ALS Reviews 2004
(44 References)
Ashworth, N. L., L. E. Satkunam, et al. (2004). "Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease." Cochrane Database Syst Rev(1): CD004156.
BACKGROUND: Spasticity commonly affects patients with motor neuron disease and it is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life. OBJECTIVES: The objective of this review is to systematically review all types of treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised trials register (searched January 2003), MEDLINE (January 1966 to January 2003), EMBASE (January 1980 to January 2003), CINAHL (January 1982 to January 2003), AMED (January 1985 to January 2003) and LILACS (January 1982 to January 2003) for randomized controlled trials. We reviewed the bibliographies of the randomized trials identified, and contacted trial authors and known experts in the field. SELECTION CRITERIA: We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, serious adverse events, and measures of cost. DATA COLLECTION AND ANALYSIS: We identified only one randomized controlled trial that met the inclusion criteria for this review. Two authors extracted the data. We also contacted the author of the paper and obtained further information not available in the published article. MAIN RESULTS: The included study was a trial of moderate intensity, endurance type exercise versus 'usual activities' in 25 patients with amyotrophic lateral sclerosis. At three months patients performing the 15 minute twice daily exercises had significantly less spasticity (mean reduction of 0.43 Ashworth grades versus an increase of 0.25 in controls), as measured by the Ashworth scale. REVIEWER'S CONCLUSIONS: Individualized, moderate intensity, endurance type exercises for the trunk and limbs may help to reduce spasticity in motor neuron disease. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population.
Barnham, K. J., C. L. Masters, et al. (2004). "Neurodegenerative diseases and oxidative stress." Nat Rev Drug Discov 3(3): 205-14.
Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.
Beghi, E. and T. Mennini (2004). "Basic and clinical research on amyotrophic lateral sclerosis and other motor neuron disorders in Italy: recent findings and achievements from a network of laboratories." Neurol Sci 25 Suppl 2: S41-60.
An Italian collaborative group on motor neuron disorders, including amyotrophic lateral sclerosis (ALS) and its variants, has been recently created, combining various academic groups and laboratories involved in basic and clinical research. The aim is to exploit all the specific expertise and combine efforts at a national level to better understand and fight these fatal diseases. This review summarizes the achievements of the different groups and outlines prospects for future research. Basic research deals with the etiopathogenesis of motor neuron diseases. In vitro and in vivo models of superoxide dismutase 1 (SOD1) mutations are used to investigate the mechanisms of motor neuron death associated with this gene defect. The role of excitotoxicity, immune response, intracellular aggregates and mitochondrial alterations is studied with an integrated approach, at the molecular and cellular levels. Transgenic mice carrying the human mutated SOD1, and the wobbler mouse, a spontaneous model for motor neuron degeneration, offer unique opportunities for testing new therapies in vivo related or not to SOD1 mutations. Clinical research has focused mostly on the incidence and determinants of ALS in several areas of Italy. The incidence of the disease is now among the highest according to the results of population-based regional registries. Compared to earlier studies, more recent Italian investigations show an increase in the incidence and mortality related to ALS. Findings on the role of environmental risk factors are inconsistent. Methodological issues have also been raised by Italian groups regarding the diagnosis and treatment. The validity of the El Escorial diagnostic classification has been questioned where investigators and carers have not received formal training. Pitfalls and methodological drawbacks of randomized clinical trials have been highlighted based on the results of collaborative trials by Italian investigators. Information is now available on non-pharmacological treatments and palliative care, and the economic aspects and quality of life of ALS patients are being investigated.
Bevilacqua, J. A., D. Dellarossa, et al. (2004). "[Chiari type I malformation in a patient with bulbar onset amyotrophic lateral sclerosis]." Rev Neurol 38(3): 247-9.
INTRODUCTION: Diagnosis of amyotrophic lateral sclerosis (ALS) requires of the exclusion of several pathologies of the cranio cervical junction that mimic ALS. The importance of such exclusion is in fact sustained by the prognostic implications that ALS has. CASE REPORT: We report the case of a 58-year-old woman with bulbar onset sporadic ALS associated with Chiari type I malformation on the MRI of the craniocervical junction. At the time of consultation, ALS was clinically defined but some of the symptoms were contributed by cerebellar amygdala compression of the medulla. CONCLUSION: To our knowledge this is the first time were both diseases are reported symptomatic on the same patient, and despite its rarity, it is important to be aware of this possible association for the diagnostic, therapeutic and prognostic implications it has.
Boillee, S. and D. W. Cleveland (2004). "Gene therapy for ALS delivers." Trends Neurosci 27(5): 235-8.
Boje, K. M. (2004). "Nitric oxide neurotoxicity in neurodegenerative diseases." Front Biosci 9: 763-76.
Nitric oxide (nitrogen monoxide; NO) is a simple molecule with diverse biological functions. NO and related reactive nitrogen oxide species (RNOS) mediate intricate physiological and pathophysiological effects in the central nervous system. Depending on environmental conditions, NO and RNOS can initiate and mediate neuroprotection or neurotoxicity either exclusively or synergistically with other effectors. The focus of this review is limited to the neuroprotectant/neurotoxic role of NO in Acquired Immune Deficiency Syndrome (AIDS) Dementia Complex (aka HIV--Associated Dementia; HAD) Amyotrophic Lateral Sclerosis (aka Lou Gehrig's Disease), Alzheimer's Disease, Huntington's Disease, Multiple Sclerosis and Parkinson's Disease. This review will shed light on the question: "How important is NO in neurodegenerative diseases?"
Bourke, S. C. and G. J. Gibson (2004). "Non-invasive ventilation in ALS: current practice and future role." Amyotroph Lateral Scler Other Motor Neuron Disord 5(2): 67-71.
Bruneteau, G., S. Demeret, et al. (2004). "[Physiopathology of ALS: therapeutic approach]." Rev Neurol (Paris) 160(2): 235-41.
The finding in 1993 of a mutation of the copper zinc super oxyde dismutase (SOD1) provides a major breakthrough in the understanding of the etiopathogenic mechanism of amyotrophic lateral sclerosis. Various mechanisms are commonly implied in the motor neurons degeneration. Excitotoxicity and calcium metabolism abnormalities are one of the most frequently confirmed hypotheses. It allowed proposing riluzole which remains the only one drug proved to be active in the disease. The role of growth factors remains controversial and all therapeutic trials performed with these molecules remained negative. Oxidative stress abnormalities are demonstrated by number of studies but their direct therapeutic application remains to be demonstrated. Apoptosis and the role of mitochondria has been definitely confirmed and open a new therapeutic avenue for the next few years.
Bryant, P. R., C. C. Geis, et al. (2004). "Stroke and neurodegenerative disorders. 4. Neurodegenerative disorders." Arch Phys Med Rehabil 85(3 Suppl 1): S21-33.
This self-directed learning module highlights diagnosis, treatment, and rehabilitation issues in patients with neurodegenerative disorders, including multiple sclerosis (MS), Parkinson's disease, and amyotrophic lateral sclerosis (ALS). It is part of the study guide on stroke and neurodegenerative disorders in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on the differential diagnosis, diagnostic evaluation, medical management, and rehabilitation issues in MS. Similarly, the differential diagnosis treatment and rehabilitation in Parkinson's disease is discussed. Electrodiagnosis, pharmacologic treatment, and rehabilitation options for ALS are also discussed. OVERALL ARTICLE OBJECTIVES: To review the differential diagnosis, evaluation, medical treatment, and rehabilitation management of patients with MS, Parkinson's disease, and ALS.
Consilvio, C., A. M. Vincent, et al. (2004). "Neuroinflammation, COX-2, and ALS--a dual role?" Exp Neurol 187(1): 1-10.
Although the root cause of many neurodegenerative diseases is unknown, neuroinflammation may play a key role in these types of disease, including amyotrophic lateral sclerosis (ALS). In the context of neurodegeneration, it is unclear if the disease is propagated through inflammation, or whether in contrast, evidence of inflammation reflects an attempt to protect against further cellular injury. Inflammatory pathways involving the cyclooxygenase (COX) enzymes and subsequent generation of prostaglandins are potential target sites for treatments to halt the progression of ALS. In the CNS, COX enzymes are localized to neurons, astrocytes, and microglia and can be induced under various conditions. In addition, there appears to be a dual role for the prostaglandin products of COX enzymes in the nervous system. Some prostaglandins promote the survival of neurons, while others promote apoptosis. In this review, the pathways of COX activity and prostaglandin production form the center of the debate regarding the dual nature of neuroinflammation. We will also discuss how this duality may affect future treatments for neurodegenerative diseases such as ALS.
Couratier, P., J. C. Desport, et al. (2004). "[Review of nutritional and respiratory support in ALS]." Rev Neurol (Paris) 160(2): 243-50.
During the evolution of amyotrophic lateral sclerosis (ALS), quality of life and survival of patients are related to respiratory and nutritional status. After diagnosis, a multidisciplinary care has to be promptly organized and coordinated by the referring neurologist. The nutritional and respiratory support imply that neurologists know their specific means of evaluation with their sensitivity and sensibility and be able to recognize clinical risk situations. The informations of patients on assisted-ventilation and nutritional support by using gastrostomy may be done early, precisely and trustfully. Well informed patient's choices must be respected. Nutritional and respiratory supports may be based on recommendations established by the American Academy of Neurology. This review will present and discuss their main aspects in patients with ALS.
Cova, L., A. Ratti, et al. (2004). "Stem cell therapy for neurodegenerative diseases: the issue of transdifferentiation." Stem Cells Dev 13(1): 121-31.
In the past few years research on stem cells has exploded as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several events such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation (adult cell acquisition of new unexpected identities) may explain therapeutic success, in addition to replacement of lost cells. This issue needs to be clarified further to maximize the potential for effective therapies. Preliminary stem transplantation trials have already been performed for some neurodegenerative diseases. There is no effective pharmacological treatment for amyotrophic lateral sclerosis, but recent preliminary data both in experimental and clinical settings have targeted it as an ideal candidate disease for the development of stem cell therapy in humans. This review summarizes recent advances gained in stem cell research applied to neurodegenerative diseases with a special emphasis to the criticisms put forward.
Dupuis, L., A. Muller, et al. (2004). "[Molecular mechanisms of amyotrophic lateral sclerosis: recent contributions from studies in animal models]." Rev Neurol (Paris) 160(1): 35-43.
Amyotrophic Lateral Sclerosis is a neurodegenerative condition defined by loss of both upper and lower motor neurons. The molecular mechanisms underlying this pathology are currently elucidated using transgenic mice lines expressing mutated alleles of the copper-zinc superoxide dismutase, an enzyme mutated in about 2 p. cent of ALS cases. These transgenic mice also provide a valuable animal model to set up new therapeutic tools.
Ekshyyan, O. and T. Y. Aw (2004). "Apoptosis in acute and chronic neurological disorders." Front Biosci 9: 1567-76.
Programmed cell death or apoptosis is a physiologically important process in neurogenesis wherein approximately 50% of the neurons apoptose during maturation of the nervous system. However, premature apoptosis and/or aberrations in apoptosis control contribute to the pathogenesis of a variety of neurological disorders including acute brain injury such as trauma, spinal cord injury, ischemic stroke and ischemia/reperfusion as well as chronic disease states such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, spinal muscular atrophy, and diabetic neuropathy. The current review will focus on two major topics, namely, the general concepts of our current understanding of the apoptosis death machinery, its mediators and regulation, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. This knowledge of apoptosis mechanisms will underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.
Fendyur, A., I. Kaiserman, et al. (2004). "The burst of mitochondrial diseases: neurons and calcium." Isr Med Assoc J 6(6): 356-9.
Gordon, T., J. Hegedus, et al. (2004). "Adaptive and maladaptive motor axonal sprouting in aging and motoneuron disease." Neurol Res 26(2): 174-85.
Motor unit (MU) enlargement by sprouting is an important compensatory mechanism for loss of functional MUs during normal aging and neuromuscular disease. Perisynaptic Schwann cells at neuromuscular junctions extend processes that bridge between denervated and reinnervated endplates, and guide axonal sprouts to reinnervate the denervated endplates. In a rat model of partial denervation, high levels of daily neuromuscular activity have been shown to inhibit the outgrowth of sprouts by preventing Schwann cell bridging. In this review, we consider (1) the relative roles of increasing levels of oxidative stress and neuromuscular activity to the destabilization of neuromuscular junctions with age and disease, and (2) how a progressive increase in the neuromuscular activity of declining numbers of functional MUs contributes to the progressive failure of adaptive sprouting and, in turn, to the progressive muscle weakness in the motoneuron diseases of post-polio syndrome and amyotrophic lateral sclerosis. We conclude that there is a time-related progression of MU loss, adaptive sprouting followed by maladaptive sprouting, and continuing recession of terminals during normal aging. The progression is accelerated in motoneuron disease, progressing more rapidly in the post-polio syndrome after prolonged denervation and extremely rapidly in ALS.
Grimby, G. (2004). "[Positive effect of physical training in neuromuscular diseases. Training programs must be adapted to the underlying pathology]." Lakartidningen 101(23): 2008-12.
Hasnain, S. S. (2004). "Synchrotron techniques for metalloproteins and human disease in post genome era." J Synchrotron Radiat 11(Pt 1): 7-11.
Metalloproteins make up some 30% of proteins in known genomes. Metalloproteins are a special class of proteins that utilise the unique properties of metal atoms in conjunction with the macromolecular assembly to perform life-sustaining processes. A number of metalloproteins are known to be involved in many disease states including ageing processes. The incorporation of the metal ion is a very tightly regulated process that, in vivo, very often requires specific chaperones to deliver and help incorporate the metal atom in the macromolecule. The lack of or inappropriate incorporation of metals along with genetic factors can lead to the mis-function of these proteins leading to disease. The mis-functions due to genetic alterations that lead to diseases like ALS (amyotrophic lateral sclerosis or motor neuron disease) and Creutzfeld Jacob disease (CJD) are now well recognised. Synchrotron radiation sources provide a unique set of structural tools, which in combination can prove extremely powerful in providing a comprehensive picture of these complex biological systems. In particular for metalloproteins, the combined use of X-ray crystallography, X-ray solution scattering and X-ray spectroscopy (XAFS) is extremely useful. We are currently engaged in a structural study where our aim is to characterize structurally and functionally metalloproteins and then transfer this knowledge to afford the problem of the mis-function of metalloproteins that lead to these terminal illnesses, either due to a gain of function/property or a loss of function/property. In this context, the benefits of adopting the 'philosophy' being developed for the structural genomics effort are highlighted.
Heffernan, C., C. Jenkinson, et al. (2004). "Nutritional management in MND/ALS patients: an evidence based review." Amyotroph Lateral Scler Other Motor Neuron Disord 5(2): 72-83.
Jafari-Schluep, H. F., J. Khoris, et al. (2004). "[Superoxyde dismutase 1 gene abnormalities in familial amyotrophic lateral sclerosis: phenotype/genotype correlations. The French experience and review of the literature]." Rev Neurol (Paris) 160(1): 44-50.
About 20 p. cent of cases of amyotrophic lateral sclerosis are familial (FALS). Fifteen percent of FALS cases are associated with an abnormality in the superoxide dismutase 1 (SOD1) gene. To date, more than 100 different genetic abnormalities have been reported, all except two are autosomal dominant. The clinical characteristics of patients presenting with FALS associated with an SOD1 abnormality is homogeneous when there is no doubt about the hereditary aspect of the genetic abnormality: mean age at onset 42 years, limb onset, slow evolution. Except when present in the setting of a clearly inherited disease (FALS) (several patients through several generations), the causality of a given SOD1 mutation often remains an open question. Consequently, search for SOD1 mutation is not warranted when atypical features such as young age at onset or slow progression are present. Conversely, a complete family study is justified to determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode, and the non-exceptional absence of proven causality for ALS. Specific cases where a frequent SOD1 mutation with a recognized causal effect is recognized (no more than 15 out of more than 90 mutations) would be an exception.
Kuzuhara, S. (2004). "[Amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii peninsula of Japan]." Nippon Rinsho 62 Suppl: 141-6.
Lariviere, R. C. and J. P. Julien (2004). "Functions of intermediate filaments in neuronal development and disease." J Neurobiol 58(1): 131-48.
Five major types of intermediate filament (IF) proteins are expressed in mature neurons: the three neurofilament proteins (NF-L, NF-M, and NF-H), alpha-internexin, and peripherin. While the differential expression of IF genes during embryonic development suggests potential functions of these proteins in axogenesis, none of the IF gene knockout experiments in mice caused gross developmental defects of the nervous system. Yet, deficiencies in neuronal IF proteins are not completely innocuous. Substantial developmental loss of motor axons was detected in mice lacking NF-L and in double knockout NF-M;NF-H mice, supporting the view of a role for IFs in axon stabilization. Moreover, the absence of peripherin resulted in approximately 30% loss of small sensory axons. Mice lacking NF-L had a scarcity of IF structures and exhibited a severe axonal hypotrophy, causing up to 50% reduction in conduction velocity, a feature that would be very detrimental for large animal species. Unexpectedly, the NF-M rather than NF-H protein turned out to be required for proper radial growth of large myelinated axons. Studies with transgenic mice suggest that some types of IF accumulations, reminiscent of those found in amyotrophic lateral sclerosis (ALS), can have deleterious effects and even cause neurodegeneration. Additional evidence for the involvement of IFs in pathogenesis came from the recent discovery of neurofilament gene mutations linked to ALS and Charcot-Marie-Tooth disease (CMT2E). Conversely, we discuss how certain types of perikaryal neurofilament aggregates might confer protection in motor neuron disease.
Leigh, P. N., M. Swash, et al. (2004). "Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial." Amyotroph Lateral Scler Other Motor Neuron Disord 5(2): 84-98.
In November 2002, an advisory board meeting was convened by Novartis Pharma to provide recommendations and rationale for clinical trials designed to evaluate new treatments, such as TCH346, for amyotrophic lateral sclerosis (ALS). In terms of selecting appropriate outcome measures, the panel recommended the use of the ALS Functional Rating Scale (ALSFRS-R) to measure primary endpoints. A review of other key issues in this area including regional variations in the epidemiology, diagnosis and management of ALS, defining patient populations and doses of trial medication, and accommodating the likelihood of co-medication with pre-existing treatment in trial design, are discussed.
Mandel, S., O. Weinreb, et al. (2004). "Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases." J Neurochem 88(6): 1555-69.
Accumulating evidence supports the hypothesis that brain iron misregulation and oxidative stress (OS), resulting in reactive oxygen species (ROS) generation from H2O2 and inflammatory processes, trigger a cascade of events leading to apoptotic/necrotic cell death in neurodegenerative disorders, such as Parkinson's (PD), Alzheimer's (AD) and Huntington's diseases, and amyotrophic lateral sclerosis (ALS). Thus, novel therapeutic approaches aimed at neutralization of OS-induced neurotoxicity, support the application of ROS scavengers, transition metals (e.g. iron and copper) chelators and non-vitamin natural antioxidant polyphenols, in monotherapy, or as part of antioxidant cocktail formulation for these diseases. Both experimental and epidemiological evidence demonstrate that flavonoid polyphenols, particularly from green tea and blueberries, improve age-related cognitive decline and are neuroprotective in models of PD, AD and cerebral ischemia/reperfusion injuries. However, recent studies indicate that the radical scavenger property of green tea polyphenols is unlikely to be the sole explanation for their neuroprotective capacity and in fact, a wide spectrum of cellular signaling events may well account for their biological actions. In this article, the currently established mechanisms involved in the beneficial health action and emerging studies concerning the putative novel molecular neuroprotective activity of green tea and its major polyphenol (-)-epigallocatechin-3-gallate (EGCG), will be reviewed and discussed.
Mattson, M. P. (2004). "Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders." Ann N Y Acad Sci 1012: 37-50.
Membrane lipid peroxidation and oxidative modification of various membrane and associated proteins (e.g., receptors, ion transporters and channels, and signal transduction and cytoskeletal proteins) occur in a range of neurodegenerative disorders. This membrane-associated oxidative stress (MAOS) is promoted by redox-active metals, most notably iron and copper. The mechanisms whereby different genetic and environmental factors initiate MAOS in specific neurological disorders are being elucidated. In Alzheimer's disease (AD), the amyloid beta-peptide generates reactive oxygen species and induces MAOS, resulting in disruption of cellular calcium homeostasis. In Parkinson's disease (PD), mitochondrial toxins and perturbed ubiquitin-dependent proteolysis may impair ATP production and increase oxyradical production and MAOS. The inheritance of polyglutamine-expanded huntingtin may promote neuronal degeneration in Huntington's disease (HD), in part, by increasing MAOS. Increased MAOS occurs in amyotrophic lateral sclerosis (ALS) as the result of genetic abnormalities (e.g., Cu/Zn-superoxide dismutase mutations) or exposure to environmental toxins. Levels of iron are increased in vulnerable neuronal populations in AD and PD, and dietary and pharmacological manipulations of iron and copper modify the course of the disease in mouse models of AD and PD in ways that suggest a role for these metals in disease pathogenesis. An increasing number of pharmacological and dietary interventions are being identified that can suppress MAOS and neuronal damage and improve functional outcome in animal models of AD, PD, HD, and ALS. Novel preventative and therapeutic approaches for neurodegenerative disorders are emerging from basic research on the molecular and cellular actions of metals and MAOS in neural cells.
Nagata, K. (2004). "[Cigarette smoking and neurological disease]." No To Shinkei 56(3): 205-23.
Naumann, M. and W. Jost (2004). "Botulinum toxin treatment of secretory disorders." Mov Disord 19 Suppl 8: S137-41.
Botulinum neurotoxin serotype A (BoNT/A) has revolutionised the treatment of a variety of autonomic hypersecretory disorders. Several open and controlled studies indicate that BoNT/A is a safe and effective treatment for focal hyperhidrosis of the axillae and palms, for gustatory sweating, and for some other rare conditions associated with focal hyperhidrosis. There is class I evidence for the efficacy of botulinum toxin in axillary hyperhidrosis and class II evidence for palmar hyperhidrosis and gustatory sweating. BoNT/A has the potential to replace current invasive and surgical techniques and should at least be considered as a viable alternative. The results of pilot studies to treat sialorrhea are encouraging. However, the optimal dose, best mode of application, side effects, and duration of BoNT/A action in this condition remain uncertain. We need further formal clinical trials to evaluate risks and benefits of BoNT/A for palliative treatment in of sialorrhea in Parkinson's disease and in bulbar amyotrophic lateral sclerosis. Based on the few reports published, BoNT/A injections into the lacrimal gland for hyperlacrimation may be an elegant method to treat this sometimes disabling condition. Again, larger studies are needed to evaluate the risks and long-term benefits of this treatment option.
Niwa, J. and G. Sobue (2004). "[Motor neuron disease]." Tanpakushitsu Kakusan Koso 49(7 Suppl): 1127-8.
Okumura, H. and K. Tashiro (2004). "[Amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam]." Nippon Rinsho 62 Suppl: 136-40.
Peel, A. L. (2004). "PKR activation in neurodegenerative disease." J Neuropathol Exp Neurol 63(2): 97-105.
Interferon-inducible, double-stranded RNA-dependent protein kinase PKR is well known as an early cellular responder to viral infection. Activation of PKR has been associated with a number of downstream cell stress and cell death events, including a generalized shutdown of protein translation, activation of caspase-8, participation in JNK and p38 MAPK pathways, activation of NF-kappaB, etc. Recently, the activation of PKR has also been described in several neurodegenerative diseases, including Huntington disease, Alzheimer disease, and amyotrophic lateral sclerosis. Although the relationship between PKR and these diseases is still unclear, the overlap between known functions of PKR and biochemical events that occur in these neuropathologies are discussed here.
Piazza, O., A. L. Siren, et al. (2004). "Soccer, neurotrauma and amyotrophic lateral sclerosis: is there a connection?" Curr Med Res Opin 20(4): 505-8.
Trauma has long been hypothesized but never proven to be a risk factor for amyotrophic lateral sclerosis (ALS). This hypothesis may now have a renaissance due to recent reports in the lay press on 'the Italian motoneuron mystery', i.e. the disclosure of 33 diagnosed ALS cases in a subpopulation of 24000 soccer players of the top three Italian divisions from the 1960s to 1996. Could the repetitive brain trauma that soccer players experience for controlling and advancing the ball with their heads represent an environmental risk factor for developing ALS in genetically predisposed individuals? By critically reviewing the scarce literature and 'surrounding evidence' (Medline, CDC, lay press, Italian health officials), we have looked for a potential relationship between (1) soccer and head trauma and (2) head trauma and subsequent development of amyotrophic lateral sclerosis. Whereas the brain traumatizing effect of soccer seems to be out of the question, the findings of the few retrospective studies on ALS and neurotrauma are conflicting. Taken together, however, the literature would still support the concept of soccer, head trauma, and ALS being interrelated, with high levels of athleticism/physical activity perhaps playing an additive part. To further clarify this issue, extensive prospective epidemiological investigations on ALS following neurotrauma as well as carefully designed animal studies will have to be conducted.
Przedborski, S. (2004). "Programmed cell death in amyotrophic lateral sclerosis: a mechanism of pathogenic and therapeutic importance." Neurologist 10(1): 1-7.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease of adulthood. Mounting evidence indicates that molecular components of the programmed cell death (PCD) machinery are implicated in the demise of motor neurons in this illness. PCD, rather than being passive, is an active mechanism of cell death tightly regulated by multiple molecular pathways. REVIEW SUMMARY: Thus far, little is known about the etiology and the pathogenesis of ALS. However, several studies support the view that PCD is instrumental in ALS neurodegenerative process. Data from postmortem ALS specimens and from experimental models of ALS show that some dying motor neurons exhibit features reminiscent of apoptosis, a prominent morphologic form of PCD. In addition, many key molecular components of the PCD machinery are activated in ALS spinal cords. Supporting the significance of these alterations, genetic and pharmacological interventions aimed at mitigating these changes prolong survival and attenuate neurodegeneration in a mouse model of ALS. CONCLUSIONS: The morphologic evidence of PCD in ALS remains an equivocal. However, the molecular evidence of PCD involvement in ALS is compelling. Moreover, preclinical studies in mice demonstrate the beneficial effects of targeting PCD on ALS-like neurodegeneration. The neurologist needs to be familiar with the concept of PCD and the potential significance of targeting PCD as neuroprotective strategies for ALS.
Rao, S. D. and J. H. Weiss (2004). "Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis." Trends Neurosci 27(1): 17-23.
Reniewska, B., M. Mulak, et al. (2004). "[Coexistence of Alzheimer's disease with pseudoexfoliation syndrome PEX]." Klin Oczna 106(1-2): 107-9.
Alzheimer disease is a type of cerebral amyloidosis, which is most frequently recognized after the age of 80. In pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and age-related cataract changes in protein aggregation play important role, for that reason they form common group of diseases, called conformational diseases. Patients with Alzheimer disease have more common pseudoexfoliation syndrome (PEX), characterized by the accumulation of an abnormal pathognomonic material in the anterior segment of the eye. Regarding common feature of the structure of fibrillar pseudoexfoliation and amyloid material, it is considered that eye examination could be useful in the early diagnosis of Alzheimer disease.
Rossi, L., M. F. Lombardo, et al. (2004). "Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance." Neurochem Res 29(3): 493-504.
Copper is an essential transition metal ion for the function of key metabolic enzymes, but its uncontrolled redox reactivity is source of reactive oxygen species. Therefore a network of transporters strictly controls the trafficking of copper in living systems. Deficit, excess, or aberrant coordination of copper are conditions that may be detrimental, especially for neuronal cells, which are particularly sensitive to oxidative stress. Indeed, the genetic disturbances of copper homeostasis, Menkes' and Wilson's diseases, are associated with neurodegeneration. Furthermore, copper interacts with the proteins that are the hallmarks of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, prion diseases, and familial amyotrophic lateral sclerosis. In all cases, copper-mediated oxidative stress is linked to mitochondrial dysfunction, which is a common feature of neurodegeneration. In particular we recently demonstrated that in copper deficiency, mitochondrial function is impaired due to decreased activity of cytochrome c oxidase, leading to production of reactive oxygen species, which in turn triggers mitochondria-mediated apoptotic neurodegeneration.
Silani, V., L. Cova, et al. (2004). "Stem-cell therapy for amyotrophic lateral sclerosis." Lancet 364(9429): 200-2.
CONTEXT: With the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), and compelling preclinical data, stem-cell research has highlighted this disease as a candidate for stem-cell treatment. Stem-cell transplantation is an attractive strategy for neurological diseases and early successes in animal models of neurodegnerative disease generated optimism about restoring function or delaying degeneration in human beings. The restricted potential of adult stem cells has been challenged over the past 5 years by reports on their ability to acquire new unexpected fates beyond their embryonic lineage (transdifferentiation). Therefore, autologous or allogeneic stem cells, undifferentiated or transdifferentiated and manipulated epigenetically or genetically, could be a candidate source for local or systemic cell-therapies in ALS. STARTING POINT: Albert Clement and colleagues (Science 2003; 302: 113-17) showed that in SOD1G93A chimeric mice, motorneuron degeneration requires damage from mutant SOD1 acting in non-neuronal cells. Wild-type non-neuronal (glial) cells could delay degeneration and extend survival of mutant-expressing motorneurons. Letizia Mazzini and colleagues (Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 158-61) injected autologous bone-marrow-derived stem cells into the spinal cord of seven ALS patients. These investigators reported that the procedure had a reasonable margin of clinical safety. WHERE NEXT? The success of cell-replacement therapy in ALS will depend a lot on preclinical evidence, because of the complexity and precision of the pattern of connectivity that needs to be restored in degenerating motoneurons. Stem-cell therapy will need to be used with other drugs or treatments, such as antioxidants and/or infusion of trophic molecules.
Siniscalchi, A. (2004). "[Tolerability of riluzole: a review of the literature]." Clin Ter 155(1): 25-8.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with the fatal evolution. Recent studies in knowledge of the pathogenic mechanisms underlying ALS showed that the excitotoxicity has an important role in the neurodegeneration. The riluzole, an antagonist of glutamate, is the first drug approved by FDA for the treatment of patients with ALS. The efficacy of riluzole (dose recommended 50 mg twice a day) in prolonging the survival of patients with ALS has been demostrated in two principal controlled clinical trials. The most frequent adverse events related to riluzole treatment were: nausea, vomiting, anorexia, diarrhea, asthenia, somnolence, vertigo, circumoral paresthesia, abdominal pain and dizziness. Some events tend to be related to the dose: vertigo, diarrhea, nausea, circumoral paresthesia and anorexia appear more frequently with 200 mg/die that with lower dose. Generally with tree months from the beginning of the treatment with riluzole, an increase serum transaminase levels has been noted; mostly transient and regressing after two-sex months of treatment. A monitoring of serum transaminase levels is suggested during the first year of treatment with riluzole The clinical studies shows that the adverse events produced by riluzole are mostly reversible and dose-dependent, this demostrates a satifying profile of tolerability of the drug. Anyway, a deeper knowledge of its tolerability may lead us to a better use of riluzole, avoiding in this way the interruption of treatment.
Tuszynski, M. H. and A. Blesch (2004). "Nerve growth factor: from animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer's disease." Prog Brain Res 146: 441-9.
Over the last 20 years it has been recognized that neurotrophic factors profoundly influence the development of the nervous system and have the potential to modify disease processes in the adult nervous system. The ability of nervous system growth factors to prevent or reduce neuronal degeneration in animal models of neurodegenerative diseases has led to several clinical trials. One of the main obstacles to the success of these trials has been the method of growth factor delivery: sufficiently high doses of neurotrophic factors must be achieved in the target region of the brain to efficiently modify disease processes, but delivery must be restricted to specific brain regions to prevent adverse effects. Recent advances in molecular medicine have made gene therapy in the nervous system a potentially realistic approach for the delivery of therapeutic molecules such as growth factors. As an alternative to conventional drug delivery, several gene therapy trials for the treatment of central nervous system diseases have started or will start in the near future. This chapter reviews the development of neurotrophic factor gene therapy for neurodegenerative diseases focusing on the therapeutic potential of nerve growth factor in Alzheimer's disease, currently the subject of a phase I clinical trial.
van den Berg, L. H., J. P. van den Berg, et al. (2004). "[The symptomatic treatment of amyotrophic lateral sclerosis]." Ned Tijdschr Geneeskd 148(11): 513-8.
Patients with amyotrophic lateral sclerosis (ALS) have symptoms of progressive muscle weakness, of disturbed speech and swallowing, and in the terminal phase those of respiratory weakness. Treatment options, in particular those for excessive weight loss and respiratory weakness, should be introduced to the patients and their families when the patient is emotionally capable and before dysarthria severely hampers communication. Special equipment for keeping the patient as mobile as possible should be made available much earlier than in the case of other diseases of the muscles as in ALS progression is much faster. Cramps, pathological crying or laughter, spasms, and spasticity can all be treated by medication. When speech can no longer be understood, adaptive strategies such as sign language, mime, posture and communication apparatus varying from a note pad to advanced computer systems can be used. Sialorrhoea, caused by difficulty swallowing with its accompanying danger of aspiration can be halted by the use of medication, by radiotherapy and by the injection into the salivary glands of botulin A toxin. Weight loss, also a result of dysphagia, can be avoided by eating frequent small meals or if necessary performing a percutaneous endoscopic or radiological gastroscopy. Excess mucus in the respiratory tract can be treated with anticholinergics. Difficulty in coughing up thick and sticky mucus cannot always be adequately helped. Respiratory weakness is treatable by external respiratory supportive therapy using a nasal mask, as well as invasive respiratory support via a trachcostoma and by treating the symptoms of respiratory weakness. The latter form of treatment is palliative and forms part of terminal care. During the terminal phase restlessness, anxiety, pain, and dyspnoea require the most attention. Treatment requires careful multidisciplinary cooperation.
Wang, Y. P., J. F. Song, et al. (2004). "[CDK5 and neurodegenerative disease]." Sheng Li Ke Xue Jin Zhan 35(1): 45-8.
Weiss, M. D., P. Weydt, et al. (2004). "Current pharmacological management of amyotrophic [corrected] lateral sclerosis and a role for rational polypharmacy." Expert Opin Pharmacother 5(4): 735-46.
Amyotrophic [corrected] lateral sclerosis (ALS) is a progressive degenerative condition of motor neurons that is ultimately fatal. Even though scientific discovery over the past few decades has led to a greater understanding of the pathogenic mechanisms of ALS, effective pharmacotherapy intended to slow, arrest or reverse the disease progression remains difficult to obtain. Riluzole, a drug that has only modest benefit in extending survival, is still the only medication approved by the FDA for the treatment of ALS. However, a number of pharmacological agents are currently being investigated as potential therapy for ALS. This paper will review the pathophysiology of ALS and current pharmacological management of the disease and recent directions in research and clinical trials. Based on the available data, it is our opinion that combination drug therapies should be considered for future clinical trials.
Wokke, J. H. (2004). "Genes, trials, and care: the dynamics of neuromuscular disease." Lancet Neurol 3(1): 16.
Zhang, H., C. Andrekopoulos, et al. (2004). "The carbonate radical anion-induced covalent aggregation of human copper, zinc superoxide dismutase, and alpha-synuclein: intermediacy of tryptophan- and tyrosine-derived oxidation products." Free Radic Biol Med 36(11): 1355-65.
In this review, we describe the free radical mechanism of covalent aggregation of human copper, zinc superoxide dismutase (hSOD1). Bicarbonate anion (HCO3-) enhances the covalent aggregation of hSOD1 mediated by the SOD1 peroxidase-dependent formation of carbonate radical anion (CO3*-), a potent and selective oxidant. This species presumably diffuses out the active site of hSOD1 and reacts with tryptophan residue located on the surface of hSOD1. The oxidative degradation of tryptophan to kynurenine and N-formyl kynurenine results in the covalent crosslinking and aggregation of hSOD1. Implications of oxidant-mediated aggregation of hSOD1 in the increased cytotoxicity of motor neurons in amyotrophic lateral sclerosis are discussed.
Ziemann, U. and A. Eisen (2004). "TMS for ALS: why and why not." Clin Neurophysiol 115(6): 1237-8.