HubMed - amyotrophic lateral sclerosis AND ((English[lang]) AND (jsubsetaim[text]) )

Dyslipidemia is a protective factor in amyotrophic lateral sclerosis.

2008-10-06T15:25:56+01:00

Neurology. 2008 Sep 16; 71(12): 956; author reply 956-7
Goldstein MR, Mascitelli L, Pezzetta F

A randomized controlled trial of resistance exercise in individuals with ALS.

2008-10-06T15:25:56+01:00

Neurology. 2008 Sep 9; 71(11): 864-5; author reply 865-6
Armon C

Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.

2008-10-06T15:25:56+01:00

Arch Neurol. 2008 Sep; 65(9): 1185-9
Kühnlein P, Sperfeld AD, Vanmassenhove B, Van Deerlin V, Lee VM, Trojanowski JQ, Kretzschmar HA, Ludolph AC, Neumann M

BACKGROUND: Abnormal neuronal inclusions composed of the transactivation response DNA-binding protein 43 (TDP-43) are characteristic neuropathologic lesions in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). This makes TARDBP, the gene encoding for TDP-43, a candidate for genetic screening in ALS. OBJECTIVES: To investigate the presence and frequency of TARDBP mutations in ALS. DESIGN: Genetic analysis. SETTING: Academic research. PARTICIPANTS: One hundred thirty-four patients with sporadic ALS, 31 patients with familial non-superoxide dismutase 1 gene (non-SOD1) (OMIM 147450) ALS, and 400 healthy control subjects. MAIN OUTCOME MEASURES: We identified 2 missense mutations (G348C and the novel N352S) in TARDBP in 2 small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment. RESULTS: The mutations located in the C-terminus of TDP-43 were absent in 400 controls of white race/ethnicity. The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation, while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges. CONCLUSIONS: Mutations in TARDBP are a rare cause of familial non-SOD1 ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.

Rating the approachability of faces in ALS.

2008-10-06T15:25:56+01:00

Neurology. 2008 Aug 26; 71(9): 696; author reply 696
Gotkine M

Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden.

2008-10-06T15:25:56+01:00

Neurology. 2008 Aug 12; 71(7): 514-20
Valdmanis PN, Kabashi E, Dyck A, Hince P, Lee J, Dion P, D'Amour M, Souchon F, Bouchard JP, Salachas F, Meininger V, Andersen PM, Camu W, Dupré N, Rouleau GA

BACKGROUND: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations. METHODS: We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls). RESULTS: Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec (p value 0.026) populations as well as all three populations combined (p value 1.69 x 10(-6)). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients. CONCLUSIONS: These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.

Teaching NeuroImage: corticospinal tract.

2008-10-06T15:25:56+01:00

Neurology. 2008 Aug 5; 71(6): e10
Kuo SH, Kwan JY

Natural history of young-adult amyotrophic lateral sclerosis.

2008-10-06T15:25:56+01:00

Neurology. 2008 Sep 16; 71(12): 876-81
Sabatelli M, Madia F, Conte A, Luigetti M, Zollino M, Mancuso I, Lo Monaco M, Lippi G, Tonali P

BACKGROUND: Amyotrophic lateral sclerosis (ALS) affects people of all ages, but whether the wide range of age at onset is due to distinct diseases or merely reflects phenotypic variability of the same disorder is still unknown. The purpose of this study is to describe clinical and prognostic features of young-adult ALS, with onset before age 40 years, and to compare them with features of the common adult-onset type. METHODS: We analyzed clinical features and long-term follow-up of 57 young-adult ALS patients, with disease onset between 20 and 40 years, and compared them with 450 patients affected by adult-onset ALS. RESULTS: We found that the majority of young-adult patients showed a predominant upper motor neuron (p-UMN) ALS, characterized by marked spastic paraparesis, with lower motor neuron signs confined to the upper limbs. The proportion of patients with p-UMN ALS phenotype was 59.6% in the young-adult patients and 17.4% in the adult-onset form (p < 0.0001). Young-adult ALS with p-UMN phenotype had longer survival than did the classic phenotype: median survival was 74 months (range 10-226, 95% CI 60.61-87.38) in the former and 56 months (range 6-106, 95% CI 48.65-63.34) in the latter (p = 0.03). In the young-adult patients, a marked male excess was observed in the p-UMN ALS group (5.8:1), whereas the ratio of men to women was 1.1:1 in the classic phenotype (p = 0.01). CONCLUSIONS: Our findings show that young-adult amyotrophic lateral sclerosis with the predominant upper motor neuron phenotype represents a distinctive clinical variant characterized by a unique clinical pattern, longer survival, and male prevalence.

Management of neurologic disorders of the larynx.

2008-10-06T15:25:56+01:00

Ann Otol Rhinol Laryngol. 2008 May; 117(5): 317-26
Woodson G

OBJECTIVES: I review the literature on management of neurologic disorders of the larynx. METHODS: I reviewed the literature on laryngeal physiology, clinical evaluation of laryngeal function, and the clinical presentation and treatment of neurologic disorders that frequently affect the larynx. RESULTS: Laryngeal function is complex, as this organ is important in breathing, speech, and swallowing. Coordination of these roles is very susceptible to disruption by neurologic disorders. Diagnosis of neurologic disease is primarily based on history and physical examination; however, the diagnosis of laryngeal dysfunction is frequently overlooked, because the larynx is not easily accessible to examination by non-otolaryngologists. Evaluation of laryngeal function includes listening to the voice, systematic observation of the larynx during speech and nonspeech tasks, and, sometimes, ancillary tests. Neurologic disorders that affect laryngeal function include Parkinson's disease, essential tremor, stroke, amyotrophic lateral sclerosis, multiple sclerosis, and dystonia. The otolaryngologist can sometimes provide treatment to specifically improve symptoms of laryngeal involvement. CONCLUSIONS: Otolaryngology consultation is important in the diagnosis and treatment of neurologic disorders that affect laryngeal function. The otolaryngologist should be able to perform a systematic evaluation of laryngeal and pharyngeal function, and should be aware of the clinical presentation of neurologic disorders that affect the larynx.

Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

2008-10-06T15:25:56+01:00

Am J Pathol. 2008 Jul; 173(1): 182-94
Igaz LM, Kwong LK, Xu Y, Truax AC, Uryu K, Neumann M, Clark CM, Elman LB, Miller BL, Grossman M, McCluskey LF, Trojanowski JQ, Lee VM

TAR DNA-binding protein (TDP-43) has been recently described as a major pathological protein in both frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. However, little is known about the relative abundance and distribution of different pathological TDP-43 species, which include hyperphosphorylated, ubiquitinated, and N-terminally cleaved TDP-43. Here, we developed novel N-terminal (N-t) and C-terminal (C-t)-specific TDP-43 antibodies and performed biochemical and immunohistochemical studies to analyze cortical, hippocampal, and spinal cord tissue from frontotemporal dementia with ubiquitin-positive inclusions and amyotrophic lateral sclerosis cases. C-t-specific TDP-43 antibodies revealed similar abundance, morphology, and distribution of dystrophic neurites and neuronal cytoplasmic inclusions in cortex and hippocampus compared with previously described pan-TDP-43 antibodies. By contrast, N-t-specific TDP-43 antibodies only detected a small subset of these lesions. Biochemical studies confirmed the presence of C-t TDP-43 fragments but not extreme N-t fragments. Surprisingly, immunohistochemical analysis of inclusions in spinal cord motor neurons in both diseases showed that they are N-t and C-t positive. TDP-43 inclusions in Alzheimer's disease brains also were examined, and similar enrichment in C-t TDP-43 fragments was observed in cortex and hippocampus. These results show that the composition of the inclusions in brain versus spinal cord tissues differ, with an increased representation of C-t TDP-43 fragments in cortical and hippocampal regions. Therefore, regionally different pathogenic processes may underlie the development of abnormal TDP-43 proteinopathies.

Researchers identify neurological risks.

2008-10-06T15:25:56+01:00

JAMA. 2008 May 28; 299(20): 2375-6
Kuehn BM

Magnetic source imaging of cortical dysfunction in amyotrophic lateral sclerosis.

2008-10-06T15:25:56+01:00

Am J Phys Med Rehabil. 2008 Jun; 87(6): 427-37
Boyajian RA, Amo C, Otis SM, Romine JS, Smith RA

OBJECTIVE: The goal was to determine whether magnetic source imaging could identify a signature for cortical involvement in patients with amyotrophic lateral sclerosis (ALS), and to determine whether the method might provide insight into functional abnormalities associated with the disease process. DESIGN: Spontaneous brain activity recordings from whole-head 148-channel magnetoencephalography (MEG) were employed to look for localized dipolar sources of focal delta-theta (1-7 Hz) discharges in patients with ALS without dementia. Localized slow wave dipoles were mapped and counted by anatomic brain region, defined by MRI, and correlated against the revised ALS functional rating scale (a functional measure of ALS disability). In a substudy, defects in cortical activations mediating purposeful movement were investigated in an ALS patient with probable motor apraxia of an upper limb. RESULTS: MEG revealed localized slow wave dipole sources in 7/7 ALS patients, including two recently diagnosed patients (0/8 age-similar controls). Systematic brain mapping of dipole source generators was possible in all seven ALS patients. The slow wave bursts were being generated from frontal, temporal, and parietal cortices, but not from occipital areas. The density of slow wave dipoles in cingulate gyrus correlated with the severity of upper-extremity disability as judged by the functional ALS measure. Further magnetic source imaging in the substudy patient with unilateral limb apraxia revealed abnormal central processing of purposeful movement with absent M2 in the contralateral secondary motor areas generating slow waves. CONCLUSIONS: This exploratory study documents widespread cortical dysfunction in patients with ALS, including those with recent onset of their disease. MEG is likely to be a powerful new tool for researching the contribution of cortical dysfunction to the motor disability that characterizes the disease process.

The ALS/PDC syndrome of Guam and the cycad hypothesis.

2008-10-06T15:25:56+01:00

Neurology. 2008 May 20; 70(21): 1984-90
Steele JC, McGeer PL

There is a high incidence on Guam of a severe tauopathy known as the Parkinson- dementia complex (PDC). It is linked with an even more malignant amyotrophic lateral sclerosis (ALS) syndrome. There is great interest in determining the cause, or causes, of the Guam ALS/PDC syndrome because insight might be gained regarding ALS and the more common tauopathies found throughout the world. Research into the disorder is stimulated by hypotheses as to cause. Such hypotheses should be compatible with the known epidemiology and pathology of the syndrome. These include a high, if not exclusive, restriction to the Chamorro population, familial occurrence, a regional variation on Guam itself, a definite persistence but with declining incidence, and a possible duplication in isolated villages on the Kii peninsula of Japan. Proposed causation factors should also be able to reproduce the syndrome in experimental systems. This includes induction of neurofibrillary tangles with a tau isoform distribution similar to that of Alzheimer disease and association of the lesions with TDP-43 and Lrrk2. A recurring hypothesis as to causation is exposure to Cycas micronesica, the false Sago palm known locally as fadang. We review the reasons why this hypothesis falls short of the minimal criteria needed for further serious consideration and discuss some other possibilities that should not be excluded.

Natural history of spinal-bulbar muscular atrophy.

2008-10-06T15:25:56+01:00

Neurology. 2008 May 20; 70(21): 1967-71
Chahin N, Klein C, Mandrekar J, Sorenson E

BACKGROUND: Although spinal-bulbar muscular atrophy (SBMA) is generally believed to be associated with better survival and function compared to other motor neuron diseases, no systematic study of long-term functional status or survival has been reported. METHODS: We report the results a retrospective review of 39 patients with genetically confirmed diagnosis and compared their survival to normal, population-based, age- and gender-matched controls. We assessed the functional status of 25 of the 33 survivors by completing the revised ALS Functional Rating Scale (ALSFRS-r) by telephone. RESULTS: The subjects with SBMA had a 10-year survival of 82% compared to 95% among the age-matched controls (p = 0.053). The mean ALSFRS-r score for the survivors was 37 (range 27-43). The ALSFRS-r subscores indicated mild deficits in all areas in most, with the greatest limitation being the use of stairs. While all reported bulbar symptoms, none had disabling deficits. None of the subjects required a percutaneous endoscopic gastrostomy tube and one subject used noninvasive positive pressure ventilation. CONCLUSIONS: The long-term survival of subjects with spinal-bulbar muscular atrophy is minimally reduced from their age-matched controls. The long-term functional assessments demonstrate mild neurologic impairment in most without devastating bulbar or respiratory dysfunction and good ambulatory function years after diagnosis.

Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis.

2008-10-06T15:25:56+01:00

Arch Neurol. 2008 May; 65(5): 636-41
Geser F, Brandmeir NJ, Kwong LK, Martinez-Lage M, Elman L, McCluskey L, Xie SX, Lee VM, Trojanowski JQ

BACKGROUND: Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described. OBJECTIVE: To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS. DESIGN: Performance of an immunohistochemical whole-central nervous system scan for evidence of pathological TDP-43 in ALS patients. SETTING: An academic medical center. PARTICIPANTS: We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants. MAIN OUTCOME MEASURES: Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology. RESULTS: In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls. CONCLUSIONS: These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.

Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis.

2008-10-06T15:25:56+01:00

Brain. 2008 Jun; 131(Pt 6): 1540-50
Vucic S, Nicholson GA, Kiernan MC

Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. While 10-15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation techniques to investigate the mechanisms underlying neurodegeneration in FALS. Studies were undertaken in 14 asymptomatic and 3 pre-symptomatic SOD-1 mutation carriers, followed longitudinally for up to 3-years. The pre-symptomatic subjects were asymptomatic at the time of their initial study but developed symptoms during the follow-up period. Results were compared to 7 SOD-1 FALS patients, 50 sporadic ALS patients and 55 normal controls. Short-interval intracortical inhibition (SICI) was significantly reduced in SOD-1 FALS (-1.2 +/- 0.6%) and sporadic ALS patients (-0.7 +/- 0.3%) compared to asymptomatic SOD-1 mutation carriers (9.8 +/- 1.5%, P<0.00001) and normal controls (8.5 +/- 1.0%, P<0.00001). SICI reduction was accompanied by increases in intracortical facilitation, motor evoked potential amplitudes and the slope of the magnetic stimulus-response curve. In two pre-symptomatic SOD-1 mutation carriers SICI was completely absent (SICI patient 1, -3.2%; patients 2, -1.3%), while in one subject there was a 32% reduction in SICI prior to symptom onset. These three individuals subsequently developed clinical features of ALS. Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability develops in clinically affected SOD-1 FALS patients, similar to that seen in sporadic ALS patients, thereby suggesting that a similar pathophysiological process in evident in both familial and sporadic ALS patients. In addition, the present study has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, thereby suggesting that cortical hyperexcitability underlies neurodegeneration in FALS.

Re: What is next in ALS clinical trials?

2008-10-06T15:25:56+01:00

Neurology. 2008 Apr 15; 70(16): 1366; author reply 1366-7
Hoke A

Re: What is next in ALS clinical trials?

2008-10-06T15:25:56+01:00

Neurology. 2008 Apr 15; 70(16): 1365-6; author reply 1365-6
Harel NY

VAPB: new genetic clues to the pathogenesis of ALS.

2008-10-06T15:25:56+01:00

Neurology. 2008 Apr 1; 70(14): 1161-2
Hirano M

Estimating contraction level using root mean square amplitude in control subjects and patients with neuromuscular disorders.

2008-10-06T15:25:56+01:00

Arch Phys Med Rehabil. 2008 Apr; 89(4): 711-8
Boe SG, Rice CL, Doherty TJ

OBJECTIVES: To assess the utility of the surface electromyographic signal as a means of estimating the level of muscle force during quantitative electromyography studies by examining the relationship between muscle force and the amplitude of the surface electromyographic activity signal; and to determine the impact of a reduction in the number of motor units on this relationship, through inclusion of a sample of patients with neuromuscular disease. DESIGN: Cross-sectional, cohort study design. SETTING: Tertiary care, ambulatory, electromyography laboratory. PARTICIPANTS: A volunteer, convenience sample of healthy control subjects (n=10), patients with amyotrophic lateral sclerosis (n=9), and patients with Charcot-Marie-Tooth disease type X (n=5). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The first dorsal interosseous (FDI) and biceps brachii muscles were examined. Force values (at 10% increments) were calculated from two 4-second maximal voluntary contractions (MVCs). Surface electromyographic activity was recorded during separate 4-second voluntary contractions at 9 force increments (10% -90% of MVC). Additionally, a motor unit number estimate was derived for each subject to quantify the degree of motor unit loss in patients relative to control subjects. RESULTS: The relationships between force and surface electromyographic activity for both muscles (controls and patients) were best fit by a linear function. The variability about the grouped regression lines was quantified by 95% confidence intervals and found to be +/-6.7% (controls) and +/-8.5% (patients) for the FDI and +/-5% (controls) and +/-6.1% (patients) for the biceps brachii. CONCLUSIONS: These results suggest that the amplitude of the surface electromyographic activity signal may be used as a means of estimating the level of muscle force during quantitative electromyography studies. Future studies should be directed at examining if the variability associated with these force and surface electromyographic activity relationships is acceptable in replacing previous methods of measuring muscle force.

Dyslipidemia in ALS: good, bad, or unclear?

2008-10-06T15:25:56+01:00

Neurology. 2008 Mar 25; 70(13): 988-9
Albert SM