onset, sex, initial involvement (bulbar, upper extremities or lower extremities) and familial history. Mean time of evolution was 2.6 years, with 25% survival 5 years after onset. Patients under 45 years old had better survival than those over 45 (5.8 and 2.2 years, respectively, p < 0.002). The prognosis for women was worse (2.07 and 3.6 years for women and men, respectively, p < 0.001), probably because age of onset was later in women (61 versus 53 years, respectively, p < 0.006). Neither first symptom or familial history of the disease affected prognosis. We conclude that age at onset is a decisive prognostic factor that is inversely related to survival. In the design of clinical trials in which survival is a variable, the treatment and control groups should be matched for age.     

Prognosis in hereditary amyotrophic lateral sclerosis

Two different forms of hereditary amyotrophic lateral sclerosis (ALS) has been separated according to duration of illness. A rapid course with short survival as seen in sporadic ALS is usual, but a comparatively benign type with a mean survival of 12 years has been reported in some families. Four patients from an ALS-afflicted family with five affected members in three generations were examined and then followed up. A conspicuous variability in progression among the patients was observed, with death occurring from 26 months to 12 years after onset; one patient is alive 13 years after onset. Wide differences were also found with respect to initial site of involvement and pyramidal tract signs. Three other families with this mixed pattern of prognosis have been reported previously. Affected individuals within involved families had either short or long duration of the disease, rather than displaying a continuum. However, in view of the existence of a type of hereditary ALS with marked intrafamilial variability, prognosis, even in the presence of previous benign cases, should be cautiously given.     

Sleep-disordered breathing in amyotrophic lateral sclerosis

OBJECTIVES: Our study was designed to determined the significance of aortogenic embolism in an unselected autopsy collective. BACKGROUND: Although embolism arising from atherosclerotic plaques in the aorta has been acknowledged, the role of aortic atheromatosis among other well known sources of embolism remains to be further clarified. METHODS: We examined the proximal part of the arterial system with regard to the presence of atherosclerotic lesions as well as cardiac changes in 120 consecutive necropsy studies. Pathologic evidence of embolic events was recorded. Clinical and neuropathologic data were also surveyed in all patients. RESULTS: Among atherosclerotic lesions, fibrous plaques (p < 0.05) and calcified (p < 0.0001) and ulcerated lesions (p < 0.0001) as well as thrombi (p < 0.005) were observed significantly more frequently in the aortic arch and in the descending aorta than in the ascending aorta, whereas fatty streaks were distributed uniformly. In 40 (33%) of the 120 patients, we found pathologic evidence of arterial embolization. Multiple logistic regression analysis revealed a significant correlation between embolism and complicated atherosclerotic plaques in the aortic arch (odds ratio [OR] 5.8, 95% confidence interval [CI] 1.1 to 31.7, p < 0.05), severe ipsilateral carotid artery disease (OR 3.1, 95% CI 3.1 to 45.3, p < 0.001) and atrial fibrillation (OR 3.5, 95% CI 1.1 to 9.9, p < 0.05). CONCLUSIONS: Complicated atherosclerotic plaques in the aortic arch represent an independent risk factor for systemic embolism similar to atrial fibrillation and severe atherosclerosis of the carotid arteries.     

Skin involvement in amyotrophic lateral sclerosis

BACKGROUND: Patients with sporadic amyotrophic lateral sclerosis (ALS) show disorganised collagen and elastin of the dermis. We looked for inflammatory alterations to cutaneous blood vessels. PATIENTS AND FINDINGS: Seven patients with sporadic ALS were investigated; five were confined to bed, but none had bedsores. Light and electron microscopy of skin showed an oedematous dermis with collagen fibrils of irregular diameter. Small blood vessels were characterised by duplicated basement membranes and deposition of beta-amyloid protein, the main component of the neuronal and non-neuronal amyloid deposits in Alzheimer's disease. These skin changes were seen in all degrees of disability, but none was found in age-matched and sex-matched controls. INTERPRETATION: The skin in ALS is characterised by a distinctive pattern of alterations of connective tissue and blood vessels. Examination of skin in an additional and easily accessible investigation which may help elucidate the pathogenesis of ALS.     

Clinical aspects of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a progressive degenerative disease of upper and lower motor neurons with a prevalence of 4.3/100.000. The clinical symptoms include peripheral weakness and central spastic paresis and bulbar paralysis (weakness of mimic muscles, atrophy of the tongue, dysarthria). The prognosis leads to death within a few years. Pathogenetic factors are free O2-radicals, a disturbance of glutamate-metabolism, abnormal accumulation of neuronal proteins and autoimmunological mechanisms.     

Clinical epidemiology of amyotrophic lateral sclerosis

The introduction of palliative therapies in amyotrophic lateral sclerosis (ALS) will alter the epidemiology of ALS as it is known now. Although incidence rates will remain unchanged in the near future, prevalence rates will likely increase dramatically. Better understanding of the age-specific presentation of motor neuron diseases worldwide will shed light on the vexing questions concerning the variable incidence rates in some countries and apparent incidence gradients in North America and Europe.     

Riluzole as a treatment for amyotrophic lateral sclerosis

INTRODUCTION: The Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by the selective degeneracy of the superior motoneurons of the cortex motor and of the inferior motoneurons at level of the encephalic trunk and spinal marrow. Exist sporadic and familiar forms, being estimated an incidence of 1-2 cases by 100,000 inhabitants. The cause of the neuronal degeneracy is yet unknown, being implied, between other mechanisms, the glutamic exotoxicity is the responsible for the death neuronal. The riluzol is a benzothiazole derivative whose neuroprotector mechanism still it has not been totally clarified, though seems that reduces the neuroexcitatory action of the glutamic acid blocking his transmission. DEVELOPMENT: Two clinical trials have been accomplished with similar characteristics: multicentre, randomized, double blind, and placebo-controlled. Between both studies have been included more than 1,100 patient, obtained significant statistic results in the prolongation of the survival time, however this effect was not going accompanied of an improvement in the muscular force neither of the pulmonary capacity, what is translated in which the riluzol does not modify the quality of life of the patient. The drug presents good tolerance and mild adverse effects and as consequence of this in 1996, the FDA approved his marketing and utilization in the treatment of the ALS. The approval of the riluzol as first agent for the treatment of the ALS has raised an important number of problems about the efficiency and cost of the treatment. CONCLUSION: Though its benefits are modest, it is considered a starting point in the pharmacotherapy of the ALS.     

Long-term mechanical ventilation in amyotrophic lateral sclerosis

BACKGROUND: Acute respiratory insufficiency (ARI) with alveolar hypoventilation or incapacitating dyspnoea but without peripheral muscle involvement can be an early manifestation of respiratory involvement in amyotrophic lateral sclerosis (ALS). Some of these patients benefit from assisted ventilation. The object of this study was to analyse the results of long-term mechanical ventilation (LTMV) in ten patients with ALS. METHODS: A retrospective analysis of intensive care unit (ICU) or ambulant patients with ALS who underwent LTMV in a conventional hospital ward was performed. Erect and supine spirometry, blood gas analysis and pulse oximetry were performed before the start and during the course of ventilation. RESULTS: Ten patients on LTMV were included. Four from the ICU were ventilated via tracheostomy, and six ambulant patients had non-invasive (nasal) ventilation. In all cases, ventilation was performed in a conventional hospital ward. The ambulant patients improved symptomatically during ventilation, confirmed by measurement of gas exchange and of SaO2 by continuous pulse oximetry. Three of the ten patients survive in long-term care--two with nasal and one with tracheostomy ventilation. CONCLUSIONS: LTMV outside ICU was possible in ten patients, seven of whom returned home. Returning home is very difficult for patients dependent on a ventilator who lack family support.     

Temporal lobe pathology in amyotrophic lateral sclerosis. Do amyotrophic lateral sclerosis and Alzheimer's disease share a common etiological factor?

An autopsy study was performed on temporal lobe samples from 20 non-demented patients with amyotrophic lateral sclerosis (ALS), 17 age-matched non-demented controls and 4 Alzheimer's disease (AD) patients. Formalin fixed, paraffin embedded sections from the hippocampus with adjacent parahippocampal gyrus and from the superior temporal gyrus were stained with conventional and immunohistochemical stains. Immunohistochemical staining for the A4 protein was enhanced by pretreatment with 0.25% pepsin before 100% formic acid. The incidence and severity of AD-like pathological changes were similar in ALS patients and non-demented controls. In both groups, pathological changes increased with age. This study does not support the hypothesis that ALS and AD share an etiopathogenetic background.     

Oculomotor nuclear pathology in amyotrophic lateral sclerosis

We examined the oculomotor and/or trochlear nuclei of 27 amyotrophic lateral sclerosis (ALS) patients and 10 controls by histological and immunohistological methods. Their neurons were relatively well preserved. In 7 of 22 sporadic ALS patients (including 3/3 ALS with ophthalmoplegia) and in 4 of 5 ALS patients with dementia, some morphological changes similar to those in anterior horns (Bunina bodies, ubiquitin-positive skein-like inclusions, Lewy body-like inclusions, conglomerate inclusions and spheroids) were rarely, but clearly seen. These changes were not observed in controls. Our results suggest that the oculomotor and trochlear nuclei in ALS patients are slightly affected in a manner similar to that in the anterior horns, but the degree is less than that necessary for development of ophthalmoplegia in the majority of ALS patients.