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Amyotrophic Lateral Sclerosis (ALS)
Updated: 08/26/2004


ALS tied to agricultural chemical exposure at work: strongest link in men exposed under aged 40.

ALS tied to agricultural chemical exposure at work: strongest link in men exposed under aged 40.

Family Pract News. 1996;1-2.

Cost effectiveness of recombinant human insulin-like growth factor I therapy in patients with ALS.

Ackerman SJ, Sullivan EM, Beusterien KM, et al.

Pharmacoeconomics. 1999 Feb; 15(2):179-95.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterised by a progressive loss of voluntary motor activity. Recombinant human insulin-like growth factor I (rhIGF-I) has been shown to be useful in treating ALS. The purpose of this study was to examine the cost effectiveness of rhIGF-I therapy in patients who have ALS. DESIGN: We performed a cost-effectiveness analysis from the societal perspective on 177 patients who received treatment with rhIGF-I or placebo in a North American randomised clinical trial. We estimated the incremental cost-effectiveness ratio of rhIGF-I using resource utilisation and functional status measurements from the clinical trial. Costs were estimated from 1996 US Medicare reimbursement schedules. Utility weights were elicited from ALS healthcare providers using the standard gamble technique. MAIN OUTCOME MEASURES AND RESULTS: The overall cost per quality-adjusted life-year (QALY) gained for rhIGF-I therapy compared with placebo was $US67,440. For the subgroups of patients who were progressing rapidly or were in earlier stages of disease at enrolment, rhIGF-I cost $US52,823 and $US43,197 per QALY gained, respectively. CONCLUSIONS: Treatment with rhIGF-I is most cost effective in ALS patients who are either in earlier stages of the disease or progressing rapidly. The cost effectiveness of rhIGF-I therapy compares favourably with treatments for other chronic progressive diseases

Mercury intoxication simulating amyotrophic lateral sclerosis.

Adams CR, Ziegler DK, Lin JT.

JAMA. 1983 Aug 5; 250(5):642-3.

A 54-year-old man had a syndrome resembling amyotrophic lateral sclerosis after a brief but intense exposure to elemental mercury. The syndrome resolved as his urinary mercury levels fell. Mercury toxicity must be considered not only in individuals with recent anterior horn-cell dysfunction but also with otherwise unexplained peripheral neuropathy, tremor, ataxia, and a gamut of psychiatric symptoms including confusion and depression

Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons.

Akaike A, Tamura Y, Sato Y, et al.

Eur J Pharmacol. 1993 Sep 7; 241(1):1-6.

The effects of methylcobalamin, a vitamin B12 analog, on glutamate-induced neurotoxicity were examined using cultured rat cortical neurons. Cell viability was markedly reduced by a brief exposure to glutamate followed by incubation with glutamate-free medium for 1 h. Glutamate cytotoxicity was prevented when the cultures were maintained in methylcobalamin-containing medium. Glutamate cytotoxicity was also prevented by chronic exposure to S-adenosylmethionine, which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and S-adenosylmethionine also inhibited the cytotoxicity induced by N-methyl-D-aspartate or sodium nitroprusside that releases nitric oxide. In cultures maintained in a standard medium, glutamate cytotoxicity was not affected by adding methylcobalamin to the glutamate-containing medium. In contrast, acute exposure to MK-801, a NMDA receptor antagonist, prevented glutamate cytotoxicity. These results indicate that chronic exposure to methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity

Chronic neurologic sequelae to cholinesterase inhibition among agricultural pesticide applicators.

Ames RG, Steenland K, Jenkins B, et al.

Arch Environ Health. 1995 Nov; 50(6):440-4.

To test the hypothesis that chronic neurologic sequelae are associated with cholinesterase depression short of frank organophosphate poisoning, we compared 45 male subjects who had a history of moderate cholinesterase inhibition with 90 male subjects who had neither past cholinesterase inhibition nor current pesticide exposure. Cholinesterase-inhibited subjects were defined as having had a history of (a) red blood cell cholinesterase at 70% or less of baseline or (b) plasma cholinesterase at 60% or less of baseline absent symptoms of frank poisoning. In the subject comparison evaluation, only 1 of 27 neurologic tests (i.e., serial digit performance) was significant statistically, but it was opposite of the direction hypothesized. In a companion study for which the same battery of neurologic tests and the same subjects were used, neurologic sequelae were related to high exposures among subjects who sought treatment for organophosphate poisoning. The data in the current study, in which the subjects experienced lower exposures short of frank poisoning, provide some evidence that preventing acute organophosphate poisoning also prevents neurologic sequelae

N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.

Andreassen OA, Dedeoglu A, Klivenyi P, et al.

Neuroreport. 2000 Aug 3; 11(11):2491-3.

Increasing evidence implicates oxidative damage as a major mechanism in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage, in transgenic mice with a superoxide dismutase (SODI) mutation (G93A), used as an animal model of familial ALS. NAC was administered at 1% concentration in the drinking water from 4-5 weeks of age. The treatment caused a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC compared to control mice. These results provide further evidence for the involvement of free radical damage in the G93A mice, and support the possibility that NAC, an over-the-counter antioxidant, could be explored in clinical trials for ALS

Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation.

Andreassen OA, Jenkins BG, Dedeoglu A, et al.

J Neurochem. 2001 Apr; 77(2):383-90.

Several lines of evidence implicate excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis (ALS). Transgenic mice with a superoxide dismutase mutation (G93A) have been utilized as an animal model of familial ALS (FALS). We examined the cortical concentrations of glutamate using in vivo microdialysis and in vivo nuclear magnetic resonance (NMR) spectroscopy, and the effect of long-term creatine supplementation. NMDA-stimulated and Ltrans-pyrrolidine-2,4-dicarboxylate (LTPD)-induced increases in glutamate were significantly higher in G93A mice compared with littermate wild-type mice at 115 days of age. At this age, the tissue concentrations of glutamate were also significantly increased as measured with NMR spectroscopy. Creatine significantly increased longevity and motor performance of the G93A mice, and significantly attenuated the increases in glutamate measured with spectroscopy at 75 days of age, but had no effect at 115 days of age. These results are consistent with impaired glutamate transport in G93A transgenic mice. The beneficial effect of creatine may be partially mediated by improved function of the glutamate transporter, which has a high demand for energy and is susceptible to oxidative stress

Nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker for peroxynitrite-mediated oxidative stress in neurodegenerative diseases.

Aoyama K, Matsubara K, Fujikawa Y, et al.

Ann Neurol. 2000 Apr; 47(4):524-7.

Peroxynitrite can nitrate tyrosine residues of proteins. We examined nitrotyrosine-containing proteins in cerebrospinal fluid of 66 patients with neurogenic disease by immunoblot analysis. Nitrated tyrosine residue-containing protein was observed in the cerebrospinal fluid and was concluded to be manganese superoxide dismutase (Mn-SOD). The nitrated Mn-SOD level was strikingly elevated in amyotrophic lateral sclerosis patients and was slightly increased in Alzheimer's and Parkinson's disease patients, whereas an elevated Mn-SOD level was observed only in progressive supranuclear palsy group

Amyotrophic lateral sclerosis. Associated clinical disorders and immunological evaluations.

Appel SH, Stockton-Appel V, Stewart SS, et al.

Arch Neurol. 1986 Mar; 43(3):234-8.

We examined the family history and associated diseases in 58 patients with amyotrophic lateral sclerosis (ALS), as well as the T-cell phenotypes and functions in 46 consecutive patients with this disorder. A family history of thyroid disease was present in 19%, and an additional 21% of patients described family members with other possible autoimmune disorders. In 19% of the patients with ALS either past or present thyroid disease was documented. Eleven of 47 additional patients with ALS had significant elevations of microsomal and/or thyroglobulin antibody levels. The T-cell phenotypes and functions were comparable in the ALS and control groups, with the exception of the presence of Ia antigen. In patients with ALS, 11.9% of the T cells were positive for the la antigen, while in both a normal control population and a non-ALS neurologic disease population, only 6.4% of T cells have this antigenic determinant. These data support involvement of autoimmune mechanisms in ALS

Epidemiologic correlates of sporadic amyotrophic lateral sclerosis.

Armon C, Kurland LT, Daube JR, et al.

Neurology. 1991 Jul; 41(7):1077-84.

We evaluated 74 selected patients with amyotrophic lateral sclerosis (ALS) and 201 matched controls for risk factors for ALS by a case-control design and a sequential questionnaire/interview technique to quantitate biographic data. We analyzed occupational and recreational data only for 47 male patients and 47 corresponding patient controls; data for women were insufficient. We used nonparametric analyses to evaluate five primary comparisons of ALS patients with controls: (1) more hard physical labor, p not significant (NS); (2) greater frequency of neurodegenerative disease in family members, p NS; (3) greater exposure to lead, p less than 0.05; (4) more years lived in a rural community, p NS; and (5) more trauma or major surgery, p NS. Men with ALS had worked more frequently at blue-collar jobs (although not a statistically significant difference, p = 0.10) and at welding or soldering (p less than 0.01). These results suggest that there may be an association between ALS in men and exposure to lead vapor. The limited nature of the association favors a multifactorial etiologic mechanism of ALS

Manganese: brain transport and emerging research needs.

Aschner M.

Environ Health Perspect. 2000 Jun; 108 Suppl 3:429-32.

Idiopathic Parkinson's disease (IPD) represents a common neurodegenerative disorder. An estimated 2% of the U.S. population, age 65 and older, develops IPD. The number of IPD patients will certainly increase over the next several decades as the baby-boomers gradually step into this high-risk age group, concomitant with the increase in the average life expectancy. While many studies have suggested that industrial chemicals and pesticides may underlie IPD, its etiology remains elusive. Among the toxic metals, the relationship between manganese intoxication and IPD has long been recognized. The neurological signs of manganism have received close attention because they resemble several clinical disorders collectively described as extrapyramidal motor system dysfunction, and in particular, IPD and dystonia. However, distinct dissimilarities between IPD and manganism are well established, and it remains to be determined whether Mn plays an etiologic role in IPD. It is particularly noteworthy that as a result of a recent court decision, methylcyclopentadienyl Mn tricarbonyl (MMT) is presently available in the United States and Canada for use in fuel, replacing lead as an antiknock additive. The impact of potential long-term exposure to low levels of MMT combustion products that may be present in emissions from automobiles has yet to be fully evaluated. Nevertheless, it should be pointed out that recent studies with various environmental modeling approaches in the Montreal metropolitan (where MMT has been used for more than 10 years) suggest that airborne Mn levels were quite similar to those in areas where MMT was not used. These studies also show that Mn is emitted from the tail pipe of motor vehicles primarily as a mixture of manganese phosphate and manganese sulfate. This brief review characterizes the Mn speciation in the blood and the transport kinetics of Mn into the central nervous system, a critical step in the accumulation of Mn within the brain, outlines the potential susceptibility of selected populations (e.g., iron-deficient) to Mn exposure, and addresses future research needs for Mn

A pilot trial of dextromethorphan in amyotrophic lateral sclerosis.

Askmark H, Aquilonius SM, Gillberg PG, et al.

J Neurol Neurosurg Psychiatry. 1993 Feb; 56(2):197-200.

Assuming the presence of glutamate-induced neurotoxicity in amyotrophic lateral sclerosis 14 patients were treated with dextromethorphan, an N-methyl-D-aspartate receptor antagonist. The patients were treated with 150 mg dextromethorphan or placebo daily for 12 weeks in a double-blind crossover trial, with a wash out period of 4 weeks between the two treatment periods. Thereafter the surviving patients were treated with 300 mg dextromethorphan daily for up to 6 months in an open trial. No positive effects on clinical or neurophysiological parameters (relative number of axons, and compound muscle action potentials in the abductor digiti minimi muscle) were observed either in the double-blind trial or in the open trial

Mitochondria, free radicals, and neurodegeneration.

Beal MF.

Curr Opin Neurobiol. 1996 Oct; 6(5):661-6.

A central role for defective mitochondrial energy production, and the resulting increased levels of free radicals, in the pathogenesis of various neurodegenerative diseases is gaining increasing acceptance. Defects in energy metabolism may contribute to both excitotoxicity and oxidative damage. Evidence implicating energy defects in neurodegenerative diseases comes from similarities to known mitochondrial disorders, including delayed and variable age of onset, slow progression, and symmetric degeneration of circumscribed groups of neurons

Coenzyme Q10 administration and its potential for treatment of neurodegenerative diseases.

Beal MF.

Biofactors. 1999; 9(2-4):261-6.

Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain as well as an important antioxidant. Previous studies have suggested that it may exert therapeutic effects in patients with known mitochondrial disorders. We investigated whether it can exert neuroprotective effects in a variety of animal models. We have demonstrated that CoQ10 can protect against striatal lesions produced by both malonate and 3-nitropropionic acid. It also protects against MPTP toxicity in mice. It extended survival in a transgenic mouse model of amyotrophic lateral sclerosis. We demonstrated that oral administration can increase plasma levels in patients with Parkinson's disease. Oral administration of CoQ10 significantly decreased elevated lactate levels in patients with Huntington's disease. These studies therefore raise the prospect that administration of CoQ10 may be useful for the treatment of neurodegenerative diseases

Mitochondria, NO and neurodegeneration.

Beal MF.

Biochem Soc Symp. 1999; 66:43-54.

A role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support. Mitochondrial dysfunction may be linked to neurodegenerative diseases through a variety of different pathways, including free-radical generation, impaired calcium buffering and the mitochondrial permeability transition. This can lead to both apoptotic and necrotic cell death. Recent evidence has shown that there is a mitochondrial defect in Friedreich's ataxia, which leads to increased mitochondrial iron content, that appears to be linked to increased free-radical generation. There is evidence that the point mutations in superoxide dismutase which are associated with amyotrophic lateral sclerosis may contribute to mitochondrial dysfunction. There is also evidence for bioenergetic defects in Huntington's disease. Studies of cybrid cell lines have implicated mitochondrial defects in both Parkinson's disease and Alzheimer's disease. If mitochondrial dysfunction plays a role in neurodegenerative diseases then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process

Mitochondria and the pathogenesis of ALS.

Beal MF.

Brain. 2000 Jul; 123 ( Pt 7):1291-2.

Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure? The Italian ALS Study Group.

Beghi EFEMG.

Neurology. 1993; 43(12):2466-70.


Neuroprotective utility and neurotrophic action of neurturin in postnatal motor neurons: comparison with GDNF and persephin.

Bilak MM, Shifrin DA, Corse AM, et al.

Mol Cell Neurosci. 1999 May; 13(5):326-36.

Neurturin and persephin are recently discovered homologs of glial cell line-derived neurotrophic factor (GDNF). Here, we report that neurturin, like GDNF, increases the choline acetyltransferase activity of normal postnatal motor neurons, induces neurite outgrowth in spinal cord, and potently protects motor neurons from chronic glutamate-mediated degeneration. Persephin, in contrast, does not appear to have neurotrophic or neurite-promoting effects on mature motor neurons and may instead worsen the glutamate injury of motor neurons. This pattern in the TGF-beta family suggests certain receptor specificities, requiring at least the Ret/GFRalpha-1 receptor complex. The results predict potential benefit of neurturin, but not persephin, in the treatment of motor neuron disorders and spinal cord diseases

Protective activity of ethyl apovincaminate on ischaemic anoxia of the brain.

Biro K, Karpati E, Szporny L.

Arzneimittelforschung. 1976; 26(10a):1918-20.

Effects of ethyl apovincaminate (RGH-4405, Cavinton), a new cerebral metabolic and vasodilatory agent, on cerebral regulatory functions under ischaemic anoxia were studied on immobilized cats by EEG. Cortical resistance time increased and recovery time decreased for a long period after i.v. administration of the compound. Results point to the possibility of further enhancement of cerebral regulatory processes by specific drug effects. It is assumed that tolerance or adaptation to hypoxia might be increased by RGH-4405 if spontaneous regulatory processes are impaired

A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group.

Borasio GD, Robberecht W, Leigh PN, et al.

Neurology. 1998 Aug; 51(2):583-6.

To test the safety and efficacy of recombinant human insulin-like growth factor-I (rhIGF-I) in ALS, 183 patients from eight European centers were randomized to receive double-blind placebo (n = 59) or rhIGF-I 0.1 mg/kg/day (n = 124) subcutaneously for 9 months. At study completion, the primary efficacy outcome measure (change in disease progression as assessed by the Appel ALS rating scale) showed no significant difference between treatment groups. RhIGF-I appeared to be safe and well-tolerated

Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis.

Bowling AC, Schulz JB, Brown RH, Jr., et al.

J Neurochem. 1993 Dec; 61(6):2322-5.

The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is unknown. Recently, it was found that some patients with autosomal-dominant familial ALS (FALS) have point mutations in the gene that encodes Cu/Zn superoxide dismutase (SOD1). In this study of postmortem brain tissue, we examined SOD activity and quantified protein carbonyl groups, a marker of oxidative damage, in samples of frontal cortex (Brodmann area 6) from 10 control patients, three FALS patients with known SOD1 mutations (FALS-1), one autosomal-dominant FALS patient with no identifiable SOD1 mutations (FALS-O), and 11 sporadic ALS (SALS) patients. Also, we determined the activities of components of the electron transport chain (complexes I, II-III, and IV) in these samples. The cytosolic SOD activity, which is primarily SOD1 activity, was reduced by 38.8% (p < 0.05) in the FALS-1 patients and not significantly altered in the SALS patients or the FALS-O patient relative to the control patients. The mitochondrial SOD activity, which is primarily SOD2 activity, was not significantly altered in the FALS-1, FALS-O, or SALS patients. The protein carbonyl content was elevated by 84.8% (p < 0.01) in the SALS patients relative to the control patients. Finally, the complex I activity was increased by 55.3% (p < 0.001) in the FALS-1 patients relative to the control patients. These results from cortical tissue demonstrate that SOD1 activity is reduced and complex I activity is increased in FALS-1 patients and that oxidative damage to proteins is increased in SALS patients

Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis.

Browne SE, Bowling AC, Baik MJ, et al.

J Neurochem. 1998 Jul; 71(1):281-7.

Autosomal dominant familial amyotrophic lateral sclerosis (FALS) is associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Previous studies have implicated the involvement of metabolic dysfunction in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined SOD activity and mitochondrial oxidative phosphorylation enzyme activities in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Cytosolic SOD activity, predominantly Cu/Zn SOD, was decreased approximately 50% in all regions in FALS patients with SOD mutations but was not significantly altered in other patient groups. Marked increases in complex I and II-III activities were seen in FALS patients with SOD mutations but not in SALS patients. We also measured electron transport chain enzyme activities in a transgenic mouse model of FALS. Complex I activity was significantly increased in the forebrain of 60-day-old G93A transgenic mice overexpressing human mutant SOD1, relative to levels in transgenic wild-type animals, supporting the hypothesis that the motor neuron disorder associated with SOD1 mutations involves a defect in mitochondrial energy metabolism

Abnormal tissue distribution of lead in amyotrophic lateral sclerosis.

Conradi S, Ronnevi LO, Vesterberg O.

J Neurol Sci. 1976 Oct; 29(2-4):259-65.

The lead content of cerebrospinal fluid (CSF) was found to be significantly elevated in 12 patients with amyotrophic lateral sclerosis, when compared to 28 control subjects having non-degenerative neurological disorders. The difference could not be explained as being merely secondary to blood-CSF barrier damage. A hypothetical model of the pathogenesis of the disease is advanced and the results are discussed in relation to this model

[Peripheral neuropathy in HIV infection].

Cruz MA, Lara M, Villoslada C.

Arch Neurobiol (Madr ). 1989; 52 Suppl 1:79-92.

Neuropathy may complicate all stages of human immunodeficiency virus infection (HIV). Different types of peripheral neuropathy and myelopathy have been reported associated with HIV infection: sensory symmetrical polyneuropathy, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, sensory ataxic neuropathy (ganglioneuronitis), cauda equina syndrome, amyotrophic lateral sclerosis, spastic paraparesia, and subclinical neuropathy diagnosed by electrophysiologic study. We describe the main clinical, electrophysiological and pathological features in these different types of neuropathy and comment their pathogenesis and treatment. Results in our series of twenty-two patients are also reported. In this series we want to underline three cases in which a chronic demyelinating polyneuropathy was the first manifestation of HIV infection. Thus, patients with predominantly motor demyelinating neuropathies and suspicious risk factors should be screened for silent HIV infection

Neuromuscular diseases associated with human immunodeficiency virus infection.

Dalakas MC, Pezeshkpour GH.

Ann Neurol. 1988; 23 Suppl:S38-S48.

The types of neuromuscular diseases associated with human immunodeficiency virus (HIV) infection are described. Our classification includes: (1) six subtypes of peripheral neuropathies--namely, acute Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, mononeuritis multiplex, an axonal, predominantly sensory, painful polyneuropathy, a sensory ataxic neuropathy due to ganglioneuronitis, and an inflammatory polyradiculoneuropathy presenting as cauda equina syndrome; (2) inflammatory myopathies (e.g., polymyositis); and (3) other less common neuromuscular manifestations, such as type II muscle fiber atrophy and nemaline myopathy. Although the exact incidence of clinical and subclinical neuromuscular diseases in HIV-positive and acquired immunodeficiency syndrome (AIDS) patients is unknown, estimates vary from 15 to almost 50% of such individuals. The type of neuropathy or myopathy related to the specific stage of HIV infection, the pathogenetic mechanisms involved, and effective therapies are discussed. A neuromuscular disease not only occurs in patients with AIDS and AIDS-related complex, but it can coincide with HIV seroconversion or it can be the only clinical indication of a chronic silent HIV infection. Chronic asymptomatic HIV infection should be considered in the differential diagnosis of certain acquired inflammatory polyneuropathies or myopathies. Precautions needed when doing electromyographic studies are discussed

Growth hormone B.

Dean W.

Vitamin Research Newsletter. 2000;

Distribution and levels of insulin-like growth factor (IGF-I and IGF-II) and insulin receptor binding sites in the spinal cords of amyotrophic lateral sclerosis (ALS) patients.

Dore S, Krieger C, Kar S, et al.

Brain Res Mol Brain Res. 1996 Sep 5; 41(1-2):128-33.

The structurally related peptides, insulin and insulin-like growth factors (IGF-I and IGF-II), have neurotrophic properties and potentially could be of therapeutic value in human neurodegenerative disorders. In this study, we compared the anatomical distribution of [125I]IGF-I, [125I]IGF-II and [125I]insulin binding sites in thoracic spinal cords from patients who died of amyotrophic lateral sclerosis (ALS) and normal controls. For these three ligands, the greatest amounts of specific binding were located in the deeper layers of the dorsal horn > intermediate zone > lamina X > ventral horn > superficial layers of the dorsal horn > white matter of the spinal cord. Highly significant (P < 0.001) increases in the density of [125I]IGF-I and [125I]IGF-II binding were apparent in various laminae of the cord of ALS patients with increased binding being particularly evident in the ventral horn and the intermediate zone. Significant (P < 0.05) increases were also seen in lamina X and in the dorsal horn. In contrast, no significant differences in [125I]insulin binding were observed between ALS and control spinal cords. Taken together, these data reveal significant increases in both [125I]IGF-I and [125I]IGF-II binding levels in the spinal cords of ALS patients albeit to different extents. These findings may be of relevance for future therapeutic strategies aimed at slowing the progression of this chronic neurodegenerative disease, as recently suggested by the beneficial therapeutic effects of an IGF-I treatment in ALS patients

Pathogenic mechanisms in sporadic amyotrophic lateral sclerosis.

Eisen A, Krieger C.

Can J Neurol Sci. 1993 Nov; 20(4):286-96.

In recognition of the 100th anniversary of Charcot's death we have reviewed possible pathogenic mechanisms in amyotrophic lateral sclerosis (ALS). Advances in the last 5 years in molecular biology and genetics have identified mutations in the cytosolic dismutase (SOD1) gene in some patients with familial ALS raising the possibility that oxidative stress may be involved in the pathogenesis. An excitotoxic pathogenesis has been implicated based on elevated plasma and CSF levels of amino acids and altered contents of amino acids in the nervous system of ALS patients and changes in the number of excitatory amino acid receptors. ALS sera containing antibodies to L-type calcium channels and the development of immune mediated lower and upper and lower motor neuron models have revitalized research efforts focusing on an immune basis for ALS. Other pathogenic mechanisms which have been the subject of recent research include elemental toxicity, apoptosis and programmed cell death and possibly a deficiency or abnormality in growth factors. Pathogenic processes for ALS must account for an increasing incidence of ALS, male preponderance, and the selective vulnerability of the cortico-motoneuronal system

Amyotrophic lateral sclerosis: concepts in pathogenesis and etiology.

Eisen AA, Hudson AJ.

Can J Neurol Sci. 1987 Nov; 14(4):649-52.

The ALS symposium in Vancouver was the first of its kind in Canada and was a contribution from both American and Canadian investigators. The main points presented were (1) a definition of what is truly ALS, in the clinical and pathological sense, based on what is called "classical" ALS: (2) how neurons may be cultured to provide a valuable experimental tool; (3) the significance of lipid abnormalities in ALS and the characterization of the ALS-like syndromes produced by hexosaminidase A deficiency; (4) the possible role of autoimmune disease as it may accompany classical ALS and nerve growth factor derived from skeletal muscle; (5) the western Pacific form of ALS as it has been intensely studied and has given rise to two hypotheses on pathogenesis: mineral toxicity caused by secondary hyperparathyroidism and poisoning through ingestion of the cycad seed, and (6) the possible abiotropic interaction of one or many environmental toxins over a lifetime with the aging nervous system, depleting it of its frail reserve of neurons

Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase.

Estevez AG, Crow JP, Sampson JB, et al.

Science. 1999 Dec 24; 286(5449):2498-500.

Mutations in copper, zinc superoxide dismutase (SOD) have been implicated in the selective death of motor neurons in 2 percent of amyotrophic lateral sclerosis (ALS) patients. The loss of zinc from either wild-type or ALS-mutant SODs was sufficient to induce apoptosis in cultured motor neurons. Toxicity required that copper be bound to SOD and depended on endogenous production of nitric oxide. When replete with zinc, neither ALS-mutant nor wild-type copper, zinc SODs were toxic, and both protected motor neurons from trophic factor withdrawal. Thus, zinc-deficient SOD may participate in both sporadic and familial ALS by an oxidative mechanism involving nitric oxide

Staying mentally sharp. A new study: preventing mental incapacity with hydergine.

Faloon W.

Life Extension Magazine. 1998 4(12):17-8.

mentally sharp. Vinpocetine.

Faloon W.

Life Extension Magazine. 1998 4(12):12-4.

Pregnenolone: the memory-enhancing hormone. Life Extension Magazine.

Faloon W.

Life Extension Magazine. 2004 2(9)

Harrison's Principles of Internal Medicine.

Fauchi A.


Review of Medical Physiology.

Ganong W.


[Neuroborreliosis in a patient with progressive supranuclear paralysis. An association or the cause?].

Garcia-Moreno JM, Izquierdo G, Chacon J, et al.

Rev Neurol. 1997 Dec; 25(148):1919-21.

INTRODUCTION: Many different neurological conditions may be seen in the later stages of Lyme's Disease, such as blindness, epileptic crises, CVA, extrapyramidal disorders, amyotrophic lateral sclerosis, and dementia may be yet another form of presentation of chronic infection due to Borrelia burgdorferi (Bb). Progressive Supranuclear Paralysis (PSP), a disorder of unknown aetiology, considered to be the commonest cause of Parkinsonism-plus, one of the symptoms of which is dementia, has never been mentioned in this type of differential diagnosis. CLINICAL CASE: We present the case of a 78 year old man with sub-acute mental deterioration, Bb positive serology in both plasma and CSF, and with clinical and epidemiological features compatible with Lyme's Disease. Complementary tests were negative. The syndrome corresponded to Lyme's Disease and improved after treatment with ceftriaxona. CONCLUSIONS: We consider aspects of the aetiology of PSP which are still not clear. In our patient, the aetiology seemed to be Bb infection, according to the criteria of the original description of the disease and in view of the neuropathological findings which have shown Bb in the substancia nigra of the mid-brain and the existence of an animal model in which Bb shows a particular tendency to colonize infratentorial structures

Intraneuronal deposition of calcium and aluminium in amyotropic lateral sclerosis of Guam.

Garruto RM, Swyt C, Fiori CE, et al.

Lancet. 1985 Dec 14; 2(8468):1353.

Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis.

Gurney ME, Cutting FB, Zhai P, et al.

Ann Neurol. 1996 Feb; 39(2):147-57.

Familial amyotrophic lateral sclerosis (FALS) has been linked in some families to dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase (Cu,ZnSOD). We have used a transgenic model of FALS based on expression of mutant human Cu,ZnSOD to explore the etiology and therapy of the genetic disease. Expression of mutant, but not wild-type, human Cu,ZnSOD in mice places the brain and spinal cord under oxidative stress. This causes depletion of vitamin E, rather than the typical age-dependent increase in vitamin E content as occurs in nontransgenic mice and in mice expressing wild-type human Cu,ZnSOD. Dietary supplementation with vitamin E delays onset of clinical disease and slows progression in the transgenic model but does not prolong survival. In contrast, two putative inhibitors of the glutamatergic system, riluzole and gabapentin, prolong survival. However, riluzole did not delay disease onset. Thus, there was clear separation of effects on onset, progression, and survival by the three therapeutics tested. This suggests the hypothesis that oxidative damage produced by the expression of mutant Cu,ZnSOD causes slow or weak excitotoxicity that can be inhibited in part by alerting glutamate release or biosynthesis presynaptically

[ALS-like sequelae in chronic neuroborreliosis].

Hansel Y, Ackerl M, Stanek G.

Wien Med Wochenschr. 1995; 145(7-8):186-8.

CSF investigation in a 61-year old female patient with clinical picture of motoneuron disease gave evidence for chronic infection with Borrelia burgdorferi. Improvement of clinical and CSF findings could be observed after antibiotic therapy. The diagnosis of amyotrophic lateral sclerosis which was initially suspected had to be revised and the disorder was interpreted as chronic neuroborreliosis

Novel drug development for amyotrophic lateral sclerosis.

Hurko O, Walsh FS.

J Neurol Sci. 2000 Nov 1; 180(1-2):21-8.

Amyotrophic lateral sclerosis (ALS) has become an increasingly attractive area for the pharmaceutical industry, the most experimentally tractable of the neurodegenerative diseases. Mechanisms underlying cell death in ALS are likely to be important in more common but more complex disorders. Riluzole, the only drug launched for treatment ALS is currently undergoing industrial trials for Alzheimer's, Parkinson's, Huntington disease, stroke and head injury. Other compounds in Phase III testing for ALS (mecamserin, xaliproden, gabapentin) are also in trials for other neurodegenerative disorders. Mechanisms of action of these advanced compounds are limited to glutamate antagonism, direct or indirect growth factor activity, as well as GABA agonism and interaction with calcium channels. A broader range of mechanisms is represented by compounds in Phase I trials: glutamate antagonism (dextramethorphan/p450 inhibitor; talampanel), growth factors (leukemia inhibiting factor; IL-1 receptor; encapsulated cells secreting CNTF) and antioxidants (TR500, a glutathione-repleting agent; recombinant superoxide dismutase; procysteine.) An even broader range of mechanisms is being explored in preclinical discovery programs. Recognition of the difficulties associated with delivery of protein therapeutics to the CNS has led to development of small molecules interacting either with neurotrophin receptors or with downstream intracellular signalling pathways. Other novel drug targets include caspaces, protein kinases and other molecules influencing apoptosis. High-throughput screens of large libraries of small molecules yield lead compounds that are subsequently optimized by chemists, screened for toxicity, and validated before a candidate is selected for clinical trials. The net is cast wide in early discovery efforts, only about 1% of which result in useful drugs at the end of a decade-long process. Successful discovery and development of novel drugs will increasingly depend on collaborative efforts between the academy and industry

Lecithinized superoxide dismutase retards wobbler mouse motoneuron disease.

Ikeda K, Kinoshita M, Iwasaki Y, et al.

Neuromuscul Disord. 1995 Sep; 5(5):383-90.

Gene mutations of Cu/Zn superoxide dismutase (SOD) have been discovered in familial amyotrophic lateral sclerosis (ALS). Oxidative stress also plays a role in the pathogenesis of sporadic ALS. Whether antioxidant therapy is beneficial in this fatal disease is now crucial. We have shown that SOD treatment improves neuromuscular dysfunction and morphological changes in wobbler mouse motoneuron disease. Progressive spinal motor neuronopathy and axonopathy, predominantly in the cervical cord, occur at postnatal age 3-4 weeks, leading to muscle weakness and contracture of the forelimbs in this animal. These motor deficits rapidly increase by postnatal age 6-8 weeks, and then slowly progress. Wobbler mice were given two doses daily of phosphatidyl choline-bound Cu/Zn SOD (PC-SOD, 10(4), 10(5) U/kg) or a vehicle solution by intraperitoneal injection from postnatal 3-4 to postnatal 7-8 weeks of age. PC-SOD treatment attenuated progression of motor dysfunction, prevented denervation muscle atrophy, and delayed degeneration of spinal motoneurons in wobbler mice. This raises the possibility that PC-SOD may have therapeutic potential in human motoneuron disease

Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of five new cases, and comparison with previous reports and 73 sporadic cases of ALS.

Ince PG, Tomkins J, Slade JY, et al.

J Neuropathol Exp Neurol. 1998 Oct; 57(10):895-904.

Molecular pathology has identified 2 distinct forms of neuronal inclusion body in Amyotrophic Lateral Sclerosis (ALS). ALS-type inclusions are skeins or small dense filamentous aggregates which can only be demonstrated by ubiquitin immunocytochemistry (ICC). In contrast hyaline conglomerates (HC) are large multifocal accumulations of neurofilaments. Previous reports have failed to clarify the distinction and relationship between these inclusions. Correlation of molecular pathology with sporadic and familial cases of ALS will detect specific associations between molecular lesions and defined genetic abnormalities; and determine the relevance of molecular events in familial cases to the pathogenesis of sporadic disease. We describe the molecular pathology of 5 ALS cases linked to abnormalities of the SOD1 gene, in comparison with a series of 73 sporadic cases in which SOD1-gene abnormalities were excluded. Hyaline conglomerate inclusions were detected only in the 2 cases with the SOD1 I113T mutation and showed a widespread multisystem distribution. In contrast ALS-type inclusions characterized sporadic cases (70/73) and were restricted to lower motor neurons. Hyaline conglomerates were not seen in sproadic cases. Confocal microscopic analysis and ICC shows that HC contain equally abundant phosphorylated and nonphosphorylated neurofilament epitopes, indicating that phosphorylation is not essential for their formation. In contrast neurofilament immunoreactivity is virtually absent from typical ALS-type inclusions. The SOD1-related cases all had marked corticospinal tract and dorsal column myelin loss. In 4 cases the motor cortex was normal or only minimally affected. This further illustrates the extent to which upper motor neuron damage in ALS is usually a distal axonopathy. Previously reported pathological accounts of SOD1-related familial ALS (FALS) are reviewed. Hyaline conglomerates are so far described in cases with mutations A4V, I113T and H48Q. In only 1 of 12 cases (H48Q) reported were both HC and ALS-type inclusions present in the same case. These findings suggest the possibility that the molecular pathology of neuronal inclusions in ALS indicates 2 distinct pathogenetic cascades

Evaluation of memantine for neuroprotection in dementia.

Jain KK.

Expert Opin Investig Drugs. 2000 Jun; 9(6):1397-406.

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer's disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer's disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales

Oxidative damage in neurodegenerative disease.

Jenner P.

Lancet. 1994 Sep 17; 344(8925):796-8.

Beneficial effect of ginseng root in SOD-1 (G93A) transgenic mice.

Jiang F, DeSilva S, Turnbull J.

J Neurol Sci. 2000 Nov 1; 180(1-2):52-4.

Many patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) use natural or traditional therapies of unproven benefit. One such therapy is ginseng root. However, in some other disease models, ginseng has proven efficacious. Ginseng improves learning and memory in rats, and reduces neuronal death following transient cerebral ischemia. These effects of ginseng have been related to increases in the expression of nerve growth factor and its high affinity receptor in the rat brain, and antioxidant actions, inter alia. Since such actions could be beneficial in ALS as well, we studied the effect of ginseng (Panax quinquefolium), 40 and 80 mg/Kg, in B6SJL-TgN(SOD1-G93A)1Gur transgenic mice. The ginseng was given in drinking water, from age 30d onwards. We measured the time to onset of signs of motor impairment, and survival. There was no difference between the two ginseng groups (n=6, 6) in either measure. However, compared to controls (n=13), there was a prolongation in onset of signs (116d vs. 94d, P

Response of patients with amyotrophic lateral sclerosis to testosterone therapy: endocrine evaluation.

Jones TM, Yu R, Antel JP.

Arch Neurol. 1982 Nov; 39(11):721-2.

Four men with amyotrophic lateral sclerosis (ALS) were treated with 200 mg of intramuscular testosterone weekly. Endocrine evaluation, using a gonadotropin-releasing hormone infusion test, indicated the expected degree of suppression of pituitary luteinizing hormone and follicle-stimulating hormone production. These data suggest that testosterone's (androgen) interaction with its receptors in the hypothalamic-pituitary axis is normal in patients with ALS

Effect of ultrahigh-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study.

Kaji R, Kodama M, Imamura A, et al.

Muscle Nerve. 1998 Dec; 21(12):1775-8.

To develop a symptomatic treatment for amyotrophic lateral sclerosis, we compared the effects of ultrahigh-dose and low-dose (25 and 0.5 mg/day, intramuscularly, for 14 days) methylcobalamin on averaged compound muscle action potential amplitudes (CMAPs) in a double-blind trial. No significant changes in CMAP amplitude were found in 12 patients who had the low-dose treatment at either 2 or 4 weeks after start of treatment. By contrast, 12 patients assigned to the ultrahigh-dose group demonstrated a significant increase at 4 weeks. This method may provide a clinically useful measure to improve or retard muscle wasting, if a larger extended trial fulfills its promise

Chronic neurologic effects of pesticide overexposure.

Keifer MC, Mahurin RK.

Occup Med. 1997 Apr; 12(2):291-304.

Pesticide exposure in humans can have persistent effects, even in the absence of acute symptoms of intoxication or after their resolution. Drs. Keifer and Mahurin describe some of the most important examples of established pesticide neurotoxicity

Trace element imbalances in amyotrophic lateral sclerosis.

Khare SS, Ehmann WD, Kasarskis EJ, et al.

Neurotoxicology. 1990; 11(3):521-32.

Concentrations of 15 elements were determined by instrumental neutron activation analysis in brain, spinal cord, blood cells, serum and nails of Amyotrophic Lateral Sclerosis (ALS) patients and appropriately matched control subjects. Several significant imbalances were detected in trace element levels in ALS samples compared to control samples. Some of these changes are probably secondary to the loss of tissue mass, especially in spinal cord. However the widespread changes observed in Hg and Se levels in ALS tissues deserve special attention. The significance of these alterations in trace element levels in relation to the pathogenesis of ALS is discussed

Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture.

Kikuchi M, Kashii S, Honda Y, et al.

Invest Ophthalmol Vis Sci. 1997 Apr; 38(5):848-54.

PURPOSE: To examine the effects of methylcobalamin on glutamate-induced neurotoxicity in the cultured retinal neurons. METHODS: Primary cultures obtained from the fetal rat retina (gestation days 16 to 19) were used for the experiment. The neurotoxicity was assessed quantitatively using the trypan blue exclusion method. RESULTS: Glutamate neurotoxicity was prevented by chronic exposure to methylcobalamin and S-adenosylmethionine (SAM), which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and SAM also inhibited the neurotoxicity induced by sodium nitroprusside that release nitric oxide. By contrast, acute exposure to methylcobalamin did not protect retinal neurons against glutamate neurotoxicity. CONCLUSIONS: Chronic administration of methylcobalamin protects cultured retinal neurons against N-methyl-D-aspartate-receptor-mediated glutamate neurotoxicity, probably by altering the membrane properties through SAM-mediated methylation

[Treatment with lecithinized superoxide dismutase in amyotrophic lateral sclerosis].

Kinoshita M, Ikeda K.

No To Shinkei. 1998 Jul; 50(7):615-24.

Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis.

Kira J, Tobimatsu S, Goto I.

Intern Med. 1994 Feb; 33(2):82-6.

Serum vitamin B12 levels and unsaturated vitamin B12 binding capacities were measured in 24 patients with multiple sclerosis (MS), 73 patients with other neurological disorders and 21 healthy subjects. There was no decrease in the vitamin B12 levels, however, a significant decrease in the unsaturated vitamin B12 binding capacities was observed in patients with MS when compared with other groups. A massive dose of methyl vitamin B12 (60 mg every day for 6 months) was administered to 6 patients with chronic progressive MS, a disease which usually had a morbid prognosis and widespread demyelination in the central nervous system. Although the motor disability did not improve clinically, the abnormalities in both the visual and brainstem auditory evoked potentials improved more frequently during the therapy than in the pre-treatment period. We therefore consider that a massive dose methyl vitamin B12 therapy may be useful as an adjunct to immunosuppressive treatment for chronic progressive MS

[Treatment of diabetic neuropathy with oral alpha-lipoic acid (author's transl)].

Klein W.

MMW Munch Med Wochenschr. 1975 May 30; 117(22):957-8.

100 patients were treated with Thioctacid orally for diabetic neuropathy. A successful assessment was possible with sufficient certainty in 89 patients. Of these, 29 received 2 X 50 mg and 60 patients 2 X 100 mg Thioctacid daily. In the first group the treatment was successful in 23 patients, and in 51 of the second group. According to these findings, administration of thiotic acid is effective in diabetic neuropathy just as frequently orally as intravenously

Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis.

Klivenyi P, Ferrante RJ, Matthews RT, et al.

Nat Med. 1999 Mar; 5(3):347-50.

Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS

Role of progesterone in peripheral nerve repair.

Koenig HL, Gong WH, Pelissier P.

Rev Reprod. 2000 Sep; 5(3):189-99.

Progesterone is synthesized in the peripheral nervous system in glial cells. The functions of progesterone are indicated by the findings that it stimulates neurite outgrowth from dorsal root ganglia sensory neurones in explant cultures, accelerates the maturation of the regenerating axons in cryolesioned sciatic nerve, and enhances the remyelination of regenerated nerve fibres. The formation of myelin sheaths around axons is a sexually dimorphic process, as the sheaths are thicker in female than in male regenerating nerves. The progesterone-induced myelination is probably mediated by progesterone receptors, as it is impaired by mifepristone (RU486), a progesterone antagonist. The stimulation of neurite growth in the peripheral nervous system may be mediated by a progesterone metabolite, 5alpha-tetrahydroprogesterone, through GABA(A) receptors

Ascorbate availability and neurodegeneration in amyotrophic lateral sclerosis.

Kok AB.

Med Hypotheses. 1997 Apr; 48(4):281-96.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease in which upper and lower motoneurons progressively deteriorate and die. Neuronal damage is most evident in the lower central nervous system, and death generally occurs following central respiratory failure. Proposed and demonstrated mechanisms for amyotrophic lateral sclerosis are diverse, and include altered superoxide dismutase and neurofilament proteins, autoimmune attack, and hyperglutamatergic activity. However, they do not account for the late onset of the disease, its earlier onset in males, and the differential vulnerability of neurons located in the brainstem and spinal cord. It is proposed here that, within the context of a specific defect such as altered superoxide dismutase, age-dependent decline in ascorbate availability triggers the disease. A role for ascorbate, which is found in millimolar levels in neurons, is suggested by a number of consistencies: 1) superoxide radicals being a common substrate for superoxide dismutase and ascorbate; 2) a close association between central nervous system ascorbate levels and injury tolerance; 3) a steady decline in ascorbate plasma levels and cellular availability with age; 4) plasma ascorbate levels being lower in males; 5) an association of ascorbate release with motor activity in central nervous system regions, in vivo; 6) the coupling of brain-cell ascorbate release with glutamate uptake; 7) possible roles for ascorbate modulation of N-methyl-D-aspartate receptor activity; 9) the ability of ascorbate to prevent peroxynitrite anion formation; and 10) evidence supporting the scorbutic guinea pig as a model for amyotrophic lateral sclerosis. Emphasis is placed on the probable competition between superoxide dismutase and ascorbate within the context of a primary defect of metal-binding or metal access in high-concentration proteins such as superoxide dismutase and human heavy neurofilaments. Finally, distinct features of alpha-motoneuronal physiology suggest that cell physiological characteristics such as high metabolic activity and extensive calcium dynamics may render neurons differentially vulnerable in amyotrophic lateral sclerosis

Reduction of endogenous transforming growth factors beta prevents ontogenetic neuron death.

Krieglstein K, Richter S, Farkas L, et al.

Nat Neurosci. 2000 Nov; 3(11):1085-90.

We show that following immunoneutralization of endogenous transforming growth factors beta (TGF-beta) in the chick embryo, ontogenetic neuron death of ciliary, dorsal root and spinal motor neurons was largely prevented, and neuron losses following limb bud ablation were greatly reduced. Likewise, preventing TGF-beta signaling by treatment with a TbetaR-II fusion protein during the period of ontogenetic cell death in the ciliary ganglion rescued all neurons that normally die. TUNEL staining revealed decreased numbers of apoptotic cells following antibody treatment. Exogenous TGF-beta rescued the TGF-beta-deprived phenotype. We conclude that TGF-beta is critical in regulating ontogenetic neuron death as well as cell death following neuronal target deprivation

The clinical potential of Deprenyl in neurologic and psychiatric disorders.

Kuhn W, Muller T.

J Neural Transm Suppl. 1996; 48:85-93.

This article reviews the results of clinical studies with Deprenyl in various neurologic and psychiatric disorders except Parkinson's disease. Promising results could be observed both in narcolepsy in a dose of at least 20 mg/day in three different trials and in one study of Tourette's syndrome including attention hyperactivity disorders using an average dosis of 8.1 mg/ day. Controversial results were reported for Alzheimer's disease. On the one hand significant improvement of cognitive functions was found by various authors. On the other hand in a more recent study no effect on the progression of the disease could be observed. For depression a higher dosage of deprenyl between 30 to 60 mg/day appears to be necessary for effective treatment. No positive results were found in amyotrophic lateral sclerosis and in tardive dyskinesias

LIF (AM424), a promising growth factor for the treatment of ALS.

Kurek JB, Radford AJ, Crump DE, et al.

J Neurol Sci. 1998 Oct; 160 Suppl 1:S106-S113.

Growth factors are theoretically promising agents for ALS therapy, but have been disappointing in subcutaneous delivery due to either toxicity or lack of major efficacy. Leukaemia inhibitory factor (LIF), was named after its effect on haemopoietic cells, and belongs to a group of cytokines which includes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in the survival of both motor and sensory neurones, while reducing denervation induced muscle atrophy. Its effects in muscle also include stimulating myoblast proliferation in vitro, and up-regulation after muscle injury. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. In published studies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 microg/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF is expressed in low levels by spinal cord neurones with significant up-regulation when the neurones are damaged by BOAA toxin, an excitatory amino acid associated with a form of ALS. This augments other evidence suggesting LIF is a trauma factor playing a role in the injury response of adult neuronal tissue, and may be more effective than related growth factors. Taken together, the data suggests LIF is a physiologically relevant trophic factor with implications in clinical medicine as a therapy for ALS, and a human recombinant form (AM424), entered human clinical trials during 1998

Thiamin mono- and pyrophosphatase activities from brain homogenate of Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia patients.

Laforenza U, Patrini C, Poloni M, et al.

J Neurol Sci. 1992 Jun; 109(2):156-61.

Thiamin-pyrophosphatase (TPPase) and thiamin-monophosphatase (TMPase) were determined using a spectrophotometric method at various pH values (5.5, 7.5, and 9.0) in brain tissue obtained at autopsy from amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) patients from Guam and from Guamanian patients who died from other diseases (controls). TPPase separation by thin-layer polyacrylamide gel isoelectric focusing (IEF) was also performed using both gray and white matter. TPPase content, chemically determined at pH 9.0, was found to be significantly reduced in the frontal cortex of ALS and PD patients compared to controls. TMPase content, on the contrary, was unchanged. IEF analysis showed 9 clear-cut bands with TPPase activity in the pH range 5.4-7.2 and a broad band at pH 4.7-5.2. The enzymatic activity was higher in gray than in white matter. In one patient the pattern was clearly different, with two additional bands observed at pH 7.1 and 6.7, and thought to be due to genetic microheterogeneity

Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group.

Lai EC, Felice KJ, Festoff BW, et al.

Neurology. 1997 Dec; 49(6):1621-30.

The objective of this study was to investigate the safety and efficacy of recombinant human insulinlike growth factor-I (rhIGF-I) in the treatment of sporadic ALS. A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. Placebo or rhIGF-I (0.05 mg/kg/day or 0.10 mg/kg/day) was administered for 9 months. The primary outcome measure was disease symptom progression, assessed by the rate of change (per patient slope) in the Appel ALS rating scale total score. The Sickness Impact Profile (SIP), a patient-perceived, health-related quality of life assessment, was a secondary outcome variable. Progression of functional impairment in patients receiving high-dose (0.10 mg/kg/day) rhIGF-I was 26% slower than in patients receiving placebo (p = 0.01). The high-dose treatment group was less likely to terminate the study due to protocol-defined markers of disease symptom progression, and members in this group exhibited a slower decline in quality of life, as assessed by the SIP. Patients receiving 0.05 mg/kg/day of rhIGF-I exhibited trends similar to those associated with high-dose treatment, suggesting a dose-dependent response. The incidence of clinically significant adverse experiences was comparable among the three treatment groups. Recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects

Selegiline is ineffective in a collaborative double-blind, placebo-controlled trial for treatment of amyotrophic lateral sclerosis.

Lange DJ, Murphy PL, Diamond B, et al.

Arch Neurol. 1998 Jan; 55(1):93-6.

BACKGROUND: The cause of amyotrophic lateral sclerosis (ALS) is not known, and there is no effective treatment. Cell death may be caused by oxidative damage. Selegiline hydrochloride (Eldepryl) is a monoamine oxidase-B inhibitor with antioxidant properties. OBJECTIVE: To determine if selegiline affects the clinical course of patients with ALS. DESIGN: Six-month, double-blind, placebo-controlled study of 133 patients with classical ALS and symptoms for less than 3 years. The primary end point to indicate effectiveness was the rate of change of the Appel ALS total score, an index of disease severity that incorporates strength and function in limbs, respiratory function, and bulbar function. RESULTS: Of the 133 patients, 67 were randomized to receive selegiline and 66 to receive placebo. One hundred four patients (53 in the selegiline group and 51 in the placebo group) completed the 6-month trial. Both groups were comparable for baseline characteristics and mean Appel ALS total score (70.5 points for the selegiline group and 70.6 for the placebo group). There was no difference in the rate of progression as measured by the Appel ALS total score, showing an average increase of 22 points in 6 months. The monthly rate of change was 3.4 for the selegiline group and 3.5 for the placebo group. There was 1 adverse reaction: worsening depression. Seven patients died during the study (4 in the selegiline group and 3 in the placebo group). CONCLUSION: Selegiline treatment had no significant effect on the rate of clinical progression or outcome of ALS

Insulin-like growth factor-I: potential for treatment of motor neuronal disorders.

Lewis ME, Neff NT, Contreras PC, et al.

Exp Neurol. 1993 Nov; 124(1):73-88.

Motor neuronal disorders, such as the loss of spinal cord motor neurons in amyotrophic lateral sclerosis or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins. Normally, such proteins do not cross the blood-brain barrier, but spinal cord motor neuron axons and nerve terminals lie outside the barrier and thus may be targeted by systemic administration of protein growth factors. Insulin-like growth factor-I (IGF-I) receptors are present in the spinal cord, and, like members of the neurotrophin receptor family, IGF-I receptors mediate signal transduction via a tyrosine kinase domain. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Consistent with earlier reports that IGF-I enhances motor neuronal sprouting in vivo, subcutaneous administration of IGF-I increases muscle endplate size in rats. Subcutaneous injections of IGF-I also accelerate functional recovery following sciatic nerve crush in mice, as well as attenuate the peripheral motor neuropathy induced by chronic administration of the cancer chemotherapeutic agent vincristine in mice. Doses of IGF-I that accelerate recovery from sciatic nerve crush in mice result in elevated serum levels of IGF-I which are similar to those obtained following subcutaneous injections of formulated recombinant human IGF-I (Myotrophin) in normal human subjects. Based on these findings, together with evidence of safety in animals and man, clinical trials of recombinant human IGF-I have been initiated in patients with amyotrophic lateral sclerosis and are planned to begin soon in patients with chemotherapy-induced peripheral neuropathies

Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor.

Lindsay RM.

Neurobiol Aging. 1994 Mar; 15(2):249-51.

The recent molecular cloning of BDNF and CNTF based on traditional protein purification and protein sequencing and the identification and cloning of NT-3 and NT-4 by homology cloning strategies has led to a tremendous flurry of interest in the biology of these proteins and initiation of studies to assess their potential utility in neurological disorders ranging through degenerative disease, stroke and ischemia, trauma and peripheral neuropathies. Tissue culture studies have been very useful in identifying neuronal specificities of the neurotrophins and CNTF and in combination with localization studies of these growth factors and their receptors have provided the basis for in vivo studies. Initial animal studies with BDNF indicate efficacy of BDNF in models of Alzheimer's and Parkinson's disease and small fiber sensory neuropathy. Studies with CNTF have similarly progressed from in vitro findings, especially the discovery that CNTF is a growth factor for motor neurons, to in vivo findings where CNTF has been shown to be effective in slowing symptoms of motor neuron dysfunction in three genetic models. Based on these positive animal data, CNTF is currently in clinical trials for the potential treatment of motor neuron disease or amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease

[Nerve growth factor and neurological diseases].

Lorigados L, Pavon N, Serrano T, et al.

Rev Neurol. 1998 May; 26(153):744-8.

INTRODUCTION: The effects of Nerve Growth Factor (NGF) within and outside the nervous system have been amply discussed in recent decades. Recently clinical studies have shown the effectiveness of this growth factor in the treatment of neurodegenerative disorders. This clinical use makes it necessary to have sensitive, specific methods available to permit measurement of the level of this protein and to determine how it behaves during the course of treatment. OBJECTIVE: To describe the measurement of NGF levels in human serum using an immunoenzymatic method and evaluating the levels of this protein in some neurological disorders. Materials and methods. NGF levels were measured in the serum of healthy persons and in patients with Alzheimer's disease (AD) Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's chorea (HC) using a double site immune-enzymatic assay. Murine 27/21 anti-beta-NGF monoclonal antibody was used as the antibody to cover the plate and as conjugate. RESULTS: Adding a block pass to the method, in which the sample was incubated with an excess of 27/21 antibody effectively reduced the signal observed in the immuno-enzymatic assay. A moderate reduction in beta-NGF levels was seen in the serum of patients with ALS and MS. There was a statistically significant reduction in the patients who were carriers of PD and HC. CONCLUSIONS: The significant reduction in NGF levels in patients with PD and HC may be associated with a disorder in the use of this protein in central and peripheral tissues

Do the benefits of currently available treatments justify early diagnosis and treatment of amyotrophic lateral sclerosis? Arguments against.

Ludolph AC, Riepe MW.

Neurology. 1999; 53(8 Suppl 5):S46-S49.

Recent in vitro and experimental animal studies strongly indicate that motor neuron diseases, like other neurodegenerative diseases, may be preceded by a long preclinical period. Clinical studies have suggested that the beneficial effects of neuroprotection in human amyotrophic lateral sclerosis (ALS) may be due to a preferential effect on early phases of the disease. However, the aim of this article is to review the potential arguments that there is no justification for early neuroprotective treatment of ALS. Controversies concerning the clinical neuroprotective effects of riluzole in mice and humans exist. Side effects of riluzole are emphasized and the data that appear to indicate that ALS has a long preclinical period are questioned. On the basis of these doubts and skepticisms, we conclude that it may be premature to treat ALS early without addressing the major objections in future studies in a controlled manner

The role of mitochondria in the pathogenesis of neurodegenerative diseases.

Manfredi G, Beal MF.

Brain Pathol. 2000 Jul; 10(3):462-72.

A growing body of evidence indicates that mitochondrial dysfunction may play an important role in the pathogenesis of many neurodegenerative disorders. Because mitochondrial metabolism is not only the principal source of high energy intermediates, but also of free radicals, it has been suggested that inherited or acquired mitochondrial defects could be the cause of neuronal degeneration as a consequence of energy defects and oxidative damage. Mitochondrial respiratory chain dysfunction has been reported in association with primary mitochondrial DNA abnormalities, and also as a consequence of mutations in nuclear genes directly involved in mitochondrial functions, such as SURF1, frataxin, and paraplegin. Defects of oxidative phosphorylation and increased free radical production have also been observed in diseases that are not due to primary mitochondrial abnormalities. In these cases, the mitochondrial dysfunction is likely to be an epiphenomenon, which, nevertheless, could be of importance in precipitating a cascade of events leading to cell death. In either case, understanding the role of mitochondria in the pathogenesis of neurodegenerative diseases could be important for the development of therapeutic strategies in these disorders

[Mercury in hair of patients with ALS].

Mano Y, Takayanagi T, Ishitani A, et al.

Rinsho Shinkeigaku. 1989 Jul; 29(7):844-8.

In middle of Kii peninsula, one of the biggest mercury mine in Japan had been present until about 10 years ago. The mercury contents in water and fish are reported to be higher in this district. So we investigated the mercury in hair of patients and normal controls. In this study the subjects are 23 cases of ALS including 15 cases in Nara and Mie and 8 cases in other prefectures except in Kii peninsula, 14 cases with ataxia, 11 cases with other degenerative diseases like Parkinson's disease and Alzheimer's disease, 25 cases of cerebrovascular disease as compared to 26 normal controls. The hair are taken from 3 areas on head of patients and normal controls. They are washed in 2% sodium lauryl sulfate and stirred in distilled water several times, and they are soaked in acetone and dried in filter paper. They are inserted in fire and vaporized mercury are measured (Zeeman Effect Mercury Analyzer) in ppm. The hair mercury concentration is 2.81 ppm in ALS in total, 3.62 ppm in ALS in Nara and Mie and 1.39 ppm in outside of Kii Peninsula, 2.34 ppm in ataxia, 1.83 ppm in other degenerative diseases, 1.66 ppm in cerebrovascular disease and 1.44 ppm in normal controls. Statistically it is significant (p less than 0.05) between that in ALS in Nara and Mie and that in normal controls. 6 cases (40%) with ALS in Nara and Mie have the value above the mean +2 standard deviation of controls.(ABSTRACT TRUNCATED AT 250 WORDS)

[Amyotrophic lateral sclerosis and mercury--preliminary report].

Mano Y, Takayanagi T, Abe T, et al.

Rinsho Shinkeigaku. 1990 Nov; 30(11):1275-7.

The mercury and selenium content in the hair of 13 ALS cases was studied by neutron activation analysis. The total mercury content of the hair was 3.70 +/- 2.73 ppm (mean +/- standard deviation) in the ALS patients as a whole, 4.46 +/- 3.16 ppm in the ALS patients from the middle of Kii Peninsula, and 2.49 +/- 1.38 ppm in the ALS patients from other region. As the comparison, mercury content was 2.43 +/- 0.79 ppm in the patients with Parkinsonism, and 2.10 +/- 1.13 ppm in the patients with multiple sclerosis (MS). The selenium content of the hair was 0.36 +/- 0.35 ppm for all ALS patients as a whole, 0.45 +/- 0.25 ppm in the ALS patients from the middle of the Kii Peninsula, and 0.21 +/- 0.47 ppm in the ALS from other region. There were no cases with higher values than mean values of control group, except one case from other regions. It is well known that the selenium decreases the toxicity of mercury in the human body. From these data mercury with low content of selenium might be one of the environmental factors which are thought to be involved in producing of ALS

Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects.

Matthews RT, Yang L, Browne S, et al.

Proc Natl Acad Sci U S A. 1998 Jul 21; 95(15):8892-7.

Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases

Occupational exposures and amyotrophic lateral sclerosis. A population-based case-control study.

McGuire V, Longstreth WT, Jr., Nelson LM, et al.

Am J Epidemiol. 1997 Jun 15; 145(12):1076-88.

This population-based case-control study was conducted in three countries in western Washington State to evaluate associations between workplace exposures and the risk of amyotrophic lateral sclerosis (ALS). Cases (n = 174) were all newly diagnosed with ALS by neurologists during 1990-1994, and controls (n = 348), who were matched according to age (+/-5 years) and sex, were identified via random-digit dialing or Medicare enrollment files. Four industrial hygienists blindly assessed detailed lifetime job histories for exposures to metals, solvents, and agricultural chemicals. Case-control comparisons were made for jobs held between 15 years of age and 10 years prior to the cases' dates of diagnosis. After adjustment for age and education, ever exposure to agricultural chemicals was associated with ALS (odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.1-3.5); this association was observed separately in men (OR = 2.4, 95% CI 1.2-4.8) but not in women (OR = 0.9, 95% CI 0.2-3.8). Among men, the odds ratio for low exposure to agricultural chemicals (below the median level for exposed controls) relative to no exposure was 1.5 (95% CI 0.4-5.3), and for high exposure, it was 2.8 (95% CI 1.3-6.1) (p for trend = 0.03). Similar analyses based on the panel's assessment of exposures to metals and solvents showed no associations. These findings suggest an association between ALS and agricultural chemicals in men

[Mechanism of the effect of methylcobalamin on the recovery of neuromuscular functions in mechanical and toxin denervation].

Mikhailov VV, Mikhailov VV, Avakumov VM.

Farmakol Toksikol. 1983 Nov; 46(6):9-12.

It has been shown in experiments on rats that daily administration of methylcobalamine in a dose of 50 micrograms/100 g bw produces marked activation of the regeneration of mechanically damaged axons of motoneurons. Systematic administration of the drug has a protective action on the development of neuromuscular transmission blockade induced by botulinum toxoid

Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis.

Miller RG, Moore DH, Gelinas DF, et al.

Neurology. 2001 Apr 10; 56(7):843-8.

BACKGROUND: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. METHODS: Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations. RESULTS: Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin. CONCLUSION: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS

Transforming growth factor-beta: death takes a holiday.

Miller RJ, Ragsdale CW.

Nat Neurosci. 2000 Nov; 3(11):1061-2.

Serum levels of coenzyme Q10 in patients with amyotrophic lateral sclerosis.

Molina JA, De Bustos F, Jimenez-Jimenez FJ, et al.

J Neural Transm. 2000; 107(8-9):1021-6.

To elucidate whether serum coenzyme Q10 levels are related with the risk for amyotrophic lateral sclerosis (ALS), we compared serum levels of coenzyme Q10 and the coenzyme Q10/cholesterol ratio, in 30 patients with ALS and 42 matched controls using a high performance liquid chromatography technique. The mean serum coenzyme Q10 levels and the coenzyme Q10/cholesterol ratio did not differ significantly between the 2 study groups. These values were not influenced by the clinical form (spinal vs. bulbar) of ALS, and they did not correlate with age, age at onset, and duration of the disease. These results suggest that serum coenzyme Q10 concentrations are unrelated with the risk for ALS

Stimulation of nerve growth factor synthesis/secretion in mouse astroglial cells by coenzymes.

Murase K, Hattori A, Kohno M, et al.

Biochem Mol Biol Int. 1993 Jul; 30(4):615-21.

We examined the effect of coenzymes such as PQQ, pyrroloquinoline quinone; TOPA, 3-(2,4,5-trihydroxyphenyl)-DL-alanine, and lipoic acid on nerve growth factor (NGF) synthesis in mouse astroglial cells, BALB c/3T3 cells, and WS-1 cells in culture. These coenzymes had a stimulating effect on NGF synthesis without causing cytotoxicity. Especially PQQ showed the strongest activity of promoting NGF synthesis in astroglial cells, whereas lipoic acid had the strongest effect on BALB c/3T3 cells. The activity may not due to the catechol ring or 1,4-benzoquinone ring, but due to the oxidative or reductive activity. These results suggest that these coenzymes may play a role in NGF synthesis and neuronal survival through the stimulating effect of the NGF synthesis in brain and such compounds are good candidates as NGF inducers

Mitochondria in neurodegeneration: bioenergetic function in cell life and death.

Murphy AN, Fiskum G, Beal MF.

J Cereb Blood Flow Metab. 1999 Mar; 19(3):231-45.

The biochemical pathways to cell death in chronic and acute forms of neurodegeneration are poorly understood, limiting the ability to develop effective therapeutic approaches. As details of the apoptotic and necrotic pathways have been revealed, an appreciation for the decisive role that mitochondria play in life-death decisions for the cell has grown. As a result, the need has arisen to reevaluate the significance to cell viability of mitochondrial Ca2+ sequestration, reactive oxygen species generation, and the membrane permeability transition. This review provides basic information on these mitochondrial functions as they relate to control over cell death

Endocrinologic regulation of carbohydrate metabolism. Amyotrophic lateral sclerosis and Parkinsonism-dementia on Guam.

Nagano Y, Tsubaki T, Chase TN.

Arch Neurol. 1979 Apr; 36(4):217-20.

Studies of the endocrinologic control of carbohydrate metabolism were conducted in Guamanians with parkinsonism-dementia (PD) or amyotrophic lateral sclerosis (ALS) and in Guamanian control patients who had various other neuromuscular disorders. Intravenously infused arginine tended to produce a more prolonged elevation in serum glucose levels in PD and ALS patients than in control subjects. On the other hand, the serum insulin response to arginine was significantly less in both PD and ALS patients than in controls. Arginine stimulated the release of growth hormone to a similar degree in all three patient groups. These observations support and extend previous reports of endocrinologic abnormalities in parkinsonism and ALS and might suggest that a defect in pancreatic islet cell function attends these disorders

Protection of cultured spinal motor neurons by estradiol.

Nakamizo T, Urushitani M, Inoue R, et al.

Neuroreport. 2000 Nov 9; 11(16):3493-7.

Estrogens have been reported to exert neuroprotection in the brain, but there have been no reports of such neuroprotection in spinal motor neurons, the neurons selectively involved in amyotrophic lateral sclerosis (ALS). In this study, we demonstrated that 17beta-estradiol and its biologically inactive stereoisomer, 17alpha-estradiol, prevented glutamate- and nitric oxide (NO)-induced selective motor neuronal death observed in primary cultures of the rat spinal cord. The dose of estradiols required for motor neuron protection was greatly reduced by co-administration with glutathione. The results of this study shows that estradiol protects spinal motor neurons from excitotoxic insults in vitro, and may have application as a treatment for ALS

Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. II. Diet.

Nelson LM, Matkin C, Longstreth WT, Jr., et al.

Am J Epidemiol. 2000 Jan 15; 151(2):164-73.

The association of nutrient intake with the risk of amyotrophic lateral sclerosis (ALS) was investigated in a population-based case-control study conducted in three counties of western Washington State from 1990 to 1994. Incident ALS cases (n = 161) were identified and individually matched on age and gender to population controls (n = 321). A self-administered food frequency questionnaire was used to assess nutrient intake. Conditional logistic regression analysis was used to compute odds ratios adjusted for education, smoking, and total energy intake. The authors found that dietary fat intake was associated with an increased risk of ALS (highest vs. lowest quartile, fiber-adjusted odds ratio (OR) = 2.7, 95% confidence interval (CI): 0.9, 8.0; p for trend = 0.06), while dietary fiber intake was associated with a decreased risk of ALS (highest vs. lowest quartile, fat-adjusted OR = 0.3, 95% CI: 0.1, 0.7; p for trend = 0.02). Glutamate intake was associated with an increased risk of ALS (adjusted OR for highest vs. lowest quartile = 3.2, 95% CI: 1.2, 8.0; p for trend < 0.02). Consumption of antioxidant vitamins from diet or supplement sources did not alter the risk. The positive association with glutamate intake is consistent with the etiologic theory that implicates glutamate excitotoxicity in the pathogenesis of ALS, whereas the associations with fat and fiber intake warrant further study and biologic explanation

Anti-neural antibodies in serum and cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients.

Niebroj-Dobosz I, Jamrozik Z, Janik P, et al.

Acta Neurol Scand. 1999 Oct; 100(4):238-43.

OBJECTIVES: An autoimmune basis has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). This hypothesis is supported by the presence of antibodies that interact with motoneuron antigens in serum of these patients. Against autoimmunity are the discrepances in the frequency of the antibodies appearance and also failure of immunosuppression. The aim of our study was to evaluate the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and anti-sulfatides in paired serum and cerebrospinal fluid samples in the ALS patients. MATERIAL AND METHODS: Serum of 103 and CSF of 79 patients with ALS was examined. The "disease controls" consisted of 22 cases of other motor neuron diseases and 50 healthy, age-matched normals. CSF was drawn at the same time from 79 ALS patients, 6 cases of the "disease controls" and 50 normals. To study the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and sulfatides the ELISA technique has been applied. RESULTS: An increased titer against GM1-gangliosides, AGM1-gangliosides and sulfatides in ALS appeared in serum in 18%, 32%, and 11%, resp., in the "disease controls" the increased antibodies titer appeared in single cases. In CSF the appropriate values in ALS were 20%, 15%, 8%, resp. In the "disease controls" a high antibodies titer was a rare finding. CONCLUSIONS: It is concluded that in some ALS cases and also in some patients with other motor neuron diseases an autoimmune mechanism may contribute to motor neuron injury

Dietary antioxidant supplementation reverses age-related neuronal changes.

O'Donnell E, Lynch MA.

Neurobiol Aging. 1998 Sep; 19(5):461-7.

Evidence suggests that reactive oxygen species in brain may play a role in the development of age-related neuronal impairments, and that the increase in the concentration of the proinflammatory cytokine, interleukin-1beta (IL-1beta), in aged brain tissue, may also be a contributory factor. In this study, we have analyzed changes in enzymatic and nonenzymatic antioxidant levels, in parallel with interleukin-1beta concentration, in cortical tissue prepared from young and aged rats. We report that there was an age-related increase in the activity of superoxide dismutase without concomitant changes in the activity of catalase or glutathione peroxidase and an age-related decrease in the concentrations of alpha-tocopherol and ascorbate. These observations, coupled with age-related increases in lipid peroxidation and interleukin-1beta concentration, are consistent with a compromised antioxidant defense in cortex of aged rats, a proposal supported by the finding that these changes were not observed in cortical tissue prepared from rats fed on a diet supplemented with alpha-tocopherol and ascorbate for 12 weeks

The Little Black Book of Primary Care.

Onion DK.


Evaluation of antioxidants, protein, and lipid oxidation products in blood from sporadic amyotrophic lateral sclerosis patients.

Oteiza PI, Uchitel OD, Carrasquedo F, et al.

Neurochem Res. 1997 Apr; 22(4):535-9.

Several parameters indicators of oxidative stress were evaluated in blood from individuals with the sporadic form of amyotrophic lateral sclerosis (SALS) and compared to healthy controls. Plasma levels of 2-thiobarbituric-reactive substances (TBARS), products of lipid peroxidation, were significantly higher (p < 0.03) in the SALS patients compared to controls. The concentration of plasma antioxidants (alpha-tocopherol, beta-carotene, ubiquinol-10 and glutathione) and the activity of red blood cell CuZn superoxide dismutase were not significantly different between the groups. The ratio TBARS/alpha-tocopherol was 47% higher in the SALS individuals than in controls. Protein thiols and protein-associated carbonyls in red blood cell membranes and supernates were similar for both groups. A positive correlation (r2 = "0.91)" was found between the concentration of protein-associated carbonyls in red blood cells and the onset of clinical symptoms. These findings are in agreement with several reports showing higher levels of oxidative damage to cell components in ALS

Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist--a review of preclinical data.

Parsons CG, Danysz W, Quack G.

Neuropharmacology. 1999 Jun; 38(6):735-67.

N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS) to symptomatic treatment (e.g. epilepsy, Parkinson's disease, drug dependence, depression, anxiety and chronic pain). However, many NMDA receptor antagonists also produce highly undesirable side effects at doses within their putative therapeutic range. This has unfortunately led to the conclusion that NMDA receptor antagonism is not a valid therapeutic approach. However, memantine is clearly an uncompetitive NMDA receptor antagonist at therapeutic concentrations achieved in the treatment of dementia and is essentially devoid of such side effects at doses within the therapeutic range. This has been attributed to memantine's moderate potency and associated rapid, strongly voltage-dependent blocking kinetics. The aim of this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal models of chronic neurodegenerative diseases. The ultimate purpose is to provide evidence that it is indeed possible to develop clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine

BrainRecovery.com: Powerful Therapy for Challenging Brain Disorders.

Perlmutter D.


Serum antibodies to GM1 ganglioside in amyotrophic lateral sclerosis.

Pestronk A, Adams RN, Clawson L, et al.

Neurology. 1988 Sep; 38(9):1457-61.

We report the presence of serum antibodies directed against GM1 ganglioside, a defined neural antigen, in many patients with amyotrophic lateral sclerosis (ALS). We examined serum from a series of patients with well-documented clinical diagnoses. Serum antibodies to GM1 ganglioside were measured using ELISA assays. Our results showed that polyclonal IgM anti-GM1 antibodies were present at dilutions of 1:25 to 1:2,000 in 42 of 74 (57%) patients with ALS. The anti-GM1 antibodies were especially frequent in patients with prominent lower motor neuron signs (41/59; 69%). Few normal controls (2/23) and motor-sensory neuropathy patients (3/27) had similar antibodies. Anti-GM1 antibodies did occur in patients with nonneural autoimmune disorders. However, the anti-GM1 antibodies in these patients tended to differ from those in ALS based on an analysis of their light chain types. Further examination of the role and spectrum of serum antiganglioside antibody activity in motor neuron syndromes is warranted

A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside.

Pestronk A, Cornblath DR, Ilyas AA, et al.

Ann Neurol. 1988 Jul; 24(1):73-8.

We report 2 patients with a treatable, immune-mediated motor polyneuropathy associated with antibodies to defined neural antigens. In these patients asymmetrical weakness developed in one arm and progressed over 2 to 3 years to involve the other arm, legs, and trunk. Both patients were initially diagnosed as having lower motor neuron forms of amyotrophic lateral sclerosis. However, repeated electrophysiological testing eventually showed multifocal conduction blocks in motor but not sensory fibers compatible with patchy selective demyelination. Serum testing by thin-layer chromatography and enzyme-linked immunosorbent assay revealed that both patients had high titers of antibody directed against GM1 and other gangliosides. Initial therapeutic trials of prednisone (100 mg daily for 4 to 6 months) and plasmapheresis were unsuccessful. Treatment with cyclophosphamide, however, was followed by marked improvement in strength in both patients

Patterns of serum IgM antibodies to GM1 and GD1a gangliosides in amyotrophic lateral sclerosis.

Pestronk A, Adams RN, Cornblath D, et al.

Ann Neurol. 1989 Jan; 25(1):98-102.

We studied the incidence and clinical correlates of serum antibodies to GM1 and GD1a gangliosides in patients with classical amyotrophic lateral sclerosis (ALS) and other "motor nerve" syndromes. Serum antibodies to GM1 and GD1a gangliosides were measured using enzyme-linked immunosorbent assays. Our results showed that polyclonal immunoglobulin M (IgM) antibodies to the GM1 or GD1a ganglioside or both were present at serum dilutions of 1:25 to 1:4,000 in 78% (57/73) of patients with ALS. Only 8% of normal controls had similar antibodies. The pattern of serum antibody reactivity correlated with the pattern of clinical involvement in our patients. Selective reactivity to GD1a ganglioside was common when upper motor neuron signs were prominent. IgM reactivity to GM1 ganglioside was common in ALS patients with prominent lower motor neuron signs. Most patients with motor neuropathies had serum reactivity to both GM1 and GD1a gangliosides. These results provide further evidence of ongoing autoimmune processes in ALS patients. There is a strong relationship between serum antiganglioside antibodies and patterns of clinical involvement in ALS

Altered metabolism of excitatory amino acids, N-acetyl-aspartate and N-acetyl-aspartyl-glutamate in amyotrophic lateral sclerosis.

Plaitakis A, Constantakakis E.

Brain Res Bull. 1993; 30(3-4):381-6.

Since recent studies provided evidence for abnormal glutamate metabolism in amyotrophic lateral sclerosis, we measured amino acid levels in the fasting plasma of 52 ALS patients and an equal number of controls of a similar age. In addition, the content of amino acids, N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG) were measured in spinal cord and brain tissue obtained at autopsy from patients dying of ALS. Results showed significant elevations (by about 70%) in the plasma levels of glutamate in the ALS patients as compared to controls. In contrast, glutamate levels were significantly decreased in all CNS regions studied of ALS patients (by 21-40%), with the greatest changes occurring in the spinal cord. The ratio of glutamine to glutamate was altered significantly in the spinal cord ALS tissue. In addition, reductions in the levels of aspartate (by 32-35%), NAA, and NAAG (by 40-48%) were found in the spinal cord of ALS patients. These results are consistent with a generalized defect in the metabolism of neuroexcitotoxic amino acids. An altered distribution of these compounds may occur between their intracellular and extracellular pools with resultant abnormal potentiation of excitatory transmission mediated by glutamate receptors and selective degeneration of motor neurons

Thiamin monophosphate in the CSF of patients with amyotrophic lateral sclerosis.

Poloni M, Patrini C, Rocchelli B, et al.

Arch Neurol. 1982 Aug; 39(8):507-9.

Free thiamin and thiamin monophosphate levels were determined by an electrophoretic fluorometric micromethod in plasma and CSF of patients with amyotrophic lateral sclerosis (ALS), alcoholics, and controls. In plasma of patients with ALS as well as in plasma and CSF of alcholics, both thiamin and thiamin monophosphate concentrations were decreased so that the thiamin-thiamin monophosphate (T/TMP) ratio remained unchanged compared with that of controls. In CSF of patients with ALS, however, thiamin monophosphate values decreased much more than thiamin levels, so that the T/TMP ratio was significantly increased. The selective impairment of thiamin monophosphate production by nerve cells is likely to result from the reduction of the activity of thiamin pyrophosphatase, an enzyme synthetized and highly concentratd in the Golgi complex. Thiamin pyrophosphatase is known to diminish in ALS as well as in experimental motor neuronal degeneration or axotomy. Thus, the T/TMP ratio could be taken as an index of the impairment of neuronal protein synthesis in ALS

Inversion of T/TMP ratio in ALS: a specific finding?

Poloni M, Mazzarello P, Patrini C, et al.

Ital J Neurol Sci. 1986 Jun; 7(3):333-5.

Thiamine (T) and thiamine monophosphate (TMP) levels were determined by an electrophoretic fluorometric method in the CSF of patients with typical sporadic ALS (50 cases), in other motor neuron diseases (MND) (14 cases) and in patients with upper and/or lower motor neuron lesions of varying origin (disseminated sclerosis, polyneuropathy, spondylotic myelopathy). T/TMP ratio was greater than or equal to 1 in a high percentage of patients with typical sporadic ALS (94%), in 35.7% of cases with other MND, while it was below 1 in the all other patients. The decrease of TMP with the inversion of the T/TMP ratio is a finding highly specific to typical sporadic ALS

[Neurologic manifestations in the course of pesticide intoxication].

Prazmo A.

Neurol Neurochir Pol. 1978 May; 12(3):327-31.

[Free radicals in immunology and infectious diseases].

Racek J, Holecek V, Sedlacek D, et al.

Epidemiol Mikrobiol Imunol. 2001 Apr; 50(2):87-91.

Free radicals contribute significantly in modification of immune processes and inflammatory reactions. They are produced by activated phagocytes which use them for killing microorganisms. Free radicals facilitate production of cytokines, which are important as modifiers of inflammatory reactions. Formation of free radicals is influenced by antioxidants which can thus modify the intensity of inflammatory reaction and immune response. The authors describe in detail the contribution of free radicals in etiology and pathogenesis of autoimmune diseases including rheumatoid arthritis, multiple sclerosis or amyotrophic lateral sclerosis. The role of free radicals and modifying influence of antioxidants in viral, bacterial, parasitic and mycotic diseases is described in the second part of the review. Finally, influence of free radicals and antioxidants on immunity changes in patients with malignant tumours, during aging and physical exercise is discussed

Lou Gehrig and amyotrophic lateral sclerosis. Is vitamin E to be revisited?

Reider CR, Paulson GW.

Arch Neurol. 1997 May; 54(5):527-8.

Investigators are beginning to reexamine the use of vitamin E for the treatment of amyotrophic lateral sclerosis. Vitamin E was isolated in the 1920s, and the results of animal studies led rapidly to clinical use. Regrettably, vitamin E did not ameliorate the progression of amyotrophic lateral sclerosis for Lou Gehrig, but more recent advances may identify subpopulations that do respond to vitamin E

Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy.

Reljanovic M, Reichel G, Rett K, et al.

Free Radic Res. 1999 Sep; 31(3):171-9.

Short-term trials with the antioxidant thioctic acid (TA) appear to improve neuropathic symptoms in diabetic patients, but the long-term response remains to be established. Therefore, Type 1 and Type 2 diabetic patients with symptomatic polyneuropathy were randomly assigned to three treatment regimens: (1) 2 x 600(mg of TA (TA 1200), (2) 600)mg of TA plus placebo (PLA) (TA 600) or (3) placebo and placebo (PLA). A trometamol salt solution of TA of 1200 or 600 mg or PLA was intravenously administered once daily for five consecutive days before enrolling the patients in the oral treatment phase. The study was prospective, PLA-controlled, randomized, double-blind and conducted for two years. Severity of diabetic neuropathy was assessed by the Neuropathy Disability Score (NDS) and electrophysiological attributes of the sural (sensory nerve conduction velocity (SNCV), sensory nerve action potential (SNAP)) and the tibial (motor nerve conduction velocity (MNCV), motor nerve distal latency (MNDL)) nerve. Statistical analysis was performed after independent reviewers excluded all patients with highly variable data allowing a final analysis of 65 patients (TA 1200: n = 18, TA 600: n = 27; PLA: n = 20). At baseline no significant differences were noted between the groups regarding the demographic variables and peripheral nerve function parameters for these 65 patients. Statistically significant changes after 24 months between TA and PLA were observed (mean +/- SD) for sural SNCV: +3.8 +/- 4.2 m/s in TA 1200, +3.0+/-3.0m/s in TA 600, -0.1+/-4.8m/s in PLA (p < 0.05 for TA 1200 and TA 600 vs. PLA); sural SNAP: +0.6+/-2.5 microV in TA 1200, +0.3+/-1.4 microV in TA 600, -0.7 +/- 1.5 microV in PLA (p = "0.076" for TA 1200 vs. PLA and p < 0.05 for TA 600 vs. PLA), and in tibial MNCV: +/- 1.2 +/- 3.8 m/s in TA 1200, -0.3 +/- 5.2 m/s in TA 600, 1.5 +/- 2.9 m/s in PLA (p < 0.05 for TA 1200 vs. PLA). No significant differences between the groups after 24 months were noted regarding the tibial MNDL and the NDS. We conclude that in a subgroup of patients after exclusion of patients with excessive test variability throughout the trial, TA appeared to have a beneficial effect on several attributes of nerve conduction

Insulin resistance in amyotrophic lateral sclerosis.

Reyes ET, Perurena OH, Festoff BW, et al.

J Neurol Sci. 1984 Mar; 63(3):317-24.

Over the last 30 years glucose intolerance has been reported in a significant percentage of patients with amyotrophic lateral sclerosis (ALS). Currently, a controversy exists in determining whether the carbohydrate abnormality is disease-specific or secondary to decreased glucose utilization due to muscle atrophy. A reduction in glucose receptor space had been postulated for a number of neuromuscular diseases including ALS. In order to clarify this issue we have estimated in vivo insulin sensitivity, using the euglycemic insulin clamp technique, in ALS patients and two control groups, matched according to percent ideal weight. The results showed that the glucose infusion rate, an estimate of in vivo insulin sensitivity, ws significantly diminished in ALS patients compared to both normal and disease controls. These results demonstrate that the insulin resistance in this disorder cannot be explained by a decrease in glucose-receptor space and suggest a primary carbohydrate aberration in the disease process itself

Genetics of amyotrophic lateral sclerosis.

Robberecht W.

J Neurol. 2000 Dec; 247:2-6.

The genetic cause of amyotrophic lateral sclerosis (ALS) is known in a minority of cases. Mutations in SOD1, the gene encoding a superoxide dismutase on chromosome 21, are indeed found in 20% of familial ALS patients, who constitute only 5 or 10% of all ALS patients. In rare cases, a mutation in NFH, the gene encoding the heavy subunit of neurofilament, is present. Familial ALS has been linked to other loci but the genes involved remain to be identified. A genetic component is also thought to at least contribute to the pathogenesis of sporadic ALS. Their identification is now possible thanks to progress in molecular genetics

Amyotrophic lateral sclerosis with antecedent poliomyelitis.

Roos RP, Viola MV, Wollmann R, et al.

Arch Neurol. 1980 May; 37(5):312-3.

Histopathological and virological studies were performed on autopsy tissue from a 47-year-old man who had a history of acute poliomyelitis at age 15 years and died after a three-year course of amyotrophic lateral sclerosis (ALS). The poliovirus serologic tests suggested prior infection with poliovirus type 3 but no ongoing poliovirus infection. The CNS showed typical features of ALS with no inclusion bodies or inflammatory cells. Attempts to isolate poliovirus in the CNS were unsuccessful and results of immunofluorescence studies for poliovirus antigen were negative. Molecular hybridization experiments using a DNA copy of the complete poliovirus genome failed to demonstrate poliovirus-related RNA or DNA sequences in the CNS. These studies, using sensitive techniques, indicate that there was no evidence of the continuing presence of poliovirus in this patient with ALS and antecedent poliomyelitis

Observations on the treatment of amylotropic lateral sclerosis with vitamin E.

Rosenberger A.

Med Rec. 1971;(154):97-101.

Controversies about amyotrophic lateral sclerosis.

Rowland LP.

Neurologia. 1996 Dec; 11 Suppl 5:72-4.

Controversy regarding amyotrophic lateral sclerosis (ALS) concerns aspects of relatively little consequence (such as the role of lead intoxication or trauma in the pathogenesis of the disease) and others of greater relevance, particularly the two following questions regarding treatment options: 1) Are we in a new era of therapy for ALS? Prior to the 1990's no controlled study showed consistent benefit from any of the treatments tried. We have now had announcements of benefit for four entirely different agents: riluzole, insulin-like growth hormone, brain derived neurotrophic hormone and gabapentin. The benefit, at most, is marginal or questionable. The effect is of statistical significance but of little clinical relevance, and 2) what is the role of peripheral nerves in ALS? The syndrome of multifocal motor neuropathy and conduction block (MMNCB) shares some clinical data (active tendon jerks in weak, wasted and fasciculating muscles) and pathological features (anterior horn cell loss and glions) with "typical" ALS. This is relevant because MMNCB is reversible with immunoglobulin therapy. The rigid separation between ALS (a disease of the motor neuron perikaryon) and MMNCB (a disease of the motor neuron axon) is no longer tenable

Estrogen replacement therapy in women with amyotrophic lateral sclerosis.

Rudnicki SA.

J Neurol Sci. 1999 Oct 31; 169(1-2):126-7.

Amyotrophic Lateral Sclerosis (ALS) occurs more commonly in men than in women, and women get the disease later in life compared to men. This epidemiologic aspect of the disease raises the question as to whether estrogen may be neuroprotective in delaying or preventing ALS. Postmenopausal women with ALS were separated into two groups dependent upon whether or not they took estrogen replacement therapy. Women who used estrogen had onset of their disease at an earlier age compared to those not taking hormonal replacement. There was no difference in survival in those patients taking estrogen compared to those not on the medication. Women with ALS were more likely to take estrogen compared to a control group of patients with neurological diseases other than motor neuron disease. Therefore, no evidence for a neuroprotective role of estrogen in postmenopausal women with ALS was found

Amyotrophic lateral sclerosis and viruses.

Salazar-Grueso EF, Roos RP.

Clin Neurosci. 1995; 3(6):360-7.

Amyotrophic lateral sclerosis (ALS) is a disease of unknown etiology. A number of theories have been pursued to explain the cause of ALS, including viral infection. This review examines the evidence implicating viruses in the pathogenesis of ALS, as well as current studies of naturally occurring and experimental models of virus-induced motor neuron disease (MND). The association of viruses and ALS remains to be established. The study of animal models of virus-induced MND may shed light on processes relevant to the etiology of ALS

Physiologic and metabolic response to progressive and prolonged exercise in amyotrophic lateral sclerosis.

Sanjak M, Paulson D, Sufit R, et al.

Neurology. 1987 Jul; 37(7):1217-20.

Physical work capacity in 35 ALS patients and 6 untrained controls was evaluated during progressive bicycle ergometry. In the ALS patients, maximum oxygen consumption (VO2max) and work capacity (Wmax) drop in relation to the decrease in ALS functional score. However, the oxygen cost (ml O2/kpm) of submaximal exercise was significantly increased. Prolonged submaximal exercise tests in six ALS patients and six matched untrained controls indicated that the exercise-induced increase in plasma free fatty acids, beta-hydroxybutyrate, esterified carnitine, and muscle esterified carnitine was significantly retarded in ALS patients

Hypovitaminosis D and decreased bone mineral density in amyotrophic lateral sclerosis.

Sato Y, Honda Y, Asoh T, et al.

Eur Neurol. 1997; 37(4):225-9.

To assess the bone health of patients with amyotrophic lateral sclerosis (ALS), we evaluated the bone density and serum biochemical indices of bone metabolism in 11 ALS patients. The serum concentration of 25-hydroxyvitamin D (25-OHD) was significantly lower in patients (14.0 +/- 3.7 ng/ml) than in controls (25.2 +/- 4.0 ng/ml), at deficient levels (< 10 ng/ml) in 2, and at insufficient levels (10-20 ng/ml) in 9 patients. Serum levels of parathyroid hormone (PTH) and ionized calcium were elevated in 8 and 6 patients, respectively. Dietary intake of vitamin D was below the recommended level (100 IU) in 10 patients, and 10 patients were in a sunlight-deprived state. The metacarpal bone density (MBD) and the metacarpal index (MCI) of the second metacarpal bone were measured by computed X-ray densitometry. Z scores of the MBD and the MCI were negative in 7 and 6 patients, respectively. The serum concentration of 25-OHD was positively correlated with the Z score of the MBD (p < 0.05, r = "0.727)" and negatively with the PTH level (p < 0.05, r = "-0.410)." The degree of dysfunction of hand grip also correlated with the Z score of the MBD (p < 0.05, r = "0.749)." These data underscore the importance of hypovitaminosis D and compensatory hyperparathyroidism in the development of osteopenia in patients with ALS

Blood pressure elevations in riluzole-treated patients with amyotrophic lateral sclerosis.

Scelsa SN, Khan I.

Eur Neurol. 2000; 43(4):224-7.

OBJECTIVE: To determine whether riluzole is associated with blood pressure elevations in patients with amyotrophic lateral sclerosis (ALS). BACKGROUND: Though previously reported, hypertension is not considered a frequent adverse effect of riluzole. METHODS: We reviewed data from 35 consecutive ALS patients on riluzole, and 88 randomly selected controls without and 20 patients with ALS who were not on riluzole. RESULTS: A significantly greater number of ALS patients on riluzole had blood pressure elevations (28 of 35 patients) compared to controls (26 of 88, p

Glutathione, oxidative stress and neurodegeneration.

Schulz JB, Lindenau J, Seyfried J, et al.

Eur J Biochem. 2000 Aug; 267(16):4904-11.

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed

Amyotrophic lateral sclerosis after accidental injection of mercury.

Schwarz S, Husstedt I, Bertram HP, et al.

J Neurol Neurosurg Psychiatry. 1996 Jun; 60(6):698.

Is systemic lupus erythematosus, amyotrophic lateral sclerosis, or fibromyalgia associated with Persian Gulf War service? An examination of Department of Defense hospitalization data.

Smith TC, Gray GC, Knoke JD.

Am J Epidemiol. 2000 Jun 1; 151(11):1053-9.

Since the Persian Gulf War ended in 1991, veterans have reported diverse, unexplained symptoms. Some have wondered if their development of systemic lupus erythematosus, amyotrophic lateral sclerosis, or fibromyalgia might be related to Gulf War service. The authors used Cox proportional hazard modeling to determine whether regular, active-duty service personnel deployed to the Persian Gulf War (n = 551,841) were at increased risk of postwar hospitalization with the three conditions compared with nondeployed Gulf War era service personnel (n = 1,478,704). All hospitalizations in Department of Defense facilities from October 1, 1988, through July 31, 1997, were examined. With removal of personnel diagnosed with any of the three diseases before August 1, 1991, and adjustment for multiple covariates, Gulf War veterans were not at increased risk of postwar hospitalization due to systemic lupus erythematosus (risk ratio (RR) = 0.94, 95% confidence interval (CI): 0.65, 1.35). Because of the small number of cases and wide confidence limits, the data regarding amyotrophic lateral sclerosis were inconclusive. Gulf War veterans were slightly at risk of postwar hospitalization for fibromyalgia (RR = 1.23, 95% Cl: 1.05, 1.43); however, this risk difference was probably due to the Gulf War veteran clinical evaluation program beginning in 1994. These data do not support Gulf War service and disease associations

Effect of ethyl apovincaminate on the cerebral circulation. Studies in patients with obliterative cerebral arterial disease.

Solti F, Iskum M, Czako E.

Arzneimittelforschung. 1976; 26(10a):1945-7.

The effect of ethyl apovincaminate (RGH-4405, Cavinton) on the cerebral and systemic circulations has been studied in detail in ten cases of cerebrovascular disease. 10 mg doses of Cavinton were given as infusion within 4-6 min; circulatory tests were carried out prior to administration of the drug and 3-6 min after. The principal results showed the following: On Cavinton cerebral vascular resistance was strongly reduced, while cerebral fraction of cardiac output significantly increased. On acute effect of the drug arterial mean pressure slightly decreased but cerebral blood flow nevertheless increased in general. Total vascular resistance also decreased but this decrease was less marked than that registered in cerebral vascular resistance

Possible supportive effects of co-dergocrine mesylate on antioxidant enzyme systems in aged rat brain.

Sozmen EY, Kanit L, Kutay FZ, et al.

Eur Neuropsychopharmacol. 1998 Feb; 8(1):13-6.

Free radical damage is implicated in the course of many diseases, including age-related dementias. Oxidative deamination of primary monoamino oxidase (MAO) produces NH3 and H2O2 with established or potential toxicity. MAO activity is increased in aged rat brain and significantly lowered by chronic hydergine (codergocrine mesylate, Sandoz) treatment. The aim of this study was to investigate the effects of hydergine on enzymatic antioxidant defense systems. Hydergine or vehicle was administered systemically to young (3 months) and aged (18 months) Sprague-Dawley rats for 20 days and 24 h after the termination of the treatment, superoxide dismutase (SOD) and catalase (CAT) activities were determined in some brain regions. SOD and CAT activities were higher in the aged animals and were further increased with hydergine treatment. The increase in SOD levels caused by hydergine treatment in the aged animals were the most prominent in the hippocampus and in the corpus striatum. There was no region-specific effect of hydergine treatment on CAT levels in aged animals. The possible causal relationship between increased MAO activity, a generator of free radicals, and increased antioxidant defense in aging brain require further investigation. Decreasing MAO levels and supporting the antioxidant enzymes may underlie the efficacy of hydergine in the treatment of age related cognitive decline

Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain.

Surtees R.

J Inherit Metab Dis. 1993; 16(4):762-70.

In humans, subacute combined degeneration of the spinal cord and brain, a primary demyelinating disease, is caused by cobalamin or methyltetrahydrofolate deficiency. Experimental studies into its pathogenesis suggest that dysfunction of the methyl-transfer pathway may be the cause. Compelling evidence for this comes from the study of inborn errors of cobalamin metabolism where deficiency of methylcobalamin, but not deoxyadenosylcobalamin, is associated with demyelination. Recent studies have focused upon inborn errors of the methyl-transfer pathway. Cerebrospinal fluid concentrations of metabolites of the methyl-transfer pathway have been measured in humans with sequential errors of the pathway and correlated with demyelination demonstrated on magnetic resonance imaging of the brain. This has provided new data suggesting that deficiency of S-adenosylmethionine is critical to the development of demyelination in cobalamin deficiency

[Assessment of the efficacy of treatment with pimozide in patients with amyotrophic lateral sclerosis. Introductory notes].

Szczudlik A, Tomik B, Slowik A, et al.

Neurol Neurochir Pol. 1998 Jul; 32(4):821-9.

The aim of the study was to assess the effect of pimozide voltage-dependent calcium channel blocker on the progression of ALS patients as compared to the potentially neuroprotective drugs, selegiline and vitamin E. There were 44 patients (17 females and 27 males, aged from 30 to 80 years, mean age: 56.2 years) diagnosed as either definite or possible ALS. The study design was open randomised. Patients were treated 3-12 months; the daily dose of pimozide was 1 mg. The disease progression index was calculated as a difference between scores of Norris scale before and after treatment. Statistical analysis showed a significant decrease of the index of progression of the disease in pimozide treated patients as compared to the others. This effect was neither related to the progression of the disease nor advance of the disease at the beginning of treatment

Ethyl apovincaminate therapy in neurovascular diseases.

Szobor A, Klein M.

Arzneimittelforschung. 1976; 26(10a):1984-9.

Of a series of 100 patients 46 were given combined (i.m. and oral) treatment with ethyl apovincaminate (RGH-4405, Cavinton) in daily doses of 10-30 mg; 54 were put on oral Cavinton (30-45 mg daily). Significant and relatively quick improvement was obtained in reversible vascular diseases, such as hypertensive encephalopathy, intermittent vascular cerebral insufficiency, in the early stage or light cases of cerebral endarteriitis and cerebral arteriosclerosis. On Cavinton effect hypoxic character of the EEG improved, and so did performance in psychodiagnostic tests, alertness and memory in the first place, furthermore changes of the eyeground. The doses administered did not damage parenchymal organs, they did not cumulate and when used in combination incompatibility could not be observed

Creatine monohydrate increases strength in patients with neuromuscular disease.

Tarnopolsky M, Martin J.

Neurology. 1999 Mar 10; 52(4):854-7.

Creatine monohydrate has been shown to increase strength in studies of young healthy subjects and in a few studies with patients. Creatine monohydrate (10 g daily for 5 days to 5 g daily for 5 days) was administered to patients with neuromuscular disease in a pilot study (Study 1; n = 81), followed by a single-blinded study (Study 2; n = 21). Body weight, handgrip, dorsiflexion, and knee extensor strength were measured before and after treatment. Creatine administration increased all measured indices in both studies. Short-term creatine monohydrate increased high-intensity strength significantly in patients with neuromuscular disease

Potential benefits of creatine monohydrate supplementation in the elderly.

Tarnopolsky MA.

Curr Opin Clin Nutr Metab Care. 2000 Nov; 3(6):497-502.

Creatine plays a role in cellular energy metabolism and potentially has a role in protein metabolism. Creatine monohydrate supplementation has been shown to result in an increase in skeletal muscle total and phosphocreatine concentration, increase fat-free mass, and enhance high-intensity exercise performance in young healthy men and women. Recent evidence has also demonstrated a neuroprotective effect of creatine monohydrate supplementation in animal models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and after ischemia. A low total and phosphocreatine concentration has been reported in human skeletal muscle from aged individuals and those with neuromuscular disorders. A few studies of creatine monohydrate supplementation in the elderly have not shown convincing evidence of a beneficial effect with respect to muscle mass and/or function. Future studies will be required to address the potential for creatine monohydrate supplementation to attenuate age-related muscle atrophy and strength loss, as well as to protect against age-dependent neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease

Mechanisms of action of gabapentin.

Taylor CP.

Rev Neurol (Paris). 1997; 153 Suppl 1:S39-S45.

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important

A summary of mechanistic hypotheses of gabapentin pharmacology.

Taylor CP, Gee NS, Su TZ, et al.

Epilepsy Res. 1998 Feb; 29(3):233-49.

Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t)

alpha-Tocopherol quinone level is remarkably low in the cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis.

Tohgi H, Abe T, Saheki M, et al.

Neurosci Lett. 1996 Mar 22; 207(1):5-8.

In order to investigate the role of free radicals in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), the concentrations of alpha-tocopherol (alpha-TOH) and its oxidized form alpha-tocopherol quinone (alpha-TQ) in the cerebrospinal fluid (CSF) of SALS patients were determined. The alpha-TOH level was 31% lower (P < 0.05) and the alpha-TQ level was 75% lower (P < 0.001) in SALS patients than in normal subjects. The results of the present study do not support the hypothesis that activated lipid peroxidation accelerates oxidation of alpha-TOH into alpha-TQ in SALS patients

The peripheral insulin-like growth factor system in amyotrophic lateral sclerosis and in multiple sclerosis.

Torres-Aleman I, Barrios V, Berciano J.

Neurology. 1998 Mar; 50(3):772-6.

A lack of trophic support may lead to degeneration of adult nerve cells. Several growth factors, including insulin-like growth factor I (IGF-I), control the survival of spinal motor neurons during development as well as after experimental injury. These neurons are selectively affected in patients with amyotrophic lateral sclerosis (ALS). Thus, we analyzed whether reduced levels of circulating IGF-I may be present in this disease. Significant increases were found in three of four of the main circulating IGF-binding proteins in ALS patients, whereas serum IGF-I and insulin levels were significantly reduced. On the contrary, multiple sclerosis patients did not show any significant change in the IGF-I trophic system even though oligodendrocytes are known targets of the trophic action of IGF-I. These results suggest an involvement of the peripheral IGF-I trophic system in ALS

Genistein is neuroprotective in murine models of familial amyotrophic lateral sclerosis and stroke.

Trieu VN, Uckun FM.

Biochem Biophys Res Commun. 1999 May 19; 258(3):685-8.

Amyotrophic lateral sclerosis (ALS), whether sporadic or familial (FALS), is a progressive, fatal neurodegenerative disorder involving the motor neurons of the cortex, brain stem, and spinal cord. In some studies, the male/female ratio of ALS patients was as high as 2 to 1. In FALS mice, disease onset and mortality were earlier among males than among females. This sexual dimorphism was due to estrogen, as treatment with genistein, a phytoestrogen, eliminated the observed sexual dimorphism in FALS mice. Genistein treatment also protected against oxygen singlet-induced cerebral damage in vivo. However, sexual dimorphism was not observed in this model of stroke; and genistein was equally effective in males and females. These data suggest that genistein has both estrogen-dependent and estrogen-independent neuroprotective activities and it should be investigated as a prophylactic agent against pathologic conditions such as ALS and stroke

Comparative study of the effect of ethyl apovincaminate and xantinol nicotinate in cerebrovascular diseases. Immediate drug effects on the concentrations of carbohydrate metabolites and electrolytes in blood and CSF.

Vamosi B, Molnar L, Demeter J, et al.

Arzneimittelforschung. 1976; 26(10a):1980-4.

Randomly selected 34 cerebrovascular patients were treated with ethyl apovincaminate (RGH-4405, Cavinton) and 109 with xanitinol nicotinate. The effects of drugs given in slow i.v. infusions on the concentration of carbohydrate metabolites and electrolytes in serum and CSF were observed. Cavinton improved the paresis in 60.6% of patients while xantinol nicotinate did so only in 47.1%. On the basis of the biochemical changes it can be concluded that Cavinton enhances both the glycolytic and the oxidative glucose breakdown in CNS

Adipose tissue cellularity in patients with amyotrophic lateral sclerosis.

Van den BR, Swerts L, Hendrikx A, et al.

Clin Neurol Neurosurg. 1977; 80(4):226-39.

The subcutaneous mean fat-cell volumes as measured in 20 patients suffering from amyotrophic lateral sclerosis (ALS) were definitely larger than those measured in a control group. In contrast with the control subjects, the mean fat-cell volume in patients with ALS appeared to be independent of body weight. The noted disturbances in carbohydrate-insulin metabolism in patients with ALS and the increase in serum triglycerides as observed in some patients may be related to the enlarged fat cells. The possibility that the enlargement of the fat-cells may, at least partially, have a neurogenic basis cannot be ignored. The hypothesis is put forward that in patients with ALS there is not only a lesion of the anterior horn, but also an involvement of sympathic structures responsible for the innervation of adipose tissue vessels. This involvement may lead to an inhibition of the lipolysis, and consequently to an enlargemnt of the fat cell. Interaction between the interference with metabolic and neurogenic factors may be at play

Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants.

Vyth A, Timmer JG, Bossuyt PM, et al.

J Neurol Sci. 1996 Aug; 139 Suppl:99-103.

Between 1983 and 1988 we treated 36 patients with sporadic amyotrophic lateral sclerosis (ALS) by an array of antioxidants and added other drugs to the regimen whenever a patient reported deterioration. Our customary prescription sequence was N-acetylcysteine (NAC); vitamins C and E; N-acetylmethionine (NAM); and dithiothreitol (DTT) or its isomer dithioerythritol (DTE). Patients with a history of heavy exposure to metal were also given meso 2,3-dimercaptosuccinic acid (DMSA). NAC, NAM, DTT, and DTE were administered by subcutaneous injection or by mouth or by both routes, the other vitamins and DMSA by mouth alone. The hospital pharmacy supplied NAC and NAM injections fluid as 100 ml bottles of 5.0 and 5.85% solutions, respectively. DTT was delivered in special double-walled capsules of 200 mg. DTT/DTE injection fluid was added to the NAC and NAM bottles, the final DTT/DTE concentrations never exceeding 0.5%. DMSA was provided in 250 mg capsules. All of the 36 patients used NAC and DTT/DTE; 29 also used vitamins C and E; 21 also used NAM; and 7 also used DMSA, DMSA, NAM, vitamins C and E were tolerated well. In many patients, DTT, DTE, NAC and NAM induced pain, redness and swelling at the injection sites in that order of decreasing frequency. DTT and DTE did often and NAC did sometimes cause gastric pain, nausea and other abdominal discomfort. Comparison of survival in the treated group and in a cohort of untreated historical controls, disclosed a median survival of 3.4 years (95% confidence interval: 3.0-4.2) in the treated and of 2.8 (95% confidence interval 2.2-3.1) years in the control patients. This difference may be explained by self-selection of our highly motivated treated group and by its initial survival of diagnosis for an average of 8.5 months before onset of treatment. We conclude that antioxidants neither seem to harm ALS patients, nor do they seem to prolong survival

Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study.

Walter MC, Lochmuller H, Reilich P, et al.

Neurology. 2000 May 9; 54(9):1848-50.

The authors assessed the safety and efficacy of creatine monohydrate (Cr) in various types of muscular dystrophies in a double-blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, 8 patients with Duchenne dystrophy, and 6 patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive Cr or placebo for 8 weeks. There was mild but significant improvement in muscle strength and daily-life activities by Medical Research Council scales and the Neuromuscular Symptom Score. Cr was well tolerated throughout the study period

Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy.

Watanabe T, Kaji R, Oka N, et al.

J Neurol Sci. 1994 Apr; 122(2):140-3.

Despite intensive searches for therapeutic agents, few substances have been convincingly shown to enhance nerve regeneration in patients with peripheral neuropathies. Recent biochemical evidence suggests that an ultra-high dose of methylcobalamin (methyl-B12) may up-regulate gene transcription and thereby protein synthesis. We examined the effects of ultra-high dose of methyl-B12 on the rate of nerve regeneration in rats with acrylamide neuropathy, using the amplitudes of compound muscle action potentials (CMAPs) after tibial nerve stimulation as an index of the number of regenerating motor fibers. After intoxication with acrylamide, all the rats showed equally decreased CMAP amplitudes. The animals were then divided into 3 groups; rats treated with ultra-high (500 micrograms/kg body weight, intraperitoneally) and low (50 micrograms/kg) doses of methyl-B12, and saline-treated control rats. Those treated with ultra-high dose showed significantly faster CMAP recovery than saline-treated control rats, whereas the low-dose group showed no difference from the control. Morphometric analysis revealed a similar difference in fiber density between these groups. Ultra-high doses of methyl-B12 may be of clinical use for patients with peripheral neuropathies

Possible role of androgen receptors in amyotrophic lateral sclerosis. A hypothesis.

Weiner LP.

Arch Neurol. 1980 Mar; 37(3):129-31.

Androgen receptors have been demonstrated in both cranial nerve and spinal motor neurons. This article proposes that amyotrophic lateral sclerosis (ALS) may be a disease in which androgen receptors in motor neurons are lost or not functioning. This is suggested by the male-to-female ratio of the disease, the age of onset, and the sparing of neurons of cranial nerves III, IV, and VI that coincidentally lack androgen receptors. The hypothesis is that ALS may be due to a loss of androgen receptors that results in an inability to respond to a variety of insults including axonal damage

Neuromuscular Degeneration. Nutritional Influences on Illness.

Werbach M.


[Pharmacological studies on degeneration and regeneration of peripheral nerves. (1) Effects of methylcobalamin and cobamide on EMG patterns and loss of muscle weight in rats with crushed sciatic nerve].

Yamatsu K, Kaneko T, Kitahara A, et al.

Nippon Yakurigaku Zasshi. 1976 Mar; 72(2):259-68.

Experiments were performed to investigate the effects of Vitamin B12, i.e., methylcobalamin and cobamide, on the neural degeneration and regeneration. Male Wistar rats (140 to 150 g) under conditions of experimental unilateral sciatic nerve crushing were treated consecutively with methylcobalamin (50 and 500 mug/kg/day i.p.), cobamide (50 and 500 mug/kg/day i.p.) or saline. EMG recordings were periodically carried out and rats of each group were sacrificed to determine the weight-loss of denervated muscles 1, 2, 3 and 4 weeks after crush. Neither methylcobalamin nor cobamide exerted any significant effect on body-weight gain of the nerve-crushed rats with a daily injection of 50 and 500 mug/kg i.p.. The EMG pattern of the denervated biceps femoris muscle showed a total lack of fibrillation for 2 days after the nerve-crush. Thereafter, the fibrillation appeared and continued for 10 to 14 days until the nerve had regenerated, as evidenced by the appearance of a complex NMU voltage. The occurrence of fibrillation voltage was slightly delayed in methylcobalamin group (500 mug/kg/day) as compared with the saline control group. The re-appearance of normal NMU voltage was more rapid in the methylcobalamin 500 mug/kg group than in controls and other experimental groups. Neither methylcobalamin nor cobamide had any significant effect on the weight-loss of the gastrocnemius and tibialis anterior muscles following crush of the sciatic nerve. However, a daily injection of 500 mug/kg of methylcobalamin produced a significant increase in the weight of the soleus muscle which recovered to the extent of being the same weight of the contralateral 4 weeks after the nerve-crush. These results suggest that methylcobalamin may have an inhibitory effect on Wallerian degeneration and also a facilitatory effect on the neural regeneration of the crushed sciatic nerve of rats

[Pharmacological studies on degeneration and regeneration of the peripheral nerves. (2) Effects of methylcobalamin on mitosis of Schwann cells and incorporation of labeled amino acid into protein fractions of crushed sciatic nerve in rats].

Yamatsu K, Yamanishi Y, Kaneko T, et al.

Nippon Yakurigaku Zasshi. 1976 Mar; 72(2):269-78.

Male Wistar rats (140 to 150 g) in which the unilateral sciatic nerve had been crushed were treated consecutively with methylcobalamin (5, 50 and 500 mug/kg/day i.p.) or saline immediately after the nerve-crush. Thereafter, they were periodically sacrificed for biochemical and histological examinations. At different intervals after the nerve-crush, L-leucine-4,5-T (20 mu Ci/100g, specific activity 15 mCi/m mole) or L-leucine -14C(U) (15 muCi/100g, specific activity 270 mCi/m mole) was given i.p. to some rats of each group and 3 hr later they were sacrificed to determine the rate of leucine incorporation into protein fractions of the crushed nerve and the denervated muscles. The nerve and muscles of the contralateral side served as control. Longitudinal sections of proximal and distal stumps of the sciatic nerve were prepared and stained with hematoxylin and eosin. As compared with saline group, repeated injections of 5, 50 and 500 mug/kg/day of methyl-cobalamin caused a significant increase of the in vivo incorporation of radioactive leucine into the protein fraction of the crushed sciatic nerve 5 to 7 days after the crush. In contrast, a recovery of the increased incorporation of leucine into the crushed nerve was more rapid in methylcobalamin groups than in the saline group. On the other hand, methylcobalamin (5 approximately 500 mug/kg/day i.p.) had no significant effect on the leucine incorporation into the denervated muscles (m. gastrocnemius, m. tibialis anterior and m. soleus). In addition, consecutive injections of methylcobalamin (5 approximately 500 mug/kg/day) did not affect the mitosis of Schwann cells during the period of Wallerian degeneration of the crushed sciatic nerve. These results suggest that methylcobalamin possesses a stimulating effect on proteosynthesis in Schwann cells at the initial stage of axon regeneration and it may facilitate neural regeneration

Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse.

Yamazaki K, Oda K, Endo C, et al.

Neurosci Lett. 1994 Mar 28; 170(1):195-7.

We examined the effects of methylcobalamin (methyl-B12, mecobalamin) on degeneration of motor nerve terminals in the anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mice. GAD mice received orally methyl-B12 (1 mg/kg body wt/day) from the 40th day after birth for 25 days. In the distal endplate zone of the muscle, although most terminals were degenerated in both the untreated and methyl-B12-treated GAD mice, sprouts were more frequently observed in the latter. In the proximal endplate zone, where few degenerated terminals were seen in both groups of the mice, the perimeter of the terminals was increased and the area of the terminals was decreased significantly in the methyl-B12-treated GAD mice. These findings indicate that methyl-B12 promotes regeneration of degenerating nerve terminals in GAD mice

Calcium and vitamin D metabolism in Guamanian Chamorros with amyotrophic lateral sclerosis and parkinsonism-dementia.

Yanagihara R, Garruto RM, Gajdusek DC, et al.

Ann Neurol. 1984 Jan; 15(1):42-8.

We evaluated 16 Guamanian Chamorros with amyotrophic lateral sclerosis and 33 patients with parkinsonism-dementia for disturbances of calcium and vitamin D metabolism. The serum immunoreactive parathyroid hormone level was mildly elevated in 6 patients with amyotrophic lateral sclerosis and in 5 patients with parkinsonism-dementia. There were significant positive correlations between serum immunoreactive parathyroid levels and duration of illness in male patients with motor neuron disease, but not in female patients or in patients with parkinsonism-dementia. Intestinal absorption of calcium, as assessed by serum and urinary activity of calcium 47 following oral administration, was decreased in 2 patients with amyotrophic lateral sclerosis and in 4 patients with parkinsonism-dementia, all of whom had low levels of serum 1,25-dihydroxyvitamin D. Reductions in cortical bone mass were striking in patients with motor neuron disease. A significant negative correlation was found between the percentage of cortical area of the second metacarpal bone and muscle atrophy and weakness, and significant positive correlations were found between degree of immobility and ratio of urinary hydroxyproline to creatinine in patients with amyotrophic lateral sclerosis and parkinsonism-dementia. In general, abnormalities in calcium metabolism were subtle. Thus, if the demonstrated deposition of metals, particularly calcium and aluminum, in central nervous system tissues of Guamanians with these two conditions is a cause of the diseases and of the early appearance of neurofibrillary tangles in neurons, the accumulation has apparently occurred long before onset of symptoms, and detectable abnormalities of calcium and vitamin D metabolism may already have been corrected

High aluminum deposition in the central nervous system of patients with amyotrophic lateral sclerosis from the Kii Peninsula, Japan: two case reports.

Yasui M, Yase Y, Ota K, et al.

Neurotoxicology. 1991; 12(2):277-83.

We report two cases of amyotrophic lateral sclerosis (ALS), in which metal analysis revealed markedly higher aluminum concentration in the central nervous system (CNS) as well as higher calcium and lower magnesium concentration and higher Ca/Mg ratios compared with controls. Case 1 was a 55-year-old housewife and total duration of illness was 2 years and 2 mon from onset of clinical symptom. Case 2 was a 80-year-old woman and total duration of illness was 10 mon. Results showed that neither were exposed to toxic environments nor any neurologic disease in the past history. Postmortem examination disclosed motor neuron death and degeneration of pyramidal tracts. The significance of metal metabolism in pathogenesis of amyotrophic lateral sclerosis is discussed

Aluminum deposition in the central nervous system of patients with amyotrophic lateral sclerosis from the Kii Peninsula of Japan.

Yasui M, Yase Y, Ota K, et al.

Neurotoxicology. 1991; 12(3):615-20.

Chronic dietary deficiency of calcium (Ca) and magnesium (Mg) with excessive intake of aluminum (Al) and manganese (Mn) has been implicated in the pathogenesis of high incidence amyotrophic lateral sclerosis (ALS) in the Western Pacific. We report two cases of ALS from the Kii Peninsula of Japan with markedly elevated concentrations of Al in central nervous system (CNS) tissues. Six pathologically verified cases of ALS and five neurologically normal controls were studied. Levels of Al, Ca and phosphorus (P) were determined simultaneously by neutron activation analysis (NAA), and Mg concentration was measured by inductively coupled plasma emission spectrometry (ICP) in 26 CNS regions. Al concentrations in the precentral gyrus, internal capsule, crus cerebri and spinal cord were significantly increased in two ALS patients, compared with those of controls. Mean Al concentrations of the 26 CNS regions in these two patients were also higher than those of controls and of the four other ALS cases (p less than 0.01). By contrast, Mg concentrations in the 26 CNS regions were markedly reduced in the ALS cases, compared with controls (p less than 0.01), and the Ca/Mg ratios were significantly increased in the ALS cases (p less than 0.01). Our data indicate that high-incidence ALS in the Western Pacific may result from Ca-Mg dysmetabolism with resultant deposition of Al

Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study).

Ziegler D, Hanefeld M, Ruhnau KJ, et al.

Diabetologia. 1995 Dec; 38(12):1425-33.

Anti-oxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes mellitus, thus providing a rationale of potential therapeutic value for diabetic patients. The effects of the anti-oxidant alpha-lipoic acid (thioctic acid) were studied in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy; ALADIN) in 328 non-insulin-dependent diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (1200, 600, or 100 mg ALA) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and at each visit (days 2-5, 8-12, and 15-19) prior to infusion. In addition, the Hamburg Pain Adjective List, a multidimensional specific pain questionnaire, and the Neuropathy Symptom and Disability Scores were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score in the feet decreased from baseline to day 19 by -4.5 +/- 3.7 (-58.6%) points (mean +/- SD) in ALA 1200, -5.0 +/- 4.1 (-63.5%) points in ALA 600, -3.3 +/- 2.8 (-43.2%) points in ALA 100, and -2.6 +/- 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA 600 vs PLAC: p < 0.001). The response rates after 19 days, defined as an improvement in the total symptom score of at least 30%, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC; p = "0.002)." The total scale of the Pain Adjective List was significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19 days (both p < 0.01). The rates of adverse events were 32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings substantiate that intravenous treatment with alpha-lipoic acid using a dose of 600 mg/day over 3 weeks is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions