Recent ALS publications

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Lithium Slows ALS Progression in Human Study

The publication has caused a frenzy of excitement in the neurology community and is extremely significant as until now only one other drug (riluzole / rilutek) has shown positive effects in patients. The effects of lithium seem to be additive to the effects of riluzole. You can download the full article below.

Daily doses of lithium, a drug used to treat bipolar disorder, have been found to delay progression of amyotrophic lateral sclerosis (ALS) in an Italian study of 44 people with the disease.

No other treatment to date has shown such a dramatic effect on this paralyzing and fatal disease of adults, which affects some 30,000 Americans.

Francesco Fornai at the University of Pisa (Italy), with colleagues at the University of Novara (Italy) and the Santa Lucia Foundation in Rome, announced their results online today in Proceedings of the National Academy of Sciences.

At the end of a 15-month trial that began in October 2005, about 30 percent of the patients that took riluzole, a drug known to have modest benefit in ALS, had died, while all those receiving riluzole plus lithium had survived. The disease progressed markedly in the riluzole-only group but progressed very slowly in the riluzole-plus-lithium group.

“Although the number of study participants is small, the results are very intriguing,” said Dr. Valerie Cwik, MDA medical director and vice president of Research. “MDA has already had conversations with researchers in the United States to follow up on these results with a larger, confirmatory study.”

Sixteen trial participants were randomly selected to receive 50 milligrams a day of riluzole plus two daily doses of 150 milligrams of lithium carbonate. (If necessary, doses were adjusted up to 450 milligrams a day during the study to maintain targeted blood levels.)

The remaining 28 participants were randomly assigned to receive riluzole only.

The two groups were carefully matched with respect to the number of patients with bulbar ALS, the most rapidly progressive form, and pulmonary function.

A parallel study in mice with a genetic form of ALS suggested that lithium works by increasing autophagy, a process in which worn-out or abnormal cellular components are destroyed, and boosting the number of mitochondria, the energy-producing units of cells.

Lithium must be taken under a doctor’s supervision and with frequent monitoring of blood levels. Early signs of lithium toxicity include diarrhea, vomiting, drowsiness, weakness and lack of coordination. Later signs include giddiness, blurred vision, ringing in the ears and a large output of dilute urine.

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The clinical diagnostic utility of transcranial magnetic stimulation: Report of an IFCN committee. Related Articles

The clinical diagnostic utility of transcranial magnetic stimulation: Report of an IFCN committee.

Clin Neurophysiol. 2007 Dec 4;

Recent ALS publications :- Authors: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, Mills K, Rösler KM, Triggs WJ, Ugawa Y, Ziemann U

The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

Recent ALS publications :- PMID: 18063409 [PubMed - as supplied by publisher]Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice. Related Articles

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice.

Neuroscience. 2007 Oct 30;

Recent ALS publications :- Authors: Smittkamp SE, Brown JW, Stanford JA

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease affecting upper and lower motor neurons. Symptom onset may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Bulbar involvement is particularly important in ALS as it is associated with increased morbidity and mortality. The purpose of this study was to characterize bulbar motor deficits in the B6SJL-Tg(SOD1-G93A)1Gur/J (SOD1-G93A) mouse model of familial ALS. We measured orolingual motor function by placing thirsty mice in a customized operant chamber that allows for measurement of tongue force and lick rhythm as animals lick water from an isometric disc. Testing spanned the pre-symptomatic, symptomatic, and end-stage segments of the disease. Rotarod performance, fore- and hindlimb grip strength, and locomotor activity were also monitored regularly during this period. We found that spinal involvement was apparent first, with both fore- and hindlimb grip strength being affected in SOD1-G93A mice from the onset of testing (64 days of age). Rotarod performance was affected by 71 days of age. Locomotor activity was not affected, even near end-stage. Bulbar involvement appeared much later, with tongue motility being affected by 100 days of age. Tongue force was affected by 115 days of age. To our knowledge, these findings are the first to describe the onset of bulbar versus spinal motor signs and characterize orolingual motor deficits in this preclinical model of ALS.

Recent ALS publications :- PMID: 18061359 [PubMed - as supplied by publisher]Birth order and the genetics of amyotrophic lateral sclerosis. Related Articles

Birth order and the genetics of amyotrophic lateral sclerosis.

J Neurol. 2007 Dec 7;

Recent ALS publications :- Authors: Vivekananda U, Johnston C, McKenna-Yasek D, Shaw CE, Leigh PN, Brown RH, Al-Chalabi A

The cause of ALS remains largely unknown for the 90% with no known family history, but spontaneous mutation to risk alleles of as yet unidentified genes is possible. It has long been recognized that genetic diseases may be more likely to occur in the last born children of a sibship because increased paternal age is associated with an increased spontaneous point mutation rate in sperm. To test the hypothesis that such a mechanism is responsible for sporadic ALS, we have performed a retrospective analysis of birth order position. We have analyzed sibships of size greater than four using a binomial test for birth position. The 478 pedigrees studied show no birth order effect, suggesting that any genetic contributions to sporadic ALS are more likely to be through deletion in large genes or interactions of common polymorphisms, rather than frequent spontaneous point mutation. This is encouraging for the prospect of finding sporadic ALS susceptibility genes using genome-wide association mapping.

Recent ALS publications :- PMID: 18060566 [PubMed - as supplied by publisher]Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery. Related Articles

Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.

PLoS ONE. 2007;2(12):e1254

Recent ALS publications :- Authors: Gwinn K, Corriveau RA, Mitsumoto H, Bednarz K, Brown RH, Cudkowicz M, Gordon PH, Hardy J, Kasarskis EJ, Kaufmann P, Miller R, Sorenson E, Tandan R, Traynor BJ, Nash J, Sherman A, Mailman MD, Ostell J, Bruijn L, Cwik V, Rich SS, Singleton A, Refolo L, Andrews J, Zhang R, Conwit R, Keller MA,

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

Recent ALS publications :- PMID: 18060051 [PubMed - in process]Calcium-influx increases SOD1 aggregates via nitric oxide in cultured motor neurons. Related Articles

Calcium-influx increases SOD1 aggregates via nitric oxide in cultured motor neurons.

Exp Mol Med. 2007 Oct 31;39(5):574-82

Recent ALS publications :- Authors: Kim HJ, Im W, Kim S, Kim SH, Sung JJ, Kim M, Lee KW

Familial amyotrophic lateral sclerosis (fALS) is caused by mutations in Cu/Zn-superoxide dismutase (SOD1), and SOD1 aggregation and calcium toxicity are involved in neuronal death. However, the effect of altered calcium homeostasis on the SOD1 aggregation is unknown. To investigate whether calcium triggers mutant SOD1 aggregation in vitro, human mutant SOD1 (G93A) was transfected into motor neuronal cell line (VSC 4.1 cells). These cells were then treated with calcium ionophore A23187 or agents that induce intracellular calcium release like cyclic ADP ribose, ryanodine or thapsigargin. A23187 was found to increase mutant SOD1 aggregation and neuronal nitric oxide synthase (nNOS) expression. Moreover, the NOS inhibitor (L-NAME) and a NO-dependent cyclic GMP cascade inhibitor (ODQ) reduced SOD1 aggregation, whereas an exogenous NO donor (GSNO) increased mutant SOD1 aggregation, which was also prevented by NOS or cGMP cascade inhibitor. Our data demonstrate that calcium-influx increases SOD1 aggregation by upregulating NO in cultured motor neuronal cells.

Recent ALS publications :- PMID: 18059133 [PubMed - in process]WNKs: protein kinases with a unique kinase domain. Related Articles

WNKs: protein kinases with a unique kinase domain.

Exp Mol Med. 2007 Oct 31;39(5):565-73

Recent ALS publications :- Authors: Huang CL, Cha SK, Wang HR, Xie J, Cobb MH

Familial amyotrophic lateral sclerosis (fALS) is caused by mutations in Cu/Zn-superoxide dismutase (SOD1), and SOD1 aggregation and calcium toxicity are involved in neuronal death. However, the effect of altered calcium homeostasis on the SOD1 aggregation is unknown. To investigate whether calcium triggers mutant SOD1 aggregation in vitro, human mutant SOD1 (G93A) was transfected into motor neuronal cell line (VSC 4.1 cells). These cells were then treated with calcium ionophore A23187 or agents that induce intracellular calcium release like cyclic ADP ribose, ryanodine or thapsigargin. A23187 was found to increase mutant SOD1 aggregation and neuronal nitric oxide synthase (nNOS) expression. Moreover, the NOS inhibitor (L-NAME) and a NO-dependent cyclic GMP cascade inhibitor (ODQ) reduced SOD1 aggregation, whereas an exogenous NO donor (GSNO) increased mutant SOD1 aggregation, which was also prevented by NOS or cGMP cascade inhibitor. Our data demonstrate that calcium-influx increases SOD1 aggregation by upregulating NO in cultured motor neuronal cells.

Recent ALS publications :- PMID: 18059132 [PubMed - in process]A genome-wide association study of sporadic ALS in a homogenous Irish population. Related Articles

A genome-wide association study of sporadic ALS in a homogenous Irish population.

Hum Mol Genet. 2007 Dec 5;

Recent ALS publications :- Authors: Cronin S, Berger S, Ding J, Schymick JC, Washecka N, Hernandez DG, Greenway MJ, Bradley DG, Traynor BJ, Hardiman O

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive limb or bulbar weakness. Efforts to elucidate the disease-associated loci have to date produced conflicting results. One strategy to improve power in genome-wide studies is to genotype a genetically homogenous population. Such populations exhibit extended linkage disequilibrium and lower allelic heterogeneity to facilitate disease gene mapping. We sought to identify associated variants for ALS in the Irish, a stable population of relatively homogenous genetic background, and to replicate these findings in larger genetically out-bred populations. We conducted a genome-wide association study in 432 Irish individuals using Illumina HumanHap 550K SNP chips. We demonstrated extended linkage disequilibrium and increased homogeneity in the Irish sample when compared to an out-bred population of mixed European ancestry. The Irish scan identified 35 loci associated with p values below 0.0001. For replication, we identified seven chromosomal regions commonly associated in a joint analysis of genome-wide data on 958 ALS cases and 932 controls from Ireland and the previously published datasets from the US and The Netherlands. When pooled, the strongest association was a variant in the gene encoding DPP6, a component of type A neuronal transmembrane potassium channels. Further confirmation of these candidate loci is warranted in additional genome-wide datasets. We have made our individual genotyping data publicly available, contributing to a powerful world-wide resource to refine our understanding of the genetics of sporadic ALS.

Recent ALS publications :- PMID: 18057069 [PubMed - as supplied by publisher]Insulin increases retinal hemorrhage in mild oxygen-induced retinopathy in the rat: inhibition by riluzole. Related Articles

Insulin increases retinal hemorrhage in mild oxygen-induced retinopathy in the rat: inhibition by riluzole.

Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5671-6

Recent ALS publications :- Authors: Yoo MH, Yoon YH, Chung H, Cho KS, Koh JY

PURPOSE: Although hyperglycemia is likely the main stimulus for VEGF induction in diabetic retinopathy (DR), a switch from oral hypoglycemic therapy to parenteral insulin injection, despite producing better glucose control, sometimes paradoxically aggravates DR. The induction of VEGF by insulin, as observed in certain conditions, may be a plausible mechanism for this phenomenon. In the present study, to determine the role of insulin in proliferative diabetic retinopathy, the Recent ALS publications :- Authors examined whether insulin treatment affected the outcome of oxygen-induced retinopathy (OIR) in rats and whether the anti-amyotrophic lateral sclerosis (ALS) drug riluzole with protein kinase C-inhibiting activity can attenuate the effects of insulin. METHODS: To examine in vivo the effects of insulin, mild OIR was produced in 7-day-old rat pups by raising them with a nursing mother in a 55% oxygen environment for 5 days. After that, rat pups were injected daily with subcutaneous saline or insulin (4 U/d) with or without additional riluzole injection (10 mg/kg/d, intraperitoneally) for 5 days in room air. RESULTS: Insulin treatment substantially increased VEGF levels, extraretinal vessel formation, matrix metalloproteinase activity, and the extent of retinal hemorrhage in rat pups with mild OIR compared with saline controls. Riluzole substantially reduced all these changes induced by insulin. CONCLUSIONS: In the present study, OIR was used as a surrogate model for DR because the core pathology and the VEGF-mediated mechanism are shared by both conditions. As in human DR, in rat pups with mild OIR, insulin treatment aggravated retinal hemorrhage, which was blocked by riluzole. Riluzole is a Food and Drug Administration-approved anti-ALS drug with a favorable adverse effect profile. It may be useful as an anti-VEGF treatment in DR, especially in reducing the retinal hemorrhage that often occurs shortly after the switch from oral hypoglycemics to parenteral insulin.

Recent ALS publications :- PMID: 18055818 [PubMed - in process]Auditory event-related potentials in non-demented patients with sporadic amyotrophic lateral sclerosis. Related Articles

Auditory event-related potentials in non-demented patients with sporadic amyotrophic lateral sclerosis.

Clin Neurophysiol. 2007 Dec 3;

Recent ALS publications :- Authors: Raggi A, Consonni M, Iannaccone S, Perani D, Zamboni M, Sferrazza B, Cappa SF

OBJECTIVE: To investigate the presence of sub-clinical cognitive dysfunction in non-demented patients with amyotrophic lateral sclerosis (ALS) using auditory event-related potentials (ERPs). METHODS: Ten subjects with ALS and 10 age- and sex-matched controls performed a passive three-stimulus paradigm with standard (80%), deviant (16%) and distracter (4%) stimuli. To quantify the mismatch component, the evoked response to the standard tones was subtracted from the corresponding deviant stimuli and novel response; the P3a component was obtained by subtracting the response to the standard tone from that to the novel stimuli. The amplitude and latency for the N1 component obtained with the standard stimuli were also measured. Clinical features, disability, cognitive status and depression were evaluated with standardised scales. RESULTS: There were no significant differences between patients and controls for latencies, while the N1, P3a and MMN (obtained by the subtraction Novel-Standard) were of lower amplitude in patients than in controls. In the patient group, the P3a latency correlated with months from disease onset and symptoms severity, measured with the amyotrophic lateral sclerosis severity scale. CONCLUSIONS: Our findings confirm the hypothesis of a sub-clinical cognitive impairment in non-demented ALS patients, suggesting pathological involvement beyond the motor areas. SIGNIFICANCE: ERPs seem to be a promising technique to detect the possible impairment of extra-motor sub-clinical dysfunction in ALS, and an appropriate technique for the cognitive follow-up, as passive tasks, not requiring motor responses, are particularly adequate in a disorder leading to severe loss of motor function.

Recent ALS publications :- PMID: 18055257 [PubMed - as supplied by publisher]SOD1(A4V)-mediated ALS: Absence of a closely linked modifier gene and origination in Asia. Related Articles

SOD1(A4V)-mediated ALS: Absence of a closely linked modifier gene and origination in Asia.

Neurosci Lett. 2007 Nov 6;

Recent ALS publications :- Authors: Broom WJ, Johnson DV, Auwarter KE, Iafrate AJ, Russ C, Al-Chalabi A, Sapp PC, McKenna-Yasek D, Andersen PM, Brown RH

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS. Approximately 20% of cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. Carriers of the SOD1(A4V) mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3-5 years with other dominant SOD1 mutations). Previous studies of SOD1(A4V) carriers identified a common haplotype around the SOD1 locus, suggesting a common founder for most SOD1(A4V) patients. In the current study we sequenced the entire common haplotypic region around SOD1 to test the hypothesis that polymorphisms in either previously undescribed coding regions or non-coding regions around SOD1 are responsible for the more aggressive phenotype in SOD1(A4V)-mediated ALS. We narrowed the conserved region around the SOD1 gene in SOD1(A4V) ALS to 2.8Kb and identified five novel SNPs therein. None of these variants was specifically found in all SOD1(A4V) patients. It therefore appears likely that the aggressive nature of the SOD1(A4V) mutation is not a result of a modifying factor within the region around the SOD1 gene. Founder analysis estimates that the A4V mutation occurred 540 generations ( approximately 12,000 years) ago (95% CI 480-700). The conserved minimal haplotype is statistically more similar to Asian than European population DNA sets, suggesting that the A4V mutation arose in native Asian-Americans who reached the Americas through the Bering Strait.

Recent ALS publications :- PMID: 18055113 [PubMed - as supplied by publisher]Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis: The effect of riluzole treatment. Related Articles

Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis: The effect of riluzole treatment.

Clin Neurol Neurosurg. 2007 Dec 3;

Recent ALS publications :- Authors: Andreadou E, Kapaki E, Kokotis P, Paraskevas GP, Katsaros N, Libitaki G, Zis V, Sfagos C, Vassilopoulos D

OBJECTIVES: Defective glutamate (glu) metabolism and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Moreover, glycine (gly) has been shown to potentiate excitatory transmission. The "antiglutamatergic" agent riluzole has been shown to prolong survival in ALS. The aim of the study was to investigate a possible effect of riluzole on plasma glu and gly levels, correlating with clinical response to treatment. PATIENTS AND METHODS: Plasma concentrations of glu and gly were measured in 20 healthy volunteers and 22 ALS patients before treatment and after 6 months on riluzole. RESULTS: At baseline, increased plasma glu correlated with spinal onset and male gender whereas gly levels did not differ between patients and controls. No significant change was observed for both amino acids post-treatment, despite a lower rate of disease progression. CONCLUSION: These results suggest that riluzole may affect disease progression without a significant impact on plasma glu and gly levels, possibly indicating different mechanisms of drug action.

Recent ALS publications :- PMID: 18055102 [PubMed - as supplied by publisher]Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice. Related Articles

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice.

J Neurol Sci. 2007 Dec 3;

Recent ALS publications :- Authors: Choi CI, Lee YD, Gwag BJ, Cho SI, Kim SS, Suh-Kim H

Amyotrophic lateral sclerosis (ALS) is a progressive disease which is caused by degeneration of motor neurons in the central nervous system. The incidence of ALS is higher in men than women, but the female advantage disappears with increased age. Here, we report evidence that the female advantage is due to the protective role of estrogen. In an ALS mouse model carrying the human Cu/Zn superoxide dismutase (hSOD1) G93A transgene, ovariectomy did not alter the onset age of the disease while reducing the female lifespan by 7 days and making it comparable to that of the male transgenic mice. Treatment of ovariectomized females with 17beta-estradiol (E2) did not delay the onset of disease, but prevented progression of ALS motor dysfunctions as shown by extension reflex test for a limited time window. Importantly, E2 treatment rescued the lifespans in overiectomized females. These findings will provide important new insights to interpretation of disease progression in post-menopausal female ALS patients.

Recent ALS publications :- PMID: 18054961 [PubMed - as supplied by publisher]The contribution of mitochondrial dysfunction to a gene-environment model of Guamanian ALS and PD. Related Articles

The contribution of mitochondrial dysfunction to a gene-environment model of Guamanian ALS and PD.

Mitochondrion. 2007 Oct 9;

Recent ALS publications :- Authors: Lynch D, Wanglund C, Spathis R, Chan CW, Reiff DM, Lum JK, Garruto RM

Scientific investigations of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) of Guam have implicated genetic and environmental risk factors in their etiology. Using brain tissue, we investigated mitochondrial dysfunction and report a higher frequency of somatic mutations in the light strand promoter (LSP) of the mitochondrial control region in Guam ALS and PD patients than in Guam controls, along with the presence of inherited mutations that may contribute to a novel gene-environment interaction risk model. Along with other risk factors, they demonstrate both the importance and significance of genetic and environmental contributions to Guam ALS and PD etiology.

Recent ALS publications :- PMID: 18054291 [PubMed - as supplied by publisher]Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology. Related Articles

Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology.

Neurobiol Dis. 2007 Oct 23;

Recent ALS publications :- Authors: Wang L, Sharma K, Deng HX, Siddique T, Grisotti G, Liu E, Roos RP

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons (MNs). Approximately 10% of ALS cases are familial (known as FALS), and approximately 20% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase type 1 (SOD1). Mutant (MT) SOD1 induces FALS as a result of a toxicity that remains poorly defined. Several studies suggest that the toxicity involves a non-cell autonomous mechanism. In this study, we generated transgenic mice that had a restricted and repressible expression of MTSOD1 in spinal MNs and interneurons. Although the transgenic mice were not weak, they weighed less than control mice and had pathological and immunohistochemical abnormalities of MNs confined to cells that expressed MTSOD1. These results suggest that MTSOD1-induced MN degeneration is at least partly cell autonomous. Mouse models similar to the one presented here will be valuable for spatially and temporally controlling expression of mutant genes involved in neurodegenerative diseases.

Recent ALS publications :- PMID: 18054242 [PubMed - as supplied by publisher]Neurodegeneration and peroxidases. Related Articles

Neurodegeneration and peroxidases.

Neurobiol Aging. 2007 Nov 27;

Recent ALS publications :- Authors: Everse J, Coates PW

Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that affect different parts of the central nervous system. However, a review of the literature indicates that certain biochemical reactions involved in neurodegeneration in these three diseases are quite similar and could be partly identical. This article critically examines the similarities and, based on data from our own and other laboratories, proposes a novel explanation for neurodegeneration in these three diseases. We identified about 20 commonalities that exist in the neurodegenerative process of each disease. We hypothesize that there are two enzyme-catalyzed pathways that operate in affected neurons: an oxidative pathway leading to destruction of various neuronal proteins and lipids, and an apoptotic pathway which the body normally uses to remove unwanted and dysfunctional cells. Data from many laboratories indicate that oxidative reactions are primarily responsible for neurodegeneration, whereas apoptosis may well be a secondary response to the presence of neurons that have already been severely damaged by oxidative reactions. Attempts to inhibit apoptosis for the purpose of attenuating progression of these diseases may therefore be only of marginal benefit. Specific oxidative reactions within affected neurons led us to propose that one or more heme peroxidases may be the catalyst(s) involved in oxidation of proteins and lipids. Support for this proposal is provided by the recent finding that amyloi-beta peptide may act as a peroxidase in AD. Possible participation of the peroxidase activity of cytochrome c, herein designated as cytochrome c(px) to distinguish it from yeast cytochrome c peroxidase, is discussed. Of special interest is our recent finding that many compounds that cause attenuation of neurodegeneration are inhibitors of the peroxidase activity of cytochrome c. Several inhibitors were subsequently identified as suicide substrates. Such inhibitors could be ideally suited for targeted clinical approaches aimed at arresting progression of neurodegeneration. Finally, it is possible that immobilized yet still active peroxidase(s) may be present in protein aggregates in AD, PD, and ALS. This activity could be the catalyst for the slow, self-perpetuating and irreversible degeneration of affected neurons that occurs over long periods of time in these neurodegenerative diseases.

Recent ALS publications :- PMID: 18053617 [PubMed - as supplied by publisher]Neonatal Intraperitoneal or Intravenous Injections of Recombinant Adeno-Associated Virus Type 8 Transduce Dorsal Root Ganglia and Lower Motor Neurons. Related Articles

Neonatal Intraperitoneal or Intravenous Injections of Recombinant Adeno-Associated Virus Type 8 Transduce Dorsal Root Ganglia and Lower Motor Neurons.

Hum Gene Ther. 2007 Dec 1;

Recent ALS publications :- Authors: Foust KD, Poirier A, Pacak CA, Mandel RJ, Flotte TR

Targeting lower motor neurons (LMNs) for gene delivery could be useful for disorders such as spinal muscular atrophy and amyotrophic lateral sclerosis. LMNs reside in the ventral gray matter of the spinal cord and send axonal projections to innervate skeletal muscle. Studies have used intramuscular injections of adenoassociated virus type 2 (AAV2) to deliver viral vectors to LMNs via retrograde transport. However, treating large areas of the spinal cord in a human would require numerous intramuscular injections, thereby increasing viral titer and risk of immune response. New AAV serotypes, such as AAV8, have a dispersed transduction pattern after intravenous or intraperitoneal injection in neonatal mice, and may transduce LMNs by retrograde transport or through entry into the nervous system. To test LMN transduction after systemic injection, we administered recombinant AAV8 (rAAV8) carrying the green fluorescent protein (GFP) gene by intravenous or intraperitoneal injection to neonatal mice on postnatal day 1. Tissues were harvested 5 and 14 days postinjection and analyzed by real-time polymerase chain reaction and GFP immunohistochemistry to assess the presence of AAV genomes and GFP expression, respectively. Spinal cords were positive for AAV genomes at both time points. GFP immunohistochemistry revealed infrequent labeling of LMNs across all time points and injection routes. Somewhat surprisingly, there was extensive labeling of fibers in the dorsal horns and columns, indicating dorsal root ganglion transduction across all time points and injection routes. Our data suggest that systemic injection of rAAV8 is not an effective delivery route to target lower motor neurons, but could be useful for targeting sensory pathways in chronic pain.

Recent ALS publications :- PMID: 18052722 [PubMed - as supplied by publisher]Oxidative Stress and Neurotoxicity. Related Articles

Oxidative Stress and Neurotoxicity.

Chem Res Toxicol. 2007 Dec 4;

Recent ALS publications :- Authors: Sayre LM, Perry G, Smith MA

There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field.

Recent ALS publications :- PMID: 18052107 [PubMed - as supplied by publisher]Glutathione production is regulated via distinct pathways in stressed and non-stressed cortical neurons. Related Articles

Glutathione production is regulated via distinct pathways in stressed and non-stressed cortical neurons.

Brain Res. 2007 Nov 4;

Recent ALS publications :- Authors: Burdo J, Schubert D, Maher P

Peroxynitrite-mediated damage has been linked to numerous neurological and neurodegenerative diseases, including stroke, Alzheimer's and Parkinson's Diseases, amyotrophic lateral sclerosis and multiple sclerosis. Studies on the toxic effects of peroxynitrite in neurons have focused primarily on adverse effects resulting from the nitration of cellular proteins as the principal mode of toxicity while the consequences of the modulation of kinase pathways by peroxynitrite have received relatively less attention. Our results show that treatment of primary rat neurons with the peroxynitrite donor, SIN-1, leads to decreases in glutathione (GSH) levels and cell viability via a novel extracellular-signal-related kinase (ERK)/c-Myc phosphorylation pathway and a reduction in the nuclear expression of NF-E2-related factor-2 (Nrf2) that down-regulate the expression of glutamate cysteine ligase, the rate limiting enzyme for GSH synthesis. The flavonoid fisetin protects against the SIN-1-mediated alterations in ERK/c-Myc phosphorylation, nuclear Nrf2 levels, glutamate cysteine ligase levels, GSH concentration and cell viability. We also show that inhibition of mitogen-activated protein kinase kinase or Raf kinase can increase GSH levels in unstressed primary rat neurons through the same ERK/c-Myc phosphorylation pathway. Together, these results demonstrate that distinct signaling pathways modulate GSH metabolism in unstressed and stressed cortical neurons.

Recent ALS publications :- PMID: 18048013 [PubMed - as supplied by publisher]Exogenous delivery of heat shock protein 70 increases lifespan in a mouse model of amyotrophic lateral sclerosis. Related Articles

Exogenous delivery of heat shock protein 70 increases lifespan in a mouse model of amyotrophic lateral sclerosis.

J Neurosci. 2007 Nov 28;27(48):13173-80

Recent ALS publications :- Authors: Gifondorwa DJ, Robinson MB, Hayes CD, Taylor AR, Prevette DM, Oppenheim RW, Caress J, Milligan CE

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder that results in the progressive loss of motoneurons (MNs) in the CNS. Several survival and death mechanisms of MNs have been characterized and it has been determined that MNs do not appear to mount a complete stress response, as determined by the lack of heat shock protein 70 (Hsp70) upregulation after several stress paradigms. Hsp70 has been shown to confer neuroprotection and the insufficient availability of Hsp70 may contribute to MNs' susceptibility to death in ALS mice. In this study, recombinant human Hsp70 (rhHsp70) was intraperitoneally injected three times weekly, beginning at postnatal day 50 until endstage, to G93A mutant SOD1 (G93A SOD1) mice. The administration of rhHsp70 was effective at increasing lifespan, delaying symptom onset, preserving motor function and prolonging MN survival. Interestingly, injected rhHsp70 localized to skeletal muscle and was not readily detected in the CNS. Treatment with rhHsp70 also resulted in an increased number of innervated neuromuscular junctions compared with control tissue. Together these results suggest rhHsp70 may delay disease progression in the G93A SOD1 mouse via a yet to be identified peripheral mechanism.

Recent ALS publications :- PMID: 18045911 [PubMed - in process]Neurotoxicity from glutathione depletion is mediated by Cu-dependent p53 activation. Related Articles

Neurotoxicity from glutathione depletion is mediated by Cu-dependent p53 activation.

Free Radic Biol Med. 2008 Jan 1;44(1):44-55

Recent ALS publications :- Authors: Du T, Ciccotosto GD, Cranston GA, Kocak G, Masters CL, Crouch PJ, Cappai R, White AR

Loss of intracellular neuronal glutathione (GSH) is an important feature of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The consequences of GSH depletion include increased oxidative damage to proteins, lipids, and DNA and subsequent cytotoxic effects. GSH is also an important modulator of cellular copper (Cu) homeostasis and altered Cu metabolism is central to the pathology of several neurodegenerative diseases. The cytotoxic effects of Cu in cells depleted of GSH are not well understood. We have previously reported that depletion of neuronal GSH levels results in cell death from trace levels of extracellular Cu due to elevated Cu(I)-mediated free radical production. In this study we further examined the molecular pathway of trace Cu toxicity in neurons and fibroblasts depleted of GSH. Treatment of primary cortical neurons or 3T3 fibroblasts with the glutathione synthetase inhibitor buthionine sulfoximine resulted in substantial loss of intracellular GSH and increased cytotoxicity. We found that both neurons and fibroblasts revealed increased expression and activation of p53 after depletion of GSH. The increased p53 activity was induced by extracellular trace Cu. Furthermore, we showed that in GSH-depleted cells, Cu induced an increase in oxidative stress resulting in DNA damage and activation of p53-dependent cell death. These findings may have important implications for neurodegenerative disorders that involve GSH depletion and aberrant Cu metabolism.

Recent ALS publications :- PMID: 18045546 [PubMed - in process]High-dimensional spatial normalization of diffusion tensor images improves the detection of white matter differences: an example study using amyotrophic lateral sclerosis. Related Articles

High-dimensional spatial normalization of diffusion tensor images improves the detection of white matter differences: an example study using amyotrophic lateral sclerosis.

IEEE Trans Med Imaging. 2007 Nov;26(11):1585-97

Recent ALS publications :- Authors: Zhang H, Avants BB, Yushkevich PA, Woo JH, Wang S, McCluskey LF, Elman LB, Melhem ER, Gee JC

Spatial normalization of diffusion tensor images plays a key role in voxel-based analysis of white matter (WM) group differences. Currently, it has been achieved using low-dimensional registration methods in the large majority of clinical studies. This paper aims to motivate the use of high-dimensional normalization approaches by generating evidence of their impact on the findings of such studies. Using an ongoing amyotrophic lateral sclerosis (ALS) study, we evaluated three normalization methods representing the current range of available approaches: low-dimensional normalization using the fractional anisotropy (FA), high-dimensional normalization using the FA, and high-dimensional normalization using full tensor information. Each method was assessed in terms of its ability to detect significant differences between ALS patients and controls. Our findings suggest that inadequate normalization with low-dimensional approaches can result in insufficient removal of shape differences which in turn can confound FA differences in a complex manner, and that utilizing high-dimensional normalization can both significantly minimize the confounding effect of shape differences to FA differences and provide a more complete description of WM differences in terms of both size and tissue architecture differences. We also found that high-dimensional approaches, by leveraging full tensor features instead of tensor-derived indices, can further improve the alignment of WM tracts.

Recent ALS publications :- PMID: 18041273 [PubMed - in process]Microglia as a pharmacological target in infectious and inflammatory diseases of the brain. Related Articles

Microglia as a pharmacological target in infectious and inflammatory diseases of the brain.

J Neuroimmune Pharmacol. 2006 Jun;1(2):117-26

Recent ALS publications :- Authors: Rock RB, Peterson PK

Following an eclipse of scientific inquiry regarding the biology of microglia that lasted 50 years, recognition toward the end of the 20th century of their neuropathogenic role in HIV-associated dementia and in neuroinflammatory/neurodegenerative diseases fueled a renaissance of interest in these resident macrophages of the brain parenchyma. Results of a large number of in vitro studies, using isolated microglial cells or glial/neuronal cell cultures, and parallel findings emerging from animal models and clinical studies have demonstrated that activated microglia produce a myriad of inflammatory mediators that both serve important defense functions against invading neurotropic pathogens and have been implicated in brain damage in infectious as well as neuroinflammatory/neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review provides a brief background regarding the physiological and pathophysiological roles of microglia and highlights current pharmacological approaches that target activated microglia with the goal of ameliorating infectious and neuroinflammatory/neurodegenerative diseases of the brain. Although this aspect of the field of neuroimmunopharmacology is in its infancy, it holds great promise for developing new treatments and prevention of diseases that are, in many cases, epidemic throughout the world.

Recent ALS publications :- PMID: 18040778 [PubMed - in process]Cross-sectional and longitudinal correlations between disease progression and different health-related quality of life domains in persons with amyotrophic lateral sclerosis. Related Articles

Cross-sectional and longitudinal correlations between disease progression and different health-related quality of life domains in persons with amyotrophic lateral sclerosis.

Amyotroph Lateral Scler. 2007 Dec;8(6):356-61

Recent ALS publications :- Authors: De Groot IJ, Post MW, van Heuveln T, Berg LH, Lindeman E

In ALS it would be expected that quality of life (QoL) would be decreased. However, studies to date show diverging results. Our study focuses on how ALS affects QoL on the different domains of the SF-36 cross-sectionally and during progression. The method used was a prospective cohort study, with assessments at baseline, at six months, and at one year. Patients were included with possible, probable or definite ALS according to the revised El Escorial criteria and were between 30 and 70 years of age. ALS functional rating scale was used to establish disease status, SF-36 as QoL scale. At baseline 73 completed ALSFRS forms were available and 62 completed SF-36 forms.The ALSFRS showed disease progression. SF-36 scores showed lower QoL scores of persons with ALS compared to the general population both in cross-sectional and longitudinal aspects in the domains of Physical Functioning, Role Physical, and Social Functioning, but similar compared with the general population in the Mental Health and Role Emotional domains. This study shows deteriorating physical health but stable mental health, thereby illustrating the diverging correlations between ALS severity and HRQoL. The diverging pattern of physical and mental health suggests a frame-shift in the experience of HRQoL.

Recent ALS publications :- PMID: 18033593 [PubMed - in process]Volumetric cortical loss in sporadic and familial amyotrophic lateral sclerosis. Related Articles

Volumetric cortical loss in sporadic and familial amyotrophic lateral sclerosis.

Amyotroph Lateral Scler. 2007 Dec;8(6):343-7

Recent ALS publications :- Authors: Turner MR, Hammers A, Allsop J, Al-Chalabi A, Shaw CE, Brooks DJ, Leigh PN, Andersen PM

Patients homozygous for the D90A mutation of the SOD1 gene (homD90A) demonstrate markedly slower progression of disease than those patients with sporadic ALS (SALS). PET studies have demonstrated a different cortical vulnerability in the two groups, reflected also in neurophysiological studies showing reduced cortical excitability in homD90A. Voxel-based morphometric analysis of magnetic resonance images (MRIs) enables the detection of regional differences in grey matter volume, and can be used to localize cortical atrophy in vivo. In this study, segmented, spatially normalized, modulated and smoothed grey matter portions of the MRIs from 23 SALS and seven homD90A patients with similar disability, were compared with those from 28 healthy control subjects. The SALS group showed bilateral areas of atrophy mainly confined to motor and pre-motor cortices. Cortical changes in the homD90A group were more pronounced within the frontal lobes when both were compared with healthy controls. This study provides further evidence for a different pattern of cortical neuronal vulnerability in homD90A versus SALS patients that may provide insight as to their slower rate of disease progression.

Recent ALS publications :- PMID: 18033592 [PubMed - in process]Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. Related Articles

Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis.

J Neurosci. 2007 Nov 21;27(47):12989-99

Recent ALS publications :- Authors: Steckley D, Karajgikar M, Dale LB, Fuerth B, Swan P, Drummond-Main C, Poulter MO, Ferguson SS, Strasser A, Cregan SP

Oxidative stress has been implicated as a key trigger of neuronal apoptosis in stroke and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The Bcl-2 homology 3 (BH3)-only subfamily of Bcl-2 genes consists of multiple members that can be activated in a cell-type- and stimulus-specific manner to promote cell death. In the present study, we demonstrate that, in cortical neurons, oxidative stress induces the expression of the BH3-only members Bim, Noxa, and Puma. Importantly, we have determined that Puma-/- neurons, but not Bim-/- or Noxa-/- neurons, are remarkably resistant to the induction of apoptosis by multiple oxidative stressors. Furthermore, we have determined that Bcl-2-associated X protein (Bax) is also required for oxidative stress induced cell death and that Puma plays a dominant role in regulating Bax activation. Specifically, we have established that the induction of Puma, but not Bim or Noxa, is necessary and sufficient to induce a conformational change in Bax to its active state, its translocation to the mitochondria and mitochondrial membrane permeabilization. Finally, we demonstrate that whereas both Puma and Bim(EL) can bind to the antiapoptotic family member Bcl-X(L), only Puma was found to associate with Bax. This suggests that in addition to neutralizing antiapoptotic members, Puma may play a dominant role by complexing with Bax and directly promoting its activation. Overall, we have identified Puma as a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis, and suggest that Puma may be an effective therapeutic target for the treatment of a number of neurodegenerative conditions.

Recent ALS publications :- PMID: 18032672 [PubMed - in process]How Would Terminally Ill Patients Have Others Make Decisions for Them in the Event of Decisional Incapacity? A Longitudinal Study. Related Articles

How Would Terminally Ill Patients Have Others Make Decisions for Them in the Event of Decisional Incapacity? A Longitudinal Study.

J Am Geriatr Soc. 2007 Nov 20;

Recent ALS publications :- Authors: Sulmasy DP, Hughes MT, Thompson RE, Astrow AB, Terry PB, Kub J, Nolan MT

OBJECTIVES: To determine the role terminally ill patients would opt to have their loved ones and physicians play in healthcare decisions should they lose decision-making capacity and how this changes over time. DESIGN: Serial interviews. SETTING: The study institutions were The Johns Hopkins Medical Institutions in Baltimore, Maryland, and St. Vincent's Hospital, in New York. PARTICIPANTS: One hundred forty-seven patients with cancer, amyotrophic lateral sclerosis, or heart failure, at baseline and 3 and 6 months. RESULTS: Patients' baseline decision control preferences varied widely, but most opted for shared decision-making, leaning slightly toward independence from their loved ones. This did not change significantly at 3 or 6 months. Fifty-seven percent opted for the same degree of decision control at 3 months as at baseline. In a generalized estimating equation model adjusted for time, more-independent decision-making was associated with college education (P=.046) and being female (P=.01), whereas more-reliant decision-making was associated with age (P<.001). Patients leaned toward more reliance upon physicians to make best-interest determinations at diagnosis but opted for physicians to decide based upon their own independent wishes (substituted judgment) over time, especially if college educated. CONCLUSION: Terminally ill patients vary in how much they wish their own preferences to control decisions made on their behalf, but most would opt for shared decision-making with loved ones and physicians. Control preferences are stable over time with respect to loved ones, but as they live longer with their illnesses, patients prefer somewhat less reliance upon physicians.

Recent ALS publications :- PMID: 18031490 [PubMed - as supplied by publisher]Involvement of spinal motor neurons in parkin-positive autosomal recessive juvenile parkinsonism. Related Articles

Involvement of spinal motor neurons in parkin-positive autosomal recessive juvenile parkinsonism.

Neuropathology. 2007 Nov 20;

Recent ALS publications :- Authors: Sasaki S, Shirata A, Yamane K, Iwata M

We intensively examined the spinal cord of an autosomal recessive juvenile parkinsonism (ARJP) female patient with a homozygous exon 3 deletion in the parkin gene, anticipating a possible involvement of anterior horn neurons. Although the clinical features of the patient were consistent with parkinsonism as a result of parkin mutation, her tendon reflex was abolished in the lower limbs. This feature was in contrast with hyperreflexia, usually found in previous reports of ARJP. Histologically, on the level of the cervical, thoracic, and sacral spinal cord, anterior horn neurons were well preserved and normal. However, the lumbar spinal cord exhibited many swellings of proximal axons (spheroids) and degenerative changes in the somata of the large anterior horn neurons such as central chromatolysis, cystatin C-negative small eosinophilic inclusions, and eosinophilic Lewy body-like inclusions. Ultrastructurally, accumulations of neurofilaments and abnormal structures, such as inclusion bodies similar to skein-like inclusions and disorganized rough endoplasmic reticulum, were observed in the somata and neuronal processes. Lewy body-like inclusions in this study were positively immunostained for both alpha-synuclein and ubiquitin that closely resemble Lewy bodies, but are different from Lewy body-like inclusions negatively immunostained for alpha-synuclein in amyotrophic lateral sclerosis. These findings suggest that eosinophilic inclusions that closely resemble Lewy bodies may be formed in the spinal motor neurons of ARJP patients with parkin mutations and the motor neurons of these patients may be vulnerable to neurodegeneration.

Recent ALS publications :- PMID: 18031467 [PubMed - as supplied by publisher]How is protein aggregation in amyloidogenic diseases modulated by biological membranes? Related Articles

How is protein aggregation in amyloidogenic diseases modulated by biological membranes?

Eur Biophys J. 2007 Nov 21;

Recent ALS publications :- Authors: Aisenbrey C, Borowik T, Byström R, Bokvist M, Lindström F, Misiak H, Sani MA, Gröbner G

The fate of proteins with amyloidogenic properties depends critically on their immediate biochemical environment. However, the role of biological interfaces such as membrane surfaces, as promoters of pathological aggregation of amyloidogenic proteins, is rarely studied and only established for the amyloid-beta protein (Abeta) involved in Alzheimer's disease, and alpha-synuclein in Parkinsonism. The occurrence of binding and misfolding of these proteins on membrane surfaces, is poorly understood, not at least due to the two-dimensional character of this event. Clearly, the nature of the folding pathway for Abeta protein adsorbed upon two-dimensional aggregation templates, must be fundamentally different from the three-dimensional situation in solution. Here, we summarize the current research and focus on the function of membrane interfaces as aggregation templates for amyloidogenic proteins (and even prionic ones). One major aspect will be the relationship between membrane properties and protein association and the consequences for amyloidogenic products. The other focus will be on a general understanding of protein folding pathways on two-dimensional templates on a molecular level. Finally, we will demonstrate the potential importance of membrane-mediated aggregation for non-amphiphatic soluble amyloidogenic proteins, by using the SOD1 protein involved in the amyotrophic lateral sclerosis syndrome.

Recent ALS publications :- PMID: 18030461 [PubMed - as supplied by publisher]Preferential involvement of the basolateral limbic circuit in an amyotrophic lateral sclerosis patient. Related Articles

Preferential involvement of the basolateral limbic circuit in an amyotrophic lateral sclerosis patient.

Eur J Neurol. 2007 Dec;14(12):e5-6

Recent ALS publications :- Authors: Takeda T, Uchihara T, Chikugo T, Hiraga T, Kitaguchi M, Kojima H

Recent ALS publications :- PMID: 18028185 [PubMed - in process]Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis. Related Articles

Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis.

Expert Opin Ther Targets. 2007 Nov;11(11):1415-28

Recent ALS publications :- Authors: Corona JC, Tovar-y-Romo LB, Tapia R

Two forms of amyotrophic lateral sclerosis (ALS) are known, the familial (FALS), due in part to mutations in superoxide dismutase 1 (SOD1), and the sporadic (SALS), which accounts for > 90% of all cases. The cause of SALS is not known, but excitotoxicity due to overactivation of glutamate receptors may mediate the motor neuron degeneration in the spinal cord, which is the hallmark of this disease. Overactivation of calcium-permeable alpha-amino-3-hydroxy-5-isoxazole propionate receptors lacking the subunit glutamate receptor 2, leading to an increase in calcium cytoplasmic concentration, seems to play an important role in the mechanism of neuronal death. The knowledge of this mechanism, in addition to other factors, provides several possible targets for therapeutic strategies that are reviewed in this article. Some of these strategies have proven to be partially effective in both human mutant superoxide dismutase 1 transgenic rodents (FALS model) and the few existing in vivo models of spinal motor neurodegeneration induced by excitotoxicity (SALS models), although observable benefits are still to be shown in clinical trials.

Recent ALS publications :- PMID: 18028007 [PubMed - in process]Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences. Related Articles

Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences.

Acta Neuropathol. 2008 Jan;115(1):97-114

Recent ALS publications :- Authors: Kato S

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. The author initially summarizes the principal features of human ALS neuropathology, and subsequently describes in detail ALS animal models mainly from the viewpoint of pathological similarities and differences. ALS animal models in this review include strains of rodents that are transgenic for superoxide dismutase 1 (SOD1), ALS2 knockout mice, and mice that are transgenic for cytoskeletal abnormalities. Although the neuropathological results obtained from human ALS autopsy cases are valuable and important, almost all of such cases represent only the terminal stage. This makes it difficult to clarify how and why ALS motor neurons are impaired at each clinical stage from disease onset to death, and as a consequence, human autopsy cases alone yield little insight into potential therapies for ALS. Although ALS animal models cannot replicate human ALS, in order to compensate for the shortcomings of studies using human ALS autopsy samples, researchers must inevitably rely on ALS animal models that can yield very important information for clarifying the pathogenesis of ALS in humans and for the establishment of reliable therapy. Of course, human ALS and all ALS animal models share one most important similarity in that both exhibit motor neuron degeneration/death. This important point of similarity has shed much light on the pathomechanisms of the motor neuron degeneration/death at the cellular and molecular levels that would not have been appreciated if only human ALS autopsy samples had been available. On the basis of the aspects covered in this review, it can be concluded that ALS animal models can yield very important information for clarifying the pathogenesis of ALS in humans and for the establishment of reliable therapy only in combination with detailed neuropathological data obtained from human ALS autopsy cases.

Recent ALS publications :- PMID: 18026741 [PubMed - in process]Outcome and attitudes toward home tracheostomy ventilation of consecutive patients: A 10-year experience. Related Articles

Outcome and attitudes toward home tracheostomy ventilation of consecutive patients: A 10-year experience.

Respir Med. 2007 Nov 13;

Recent ALS publications :- Authors: Marchese S, Lo Coco D, Lo Coco A

OBJECTIVES: To describe survival, predictors of long-term outcome and attitudes in patients treated at home by tracheostomy-intermittent positive-pressure ventilation (TIPPV) for respiratory failure during a 10-year period (1995-2004). METHODS: Seventy-seven consecutive patients were treated by TIPPV at home. Patients were divided into three groups: neuromuscular, pulmonary, and non-pulmonary patients. Effects of TIPPV on survival, factors influencing outcome after TIPPV, and attitudes of patients and caregivers regarding mechanical ventilation were studied. RESULTS: Forty-one patients (53%) were neuromuscular, 19 (25%) were affected by pulmonary diseases, and 17 (22%) by non-pulmonary diseases. The median survival time after TIPPV in the group was 49 months (range 3-149 months). There was statistically significant longer survival in neuromuscular compared to pulmonary patients (p=0.006), and a trend toward longer survival for non-pulmonary when compared to pulmonary patients (p=0.048). Chronic obstructive pulmonary disease (COPD) patients (n=14) showed the poorest outlook (median survival 26 months, range 3-45 months) and the highest number of emergency readmissions to hospital. The median survival in amyotrophic lateral sclerosis (ALS) patients was 49 months (range 30-61), lower than the whole group of neuromuscular patients. Major tracheostomy complications were low: 2.6%. Multivariate analysis showed that COPD and ALS patients had a three-fold higher risk of death than patients with other diagnoses. Lastly, 64 patients (83%) were pleased they had chosen TIPPV and 69 (90%) would choose it again. Forty-two caregivers (55%) were pleased the patients had chosen home ventilation, but 29 (38%) reported major burdens. CONCLUSIONS: TIPPV is well-received by the patients, is safe, and provides survival for long periods of time. Underlying conditions (COPD and ALS) might represent important prognostic factors for survival.

Recent ALS publications :- PMID: 18023334 [PubMed - as supplied by publisher]Abnormal diffusion tensor in nonsymptomatic familial amyotrophic lateral sclerosis with a causative superoxide dismutase 1 mutation. Related Articles

Abnormal diffusion tensor in nonsymptomatic familial amyotrophic lateral sclerosis with a causative superoxide dismutase 1 mutation.

J Magn Reson Imaging. 2007 Nov 16;

Recent ALS publications :- Authors: Ng MC, Ho Frcr JT, Ho SL, Lee Frcr R, Li G, Cheng TS, Song YQ, Ho PW, Fong GC, Mak W, Chan KH, Li LS, Luk KD, Hu Y, Ramsden DB, Leong Frcr LL

PURPOSE: To determine whether diffusion abnormalities can be observed in nonsymptomatic family members with a known causative Cu/Zn superoxide dismutase mutation (asymptomatic familial amyotrophic lateral sclerosis; AFALS(+SOD1)) in a family with autosomal dominant familial amyotrophic lateral sclerosis (ALS) using diffusion tensor imaging (DTI). MATERIALS AND METHODS: A total of eight AFALS(+SOD1) subjects (aged 17-43 years) were age-matched with 13 healthy controls (aged 19-45 years) without SOD1 mutations. DTI was carried out on a 1.5T scanner. The diffusion index maps derived were then normalized spatially for voxel-based analysis. region of interest (ROI)-based analysis was also carried out. RESULTS: Our voxel-based and ROI-based analysis showed that AFALS(+SOD1) subjects have decreased fractional anisotropy (FA) (0.5401 vs. 0.5168, P < 0.05) and increased tensor trace (TT) (2.5854 x 10(-3) mm(2)/second vs. 2.6226 x 10(-3) mm(2)/second, P < 0.04) at the posterior limb of the internal capsule compared to the control subjects. Increased radial diffusivity (E((2,3)/2)) was detected on both sides (right = 0.5710 x 10(-3) mm(2)/second vs. 0.5943 x 10(-3) mm(2)/second, P < 0.05; left = 0.5666 x 10(-3) mm(2)/second vs. 0.5872 x 10(-3) mm(2)/second, P < 0.05). No significant change in axial diffusivity (E(1)) was detected. CONCLUSION: Abnormal diffusivity was found at the posterior limb of the internal capsule in AFALS(+SOD1) subjects, hitherto unreported. Our results suggest that DTI may detect diffusion abnormalities in AFALS(+SOD1) subjects before symptoms develop. J. Magn. Reson. Imaging 2007. (c) 2007 Wiley-Liss, Inc.

Recent ALS publications :- PMID: 18022844 [PubMed - as supplied by publisher]Predictors of long survival in amyotrophic lateral sclerosis: A population-based study. Related Articles

Predictors of long survival in amyotrophic lateral sclerosis: A population-based study.

J Neurol Sci. 2007 Nov 14;

Recent ALS publications :- Authors: Zoccolella S, Beghi E, Palagano G, Fraddosio A, Guerra V, Samarelli V, Lepore V, Simone IL, Lamberti P, Serlenga L, Logroscino G

BACKGROUND: Although amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder, some ALS cases can survive beyond 10 years. However, the predictors of long survival in ALS patients remain uncertain. OBJECTIVE: To define clinical predictors of long survival in a cohort of ALS incident cases. METHODS: One hundred-thirty incidents cases, diagnosed in 1998-1999 and classified according to the El Escorial criteria (EEC), were enrolled from a prospective population-based registry established in Puglia, Italy. All but two cases were followed-up until death or November 30, 2006. RESULTS: Thirteen patients (high 10% of the survivors) were classified as long survivors (LS), 13 as short survivors (SS) (low 10%), and 102 as average survivors (AS). LS presented a lower frequency of bulbar onset (8% versus 29% of AS and 39% of SS; p=0.1) and a significantly longer time between symptom onset to diagnosis [(ODI): 13 months versus 10 and 6; p=0.0005]. In multivariate analysis, predictors of long survival were younger age at diagnosis (>65 compared to 9 months, OR: 7.9; 95%CI: 1.3-47; p=0.02) and clinical features with predominant upper motor neuron signs (OR: 8.5; 95%CI: 1.1-64.2; p=0.04). CONCLUSIONS: In this population-based study, younger age, longer interval onset to diagnosis, and clinical features with predominance of upper motor signs predicted long survival, while EEC category at diagnosis did not.

Recent ALS publications :- PMID: 18021808 [PubMed - as supplied by publisher]Neuropathology of mild cognitive impairment. Related Articles

Neuropathology of mild cognitive impairment.

Neuropathology. 2007 Dec;27(6):578-84

Recent ALS publications :- Authors: Saito Y, Murayama S

We aim to investigate the pathological background of mild cognitive impairment (MCI). The most recent 545 cases from the Brain Bank for Aging Research (BBAR) were studied, with a mean age of 80.7 years and male : female ratio of 324 : 221. Cases with clinical dementia rating scale (CDR) 0.5 were retrieved as the best substitute of MCI. CDR was retrospectively determined from clinical charts. Pathological examinations followed the BBAR protocol (JNEN 2004). Post mortem assessment of CDR was possible for 486 cases, and was 0 in 201 cases, 0.5 in 57 cases and 1-3 in 228 cases. CDR 0.5 group was clinicopathologically classified into 33 cases with degenerative changes, nine cases with vascular changes, four cases with combined degenerative and vascular changes, two with hippocampal sclerosis, two with trauma, one with metabolic disease and six with unremarkable changes. The degenerative group was further subclassified into groups with pure and combined pathology. The former consisted of six cases each with Alzheimer change (AC), argyrophilic grain change (AGC) and neurofibrillary tangle predominant change (NFTC), three each with Lewy body disease change without parkinsonism (DLBC) or Parkinson's disease (PDMCI) and one case with progressive supranuclear palsy. The latter consisted of three cases with AC plus AGC, two with AGC plus NFTC and one each with AC plus DLBC, DLBC plus amyotrophic lateral sclerosis and AGC plus DLBC. The pathological backgrounds of patients of class CDR 0.5 were varied and not restricted to AC.

Recent ALS publications :- PMID: 18021380 [PubMed - in process]Coexistence of amyotrophic lateral sclerosis and argyrophilic grain disease: a non-demented autopsy case showing circumscribed temporal atrophy and involvement of the amygdala. Related Articles

Coexistence of amyotrophic lateral sclerosis and argyrophilic grain disease: a non-demented autopsy case showing circumscribed temporal atrophy and involvement of the amygdala.

Neuropathology. 2007 Dec;27(6):539-50

Recent ALS publications :- Authors: Yokota O, Tsuchiya K, Noguchi Y, Akabane H, Ishizu H, Saito Y, Akiyama H

We report a case of a 68-year-old right-handed man with sporadic amyotrophic lateral sclerosis (ALS) and argyrophilic grain disease (AGD) having a 22-month duration. His initial symptoms were dysarthria and swallowing difficulty at the age of 67. Subsequently bulbar palsy and pyramidal signs developed. His cognitive functions including face recognition, personality, and behavior were not changed compared with that of before the disease onset. However, magnetic resonance imaging disclosed severe right side-predominant temporal atrophy. The neurological diagnosis was bulbar type ALS. Pathological examination disclosed histological evidence of ALS, including loss of Betz cells and lower motor neurons, corticospinal tract degeneration, and Bunina bodies. In addition, severe neuronal loss in the bilateral temporal cortex with an anterior gradient was found. Ubiquitin-positive inclusions were encountered in the spinal anterior horn cells and hippocampal dentate gyrus, while few ubiquitin-positive inclusions were noted in the affected temporal cortex. The amygdala, especially the basolateral nuclear group, was severely affected by neuronal loss with tissue rarefaction. Moderate neuronal loss was encountered in the parahippocampal gyrus, and to a lesser degree, in the ambient gyrus. Unexpectedly, many argyrophilic grains, coiled bodies, tau-positive bush-like astrocytes, pretangles, and ballooned neurons were found in the limbic system and temporal cortex. In the hippocampus, selective tau accumulation with minor neurofibrillary changes was observed in CA2 neurons. The present case suggests that (i) ALS and AGD do rarely coexist, and (ii) when ALS patients have severe temporal atrophy, not only ALS with dementia but also concurrent AGD should be considered in the differential diagnosis.

Recent ALS publications :- PMID: 18021374 [PubMed - in process]Cysteine 111 affects aggregation and cytotoxicity of mutant CU/ZN superoxide dismutase associated with familial amyotrophic lateral sclerosis. Related Articles

Cysteine 111 affects aggregation and cytotoxicity of mutant CU/ZN superoxide dismutase associated with familial amyotrophic lateral sclerosis.

J Biol Chem. 2007 Nov 15;

Recent ALS publications :- Authors: Cozzolino M, Amori I, Pesaresi MG, Ferri A, Nencini M, Carrì MT

Converging evidence indicates that aberrant aggregation of mutant Cu/Zn superoxide dismutase (mutSOD1) is strongly implicated in familial amyotrophic lateral sclerosis (FALS). MutSOD1 forms high molecular weight oligomers which disappear under reducing conditions, both in neural tissues of FALS transgenic mice and in transfected cultured cells, indicating a role for aberrant intermolecular disulfide crosslinking in the oligomerization and aggregation process. To study the contribution of specific cysteines in the mechanism of aggregation, we mutated human SOD1 in each of its four cysteine residues and using a cell transfection assay, we analysed the solubility and aggregation of those SOD1s. Our results suggest that the formation of mutSOD1 aggregates are the consequence of covalent disulfide crosslinking and non-covalent interactions. In particular, we found that the removal of Cys111 strongly reduces the ability of a range of different FALS-associated mutSOD1s to form aggregates and impair cell viability in cultured NSC-34 cells. Moreover, the removal of Cys111 impairs the ability of mutSOD1s to form disulfide crosslinkings. Treatments that deplete the cellular pool of reduced glutathione (GSH) exacerbate mutSOD1s insolubility, while an overload of intracellular GSH or overexpression of glutaredoxin-1, which specifically catalyzes the reduction of protein-SSG mixed disulfides, significantly rescues mutSOD1s solubility. These data are consistent with the view that the redox environment influences the oligomerization/aggregation pathway of mutSOD1 and point to Cys111 as a key mediator of this process.

Recent ALS publications :- PMID: 18006498 [PubMed - as supplied by publisher]Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. Related Articles

Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease.

Acta Neuropathol. 2008 Jan;115(1):123-131

Recent ALS publications :- Authors: Brandmeir NJ, Geser F, Kwong LK, Zimmerman E, Qian J, Lee VM, Trojanowski JQ

Recently, TDP-43, a 43 kDa nuclear TAR DNA-binding protein, was identified as the major disease protein in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), FTLD-U with motor neuron disease (FTLD-MND), and amyotrophic lateral sclerosis. To date, TDP-43 pathology in sporadic FTLD-MND has been reported only in select central nervous system areas. However, this distribution of lesions is insufficient to explain all clinical signs of FTLD-MND and the extent of TDP-43 pathology, throughout the brain, remains unknown. Therefore, as a pilot study, we performed an immunohistochemical whole brain scan of two cases diagnosed clinically as FTLD-MND and two control subjects. We found evidence of both neuronal and glial TDP-43 pathology in multiple brain areas including the nigro-striatal system, neo- and allocortical brain areas, with varying frequency, morphology, and degree, and nowhere in control tissue. The finding of a distinct cytopathological profile consisting of a cell nucleus devoid of endogenous TDP-43 staining coupled with diffuse/granular cytoplasmic staining ("pre-inclusion") was prominent in a couple of brain areas. These pre-inclusions were not or only weakly ubiquitin-immunoreactive. While the findings of severe involvement of extracortical or extrapyramidal areas are strongly suggestive for FTLD-MND being a TDP-43 multisystem proteinopathy rather than a disease predominantly affecting the cortex and spinal cord, more detailed clinicopathological studies of larger cohorts are needed to fully elucidate the distribution and severity of pathological TDP-43 in this disease.

Recent ALS publications :- PMID: 18004574 [PubMed - as supplied by publisher]Establishment of a cell model of ALS disease: Golgi apparatus disruption occurs independently from apoptosis. Related Articles

Establishment of a cell model of ALS disease: Golgi apparatus disruption occurs independently from apoptosis.

Biotechnol Lett. 2007 Nov 15;

Recent ALS publications :- Authors: Gomes C, Palma AS, Almeida R, Regalla M, McCluskey LF, Trojanowski JQ, Costa J

The Golgi apparatus (GA) appears disrupted in motor neurons of amyotrophic lateral sclerosis (ALS). Here, mouse motor neuron-like NSC-34 cell lines stably expressing human superoxide dismutase 1 (hSOD1)(wt) and mutant hSOD1(G93A), as an ALS cell model, were constructed. The number of cells with disrupted GA increased from 14% to 34%. Furthermore, NSC-34/hSOD1(G93A) cells showed lower levels of proliferation and differentiation. GA disruption was not caused by apoptosis as determined by several techniques including caspase-3 activation. Similarly, spinal cords from ALS patients did not show caspase-3 activation. Therefore, NSC-34/hSOD1(G93A) cells are a suitable cell model to study GA dysfunction in ALS.

Recent ALS publications :- PMID: 18004513 [PubMed - as supplied by publisher]Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model. Related Articles

Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model.

Physiol Genomics. 2007 Nov 13;

Recent ALS publications :- Authors: Gonzalez de Aguilar JL, Niederhauser-Wiederkehr C, Halter B, De Tapia M, Di Scala F, Demougin P, Dupuis L, Primig M, Meininger V, Loeffler JP

Muscle atrophy is a major hallmark of amyotrophic lateral sclerosis (ALS), the most frequent adult-onset motor neuron disease. To define the full set of alterations in gene expression in skeletal muscle during the course of the disease, we used the G86R superoxide dismutase-1 transgenic mouse model of ALS, and performed high-density oligonucleotide microarrays. We compared these data to those obtained by axotomy-induced denervation. A major set of gene regulations in G86R muscles resembled those of surgically denervated muscles but many others appeared specific to the ALS condition. The first significant transcriptional changes appeared in a subpopulation of mice before the onset of overt clinical symptoms and motor neuron death. These early changes affected genes involved in detoxification (e.g., ALDH3, metallothionein-2, and thioredoxin-1) and regeneration (e.g., BTG1, RB1 and RUNX1) but also tissue degradation (e.g., C/EBP-delta and DDIT4) and cell death (e.g., ankyrin repeat domain-1, CDKN1A, GADD45alpha and PEG3). Of particular interest, metallothionein-1 and 2, ATF3, cathepsin-Z and galectin-3 genes appeared, among others, commonly regulated in both skeletal muscle (our present data) and spinal motor neurons (as previously reported) of paralysed ALS mice. The importance of these findings is twofold. First, they designate the distal part of the motor unit as a primary site of disease. Second, they identify specific gene regulations to be explored in the search for therapeutic strategies that could alleviate disease before motor neuron death manifests clinically. Key words: atrophy, axotomy, denervation, neuromuscular disease.

Recent ALS publications :- PMID: 18000159 [PubMed - as supplied by publisher]Expression of a Cu,Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of neuroblastoma cells to infectious injury. Related Articles

Expression of a Cu,Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of neuroblastoma cells to infectious injury.

BMC Infect Dis. 2007 Nov 12;7(1):131

Recent ALS publications :- Authors: Goos M, Zech WD, Jaiswal MK, Balakrishnan S, Ebert S, Mitchell T, Carri MT, Keller BU, Nau R

ABSTRACT: BACKGROUND: Infections can aggravate the course of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Mutations in the anti-oxidant enzyme Cu,Zn superoxide dismutase (EC 1.15.1.1, SOD1) are associated with familial ALS. Streptococcus pneumoniae, the most frequent respiratory pathogen, causes damage by the action of the cholesterol-binding virulence factor pneumolysin and by stimulation of the innate immune system, particularly via Toll-like-receptor 2. METHODS: SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) and SH-SY5Y neuroblastoma cells transfected with wildtype SOD1 were both exposed to pneumolysin and in co-cultures with cultured human macrophages treated with the Toll like receptor 2 agonist N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl- [S]-lysyl-[S]-lysine x 3 HCl (Pam3CSK4). Cell viability and apoptotic cell death were compared morphologically and by in-situ tailing. With the help of the WST-1 test, cell viability was quantified, and by measurement of neuron-specific enolase in the culture supernatant neuronal damage in co-cultures was investigated. Intracellular calcium levels were measured by fluorescence analysis using fura-2 AM. RESULTS: SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) were more vulnerable to the neurotoxic action of pneumolysin and to the attack of monocytes stimulated by Pam3CSK4 than SH-SY5Y cells transfected with wild-type human SOD1. The enhanced pneumolysin toxicity in G93A-SOD1 neuronal cells depended on the inability of these cells to cope with an increased calcium influx caused by pores formed by pneumolysin. This inability was caused by an impaired capacity of the mitochondria to remove cytoplasmic calcium. Treatment of G93A-SOD1 SH-SY5Y neuroblastoma cells with the antioxidant N-acetylcysteine reduced the toxicity of pneumolysin. CONCLUSIONS: The particular vulnerability of G93A-SOD1 neuronal cells to hemolysins and inflammation may be partly responsible for the clinical deterioration of ALS patients during infections. These findings link infection and motor neuron disease and suggest early treatment of respiratory infections in ALS patients.

Recent ALS publications :- PMID: 17997855 [PubMed - as supplied by publisher]A comparison of the lengths of androgen receptor triplet repeats in brain and blood in motor neuron diseases. Related Articles

A comparison of the lengths of androgen receptor triplet repeats in brain and blood in motor neuron diseases.

J Neurol Sci. 2007 Nov 9;

Recent ALS publications :- Authors: Saunderson RB, Yu B, Trent RJ, Pamphlett R

BACKGROUND: Expansions of triplet repeats are found in a number of neurodegenerative conditions, and different tissues in the same person can have varying repeat lengths. In Kennedy disease, motor neuron loss is due to expansion of the CAG repeat length in the androgen receptor gene (AR). We hypothesised that patients with other sporadic motor neuron diseases could have AR expansions that were restricted to CNS tissue. METHODS: We measured the AR triplet repeat length in DNA extracted from the brains of 23 patients with sporadic amyotrophic lateral sclerosis (SALS) and 3 with sporadic progressive muscular atrophy (SPMA). Paired blood samples were available in 15 patients to look for blood-brain differences in CAG repeat length. RESULTS: No CAG expansions in the Kennedy disease range were found in the SALS or SPMA brains. Furthermore, no brain-blood differences were found in the lengths of AR triplet repeats. Brain AR repeat length was not associated with the duration, or age or site of onset, of disease. CONCLUSIONS: The findings indicate that a brain-specific expansion of AR triplet repeats is unlikely to underlie motor neuron loss in SALS or SPMA.

Recent ALS publications :- PMID: 17997416 [PubMed - as supplied by publisher]Amyotrophic lateral sclerosis and soccer: A different epidemiological approach strengthen the previous findings. Related Articles

Amyotrophic lateral sclerosis and soccer: A different epidemiological approach strengthen the previous findings.

J Neurol Sci. 2007 Nov 7;

Recent ALS publications :- Authors: Chiò A, Traynor BJ, Swingler R, Mitchell D, Hardiman O, Mora G, Beghi E, Logroscino G,

Recent ALS publications :- PMID: 17996254 [PubMed - as supplied by publisher]Decreased serum-soluble TRAIL levels in patients with amyotrophic lateral sclerosis. Related Articles

Decreased serum-soluble TRAIL levels in patients with amyotrophic lateral sclerosis.

Acta Neurol Scand. 2007 Nov 8;

Recent ALS publications :- Authors: Iłżecka J

Objectives - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. Previously, it was showed that apoptosis may play a role in the pathomechanisms of this disease. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with proapoptotic activity in the central nervous system. The aim of the study was to measure serum TRAIL levels in patients with ALS. Materials and methods - The study involved 25 patients with ALS and 20 controls. Serum TRAIL levels were performed by the enzyme-linked immunosorbent method. Results - Study showed that TRAIL levels were significantly decreased in the serum of patients with ALS compared with controls (P < 0.05). There was no significant correlation between serum TRAIL levels and clinical parameters of ALS (P > 0.05). Conclusion - A decrease in serum TRAIL levels in patients with ALS suggests that this cytokine may be implicated in the pathomechanisms of this disease.

Recent ALS publications :- PMID: 17995989 [PubMed - as supplied by publisher]Activity-dependent neurotrophic factor, ADNF, determines the structure characteristics of Colivelin, a fusion protein of ADNF9 and Humanin analog. Related Articles

Activity-dependent neurotrophic factor, ADNF, determines the structure characteristics of Colivelin, a fusion protein of ADNF9 and Humanin analog.

J Pept Sci. 2007 Nov 12;

Recent ALS publications :- Authors: Arakawa T, Niikura T, Arisaka F, Kita Y

A 24-amino acid long peptide, Humanin, protects neurons from Alzheimer's disease (AD)-related cell toxicities at sub-nM-uM concentrations. Activity-dependent neurotrophic factor (ADNF) is a glia-derived neurotrophic peptide, which protects neurons from tetrodoxin treatment and AD-related and amyotrophic lateral sclerosis-related insults at fM concentrations. An attempt was made to further improve the activity of Humanin by fusing this peptide to ADNF9, a 9-amino acid long core peptide of the ADNF. This fusion resulted in a novel molecule, termed Colivelin, with the neuroprotective activity at fM range, which is approximately 10(3)-10(7) fold higher than the activity of Humanin and Humanin analogs and follows the activity profile of fM-active ADNF9. We have characterized the structural properties of Colivelin and compared with those of ADNF9 and Humanin in water and phosphate-buffered saline (PBS). The secondary structure of Colivelin was similar to that of ADNF9, but not that of Humanin, and hence was not the average of the contributions of the two peptides fused. Colivelin was stable and monomeric in PBS, consistent with the monomeric property of ADNF9, while Humanin showed strong tendency to self-associate. Thus, it is evident that the structural properties of Colivelin resemble those of ADNF9, rather than those of Humanin. Copyright (c) 2007 European Peptide Society and John Wiley & Sons, Ltd.

Recent ALS publications :- PMID: 17994638 [PubMed - as supplied by publisher]Impairment of GH secretion in amyotrophic lateral sclerosis is not affected by riluzole treatment. Related Articles

Impairment of GH secretion in amyotrophic lateral sclerosis is not affected by riluzole treatment.

J Endocrinol Invest. 2007 Oct;30(9):767-70

Recent ALS publications :- Authors: Morselli LL, Bongioanni P, Genovesi M, Licitra R, Rossi B, Murri L, Bogazzi F, Cecconi E, Martino E, Gasperi M

Amyotrophic lateral sclerosis (ALS), the most common motor neurone disorder in human adults, is characterized by selective and progressive degeneration of upper and lower motor neurones in the central nervous system. The main currently available drug for ALS treatment is riluzole, a compound that acts through inhibition of glutamate release, postsynaptic receptor activation, and voltage-sensitive channel inhibition. GH secretion, evaluated by GHRH+arginine (ARG) test, has recently been reported to be impaired in most untreated ALS patients. The aim of the present study was to evaluate whether riluzole administration could interfere with GH secretion and therefore with the diagnosis of adult GH deficiency. Ten patients (6 males, 4 females, mean age 59+/-11 yr) were studied performing GHRH+ARG test before and 3 months after starting riluzole treatment (100 mg/day). Blood samples for GH were collected at baseline, at 30 and 60 min. Both before and during riluzole treatment, 5 patients showed GH deficiency and 5 patients had a normal GH response according to body mass index (BMI). Mean peak GH levels were similar before and during riluzole treatment (13.4+/-10 vs 14.2+/-10.1 microg/l, p=ns). No significant correlation was observed between GH concentrations and age, BMI, disease duration, severity or clinical (bulbar/spinal) form. In conclusion, the present data confirm that GH secretion is impaired in a new series of ALS patients and indicate that riluzole treatment does not interfere with GH secretion. Thus, evaluation of GH secretion in ALS patients can also be performed without withdrawing riluzole treatment.

Recent ALS publications :- PMID: 17993769 [PubMed - in process]Mutant SOD1 detoxification mechanisms in intact single cells. Related Articles

Mutant SOD1 detoxification mechanisms in intact single cells.

Cell Death Differ. 2007 Nov 9;

Recent ALS publications :- Authors: Ganesan S, Rohde G, Eckermann K, Sroka K, Schaefer MK, Dohm CP, Kermer P, Haase G, Wouters F, Bähr M, Weishaupt JH

Mutant superoxide dismutase 1 (mtSOD1) causes dominantly inherited amyotrophic lateral sclerosis (ALS). The mechanism for mtSOD1 toxicity remains unknown. Two main hypotheses are the impairment of proteasomal function and chaperone depletion by misfolded mtSOD1. Here, we employed FRET/FLIM and biosensor imaging to quantitatively localize ubiquitination, as well as chaperone binding of mtSOD1, and to assess their effect on proteasomal and protein folding activities. We found large differences in ubiquitination and chaperone interaction levels for wild-type (wt) SOD1 versus mtSOD1 in intact single cells. Moreover, SOD1 ubiquitination levels differ between proteasomal structures and cytoplasmic material. Hsp70 binding and ubiquitination of wt and mtSOD1 species are highly correlated, demonstrating the coupled upregulation of both cellular detoxification mechanisms upon mtSOD1 expression. Biosensor imaging in single cells revealed that mtSOD1 expression alters cellular protein folding activity but not proteasomal function in the neuronal cell line examined. Our results provide the first cell-by-cell-analysis of SOD1 ubiquitination and chaperone interaction. Moreover, our study opens new methodological avenues for cell biological research on ALS.Cell Death and Differentiation advance online publication, 9 November 2007; doi:10.1038/sj.cdd.4402262.

Recent ALS publications :- PMID: 17992192 [PubMed - as supplied by publisher]Strong P2X(4) purinergic receptor-like immunoreactivity is selectively associated with degenerating neurons in transgenic rodent models of amyotrophic lateral sclerosis. Related Articles

Strong P2X(4) purinergic receptor-like immunoreactivity is selectively associated with degenerating neurons in transgenic rodent models of amyotrophic lateral sclerosis.

J Comp Neurol. 2008 Jan 1;506(1):75-92

Recent ALS publications :- Authors: Casanovas A, Hernández S, Tarabal O, Rosselló J, Esquerda JE

The distribution of the P2X family of ATP receptors was analyzed in a rat model for amyotrophic lateral sclerosis (ALS) expressing mutated human superoxide dismutase (mSOD1(G93A)). We showed that strong P2X(4) immunoreactivity was selectively associated with degenerating motoneurons (MNs) in spinal cord ventral horn. Degenerating P2X(4)-positive MNs did not display apoptotic features such as chromatin condensation, positive TUNEL reaction, or active caspase 3 immunostaining. In contrast, these neurons showed other signs of abnormality, such as loss of the neuronal marker NeuN and recruitment of microglial cells with neuronophagic activity. Similar changes were observed in MNs from the cerebral cortex and brainstem in mSOD1(G93A) in both rat and mice. In addition, P2X(4) immunostaining demonstrated the existence of neuronal degeneration in the locus coeruleus, reticular formation, and Purkinje cells of the cerebellar cortex. It is suggested that abnormal trafficking and proteolytic processing of the P2X(4) receptor protein may underlie these changes. J. Comp. Neurol. 506:75-92, 2008. (c) 2007 Wiley-Liss, Inc.

Recent ALS publications :- PMID: 17990272 [PubMed - in process]Optimizing separation efficiency of 2-DE procedures for visualization of different superoxide dismutase forms in a cellular model of amyotrophic lateral sclerosis. Related Articles

Optimizing separation efficiency of 2-DE procedures for visualization of different superoxide dismutase forms in a cellular model of amyotrophic lateral sclerosis.

Electrophoresis. 2007 Dec;28(23):4340-7

Recent ALS publications :- Authors: Di Poto C, Iadarola P, Salvini R, Passadore I, Cereda C, Ceroni M, Bardoni AM

Neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD) have been associated with increased production of reactive oxygen species. In AD and PD patients, superoxide dismutase (SOD1) was also indicated as a major target of oxidative damage. In particular, in brain tissue of these patients, different SOD1 isoforms have been identified, although their functional role still remains to be elucidated. In the light of the possibility that different SOD1 entities could be expressed also in other neurodegenerative disorders, as a sort of unifying event with AD and PD, we have investigated amyotrophic lateral sclerosis (ALS) using human neuroblastoma SH-SY5Y cells with mutated SOD1 gene H46R as cellular model. 2-DE using a narrow-range IPG 4-7 strips in the first dimension and linear 15% SDS-PAGE in the second allowed to separate different SOD1 spots. MALDI-TOF MS and CapLC-MS/MS have been used for their complete identification. This is the first report in which the presence of SOD1 (iso)forms in a cellular model of ALS has been evidenced.

Recent ALS publications :- PMID: 17987632 [PubMed - in process]Neurodegenerative Diseases: Neurotoxins as Sufficient Etiologic Agents? Related Articles

Neurodegenerative Diseases: Neurotoxins as Sufficient Etiologic Agents?

Neuromolecular Med. 2007 Nov 6;

Recent ALS publications :- Authors: Shaw CA, Höglinger GU

A dominant paradigm in neurological disease research is that the primary etiological factors for diseases such as Alzheimer's (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS) are genetic. Opposed to this perspective are the clear observations from epidemiology that purely genetic casual factors account for a relatively small fraction of all cases. Many who support a genetic etiology for neurological disease take the view that while the percentages may be relatively small, these numbers will rise in the future with the inevitable discoveries of additional genetic mutations. The follow up argument is that even if the last is not true, the events triggered by the aberrant genes identified so far will be shown to impact the same neuronal cell death pathways as those activated by environmental factors that trigger most sporadic disease cases. In this article we present a countervailing view that environmental neurotoxins may be the sole sufficient factor in at least three neurological disease clusters. For each, neurotoxins have been isolated and characterized that, at least in animal models, faithfully reproduce each disorder without the need for genetic co-factors. Based on these data, we will propose a set of principles that would enable any potential toxin to be evaluated as an etiological factor in a given neurodegenerative disease. Finally, we will attempt to put environmental toxins into the context of possible genetically-determined susceptibility.

Recent ALS publications :- PMID: 17985252 [PubMed - as supplied by publisher]Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model. Related Articles

Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model.

J Neuropathol Exp Neurol. 2007 Nov;66(11):1037-44

Recent ALS publications :- Authors: Ishigaki A, Aoki M, Nagai M, Warita H, Kato S, Kato M, Nakamura T, Funakoshi H, Itoyama Y

Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We showed that introduction of the HGF gene into neurons of G93A transgenic mice attenuates motor neuron degeneration and increases the lifespan of these mice. Currently, treatment regimens using recombinant protein are closer to clinical application than gene therapy. To examine its protective effect on motor neurons and therapeutic potential we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic rats at doses of 40 or 200 microg and 200 microg at 100 days of age (the age at which pathologic changes of the spinal cord appear, but animals show no clinical weakness) and at 115 days (onset of paralysis), respectively, for 4 weeks each. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%, even with administration from the onset of paralysis. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in transgenic rats and should lead to the consideration for further clinical trials in amyotrophic lateral sclerosis using continuous intrathecal administration of hrHGF.

Recent ALS publications :- PMID: 17984685 [PubMed - in process]Adult olfactory bulb neural precursor cell grafts provide temporary protection from motor neuron degeneration, improve motor function, and extend survival in amyotrophic lateral sclerosis mice. Related Articles

Adult olfactory bulb neural precursor cell grafts provide temporary protection from motor neuron degeneration, improve motor function, and extend survival in amyotrophic lateral sclerosis mice.

J Neuropathol Exp Neurol. 2007 Nov;66(11):1002-18

Recent ALS publications :- Authors: Martin LJ, Liu Z

Amyotrophic lateral sclerosis is a fatal disease caused by degeneration of motor neurons (MNs). We transplanted multipotent neural precursor cell (NPC)-neurospheres from mouse olfactory bulb (OB) into the spinal cord of transgenic mice that develop MN degeneration because of human mutant superoxide dismutase-1 (mSOD1). Adult NPCs were isolated from the OB core of transgenic mice expressing green fluorescent protein, human wild-type SOD1, or human mSOD1. mSOD1 mice received lumbar spinal cord transplants of OB-NPC neurospheres at preclinical stages of disease (70 days old). Control mSOD1 mice received dead cells or recombinant green fluorescent protein. OB-NPCs attenuated the loss of motor function and wasting. They delayed disease onset to approximately 117 days, compared with control onset at approximately 90 days. The lifespan of NPC recipient mice was extended (approximately 170 days) compared with the lifespan of controls (approximately 140 days). Transplanted OB-NPCs differentiated into large spinal neurons positive for choline acetyltransferase, interneurons, and glial cells. Loss of endogenous MNs was attenuated in mSOD1 mice with transplants. New neurons formed myelinated axons and synapses. NPC-derived neurons issued axons that grew into peripheral nerve. OB-NPCs also differentiated into oligodendrocytes and astrocytes that contacted neuronal processes. We conclude that transplantation of adult OB-NPCs is therapeutic for mouse amyotrophic lateral sclerosis.

Recent ALS publications :- PMID: 17984682 [PubMed - in process]Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. Related Articles

Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease.

J Cell Biol. 2007 Nov 5;179(3):485-500

Recent ALS publications :- Authors: Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerød L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A

The endosomal sorting complexes required for transport (ESCRTs) are required to sort integral membrane proteins into intralumenal vesicles of the multivesicular body (MVB). Mutations in the ESCRT-III subunit CHMP2B were recently associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons. We show here that autophagic degradation is inhibited in cells depleted of ESCRT subunits and in cells expressing CHMP2B mutants, leading to accumulation of protein aggregates containing ubiquitinated proteins, p62 and Alfy. Moreover, we find that functional MVBs are required for clearance of TDP-43 (identified as the major ubiquitinated protein in ALS and frontotemporal lobar degeneration with ubiquitin deposits), and of expanded polyglutamine aggregates associated with Huntington's disease. Together, our data indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.

Recent ALS publications :- PMID: 17984323 [PubMed - in process]The therapeutic potential of siRNA in gene therapy of neurodegenerative disorders. Related Articles

The therapeutic potential of siRNA in gene therapy of neurodegenerative disorders.

J Neural Transm Suppl. 2007;(72):43-9

Recent ALS publications :- Authors: Koutsilieri E, Rethwilm A, Scheller C

RNA interference using small inhibitory RNA (siRNA) has become a powerful tool to downregulate mRNA levels by cellular nucleases that become activated when a sequence homology between the siRNA and a respective mRNA molecule is detected. Therefore siRNA can be used to silence genes involved in the pathogenesis of various diseases associated with a known genetic background. As for many neurodegenerative disorders a causative therapy is unavailable, siRNA holds a promising option for the development of novel therapeutic strategies. Here we discuss different siRNA target strategies aiming for an allele-specific degradation of disease-inducing mRNA and we review the literature in the field of siRNA and its application in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxia (SCA1).

Recent ALS publications :- PMID: 17982877 [PubMed - in process]Diverse roles of Rho family GTPases in neuronal development, survival, and death. Related Articles

Diverse roles of Rho family GTPases in neuronal development, survival, and death.

Front Biosci. 2008;13:657-76

Recent ALS publications :- Authors: Linseman DA, Loucks FA

Rho family GTPases (eg., RhoA, Rac1 and Cdc42) are monomeric G-proteins that act as key transducers of extracellular signals to the actin cytoskeleton. In the nervous system, Rho family GTPases are essential regulators of neuronal growth cone motility, axonal migration, and dendritic spine morphogenesis. Given these vital functions, it is perhaps not surprising that mutations in several proteins involved in Rho GTPase signaling are causative in some forms of mental retardation. In addition, numerous recent studies have identified Rho family GTPases as central players in the molecular pathways that determine neuronal survival and death. Interestingly, individual Rho family members have been shown to play either a pro-death or pro-survival role in the nervous system depending on both the type of neuron and the particular neurodegenerative insult involved. This review summarizes current work demonstrating a critical role for Rho family GTPases and their effectors in the regulation of neuronal development, survival, and death. These findings may be particularly relevant in the context of specific neurodegenerative disorders in which Rho family GTPase function is altered, such as loss-of-function of the Rac1 guanine nucleotide exchange factor, alsin, in juvenile-onset amyotrophic lateral sclerosis.

Recent ALS publications :- PMID: 17981578 [PubMed - in process]Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Related Articles

Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial.

Lancet Neurol. 2007 Dec;6(12):1045-53

Recent ALS publications :- Authors: Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, Macarthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R,

BACKGROUND: Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS). METHODS: We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723. FINDINGS: ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (-1.30 vs -1.04 units/month, 95% CI for difference -0.44 to -0.08; p=0.005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (-3.48 vs -3.01, -1.03 to 0.11; p=0.11) and MMT score (-0.30 vs -0.26, -0.08 to 0.01; p=0.11), and greater mortality during the 9-month treatment phase (hazard ratio=1.32, 95% CI 0.83 to 2.10; p=0.23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score. INTERPRETATION: Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.

Recent ALS publications :- PMID: 17980667 [PubMed - in process]2-DE and MALDI-TOF-MS for a comparative analysis of proteins expressed in different cellular models of amyotrophic lateral sclerosis. Related Articles

2-DE and MALDI-TOF-MS for a comparative analysis of proteins expressed in different cellular models of amyotrophic lateral sclerosis.

Electrophoresis. 2007 Dec;28(23):4320-9

Recent ALS publications :- Authors: Di Poto C, Iadarola P, Bardoni AM, Passadore I, Giorgetti S, Cereda C, Carrì MT, Ceroni M, Salvini R

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder characterized by the selective loss of motor neurons from the spinal cord and brain. About 10% of ALS cases are familial (FALS), and in 20% of these cases the disease has been linked to mutations in the Cu,Zn-SOD1 gene. Although the molecular mechanisms causing these forms of ALS are still unclear, evidence has been provided that motor neurons injuries associated with mutant superoxide dismutase (SOD1)-related FALS result from a toxic gain-in-fuction of the mutated enzyme. To understand better the role of these mutations in the pathophysiology of FALS we have compared the pattern of proteins expressed in human neuroblastoma SH-SY5Y cell line with those of cell lines transfected with plasmids expressing the wild-type human SOD1 and the H46R and G93A mutants. 2-DE coupled to MALDI-TOF-MS were the proteomic tools used for identification of differentially expressed proteins. These included cytoskeletal proteins, proteins that regulate energetic metabolism and intracellular redox conditions, and the ubiquitin proteasome system. The proteomic approach allowed to expand the knowledge on the pattern of proteins, with altered expression, which we should focus on, for a better understanding of the possible mechanism involved in mutated-SOD1 toxicity. The cellular models considered in this work have also evidenced biochemical characteristics common to other SOD1-mutated cellular lines connected to the pathogenesis of ALS.

Recent ALS publications :- PMID: 17979159 [PubMed - in process]Salivary gland application of botulinum toxin for the treatment of sialorrhea. Related Articles

Salivary gland application of botulinum toxin for the treatment of sialorrhea.

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