Kegg Pathway: Amyotrophic lateral sclerosis (ALS)

Neuropathology. 2009 Nov 18;
Shibata N, Yamamoto T, Hiroi A, Omi Y, Kato Y, Kobayashi M

Signal transducer and activator of transcription-3 (STAT3) is a member of the proinflammatory transcription factor STAT family. Several studies have documented implications for neuroinflammation in Amyotrophic lateral sclerosis (ALS). We recently demonstrated activation of STAT3 in spinal cords obtained at autopsy from sporadic ALS patients. To determine the involvement of STAT3 and effects of pioglitazone on STAT3 activity in familial ALS with superoxide dismutase-1 (SOD1) mutation, we performed immunoblot and immunohistochemical analyses of the active form of STAT3 (p-STAT3) in spinal cords from mice overexpressing mutant SOD1 (ALS mice) and nontransgenic littermates (control mice). Immunoblot analysis delineated significant increases in nuclear p-STAT3 levels in non-treated ALS mice as compared with pioglitazone-treated ALS mice and non-treated and pioglitazone-treated control mice. Immunohistochemical analysis revealed prominent p-STAT3 accumulations in the nucleus of motor neurons, reactive astrocytes and activated microglia in non-treated ALS mice but not pioglitazone-treated ALS mice and non-treated and pioglitazone-treated control mice. The present results provide in vivo evidence for increased phosphorylative activation and nuclear translocation of STAT3 in motor neurons and glia in mouse motor neuron disease, suggesting a common pathological process between sporadic and SOD1-mutated familial forms of ALS. Moreover, it is likely that pioglitazone may exert inhibitory effects on STAT3-mediated proinflammtory mechanisms in this disease.

Eur J Neurol. 2009 Nov 13;
Damme PV, Goris A, Race V, Hersmus N, Dubois B, Bosch LV, Matthijs G, Robberecht W

Background and purpose: Mutations in fused in sarcoma (FUS) were recently identified as a cause of familial Amyotrophic lateral sclerosis (ALS). The frequency of occurrence of mutations in FUS in sets of patients with familial ALS remains to be established. Methods: We sequenced the FUS gene in a cohort of patients with familial ALS seen at the neuromuscular clinic in Leuven. A total of 28 patients with SOD1-negative ALS from 22 families were analyzed. Results: We identified a R521H mutation in 4 patients, belonging to a kindred of dominantly inherited classical ALS. The mutation segregated with disease. Mutations in FUS were observed in 2.9% of ALS pedigrees in our cohort. Conclusions: These results show that mutations in FUS are also a significant cause of familial ALS in Belgium.

Amyotroph lateral Scler. 2009; 10(5-6): 487-489
Van Rooij FG, Schelhaas HJ, Lammers GJ, Verbeek MM, Overeem S

Hypocretin (orexin) neurotransmission is not only crucially involved in the regulation of sleep and wake, but serves in multiple autonomic and cognitive functions as well. This is reflected in the widespread connections between the hypothalamic hypocretin neurons and the rest of the brain, such as dense projections to the frontal cortex. Both frontal cognitive impairment and autonomic disturbances have been described in ALS. Furthermore, in some ALS patients there may be sleep disturbances other than sleep related breathing disorders, including REM sleep behaviour disorder. In addition, a role for the hypocretin system in the regulation of motor functions has been suggested. Hypocretin defects have been described in several neurodegenerative disorders. We therefore speculated that the hypocretin system is also involved in ALS and measured hypocretin-1 levels in cerebrospinal fluid samples from 20 patients. All results were well within the normal range (>200 pg/ml) and individual values showed no correlation with age, gender and disease duration. We conclude that it is unlikely that the hypocretin system is involved in the degenerative process of ALS.

Amyotroph lateral Scler. 2009; 10(5-6): 483-486
Sarafov S, Doitchinova M, Karagiozova Z, Slancheva B, Dengler R, Petri S, Kollewe K

There are few reports on pregnancies in sporadic and familial Amyotrophic lateral sclerosis (ALS). We report on a young woman with sporadic ALS who gave birth twice during the course of her disease. The first pregnancy occurred 13 months after the onset of symptoms, and one month after diagnosis. The pregnancy was uncomplicated and resulted in vaginal delivery of a healthy boy. Fifteen months later, when she was already bed-ridden, she became pregnant again. She received a percutaneous endoscopic gastrostomy in the 21st gestational week and underwent early Caesarean section in the 34th week of gestation. The child was ventilated for 72 h in a neonatological unit. The patient was tracheotomized and ventilated two months later, i.e. 47 months after symptom onset, and died nine months later from gastrointestinal haemorrhage. Her two children have developed without abnormalities to date. This case confirms that pregnancies in early-stage ALS can develop normally and may result in uncomplicated vaginal delivery. Pregnancies in late stages may be critical for mother and child, and early delivery by Caesarean section may become necessary although neonatal outcome can be good.

Amyotroph lateral Scler. 2009; 10(5-6): 479-482
Luigetti M, Madia F, Conte A, Marangi G, Zollino M, Grande AD, Dileone M, Tonali PA, Sabatelli M

We describe a patient with a familial form of Amyotrophic lateral sclerosis (ALS) in which a heterozygous G > A exchange at position 1087 in the SOD1 gene was detected. This mutation results in an amino acid substitution of aspartate for glycine at position 93 (G93D). The patient had a five-year history of fasciculations in all four limbs, with no clear evidence of muscular atrophy or weakness at last follow-up. However, electrophysiological examination revealed lower and upper motor neuron involvement. His mother and a cousin had died of ALS after prolonged disease. This report shows that G93D may cause a form of ALS with slow progression, long-lasting paucisymptomatic phase and both lower and upper motor neuron involvement.

Amyotroph lateral Scler. 2009; 10(5-6): 476-478
Zhou L, Pioro EP

We report a 54-year-old male with progressive and asymmetrical lower extremity weakness caused by familial Amyotrophic lateral sclerosis (FALS) with a Cu/Zn superoxidase dismutase 1 (SOD1) gene mutation. He was initially misdiagnosed with a lumbosacral polyradiculopathy because of spinal stenosis and underwent a laminectomy surgery with no benefit. He was also misdiagnosed with a myopathy due to moderate CK elevation from acute denervation and pseudomyopathic changes on muscle biopsies from chronic denervation. He eventually developed respiratory muscle weakness and upper motor neuron signs, consistent with familial ALS.

Amyotroph lateral Scler. 2009; 10(5-6): 470-475
Garvey CM, Boylan KB, Salassa JR, Kennelly KD

Our objectives were to 1) increase awareness of total laryngectomy (TL) as a treatment for complications of bulbar weakness in patients with Amyotrophic lateral sclerosis (ALS) and outline specific surgical indications; 2) educate physicians about the surgical procedure, peri-operative course and benefits from having a TL; and 3) retrospectively review the clinical course of Mayo Clinic - Florida patients with ALS who had a TL. The method used was a retrospective review of patients recommended to undergo TL for advanced bulbar symptoms related to ALS at the Mayo Clinic in Jacksonville, Florida. Between January 1999 and September 2008, 15 patients with severe bulbar symptoms associated with ALS were recommended to undergo TL. Only five patients opted for the surgery. All patients were aphonic at time of surgery with a multitude of bulbar symptoms. Average surgical time was 114 min (range 87-162 min). No intraoperative complications were reported. All patients and caregivers were pleased with the results of the TL. In conclusion, TL is a relatively safe, quick and uncomplicated surgical procedure that should be considered earlier and more frequently in the treatment plan of patients with advanced bulbar symptoms due to ALS. We recommend considering TL in patients with aspiration problems who are unable to phonate intelligibly.

Amyotroph lateral Scler. 2009; 10(5-6): 441-447
Van Es MA, Van Vught PW, Veldink JH, Andersen PM, Birve A, Lemmens R, Cronin S, Van Der Kooi AJ, De Visser M, Schelhaas HJ, Hardiman O, Ragoussis I, Lambrechts D, Robberecht W, Wokke JH, Ophoff RA, Van Den Berg LH

A genome-wide association study (GWAS) using pooled DNA samples from 386 sporadic ALS patients and 542 controls from the USA, identified genetic variation in FGGY (FLJ10986) as a risk factor, as well as 66 additional candidate SNPs. Considering the large number of hypotheses that are tested in GWAS, independent replication of associations is crucial for identifying true-positive genetic risk factors for disease. The primary aim of this study was to study the association between FGGY and sporadic ALS in large, homogeneous populations from northern Europe. Genotyping experiments were performed using Illumina Beadchips, Sequenom iPLEX assays and Taqman technology on large case-control series from The Netherlands, Belgium, Sweden and Ireland (total: 1883 sporadic ALS patients and 2063 controls). No significant association between sporadic ALS and the six previously reported associated SNPs in FGGY was observed: rs6700125 (p =0.56), rs6690993 (p =0.30), rs10493256 (p =0.68), rs6587852 (p =0.64), rs1470407 (p =0.28) and rs333662 (p =0.44). Screening of the additional candidate loci did not yield significant associations either, with the lowest p-value in joint analysis for rs7772593 (p =0.14). We concluded that common genetic variation in FGGY is not associated with susceptibility to sporadic ALS in genetically homogeneous populations from northern Europe.

Amyotroph lateral Scler. 2009; 10(5-6): 436-440
Corcia P, Camu W, Praline J, Gordon PH, Vourch P, Andres C

The human genome contains two SMN (survival motor neuron) genes: SMN1, the telomeric gene whose homozygous deletion causes spinal muscular atrophy (SMA), and SMN2, the centromeric version whose copy number modulates the phenotype of SMA. We performed a Medline search and reviewed all of the publications that focus on SMN1 and SMN2 in Amyotrophic lateral sclerosis (ALS) to analyse whether these genes also act as risk factors or phenotypic modulators in ALS. While homozygous deletion of SMN1 was not associated in ALS, abnormal SMN1 copy numbers significantly increased the risk of ALS. The role of the SMN2 gene in ALS needs further clarification. The existence of abnormal SMN1 copy numbers in ALS provides additional evidence that gene copy number variants may contribute to neurodegeneration and might open new approaches to treatment.

Amyotroph lateral Scler. 2009; 10(5-6): 430-431
Zhang Y, Wang L, Fu Y, Song H, Zhao H, Deng M, Zhang J, Fan D

We investigated the safety and efficacy of the granulocyte colony stimulating factor (G-CSF) in 13 patients with Amyotrophic lateral sclerosis (ALS). Five-day administration of 2 microg/kg once a day was followed by a six-month observation period. The primary and secondary endpoints were the changes of ALS functional rating scale (ALSFRS) and the compound muscle action potential (CMAP) amplitude, respectively. We found that the declines of ALSFRS and CMAP amplitude after G-CSF administration were significantly less than those measured prior to the treatment. The results suggest G-CSF is safe in ALS patients, and may affect the rate of motor decline.

Amyotroph lateral Scler. 2009; 10(5-6): 410-415
Lauria G, Campanella A, Filippini G, Martini A, Penza P, Maggi L, Antozzi C, Ciano C, Beretta P, Caldiroli D, Ghelma F, Ferrara G, Ghezzi P, Mantegazza R

Preclinical studies demonstrated that erythropoietin is neuroprotective in different models of peripheral and central nervous system diseases. We investigated safety and tolerability of recombinant human erythropoietin (rhEPO) in Amyotrophic lateral sclerosis (ALS). We performed a phase II double-blind, randomized, placebo-controlled study. After screening, 23 patients were randomly assigned to rhEPO or placebo arm. Patients were examined during a six-month lead-in period, and then they received fortnightly either 40,000 units of rhEPO or placebo for 24 months. Primary outcomes were adverse events, safety, and death or tracheotomy. Treatment was safe and well tolerated. One patient in the rhEPO arm dropped out for a superficial phlebitis. Median values of haematocrit, haemoglobin, red cells, and reticulocytes were non-significantly higher in rhEPO than placebo arm. Haemoglobin did not increase >1 g/dl between subsequent doses. Anti-rhEPO antibodies were not detected. Survival and slope of ALSFRS-R curves did not significantly differ between treatment groups. RhEPO treatment was safe and well tolerated in ALS patients. Our results suggest that larger studies are warranted to confirm safety of treatment and to investigate different dose schedule and efficacy.

Amyotroph lateral Scler. 2009; 10(5-6): 393-404
Stommel EW, Cohen JA, Fadul CE, Cogbill CH, Graber DJ, Kingman L, Mackenzie T, Channon Smith JY, Harris BT

Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-alpha) is thought to play an important role in the pathogenesis of Amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-alpha pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-alpha inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects.

Amyotroph lateral Scler. 2009; 10(5-6): 384-392
Cheah BC, Boland RA, Brodaty NE, Zoing MC, Jeffery SE, McKenzie DK, Kiernan MC

Respiratory impairment, due to respiratory muscle weakness, is a major cause of morbidity and mortality in patients with Amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Threshold loading may strengthen the inspiratory muscles and thereby improve patient prognosis. A phase II, double-blind, randomized-controlled trial was undertaken to determine whether a 12-week inspiratory muscle training programme attenuated the decline in respiratory function and inspiratory muscle strength in patients with ALS/MND. Nine patients were randomized to inspiratory muscle training and 10 to sham training. Primary endpoints were respiratory function (forced vital capacity, vital capacity), lung volumes and inspiratory muscle strength. Patients were assessed before, during and immediately after a 12-week training period, and at eight weeks follow-up. While improvements in inspiratory muscle strength were observed in both treatment arms, there was a non-significant increase in maximum inspiratory pressure of 6.1% in the experimental group compared to controls (standard error of mean, 6.93%; 95% confidence interval -8.58 -20.79; p=0.39). The gains in inspiratory muscle strength were partially reversed during a period of training cessation. In conclusion, inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in respiratory function in patients with ALS/MND.

Amyotroph lateral Scler. 2009; 10(5-6): 370-373
Poulletier de Gannes F, Ruffié G, Taxile M, Ladevèze E, Hurtier A, Haro E, Duleu S, Charlet de Sauvage R, Billaudel B, Geffard M, Veyret B, Lagroye I

There is some evidence from epidemiological studies of an association between occupational exposure to electromagnetic fields and Amyotrophic lateral sclerosis (ALS). Our aim was to perform, for the first time, an animal study in a controlled magnetic environment. We used the SOD-1 mouse model to assess the possible effect of ELF magnetic fields on development of the disease. Seven mice per group were exposed to 50 Hz magnetic fields at two intensities (100 and 1000 microT(rms)) before the onset of the clinical signs of ALS. Exposure lasted 7 weeks, and body weight, motor performance and life span were monitored. Our results did not reveal any evidence of a link between ELF exposure and ALS in this transgenic animal model.

Amyotroph lateral Scler. 2009; 10(5-6): 361-369
Binazzi A, Belli S, Uccelli R, Desiato MT, Talamanca IF, Antonini G, Corsi FM, Scoppetta C, Inghilleri M, Pontieri FE, Vanacore N, Als Rome Group

Several environmental and life-style factors reported as possibly associated with ALS have been analysed in the present study, focusing on the two clinical onsets of ALS. A case-control study (77 cases and 185 controls) has been performed in the province of Rome in the period 2005-2006. Increased risks were observed in bulbar cases for former smokers (OR: 4.55, 90% CI 1.72-12.08) and more than 24 pack-years, compared with spinal cases for employment in the construction sector and professional exposure to building materials (OR: 5.27, 90% CI 1.15-24.12) and metals (OR: 2.94, 90% CI 1.20-7.21). Overall and bulbar cases showed an increased risk for consumption of cold cuts and a decreased risk for vegetables intake. Regarding head injuries, differences were observed if the last injury occurred in the age range of 30-40 years, among all (OR: 14.2, 90% CI 1.04-194.42) and bulbar (OR: 17.4, 90% CI 1.70-178.5) cases, and less than 30 years among spinal cases (OR: 7.13, 90% CI 1.34-37.94). Moreover, a risk for a time period of 11-30 years since the last head injury suffered was found in bulbar cases (OR: 3.51, 90% CI 1.03-11.95). Some of the hypothesized risk factors for ALS have been found positively associated in this study, with different patterns between bulbar and spinal ALS.

Amyotroph lateral Scler. 2009; 10(5-6): 350-354
Fang DF, Zhang SS, Guo XY, Zeng Y, Yang Y, Zhou D, Shang HF

The objective of this study was to analyse clinical and genetic features of patients with sporadic ALS in south-west China. All patients diagnosed with adult-onset sporadic ALS were consecutively followed up, and their clinical characteristics were collected. The frequencies of alleles of six SNPs in the FLJ10986 gene and the association between these SNPs and the clinical features of ALS were analysed. One hundred and sixty-one patients were included in the study. The mean age of onset was 50.9+/-11.4 years. The mean diagnostic delay was 16.5+/-14.3 months and the mean disease duration was 30.7+/-23.5 months. Forty patients (24.2%) died during the period of follow-up. Positive correlation between mean delay and disease duration was found, as was negative correlation between onset age, mean delay and disease duration. The frequency of the 'G' variant of the SNP (rs10493256) was significantly higher than that in a control population. There was no significant difference in the frequencies of variant alleles regarding clinical features. In conclusion, SNP (rs10493256) in the FLJ10986 gene appears to increase the risk of developing sporadic ALS in our Chinese population. Our Clinical findings are in line with other studies. No association between the polymorphisms and clinical features was found.

Amyotroph lateral Scler. 2009; 10(5-6): 302-309
Sutedja NA, Veldink JH, Fischer K, Kromhout H, Heederik D, Huisman MH, Wokke JH, van den Berg LH

Environmental exposure to chemicals and metals may contribute to the risk of sporadic Amyotrophic lateral sclerosis (ALS). Two systematic reviews of the literature on these topics performed according to the well-established MOOSE guidelines are presented. Literature cited in MEDLINE, EMBASE, CINAHL, and Cochrane databases (up to March 2007) as well as references of relevant articles were screened for case-control or cohort studies investigating the associations between sporadic ALS and exposure to chemical agents or metals. Methodology of selected studies was appraised according to Armon's classification system for ALS risk factor studies as well as a newly developed classification system for quality of exposure assessment. Seven of the 38 studies concerning exposure to chemicals and three of the 50 studies concerning exposure to metals fulfilled the validity criteria. In two independent studies meeting the validity criteria, a significant association with increased ALS risk was reported for exposure to pesticides. This systematic review demonstrated the difficulty in attaining a high level of evidence due to lack of high quality of methodological and exposure assessment components. Although pesticide exposure was identified as candidate risk factor, more well-designed studies are needed to provide a definitive answer about exogenous factors of ALS.

Amyotroph lateral Scler. 2009; 10(5-6): 295-301
Sutedja NA, Fischer K, Veldink JH, van der Heijden GJ, Kromhout H, Heederik D, Huisman MH, Wokke JJ, van den Berg LH

Occupational and environmental exposures may contribute to the risk of developing sporadic Amyotrophic lateral sclerosis (ALS). To summarize the available evidence, a systematic review of the literature on occupation as a potential determinant of ALS was performed according to the MOOSE guidelines. From MEDLINE, EMBASE, CINAHL, and Cochrane databases, selected studies were methodologically appraised according to Armon's classification system for ALS risk factor studies. Each occupation studied was reclassified according to the International Standard Classification of Occupations (ISCO-88). The vote-counting method was applied to summarize the data. Of 3773 potentially relevant studies, 51 were initially included. Of these, 12 studies provided risk estimates for individual occupations - one case-control, two register-based case-control, and nine register-based cohort studies. All studies fell into Armon's level of evidence class IV, indicating methodological limitations. Due to the heterogeneity of study methodology, data could not be pooled. The vote-counting method revealed several candidate occupations: veterinarians and other health workers, athletes, hairdressers, power-production plant, electrical and military workers. However, well designed studies with standardized assessment of occupation are needed to provide a more definitive answer about exogenous risk factors of ALS.

Amyotroph lateral Scler. 2009; 10(5-6): 288-294
Senda J, Ito M, Watanabe H, Atsuta N, Kawai Y, Katsuno M, Tanaka F, Naganawa S, Fukatsu H, Sobue G

Our aim was to evaluate the location and extent of white matter involvement in patients with Amyotrophic lateral sclerosis (ALS) using diffusion-tensor magnetic resonance imaging (DTI). We obtained fractional anisotropy (FA) values from the internal capsule and various white matter regions of 46 patients with sporadic ALS and 19 control subjects. In ALS patients, FA values in the internal capsule, frontal white matter, genu and splenium of the corpus callosum (p<0.001), parietal and temporal lobe white matter, and posterior cingulum (p<0.05) were significantly lower than in controls. FA values in frontal white matter were lower than in parietal white matter (p<0.001). Decreased FA values in frontal, parietal, and temporal white matter, and the genu of the corpus callosum, correlated significantly with those in the internal capsule (r=0.66 and p<0.001, r=0.47 and p=0.001, r=0.33 and p=0.021, r=0.41 and p=0.005, respectively). No such correlations were found for FA values in other white matter areas or in controls. Patient FA values generally were not correlated with disease duration. DTI demonstrated more widespread involvement of the cerebral white matter in ALS patients than previously believed. The severity of involvement in the frontal, temporal and parietal white matter correlated with severity in the pyramidal tract.

Amyotroph lateral Scler. 2009; 10(5-6): 280-287
Li S, Chen Q, Yu B, Xue K, Luo C, Xu Y, Gong Q, He C, Zhou D, He L, Yao D

The purpose of this study was to explore cerebral structural and functional changes in Amyotrophic lateral sclerosis (ALS) patients with or without dysphagia compared with healthy adults. In total, five ALS patients with dysphagia, five ALS patients without dysphagia and 10 healthy controls were evaluated using diffusion tensor magnetic resonance imaging (DTI) and event-related functional magnetic resonance imaging (fMRI) while laryngeal swallow-related movements were recorded. The fMRI data were analysed using the general linear model to gain the differential statistical map (two-sample t-test) for each group. Maps of fractional anisotropy (FA) and mean diffusivity (MD) were calculated within the masks that corresponded to the different statistical functional maps of intergroup comparisons. During the voluntary saliva swallowing, prominent activation of foci corresponded to the primary sensorimotor (SM) cortex in both ALS and controls, while decreased activation of the SM cortex was observed in ALS patients with dysphagia. DTI analysis revealed that FA was significantly reduced and MD was typically increased in the posterior limb of the internal capsule, thalamus, and anterior cingulate gyrus, as well as in the insula of ALS patients compared with controls. However, in ALS patients with dysphagia, FA and MD were more sensitive to these changes than ALS patients without dysphagia. This study highlights the potential of DTI and fMRI for monitoring structural degeneration and functional changes in patients with ALS. This study is the first to demonstrate that cerebral activation map changes correspond to distribution patterns of diffusion abnormalities. Combined non-invasive neuroimaging techniques may be useful tools to assess prognosis and study rehabilitation strategies for dysphagic ALS patients, especially for patients who are MRI-negative by conventional methods.