ALS Reviews 2003
Al-Chalabi, A. and C. C. Miller (2003). "Neurofilaments and neurological disease." Bioessays 25(4): 346-55.
Neurofilaments are one of the major components of the neuronal cytoskeleton and are responsible for maintaining the calibre of axons. They are modified by post-translational changes that are regulated in complex fashions including by the interaction with neighbouring glial cells. Neurofilament accumulations are seen in several neurological diseases and neurofilament mutations have now been associated with Charcot-Marie-Tooth disease, Parkinson's disease and amyotrophic lateral sclerosis. In this review, we discuss the structure, normal function and molecular pathology of neurofilaments.
Armon, C. (2003). "An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis." Neuroepidemiology 22(4): 217-28.
An evidence-based medicine approach was applied to evaluate analytic studies of exogenous risk factors for amyotrophic lateral sclerosis (ALS) published since 1991. Classification systems for evaluating the literature and for drawing conclusions based on the class of available evidence were developed, modeled on those used by national societies. Considerations regarding the impact on the general public of confirming a role for putative risk factors were made explicit. There was evidence in support of smoking being a probable ('more likely than not') risk factor for ALS. Smoking has broad public health impact, no redeeming features, and is a modifiable risk factor. Evidence supported the conclusion that the following were probably not risk factors for ALS: trauma, physical activity, residence in rural areas and alcohol consumption. Evidence-based medicine methodology does not permit calculation of the magnitude of type I or type II errors in drawing these conclusions. New evidence may change these conclusions. Recommendations for future research include: draw on clinical trial methodology in designing future, confirmatory, case-control studies; consider utilizing cohort studies, recognizing the longer timelines for these to come to fruition; accord priority to investigating putative risk factors with greatest public health impact. Advances in study methodology may lead to development of finite research cycles for individual putative risk factors for sporadic ALS.
Authier, F. J. and R. K. Gheradi (2003). "Peripheral neuropathies in HIV-infected patients in the era of HAART." Brain Pathol 13(2): 223-8.
Bach, J. R. (2003). "Threats to "informed" advance directives for the severely physically challenged?" Arch Phys Med Rehabil 84(4 Suppl 2): S23-8.
The neuromuscular diseases, such as infantile spinal muscular atrophy, Duchenne's muscular dystrophy, and amyotrophic lateral sclerosis, are widely considered to be terminal illnesses. However, as with many neuromuscular and neurologic diseases, morbidity and mortality are caused by dysfunction of inspiratory, expiratory, and bulbar musculature. This article will discuss how inspiratory and expiratory musculature can be supported by simple, noninvasive means that are rarely considered when, as with the general population, individuals with disabilities are counseled about advance directives. Failure to use noninvasive aids almost invariably results in respiratory failure, intubation, and tracheostomy or death. When noninvasive aids are available, invasive measures referred to in advance directives (eg, intubation) are often needed only temporarily. Yet, ill-informed patients are often advised to refuse intubation and die or to be intubated and left to decide whether to undergo tracheostomy for long-term ventilatory support. Further, despite severe disability, ventilator users with neuromuscular disease report normal life satisfaction. Health care professionals, on the other hand, tend to ignore the patient's life satisfaction and consider quality of life measures not designed for the disabled to justify withholding life-saving interventions. Advance directives, although sometimes appropriate for patients with irretractable pain and advanced cancer, are inappropriate for patients with severe disability because of muscle weakness, and virtually no patients are appropriately counseled about all therapeutic options.
Campiani, G., C. Fattorusso, et al. (2003). "Neuronal high-affinity sodium-dependent glutamate transporters (EAATs): targets for the development of novel therapeutics against neurodegenerative diseases." Curr Pharm Des 9(8): 599-625.
L-Glutamate is the major excitatory neurotransmitter in mammalian central nervous system, and excitatory amino acid transporters (EAATs) are essential for terminating synaptic excitation and for maintaining extracellular glutamate concentration below toxic levels. Although the structure of these channel-like proteins has not been yet reported, their membrane topology has been hypothesised based on biochemical and protein sequence analyses. In the case of an inadequate clearance from synaptic cleft and from the extrasynaptic space, glutamate behaves as a potent neurotoxin, and it may be related to several neurodegenerative pathologies including epilepsy, ischemia, amyotrophic lateral sclerosis, and Alzheimer disease. The recent boom of glutamate is demonstrated by the enormous amount of publications dealing with the function of glutamate, with its role on modulation of synaptic transmission throughout the brain, mainly focusing: i). on the structure of its receptors, ii). on molecular biology and pharmacology of Glu transporters, and iii). on the role of glutamate uptake and reversal uptake in several neuropathologies. This review will deal with the recent and most interesting published results on Glu transporters membrane topology, Glu transporters physiopathological role and Glu transporters medicinal chemistry, highlighting the guidelines for the development of potential neuroprotective agents targeting neuronal high-affinity sodium-dependent glutamate transporters.
Carter, G. T., L. S. Krivickas, et al. (2003). "Drug therapy for amyotrophic lateral sclerosis: Where are we now?" IDrugs 6(2): 147-53.
In the 60 years since Lou Gehrig died from amyotrophic lateral sclerosis (ALS) there have been numerous advances in our understanding of this disease. However, scant progress has been made regarding disease-altering treatments. Today most physicians still recommend vitamin E, which is the treatment Gehrig himself received. In this paper we will review what is currently known about the pathophysiology of ALS as well as the history of clinical trials in ALS. We indicate current and future directions in research and clinical trials, and also argue that a logical next step for clinical trials in ALS should be combination drug treatment.
Choi, I. Y., S. P. Lee, et al. (2003). "In vivo NMR studies of neurodegenerative diseases in transgenic and rodent models." Neurochem Res 28(7): 987-1001.
In vivo magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) provide unique quality to attain neurochemical, physiological, anatomical, and functional information non-invasively. These techniques have been increasingly applied to biomedical research and clinical usage in diagnosis and prognosis of diseases. The ability of MRS to detect early yet subtle changes of neurochemicals in vivo permits the use of this technology for the study of cerebral metabolism in physiological and pathological conditions. Recent advances in MR technology have further extended its use to assess the etiology and progression of neurodegeneration. This review focuses on the current technical advances and the applications of MRS and MRI in the study of neurodegenerative disease animal models including amyotrophic lateral sclerosis, Alzheimer's, Huntington's, and Parkinson's diseases. Enhanced MR measurable neurochemical parameters in vivo are described in regard to their importance in neurodegenerative disorders and their investigation into the metabolic alterations accompanying the pathogenesis of neurodegeneration.
Crosby, A. H. (2003). "Disruption of cellular transport: a common cause of neurodegeneration?" Lancet Neurol 2(5): 311-6.
In many cases, the clinical manifestations of inherited neurodegenerative disorders appear after decades of normal function, which suggests that neurons may die through cumulative damage. Several genes that cause these diseases have been identified in recent years, but no common pathogenetic mechanism has been found. However, the most recent studies have begun to implicate the same mechanism in a range of neurodegenerative diseases, particularly those that involve motor neurons. The results of these studies suggest that the morphology and energy requirements of neurons make them particularly susceptible to the disruption of cellular transport systems.
Dawbarn, D. and S. J. Allen (2003). "Neurotrophins and neurodegeneration." Neuropathol Appl Neurobiol 29(3): 211-30.
There is growing evidence that reduced neurotrophic support is a significant factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In this review we discuss the structure and functions of neurotrophins such as nerve growth factor, and the role of these proteins and their tyrosine kinase (Trk) receptors in the aetiology and therapy of such diseases. Neurotrophins regulate development and the maintenance of the vertebrate nervous system. In the mature nervous system they affect neuronal survival and also influence synaptic function and plasticity. The neurotrophins are able to bind to two different receptors: all bind to a common receptor p75NTR, and each also binds to one of a family of Trk receptors. By dimerization of the Trk receptors, and subsequent transphosphorylation of the intracellular kinase domain, signalling pathways are activated. We discuss here the structure and function of the neurotrophins and how they have been, or may be, used therapeutically in AD, PD, Huntington's diseases, ALS and peripheral neuropathy. Neurotrophins are central to many aspects of nervous system function. However they have not truly fulfilled their therapeutic potential in clinical trials because of the difficulties of protein delivery and pharmacokinetics in the nervous system. With the recent elucidation of the structure of the neurotrophins bound to their receptors it will now be possible, using a combination of in silico technology and novel screening techniques, to develop small molecule mimetics with much improved pharmacotherapeutic profiles.
Di Matteo, V. and E. Esposito (2003). "Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis." Curr Drug Target CNS Neurol Disord 2(2): 95-107.
Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. Several studies have shown that nutritional antioxidants (especially vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB) in apoptosis, and in the pathogenesis of neurodegenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.
Dib, M. (2003). "Amyotrophic lateral sclerosis: progress and prospects for treatment." Drugs 63(3): 289-310.
Fifteen years ago, a role for excitotoxic damage in the pathology of amyotrophic lateral sclerosis (ALS) was postulated. This stimulated the development of riluzole, the only available treatment for the disease. Since then, the identification of abnormal forms of superoxide dismutase as the genetic basis of certain familial forms of ALS has provided a huge impetus to the search for new effective treatments for this devastating disease. Transgenic mouse models have been developed expressing these aberrant mutants that develop a form of motor neurone disease the progress of which can be slowed by riluzole. Studies in these mice have provided evidence for a role for excitotoxic, apoptotic and oxidative processes in the development of pathology. The mice can be used for testing molecules targeting these processes as potential therapies, to allow the most promising to be evaluated in humans. Several such agents are currently in clinical trials. Many previous clinical trials in ALS were insufficiently powered to demonstrate any relevant effect on disease progression. This situation has been to some extent remedied in the more recent trials, which have recruited many hundreds of patients. However, with the exception of studies with riluzole, the results of these have been disappointing. In particular, a number of large trials with neurotrophic agents have revealed no evidence for efficacy. Nonetheless, the need for large multinational trials of long duration limits the number that can be carried out and makes important demands on investment. For this reason, surrogate markers that can be used for rapid screening in patients of potential treatments identified in the transgenic mice are urgently needed.
Farrero, E., E. Prats, et al. (2003). "[Series 4: respiratory muscles in neuromuscular diseases and the chest cavity. Decision making in the clinical management of patients with lateral amyotrophic sclerosis]." Arch Bronconeumol 39(5): 226-32.
Friedlander, R. M. (2003). "Apoptosis and caspases in neurodegenerative diseases." N Engl J Med 348(14): 1365-75.
Gelinas, D. F. (2003). "Pulmonary function screening." Semin Neurol 23(1): 89-96.
Patients who suffer from neuromuscular diseases often have complications from respiratory insufficiencies. Some neuromuscular diseases, for example Landry Guillain-Barre syndrome, may only require temporary tracheal intubation; patients with other neuromuscular diseases, such as amyotrophic lateral sclerosis, may decide with the assistance of their doctor and family to opt for lifelong noninvasive ventilatory support. Other patients may only opt for noninvasive positive pressure ventilation. Respiratory dysfunction is caused by weakness of the upper airway muscles, which can lead to sleep apnea, abnormal swallow, and decreased respiratory muscle strength, as well as a decrease in total lung volume. Early respiratory changes in patients with neuromuscular disease are often best detected during sleep. During rapid eye movement sleep, there is a reduction in respiratory drive predisposing to hypopneas and apneas. The majority of neuromuscular patients with respiratory insufficiency may be monitored and treated in the outpatient setting, thus allowing them to remain in their homes.
Gourie-Devi, M., A. Nalini, et al. (2003). "Early or late appearance of "dropped head syndrome" in amyotrophic lateral sclerosis." J Neurol Neurosurg Psychiatry 74(5): 683-6.
BACKGROUND: "Dropped head syndrome" caused by neck extensor weakness has been reported in a variety of neuromuscular disorders. Previously published reports include isolated cases with amyotrophic lateral sclerosis (ALS). In this report, nine patients with ALS and dropped head syndrome seen during a 20 year period are described. PATIENTS AND INVESTIGATIONS: Between 1981 and 2000, 683 patients with ALS were diagnosed, based on El Escorial criteria. Nine of these had profound neck extensor weakness observed as an early feature, or developing during the later stages of the disease. The protocol for evaluation included detailed clinical history, neurological examination, electromyography, and nerve conduction studies. Investigations were undertaken to exclude malignancy, lymphoproliferative disorders, thyroid dysfunction, and collagen vascular disease. RESULTS: The incidence of dropped head syndrome was 1.3%. The mean (SD) age of the affected patients was 53.3 (10.3) years (range 33 to 65), with an equal distribution of cases in the fourth to seventh decades. In six patients, head drop was an early feature (mean interval from onset of illness 11.6 months (range 3 to 24)); in three it was late (between three and eight years after onset). In five patients, mild neck flexor weakness was present in addition to severe extensor weakness. In all nine patients there were diffuse upper and lower motor neurone signs. None of the patients had difficulty in breathing but all had difficulty in swallowing and social embarrassment, both of which could be corrected by simple measures. CONCLUSIONS: Dropped head syndrome is an important clinical sign and usually occurs as an early feature within the first one to two years after the onset of ALS. The cause of dropped head syndrome in these nine cases could be easily established as ALS by the presence of generalised signs.
Guegan, C. and S. Przedborski (2003). "Programmed cell death in amyotrophic lateral sclerosis." J Clin Invest 111(2): 153-61.
Isacson, O. (2003). "The production and use of cells as therapeutic agents in neurodegenerative diseases." Lancet Neurol 2(7): 417-24.
Although progressive neurodegenerative diseases have very different and highly specific causes, the dysfunction or loss of a vulnerable group of neurons is common to all these disorders and may allow the development of similar therapeutic approaches to the treatment of diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. When a disease is diagnosed, the first step is to instigate protective measures to prevent further degeneration. However, most patients are symptom-free until almost all of the vulnerable cells have become dysfunctional or have died. There are known molecular mechanisms and processes in stem cells and progenitor cells that may be of use in the future design and selection of cell-based replacement therapies for neurological diseases. This review provides examples of conceptual and clinical problems that have been encountered in the development of cell-based treatments, and specific criteria for the effective use of cells in the future treatment of neurodegenerative diseases.
Ischiropoulos, H. and J. S. Beckman (2003). "Oxidative stress and nitration in neurodegeneration: cause, effect, or association?" J Clin Invest 111(2): 163-9.
Ishihara, K., H. Murakami, et al. (2003). "[A case of amyotrophic lateral sclerosis with dementia presenting long clinical course]." No To Shinkei 55(2): 157-61.
We describe a patient with amyotrophic lateral sclerosis with dementia (ALS-D) displaying a long clinical course. A 68-year-old Japanese male with no family history of note was admitted complaining of severe dysarthria and dysphagia. At 63 years old, Pick's disease was diagnosed on the basis of abnormal behavior, such as "Denkfaulheit" and moria, and temporal lobe atrophy observed on magnetic resonance imaging (MRI). Five years after onset, dysarthria and dysphagia emerged, and gradually worsened. On admission, muscular weakness of the upper extremities, fasciculation, and exaggerated tendon stretch reflexes were noted. Needle electromyography performed on the left upper and lower extremities revealed neurogenic pattern changes. Based on these findings and clinical course, ALS-D was diagnosed. Due to severe bulbar palsy, verbal communication was impossible. However, neither specific symptoms of dementia nor abnormal behavior was demonstrated, although this latter had been observed 5 years ago, with only short-term memory impairment apparent. MRI disclosed severe knife-edge atrophy of bilateral temporal lobes, most prominently in the anterior regions. SPECT images revealed decreased uptake of tracer in bilateral inferior temporal lobes, predominantly on the left side. The patient died suddenly 4 months after admission, and post-mortem examination was not conducted. Total clinical course was about 8 years. Several cases of ALS-D have displayed similar clinical courses to the presented case. Some of these would also have initially been diagnosed as Pick's disease. We speculate that cases displaying psychiatric symptoms for several years and initially diagnosed as Pick's disease may finally be diagnosed as ALS-D upon the eventual emergence of motor symptoms(bulbar palsy).
Kaji, R. and H. Nodera (2003). "[New concept of multifocal motor neuropathy and conduction block]." No To Shinkei 55(7): 565-75.
Kikuchi, S., K. Shinpo, et al. (2003). "Glycation--a sweet tempter for neuronal death." Brain Res Brain Res Rev 41(2-3): 306-23.
Glycation, one of the post-translational modifications of proteins, is a nonenzymatic reaction initiated by the primary addition of a sugar aldehyde or ketone to the amino groups of proteins. In the early stage of glycation, the synthesis of intermediates leading to the formation of Amadori compounds occurs. In the late stage, advanced glycation end products (AGE) are irreversibly formed after a complex cascade of reactions. Several AGEs have been characterized chemically, while other new compounds remain to be identified. To date, studies of the contribution of glycation to diseases have been primarily focused on its relationship to diabetes and diabetes-related complications. However, glucose-induced damage is not limited to diabetic patients. Although it does not cause rapid or remarkable cell damage, glycation advances slowly and accompanies every fundamental process of cellular metabolism. It has recently become clear that glycation also affects physiological aging and neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Glycation alters the biological activity of proteins and their degradation processes. Protein cross-linking by AGE results in the formation of detergent-insoluble and protease-resistant aggregates. Such aggregates may interfere with both axonal transport and intracellular protein traffic in neurons. In addition, glycation reactions lead to the production of reactive oxygen species. Conversely, glycation is promoted by oxidative stress. We speculate on the presence of synergism between glycation and oxidative stress. In this review, we provide an outline of glycation and propose some possible mechanisms of its cytotoxicity and defense systems against it.
Li, C. Y. and F. C. Sung (2003). "Association between occupational exposure to power frequency electromagnetic fields and amyotrophic lateral sclerosis: a review." Am J Ind Med 43(2): 212-20.
BACKGROUND: For the past two decades, there has been concern over electromagnetic exposure and human health. While most research has focused on cancer and reproductive outcomes, there is interest in the relationship between electromagnetic fields (EMF) and neurodegenerative diseases. METHODS: We review epidemiological findings and evidence regarding the association between occupational exposure to power frequency EMFs and amyotrophic lateral sclerosis (ALS). Medline was searched for citations related to occupational hazards and ALS, literature reviews and epidemiological evaluations. RESULTS: Nine out of the ten epidemiological studies that have been conducted on the risk of ALS in relation to occupational exposure to EMF show moderate to strong relative risk estimates that supported a link between them. Although data from these studies was consistent, the causal inference to a link between EMF exposure and ALS is restricted mainly due to the lack of direct information on EMF exposure and incomplete consideration of the other potential risk factors for ALS at workplaces. For instance, electric shock, in particular, is more common in electrical occupations than in any other occupations. CONCLUSIONS: This review concludes that further studies should consider investigating the separate effect of EMF exposure and electrical shocks to make more specific interpretations. On-site measurements of EMF should be conducted to include information on EMF exposure from residences as well as workplaces to improve exposure assessment.
Mathisen, P. M. (2003). "Gene discovery and validation for neurodegenerative diseases." Drug Discov Today 8(1): 39-46.
Treatment of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis (ALS), represents a major challenge for the pharmaceutical industry. These disorders have common and unique molecular pathological characteristics that result in serious reductions in nervous-system functionality. Key to developing novel and efficacious therapeutics is the discovery of new gene targets. Genomic, proteomics and bioinformatic analyses are identifying vast amounts of genes whose expression is associated with the pathology of a specific disease. Extensive validation studies performed in parallel with drug development are crucial for the selection of appropriate target genes. This review outlines some of the current progress in gene discovery for neurodegenerative disease.
Mattson, M. P. (2003). "Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders." Neuromolecular Med 3(2): 65-94.
Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of antiexcitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.
Monaco, E. A., 3rd and M. L. Vallano (2003). "Cyclin-dependent kinase inhibitors: cancer killers to neuronal guardians." Curr Med Chem 10(5): 367-79.
The development of small molecule kinase inhibitors as potential cancer therapeutics is an area of intense interest, and a subset of these agents target cyclin-dependent kinase (CDK) activity. Ten distinct CDKs (1-9, 11), when paired with their cyclin activators, are integral to such diverse processes as cell cycle control, neuronal development, and transcriptional regulation. Mutation and/or aberrant expression of certain CDKs and their regulatory counterparts are associated with uncontrolled proliferation and tumorigenesis. As such, CDK selective inhibitors (CDKIs) that attenuate or prevent tumor growth have been developed. Recently, interest in the therapeutic potential of CDKIs has expanded to include neurodegenerative diseases, where dysregulated CDK activity has been linked to the pathogenesis of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke. Specifically, aberrant activation of cell cycle CDKs or CDK5 is associated with apoptosis and neuronal dysfunction in response to various neuronal stressors. To date, CDKIs have shown promise as neuroprotective agents in the research laboratory and, in the future, may prove useful in the neurology clinic.
Moris, G. and J. A. Vega (2003). "[Neurotrophic factors: basis for their clinical application]." Neurologia 18(1): 18-28.
Neurotrophic factors are molecules that regulate neuronal survival, nervous system plasticity and many other physiological functions of neuronal and glial cells, as well as some non-neuronal tissues. They have been involved in the etiopathogenesis of some neurodegenerative disorders, and some of them have been proposed as potential treatments for these diseases on the basis of in vitro experiments and animal models. The main neurotrophic factor families with potential therapeutic applications include the family of neurotrophins (NGF, BDNF or NT-3), GDNF and related neurotrophic factor, CNTF and the members of the IGF family. Some of these molecules have already been tested in clinical trials with contradictory results. One of the major challenges to their clinical use is the difficulty to deliver them into the central nervous system. Nevertheless, solid rational exists for the possible use of neurotrophic factors in the treatment of Alzheimer's and Parkinson's diseases, peripheral neuropathies or amyotrophic lateral sclerosis. This review compiles the essential aspects of neurotrophic factors and the current studies of their clinical relevance and therapeutic potentialities. Future directions for further research are also discussed.
Przedborski, S., H. Mitsumoto, et al. (2003). "Recent advances in amyotrophic lateral sclerosis research." Curr Neurol Neurosci Rep 3(1): 70-7.
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. Despite several genetic breakthroughs, the actual cause and mechanism of neurodegeneration in ALS remains a mystery. Nevertheless, recent scientific and clinical advances have led to the development of new therapeutic strategies for this progressive, fatal disorder. We review the progress of the most recent clinical trials in ALS, taking into account some of the hurdles encountered by these studies. We also discuss the potential role of retroviral infection as a cause or contributor to ALS, which is one of the most recent hypotheses for the pathogenesis of the disease. The genetic background of ALS is summarized and special attention is given to the newly identified ALS gene ALS2, and to those that are currently being investigated. The last part of this review is dedicated to the mutation in superoxide dismutase-1 (SOD1). The hypothesized deleterious mechanisms of mutant SOD1 are discussed, as well as the possibilities that the mutant protein activates the apoptotic cell death process and that these molecular alterations can be exploited to devise experimental neuroprotective therapies.
Rabinstein, A. A. and E. F. Wijdicks (2003). "Warning signs of imminent respiratory failure in neurological patients." Semin Neurol 23(1): 97-104.
Critically ill neurological patients often need ventilatory assistance. After acute central nervous system insults, the inability to protect the airway and impaired central respiratory drive can only be managed with endotracheal intubation and mechanical ventilation. In patients with acute or worsening neuromuscular disorders, diaphragmatic failure and pronounced bulbar weakness may necessitate intubation to assist in the work of breathing or to prevent upper airway obstruction. Simple respiratory function tests performed at the bedside should be used to monitor patients with progressive neuromuscular respiratory insufficiency. Noninvasive positive pressure ventilation plays an important role in the management of respiratory failure in patients with neuromuscular respiratory failure, and its indications may be expanded in the future.
Rao, M. V. and R. A. Nixon (2003). "Defective neurofilament transport in mouse models of amyotrophic lateral sclerosis: a review." Neurochem Res 28(7): 1041-7.
Neurofilament proteins synthesized in the cell body of neurons are assembled and transported into axons, where they influence axon radial growth, axonal transport, and nerve conduction velocities. In diseased states, neurofilaments accumulate in cell bodies and proximal axons of affected neurons, and these lesions are characteristic of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease type 2 (CMT2), and hereditary sensory motor neuropathy. Although the molecular mechanisms that contribute to these accumulations are not yet identified, transgenic mouse models are beginning to provide insight into the role of neurofilament transport in disease-related dysfunction of neurons. This review addresses axonal transport in mouse models of ALS and the special significance of neurofilament transport in this disease.
Rojas-Marcos, I., A. Rousseau, et al. (2003). "Spectrum of paraneoplastic neurologic disorders in women with breast and gynecologic cancer." Medicine (Baltimore) 82(3): 216-23.
We conducted the current review of the paraneoplastic neurologic syndromes (PNSs) associated with gynecologic and breast carcinomas to describe their clinical and immunologic characteristics and their relative frequency. We retrospectively reviewed 92 patients whose serum was sent to our laboratories to detect onconeural antibodies and who were diagnosed as having PNSs associated with breast or gynecologic tumors. PNSs were defined as "definitive" and "possible" (atypical PNS, no onconeural antibodies, and no improvement after tumor treatment). Forty-nine patients had breast and 43 had gynecologic cancer. Sixty-three patients had onconeural antibodies (50 Yo-ab, 5 Hu-ab, 5 Ri-ab, and 3 amphiphysin-ab). Cerebellar ataxia represented 57 (62%) of all PNSs and was associated with anti-Yo in 88%. All Yo-abnegative patients had breast cancer; 4 of them had a mild cerebellar syndrome that improved after tumor treatment. Sensorypredominant neuropathies were present in 17 (18%) patients. Seven of them had Hu-ab (5) or amphiphysin-ab (2). Other PNSs were opsoclonus-myoclonus syndrome (4 cases, Ri-ab in 2), sensorimotor neuropathy (4 cases), paraneoplastic encephalomyelitis (4 cases, Ri-ab in 3), paraneoplastic retinopathy (2 cases), amyotrophic lateral sclerosis (2 cases), stiff-person syndrome (1 with amphiphysin-ab), and limbic encephalitis (1 case). All patients with gynecologic cancer presented definitive PNS, and onconeural antibodies were diagnosed in 93% of them. In contrast, 20% of PNSs associated with breast cancer were defined as possible and the incidence of onconeural antibodies was 51%, excluding the 2 patients with paraneoplastic retinopathy in whom antiretinal antibodies were not analyzed. In patients with possible PNS, a coincidental association between the tumor and the neurologic disorder cannot be excluded.
Rothstein, J. D. (2003). "Of mice and men: reconciling preclinical ALS mouse studies and human clinical trials." Ann Neurol 53(4): 423-6.
Shigeri, Y. and K. Shimamoto (2003). "[Excitatory amino acid transporters: development of regulatory molecules for their functional analysis]." Seikagaku 75(4): 288-92.
Silani, V. and N. Leigh (2003). "Stem therapy for ALS: hope and reality." Amyotroph Lateral Scler Other Motor Neuron Disord 4(1): 8-10.
All are agreed that there is pressing need for an effective treatment for Amyotrophic Lateral Sclerosis (ALS; MND). Such treatment may derive from a combination of therapeutic strategies aimed at different aspects of the disorder, and might include drugs directed at the initial, intermediate or terminal cascade of events leading to cell death, as well as the use of stem cells to replace dead motor neurons, or to protect those that remain. The attraction of cell implantation or transplantation is that it might help to overcome the inability of the CNS to replace lost neurons. It is also clear that neural implantation will yield little benefit if the donor cells fail to integrate functionally into the recipient CNS circuitry. In this respect, ALS poses an especially difficult problem. The recent breakthroughs in stem cell research might nevertheless provide possibilities for neural implantation and cell replacement therapy for patients with ALS. The potential impact of these new approaches to neurodegenerative diseases has been emphasised by the many experiments using human foetal cell grafts in patients affected by Parkinson's and Huntington's disease. Clinical benefits in Parkinson's disease seem to be associated with integration of the donor cells into the recipient brain. Despite promising results, however, significant constraints have hampered the use of foetal cells for neural implantation and transplantation. Besides ethical concerns, the viability, purity, and final destiny of the foetal tissue have not been completely defined. Foetal cells are, in addition, post-mitotic and cannot be expanded or stored for long periods, necessitating close synchronisation of tissue donation and neurosurgery.
Valentine, J. S. and P. J. Hart (2003). "Misfolded CuZnSOD and amyotrophic lateral sclerosis." Proc Natl Acad Sci U S A 100(7): 3617-22.
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. The inherited form of the disease, familial ALS, represents 5-10% of the total cases, and the best documented of these are due to lesions in SOD1, the gene encoding copper-zinc superoxide dismutase (CuZnSOD). The mechanism by which mutations in SOD1 cause familial ALS is currently unknown. Two hypotheses have dominated recent discussion of the toxicity of ALS mutant CuZnSOD proteins: the oligomerization hypothesis and the oxidative damage hypothesis. The oligomerization hypothesis maintains that mutant CuZnSOD proteins are, or become, misfolded and consequently oligomerize into increasingly high-molecular-weight species that ultimately lead to the death of motor neurons. The oxidative damage hypothesis maintains that ALS mutant CuZnSOD proteins catalyze oxidative reactions that damage substrates critical for viability of the affected cells. This perspective reviews some of the properties of both wild-type and mutant CuZnSOD proteins, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypotheses are not necessarily mutually exclusive.
van den Berg-Vos, R. M., J. Visser, et al. (2003). "Sporadic lower motor neuron disease with adult onset: classification of subtypes." Brain 126(Pt 5): 1036-47.
The discovery of the genetic basis of hereditary lower motor neuron disease (LMND) and the recognition of multifocal motor neuropathy as a distinct clinical entity necessitate a new classification of LMND. To this end, we studied the clinical and electrophysiological features of 49 patients with sporadic adult-onset LMND in a cross-sectional study. Disease duration was more than 4 years to exclude the majority of patients with amyotrophic lateral sclerosis. Based on the pattern of weakness, we identified three groups: 13 patients with generalized weakness (group 1); eight patients with symmetrical, distal muscle weakness (group 2); and 28 patients with non-generalized asymmetrical weakness of the arms in most patients (group 3). Group 3 could be subdivided into patients with weakness in predominantly the distal (group 3a) or the proximal (group 3b) muscle groups, both with disease progression to adjacent spinal cord segments. Distinctive features of group 1 were an older age at onset, more severe weakness and muscle atrophy, lower reflexes, greater functional impairment, more widespread abnormalities on concentric needle EMG, respiratory insufficiency and serum M-protein. In groups 2 and 3, concentric needle EMG findings also suggested a more widespread disease process. Retrospectively, the prognosis of sporadic adult-onset LMND appears to be favourable, because clinical abnormalities were still confined to one limb in most patients after a median disease duration of 12 years. We propose to classify the patients in the different subgroups as slowly progressive spinal muscular atrophy (group 1), distal spinal muscular atrophy (group 2), segmental distal spinal muscular atrophy (group 3a) and segmental proximal spinal muscular atrophy (group 3b). The described clinical phenotypes may help to distinguish between different LMND forms.
Vercelletto, M., S. Belliard, et al. (2003). "[Neuropsychological and scintigraphic aspects of frontotemporal dementia preceding amyotrophic lateral sclerosis]." Rev Neurol (Paris) 159(5 Pt 1): 529-42.
Between 1993 and 2001, we observed fifteen patients (ten men and five women, mean age 63 years) with frontotemporal dementia (FTD) which preceded signs of amyotrophic lateral sclerosis (ALS) which developed 21 months later. Mean disease duration in the fourteen deceased patients was 38 months. FTD associated with ALS is characterized by rapid course, predominance of disinhibited forms (orbito-basal), presence of aphasia with neologisms, and semantic memory disorders. Performed in all patients, single-photon emission computed tomography demonstrated a bifrontal pattern of low uptake, sometimes associated with low uptake in the anterior temporal region. In one patient, neuropathology revealed neuron atrophy and loss in the frontotemporal region, the anterior horns, and the hypoglossal nucleus. Ubiquitin-positive inclusions were visible in the dentate gyrus of the hippocampus and in the anterior horns. The dementia/ALS association is classically described is uncommon. It belongs to the FTD group since the Lund and Manchester consensus. Approximately 15 p.100 of patient with FTD can be expected to develop ALS. About 250 cases have been reported in the literature, half of them in the Pacific area where the incidence of ALS is high (55/100,000 inhabitants versus 1/100,000 in the rest of the world). Intermediary forms of FTD, semantic dementia, and progressive non-fluent aphasia are discussed since several cases of non-fluent progressive aphasia associated with ALS are reported in the literature. The links between these two degenerative diseases are discussed.
Vila, M. and S. Przedborski (2003). "Targeting programmed cell death in neurodegenerative diseases." Nat Rev Neurosci 4(5): 365-75.
Waldmeier, P. C. (2003). "Prospects for antiapoptotic drug therapy of neurodegenerative diseases." Prog Neuropsychopharmacol Biol Psychiatry 27(2): 303-21.
The evidence for a role of apoptosis in the neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and in the more acute conditions of cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI) is reviewed with regard to potential intervention by means of small antiapoptotic molecules. In addition, the available animal models for these diseases are discussed with respect to their relevance for testing small antiapoptotic molecules in the context of what is known about the apoptotic pathways involved in the diseases and the models. The principal issues related to pharmacotherapy by apoptosis inhibition, i.e., functionality of rescued neurons and potential interference with physiologically occurring apoptosis, are pointed out. Finally, the properties of a number of small antiapoptotic molecules currently under clinical investigation are summarized.It is concluded that the evidence for a role of apoptosis at present is more convincing for PD and ALS than for AD. In PD, damage to dopaminergic neurons may occur through oxidative stress and/or mitochondrial impairment and culminate in activation of an apoptotic, presumably p53-dependent cascade; some neurons experiencing energy failure may not be able to complete apoptosis, end up in necrosis and give rise to inflammatory processes. These events are reasonably well reflected in some of the PD animal models, notably those involving 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone. In sporadic ALS, an involvement of pathways involving p53 and Bcl-2 family members appears possible if not likely, but is not established. The issue is important for the development of antiapoptotic compounds for the treatment of this disease because of differential involvement of p53 in different mutant superoxide dismutase (SOD) mice. Most debated is the role of apoptosis in AD; this implies that little is known about potentially involved pathways. Moreover, there is a lack of suitable animal models for compound evaluation.Apoptosis or related phenomena are likely involved in secondary cell death in cerebral ischemia, TBI, and SCI. Most of the pertinent information comes from animal experiments, which have provided some evidence for prevention of cell death by antiapoptotic treatments, but little for functional benefit. Much remains to be done in this area to explore the potential of antiapoptotic drugs.There is a small number of antiapoptotic compounds in clinical development. With some of them, evidence for maintenance of functionality of the rescued neurons has been obtained in some animal models, and the fact that they made it to phase II studies in patients suggests that interference with physiological apoptosis is not an obligatory problem. The prospect that small antiapoptotic molecules will have an impact on the therapy of neurodegenerative diseases, and perhaps also of ischemia and trauma, is therefore judged cautiously positively.