Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio~1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1–2 years. Paralysis is progressive and leads to death due to respiratory failure within 2–3 years for bulbar onset cases and 3–5 years for limb onset ALS cases. Most ALS cases are sporadic but 5–10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2–5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of upper motor neurone and lower motor neurone damage not explained by any other disease process are suggestive of ALS. The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.     

Introducing Amyotrophic lateral sclerosis

Introducing ALS at present times leads to re-define the concept of motor neuron selectivity which characterizes this disorder. In fact, multiple systems including skin, liver, and bone marrow are altered in ALS patients. The motor neuron is still the focus of the disorder and the extended pathology did not modify the concept of ALS as a devastating disorder based on motor neuron loss. Nonetheless, the involvement of non-motor neurons as well as areas outside the central nervous system leads to a different perspective to understand the causes, pathophysiology and therapy of ALS. For this reason a specific issue is dedicated to understand whether intersecting basic, pre-clinical and clinical knowledge of ALS may lead to a coherent novel scenario allowing to translate basic findings into clinical practice. Several pre-clinical issues described in this volume appear robust enough to indicate that we should modify a number of approaches when designing future therapeutic strategies. Similarly, novel investigations based on altered cell to cell communication are needed to further progress in understanding amyotrophic lateral sclerosis.     

Genetics of familial Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive and ultimately fatal neurodegenerative disease, caused by the loss of motor neurons in the brain and spinal cord. About 10% of all ALS cases are familial (FALS), and constitute a clinically and genetically heterogeneous entity. To date, FALS has been linked to mutations in 10 different genes and to four additional chromosomal loci. Research on FALS genetics, and in particular the discoveries of mutations in the SOD1, TARDBP, and FUS genes, has provided essential information toward the understanding of the pathogenesis of ALS in general. This review presents a tentative classification of all FALS-associated genes identified so far.     

Amyotrophic lateral sclerosis: all roads lead to Rome

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease characterized by degeneration of upper and lower motor neurons, generalized weakness and muscle atrophy. Most cases of ALS appear sporadically but some forms of the disease result from mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1). Several other mutated genes have also been found to predispose to ALS including, among others, one that encodes the regulator of axonal retrograde transport dynactin. As all roads lead to the proverbial Rome, we discuss here how distinct molecular pathways may converge to the same final result that is motor neuron death. We critically review the basic research on SOD1-linked ALS to propose a pioneering model of a 'systemic' form of the disease, causally involving multiple cell types, either neuronal or non-neuronal. Contrasting this, we also postulate that other neuron-specific defects, as those triggered by dynactin dysfunction, may account for a primary motor neuron disease that would represent 'pure' neuronal forms of ALS. Identifying different disease subtypes is an unavoidable step toward the understanding of the physiopathology of ALS and will hopefully help to design specific treatments for each subset of patients.     

Amyotrophic lateral sclerosis and occupational exposure to electromagnetic fields

In an hypothesis-generating case-control study of amyotrophic lateral sclerosis, lifetime occupational histories were obtained. The patients (n = 28) were clinic based. The occupational exposure of interest in this report is electromagnetic fields (EMFs). This is the first and so far the only exposure analyzed in this study. Occupational exposure up to 2 years prior to estimated disease symptom onset was used for construction of exposure indices for cases. Controls (n = 32) were blood and nonblood relatives of cases. Occupational exposure for controls was through the same age as exposure for the corresponding cases. Twenty (71%) cases and 28 (88%) controls had at least 20 years of work experience covering the exposure period. The occupational history and task data were used to classify blindly each occupation for each subject as having high, medium/high, medium, medium/low, or low EMF exposure, based primarily on data from an earlier and unrelated study designed to obtain occupational EMF exposure information on workers in “electrical” and “nonelectrical” jobs. By using the length of time each subject spent in each occupation through the exposure period, two indices of exposure were constructed: total occupational exposure (E₁) and average occupational exposure (E₂). For cases and controls with at least 20 years of work experience, the odds ratio (OR) for exposure at the 75th percentile of the E₁ case exposure data relative to minimum exposure was 7.5 (P < 0.02; 95% Cl, 1.4–38.1) and the corresponding OR for E₂ was 5.5 (P < 0.02; 95% CI, 1.3–22.5). For all cases and controls, the ORs were 2.5 (P < 0.1; 95% CI, 0.9–8.1) for E₁ and 2.3 (P = 0.12; 95% CI, 0.8–6.6) for E₂. This study should be considered an hypothesis-generating study. Larger studies, using incident cases and improved exposure assessment, should be undertaken. Bioelectromagnetics 18:28–35, 1997. © 1997 Wiley-Liss, Inc.     

The diagnosis of Amyotrophic lateral sclerosis in 2010

The diagnosis of Amyotrophic lateral sclerosis (ALS) remains in 2010 clinical with neurophysiological support in absence of specific biomarker(s). The disease is diverse in its presentation, cause, and progression. Treatable mimic syndromes must be excluded before the diagnosis is ascribed: ALS and its variants are recognized by neurologists, but 10% of patients are misdiagnosed. Delays in diagnosis are common. Less than 10% of cases are familial and associated with several interactive genes. The onset of ALS predates development of the clinical symptoms by an unknown interval which may extend several years. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and family, a positive care plan are pre-requisites for the good clinical management of ALS patients.     

Amyotrophic lateral sclerosis as a complex genetic disease

In complex diseases like ALS, there are multiple genetic and environmental factors all contributing to disease liability. The genetic factors causing susceptibility to developing ALS can be considered a spectrum from single genes with large effect sizes causing classical Mendelian ALS, to genes of smaller effect, producing apparently sporadic disease. We examine the statistical genetic principles that underpin this model and review what is known about ALS as a disease with complex genetics.     

Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells

Background

Amyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.

Methodology/Principal Findings

We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.

Conclusions/Significance

Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.     

Modeling delay to diagnosis for Amyotrophic lateral sclerosis: under reporting and incidence estimates

Background

This paper provides a strategy to obtain a reliable estimate of the incidence rate for Amyotrophic lateral sclerosis based on data from the National Registry of Rare Diseases (NRRD). In fact, unobserved cases may be due to the fact that “a long time” may intercour between the suspect of having the disease (onset) and the date the disease is diagnosed. Potential factors that may influence the probability of experiencing the event (diagnosis) conditionally on the onset (suspected) are investigated. Since we are treating rare diseases, the role of social and economic factors is not that obvious; latent as well as observed factors may influence the delay to diagnosis.

Methods

We use a semiparametric estimator based on the distribution of delay to diagnosis to account for potential underreporting. In particular, we propose to adopt an Horvitz-Thompson based estimator to correct the incidence figure that can be derived for the period 2007-2009 from the NRRD, Italy.

Results

The incidence estimates obtained by adopting the proposed approach are about 1 case per 100000 inhabitants and despite they let recovering a good part of underreporting, they are still far from ALS incidence international ranges between 1.5 and 2.5. However, by looking only at northern Italy, the incidence estimates we can derive are coherent with those known internationally.

Conclusions

These results confirm the existence of substantial differences in reporting accuracy, and point out where the system of data collection must be improved. In particular, when reliable individual characteristics will be available, they could be employed to refine the proposed estimator.

     

Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD)

There is increasing clinical, imaging and neurophatological evidence that amyotrophic lateral sclerosis (ALS) represents a multisystem neurodegenerative disease. Neurodegeneration is not restricted to motor neurons, but also includes parts of the brain other than the motor cortex, especially the prefrontal and/or anterior temporal lobe, that contribute to the clinical syndrome. In some cases an evident dementia that resembles frontotemporal degeneration (FTD) was observed. It is now suggested that ALS and FTD are closely related conditions with overlapping clinical, pathological, radiological, and genetic characteristics. The presence of a frontal dementia in ALS has also crucial practical consequences for management of the patients, whose disorder requires critical life decisions for enteral nutrition and respiratory complications. It is our intent to provide a brief overview of the relationships between ALS and FTD.     

Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.     

Amyotrophic lateral sclerosis: evidence for intact hepatocyte growth factor/met signalling axis

Hepatocyte growth factor (HGF) is a secreted cytokine which is expressed in the central nervous system (CNS) together with its specific receptor MET. Since HGF exerts strong neurotrophic activity including motoneurons, we have further analysed whether the HGF/MET axis is defective in patients with amyotrophic lateral sclerosis (ALS). Intrathecal HGF-secretion was measured in cerebrospinal fluid (CSF) from patients with amyotrophic lateral sclerosis and in controls without neurological diseases using a specific sandwich immunoassay (ELISA). MET-expression was analysed by immunohistology in spinal cord cross-sections of ALS patients and unaffected controls. The HGF concentrations in CSF were moderately but significantly increased in ALS patients compared to healthy controls (580 pg/ml vs 348 pg/ml). MET-protein was detectable in spinal cord motoneurons of patients with ALS as well as unaffected controls. The data demonstrate that ALS does not show a lack of the trophic signalling axis, HGF/MET, suggesting that the signalling system itself is not affected. The moderate increase in HGF-secretion may represent a compensatory effect.     

Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice

Objective

To demonstrate that hypolipidemia is a typical feature of the mouse model of amyotrophic lateral sclerosis (ALS) and to assess the association between hypolipidemia and disease stage, dietary intake, and sex.

Methods

We compared daily dietary intake, body weight, and serumlipid and glucose levels in ALS mice and wild-type controls at different stages of the disease.

Findings

Total cholesterol low-density lipoprotein (LDL) and LDL/high-density lipoprotein (HDL) ratio were significantly lower in ALS mice compared with controls. Subgroup analysis revealed that the incidence of hypolipidemia was significantly greater in male, but not female, ALS mice compared with control mice and that hypolipidemia was present at the presymptomatic stage of the disease. This hypolipidemia can be found without a decrease in the serum levels of other energy sources, such as glucose, in the presymptomatic stage.

Conclusions

Hypolipidemia is present at the presymptomatic stage of the ALS mouse model in the absence of malnutrition, significant neuromuscular degeneration or regeneration, and respiratory difficulty. Our findings suggest that hypolipidemia might be associated with the pathomechanism of ALS and/or lipid-specific metabolism rather than simply an epiphenomenon of neuromuscular degeneration or energy imbalance.     

Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss of motor neurons. The cause of disease is unknown other than in the rare cases of familial disease arising from mutations in the superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed - including oxidative stress, excitotoxicity, mitochondrial dysfunction and abnormal protein aggregation - based on studies of human post mortem tissue, research on animal models, and in vitro work. Here we review the evidence for the main pathogenic mechanisms and outline how they might interact to cause motor neuron death. Clinical trials have as yet failed to identify any truly effective therapies in ALS, with only riluzole providing a modest improvement in survival. Ongoing trials are exploring the value of antiglutamatergic agents, including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective therapy will involve combinations of agents acting on different mechanisms. Gene therapy with neurotrophic factors will soon be in clinical trials, while work on stem cell therapy remains preclinical. In addition to finding effective therapies, research also needs to identify early disease markers because therapy is likely to be of most benefit when given early in the course of disease.     

SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.     

Amyotrophic lateral sclerosis in pregnancy: clinical outcome during the post-partum period after stem cell transplantation into the frontal motor cortex

Background aimsAmyotrophic lateral sclerosis (ALS) is rare in pregnant patients. Stem cell therapy has been proposed as a potential therapeutic strategy for ALS.MethodsWe describe a young woman with sporadic ALS that started during the second trimester of pregnancy with a rapid progression after delivery and severe motor impairment. Several drugs and stem cell injection by lumbar puncture were performed without changes before the patient was referred to our institution.ResultsAfter bilateral autologous stem cell transplantation into the frontal motor cortices, we observed stabilization in ALS functional rating scale, significant delay of ALS progression and an extension in her life expectancy.ConclusionsStem cell transplantation may alter the clinical course of ALS and improve quality of life in pre-menopausal women.