Showing papers in "Amyotrophic Lateral Sclerosis in 2011"

How common are behavioural changes in amyotrophic lateral sclerosis

Abstract: Our objectives were to assess the frequency of behavioural changes in patients with amyotrophic lateral sclerosis (ALS) and to compare the clinical profi le of ALS patients with those with behavioural variant frontotemporal dementia (bvFTD). Ninety-two patients with ALS and their carers participated in a postal survey. ALS patients completed self-report measures of motor function and mood. Eighty-one carers of ALS patients and 25 carers of bvFTD patients completed the revised version of the Cambridge Behavioural Inventory (CBI-R). Results showed that reduced motivation was reported in more than 80% of the ALS cases, with almost 41% of them having moderate-severe apathy. Depression was present in 30% of ALS patients and did not contribute signifi cantly to the presence of behavioural symptoms. Bulbar and limb onset ALS patients did not differ. Abnormal behaviour and stereotypical and motor behaviours were present to a moderate-severe degree in around 20%, and 11% reached the criteria for FTD. The rate of behavioural symptoms was signifi cantly higher in the bvFTD group than ALS in all behavioural domains ( p 0.001). In conclusion, apathy was the most prominent feature in ALS patients. A substantial proportion of ALS patients manifested behavioural changes of the type seen in FTD, with 11% fulfi lling the criteria for FTD.

What would brain-computer interface users want? Opinions and priorities of potential users with amyotrophic lateral sclerosis

Abstract: Universal design principles advocate inclusion of end users in every design stage, including research and development. Brain-computer interfaces (BCIs) have long been described as potential tools to enable people with amyotrophic lateral sclerosis (ALS) to operate technology without moving. Therefore the objective of the current study is to determine the opinions and priorities of people with ALS regarding BCI design. This information will guide BCIs in development to meet end-user needs. A telephone survey was undertaken of 61 people with ALS from the University of Michigan's Motor Neuron Disease Clinic. With regard to BCI design, participants prioritized accuracy of command identification of at least 90% (satisfying 84% of respondents), speed of operation comparable to at least 15-19 letters per minute (satisfying 72%), and accidental exits from a standby mode not more than once every 2-4 h (satisfying 84%). While 84% of respondents would accept using an electrode cap, 72% were willing to undergo outpatient surgery and 41% to undergo surgery with a short hospital stay in order to obtain a BCI. In conclusion, people with ALS expressed a strong interest in obtaining BCIs, but current BCIs do not yet provide desired BCI performance.

The epidemiology and treatment of ALS: Focus on the heterogeneity of the disease and critical appraisal of therapeutic trials

Abstract: Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical trials.

Proposed criteria for familial amyotrophic lateral sclerosis

Abstract: There is currently no consensus on the definition of familial ALS (FALS). We propose criteria for FALS that incorporate family history and genetic analysis. The aim is to increase the yield of gene...

Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: A window of opportunity in the search for genetic modifiers

Abstract: Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1 Expression of G93A-hSOD1Tg in congenic lines with ALR, NODRag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines We hypothesize that the background differences are due to disease-modifying genes Identifi cation of modifi er genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered Most importantly, identifi ed modifi er genes provide new targets for the development of therapies

Elevated CSF TDP-43 levels in amyotrophic lateral sclerosis: Specificity, sensitivity, and a possible prognostic value

Abstract: TAR DNA binding protein of 43 kDa (TDP-43) is likely to be the major pathogenetic protein in amyotrophic lateral sclerosis (ALS). A previous study has shown that levels of TDP-43 in CSF measured by an ELISA are significantly higher for ALS patients than for controls. The aim of this study was to investigate whether elevated CSF TDP-43 levels are specific to ALS, and are associated with clinical profiles in ALS patients. We measured CSF TDP-43 levels by the same ELISA in 27 ALS patients and 50 neurodegenerative or inflammatory disease controls such as Parkinson's disease, multiple sclerosis, and Guillain-Barre syndrome. Results showed that the CSF TDP-43 levels were increased only in ALS patients. Receiver operating characteristic (ROC) analyses showed a sensitivity of 59.3% and a specificity of 96.0%. We also found that lower CSF TDP-43 levels may be associated with shorter survival time. In conclusion, the CSF TDP-43 is a potential biomarker that supports a diagnosis of ALS. Moreover, among ALS patients, lower levels of CSF TDP-43 may reflect the accumulation of TDP-43 in the cortical and spinal motor neurons and thereby shorter survival time, although this should be confirmed in larger prospective studies.

Keeping up with genetic discoveries in amyotrophic lateral sclerosis: The ALSoD and ALSGene databases

Abstract: Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous disorder that shows a characteristic dichotomy of familial forms typically displaying Mendelian inheritance patterns, and sporadic ALS showing no or less obvious familial aggregation. While the former is caused by rare, highly penetrant, and pathogenic mutations, risk for sporadic ALS is probably the result of the combined effects of common polymorphisms with minor to moderate effect sizes. Owing to recent advances in high-throughput genotyping and sequencing technologies, genetic research in both fi elds is evolving at a rapidly increasing pace making it more and more diffi cult to follow and evaluate the most signifi cant progress in the fi eld. To alleviate this problem, our groups have created dedicated and freely available online databases, ALSoD (http://alsod.iop.kcl.ac.uk/) and ALSGene (http://www.alsgene.org), which provide systematic and in-depth qualitative and quantitative overviews of genetic research in both familial and sporadic ALS. This review briefl y introduces the background and main features of both databases and provides an overview of the currently most compelling genetic fi ndings in ALS derived from analyses using these resources.

Progressive and widespread brain damage in ALS: MRI voxel-based morphometry and diffusion tensor imaging study

Abstract: We investigated 17 patients with sporadic amyotrophic lateral sclerosis (ALS) using voxel-based morphometry (VBM) and voxel-based analysis of diffusion tensor images (DTI) at baseline and after a six-month follow-up. Compared with 17 healthy controls, ALS patients at baseline showed only minimal white matter volume decreases in the inferior frontal gyrus but marked decreases in the gray matter of several regions, especially in the bilateral paracentral lobule of the premotor cortex. DTI revealed reduced fractional anisotropy in the bilateral corticospinal tracts, insula, ventrolateral premotor cortex, and parietal cortex. Increased mean diffusivity was noted bilaterally in the motor cortex, ventrolateral premotor cortex, insula, hippocampal formation, and temporal gyrus. At the six-month follow-up, ALS patients showed widespread volume decreases in gray matter, and DTI abnormalities extended mainly into the bilateral frontal lobes, while volume changes in the white matter remained minimal but more distinct. Our combined VBM and DTI techniques revealed extra-corticospinal tract neuronal degeneration mainly in the frontotemporal lobe of ALS patients. In particular, follow-up examinations in these patients showed that whole-brain DTI changes occurred predominantly in the regions of brain atrophy. These objective analyses can be used to assess the disease condition of the ALS brain.

Senataxin mutations and amyotrophic lateral sclerosis

Abstract: We studied three patients with mutations in the senataxin gene (SETX). One had juvenile onset of ALS. The second case resembled hereditary motor neuropathy. The third patient had an overlap syndrome of ataxia-tremor and motor neuron disease, phenotypes previously associated with SETX mutations. Our patients were all apparently sporadic, with no other affected relative. Two relatives of patient no. 2 carried the SETX c.4660T > G transversion but did not manifest motor neuron disease, abnormal eye movements, ataxia, or tremor suggesting that genetic or environmental modifiers may influence expression of this SETX polymorphism. Relatives of patients 1 and 3 were not available for examination or SETX mutation screening. Mutations causing ALS4 may be more frequent and heterogeneous than expected. Screening for SETX mutations should be considered in patients with apparently sporadic juvenile-onset ALS, hereditary motor neuropathy, and overlap syndromes with ataxia and motor neuron disease.

From symptom onset to a diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND): Experiences of people with ALS/MND and family carers – a qualitative study

Abstract: Our objectives were to explore the personal perspectives of the diagnostic experience for people with ALS/MND and their family carers identifying issues that could impact positively or negatively on these experiences. We conducted a qualitative study with face-to-face interviews to capture experiences from 24 people with ALS/MND and 18 current family carers. Ten former family carers were also interviewed. The diagnostic experience was fraught with difficulties. There was failure to recognize the significance of some symptoms by patients, carers and primary and secondary care health professionals, which ultimately delayed diagnosis. Delivery of the diagnosis was frequently unsatisfactory despite international guidelines on the subject. Immediate post-diagnosis support often compared negatively to that provided for people with cancer. In conclusion, this study has identified a need for a more streamlined and empathetic diagnostic pathway for people with ALS/MND. Improvements to medical curricula are required to increase awareness of the condition and reduce the likelihood of diagnostic delays resulting from a failure to recognize the need for a neurological referral. Greater public awareness of the illness is also needed. Furthermore, delivery of the diagnosis should more closely adhere to established guidelines.

Depression in amyotrophic lateral sclerosis.

Abstract: Depression is an under-recognized comorbidity associated with amyotrophic lateral sclerosis (ALS). The goals of this study were to prospectively estimate the prevalence of depression and other ALS related symptoms and to study the impact of depression on enrollment in research studies. One hundred and twenty-seven people with ALS completed the ALS Depression Inventory (ADI-12) and answered questions about ALS related symptoms and research study enrollment preferences. Demographics, ALS symptoms, medications, functional status, and research enrollment were compared between depressed and non-depressed patients. Results showed that the prevalence of mild and severe depression was 29% and 6%, respectively. More than one-third of our ALS patients were receiving anti-depressants to treat depression, sialorrhea, and pseudobulbar affect. Depression prevalence was not correlated with disease duration or progression. Except for anxiety, none of the ALS related symptoms predicted depression. The presence of depression did not have an effect on the decision to enroll in research studies. In conclusion, major depression is less common in our ALS cohort than in the general population. The diagnosis of depression can be masked by some ALS related symptoms and it has no impact on enrollment in ALS clinical trials.

Abnormalities of satellite cells function in amyotrophic lateral sclerosis.

Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by progressive denervation leading to muscle atrophy prevented, during the early phase, by compensatory reinnervation. Little is known about muscle fibre regeneration capacity in ALS. We have carried out in vivo and in vitro investigation of skeletal muscle in ALS. Seven ALS patients underwent a deltoid muscle biopsy. Immunohistochemical analysis revealed various degrees of denervation- and reinnervation-related changes in the ALS muscle biopsies including satellite cells (SCs) activation and regenerating fibres. Only 3/7 primary cultures of ALS muscle cells were successfully established and had sufficient myogenicity, as assessed by desmin positivity, to be used without further purification. This was in contrast with the cultures derived from control muscles, predominantly desmin-positive cells. Although capable to proliferate in vitro, ALS-derived SCs presented an abnormal senescent-like morphology. Markers of senescence, including senescent-associated (SA)-βGal activity and p16 expression, were increased. Furthermore, ALS-derived SCs were also unable to fully differentiate in vitro as shown by abnormal myotubes morphology and reduced MHC isoform expression, compared to control myotubes. Our study suggests that SC function is altered in ALS. This could limit the efficacy of compensatory processes and therefore could contribute to the progression of muscle atrophy and weakness.

Neuroanatomical correlates of apathy in ALS using 4 Tesla diffusion tensor MRI.

Abstract: Our objective was to determine whether apathy in amyotrophic lateral sclerosis (ALS) relates to structural changes associated with the degenerative process or disease related factors such as illness duration, physical disability, or hypoxia. Using diffusion tensor imaging (DTI) with fractional anisotropy (FA), we conducted a voxel-based analysis of whole-brain changes to investigate decline in white matter integrity as it correlates with apathy in ALS. Twenty-four patients enrolled in the study were compared with 24 age- and gender-matched controls. The relationship between FA and apathy scores was tested using a general linear model accounting for age, gender and functional disability in 16 ALS patients. Results showed that, using a spatially unbiased voxel-wise approach and the statistical map-driven region of interest (ROI), a significant negative correlation existed between FA and apathy change scores in the right anterior cingulum region, whereas ALS disease severity was significantly correlated with FA alterations in bilateral motor areas. Apathy was not correlated with clinical depression, disease duration or respiratory dysfunction. In conclusion, our findings point towards a biological basis for apathy in the anterior cingulum, consistent with research on apathy in other neurological populations.

A comparison of assisted cough techniques in stable patients with severe respiratory insufficiency due to amyotrophic lateral sclerosis

Abstract: Cough can be impaired in ALS. This can result in peak cough flows (PCFs) too low for an adequate airway clearance (<270 l/mn). There are several cough assistance techniques that aim at a better elimination of airway secretions, but which are effective, especially in bulbar patients, is not known. We designed the present investigation to compare the PCFs produced by a range of manual and mechanical techniques in patients with ALS, in non-bulbar but also in bulbar patients. In the whole study population, PCFs ranged from 84 (35-118) l/mn for the spontaneous cough manoeuvre to 488 (243-605) l/min for the in/exsufflator (p = 0.0005). In the bulbar group, these values were 42 (35-130) l/min versus 436 (244-630) l/min, respectively (p = 0.008), and 89 (40-106) l/min versus 491 (192-580) l/min, respectively, in the non-bulbar group (p = 0.019). There was no statistically significant difference between the bulbar and the non-bulbar groups. The in/exsufflator was not always the best tool. We conclude that capacity of coughing efforts to produce efficient peak cough flows can be dramatically improved with different tools, even in patients with very severe bulbar symptoms and that it appears useful to test an array of techniques to optimally tailor cough improvement techniques to individual patients.

The range and clinical impact of cognitive impairment in French patients with ALS: A cross-sectional study of neuropsychological test performance

Abstract: Our objective was to assess the spectrum and clinical associations of cognitive impairment in French patients with ALS, and determine the effect of cognitive impairment on survival in this population. One hundred and thirty-one patients were enrolled in a cross-sectional cohort study of neuropsychological test performance. ANOVA and χ(2) tests assessed differences in clinical characteristics between impaired and unimpaired patients; multiple regression determined which features contributed most strongly to cognitive status, and Cox models compared survival. Fifty-three patients (40%) were categorized as cognitively impaired based on test performance. Thirteen (10%) patients had frontotemporal dementia (FTD) clinically; all scored in the moderate to severely impaired range on testing. Impaired patients had less education (p = 0.001), and severely impaired patients were more likely to have bulbar onset than unimpaired patients (p < 0.001). Severe cognitive impairment predicted shorter survival (p = 0.007), even when controlled for motor severity (p = 0.001). In summary, 10% of a consecutive series of French ALS patients had overt dementia and 40% were cognitively impaired by neuropsychological testing. We conclude that lower education level and possibly bulbar-onset ALS were associated with impairment. As in other causes of dementia, higher education attainment may protect against clinical cognitive deterioration in ALS. French patients with severe cognitive impairment have shorter survival time.

Existential well-being and spirituality of individuals with amyotrophic lateral sclerosis is related to psychological well-being of their caregivers.

Abstract: Existential well-being (EWB) and spirituality issues are important factors in determining quality of life (QoL) in amyotrophic lateral sclerosis (ALS) patients. No conclusive data among the relation between patient's EWB, their spirituality and caregivers' QoL are available. In the mainframe of a longitudinal study, we performed a cross-sectional analysis aimed to investigate EWB and spirituality issues in sporadic ALS (SALS) patients and the relations with caregivers' psychological features. Thirty-seven SALS patients, together with their caregivers, consecutively recruited at NEuroMuscular Omnicentre, in Milan, were included in this study. EWB and spirituality questions were administrated to patients and caregivers. Caregivers also completed questionnaires about quality of life (MQoL-SI), care burden (ZBI), depression (BDI) and anxiety (STAI). Both EWBs and questions about spirituality of SALS patients showed a positive correlation with MQoL-SI and EWBs in their caregivers. Conversely, SALS patients' EWB and spirituality were negatively correlated with caregivers' STAI, BDI and ZBI scores. In conclusion, existential well-being, as well as spirituality issues, perceived by SALS patients seems to be directly related with quality of life, severity of mood disturbance and burden experienced by their caregivers.

Prevalence of major depression in ALS: Comparison of a semi-structured interview and four self-report measures

Abstract: This study aimed to compare prevalence estimates of current major depression obtained with a semi-structured interview and four frequently used self-report depression severity measures in a sample of amyotrophic lateral sclerosis (ALS) patients. Thirty-seven ALS patients (56.8% males) aged 37 – 80 years (mean 62.0 � 10.7) without respiratory insuffi ciency or dementia were studied during hospitalization or on a follow-up visit. SCID-IV interview as well as self-report Hospital Anxiety and Depression Scale (HADS), ALS Depression Inventory (ADI), Center for Epidemiological Studies-Depression scale (CES-D) and Beck Depression Inventory (BDI-I) were administered. Kappa coeffi cients of diagnostic agreement between various instruments were calculated. Results showed that 37.8% of patients had a lifetime diagnosis of depression and in 13.5% depression followed ALS onset. Percentages of patients ‘ diagnosed ’ with current major depression were: 21.6% (SCID-IV), 16.7% (HADS-D � 11), 16.2% (ADI � 29), 25% (CES-D � 24) and 24.3% (BDI-I � 16). High kappa values were recorded between CES-D, BDI-I and SCID-IV as well as between HADS-D and ADI. CES-D, BDI-I and SCID-IV gave the highest prevalence estimates of current major depression in ALS patients and were in poor agreement with estimates based on HADS and ADI; it is suggested that this is possibly because the former give a far greater emphasis on physical symptoms of depression than the latter.

Progression of white matter degeneration in amyotrophic lateral sclerosis: A diffusion tensor imaging study

Abstract: Whether longitudinal diffusion tensor MRI imaging (DTI) can capture disease progression in patients with amyotrophic lateral sclerosis (ALS) is unclear. The primary goal of this study was to determine if DTI detects progression of the corticospinal tracts (CST) degeneration in ALS. Seventeen ALS patients and 19 age- and gender-matched healthy controls were scanned with DTI at baseline for cross-sectional analyses. For longitudinal analyses, the ALS patients had repeat DTI scans after eight months. Tractography of the CST was used to guide regions-of-interest (ROI) analysis and complemented by a voxelwise analysis. Cross-sectional study found that baseline FA of the right superior CST was markedly reduced in ALS patients compared to controls. The FA reductions in this region correlated with the disease severity in ALS patients. Longitudinal study found that FA change rate of the right superior CST significantly declined over time. In conclusion, longitudinal DTI study captures progression of upper motor fiber degeneration in ALS. DTI can be useful for monitoring ALS progression and efficacy of treatment interventions.

Isolated bulbar phenotype of amyotrophic lateral sclerosis

Abstract: Typical bulbar-onset ALS generally portends a poor prognosis. To determine whether a relatively isolated bulbar phenotype (IBP) may have a better prognosis, patients with bulbar onset presentations were prospectively assessed, with IBP defined by an absence of limb progression over an initial six-month period. Clinical features and neurophysiological characteristics were compared. From a cohort of 300 consecutive referrals, 32 patients with bulbar onset disease (21 females, 11 males) were identified and compared to 23 age-matched control subjects. In total, patients were followed for 54 months. Twelve patients were identified with IBP (nine female, three male) and 20 had more typical bulbar ALS (12 female, eight male). Clinically, IBP was characterized by greater female predominance and upper motor neuron bulbar involvement. Compound motor action potential amplitudes were preserved in IBP compared to bulbar ALS (IBP, 7.1 mV; bulbar ALS, 4.2 mV, p <0.05), as was the neurophysiological index (IBP, 1.2; bulbar ALS 0.5, p <0.05). Furthermore, short interval intracortical inhibition was normal in IBP and reduced in typical bulbar ALS. In conclusion, patients with IBP were typically female with prominent upper motor neuron bulbar features and had normal cortical excitability. Biomarkers of cortical excitability may prove useful for further classifying ALS.

Neurophysiological index as a biomarker for ALS progression: Validity of mixed effects models

Abstract: Our objective was to evaluate the neurophysiological index (NI) as a biomarker for amyotrophic lateral sclerosis (ALS) and to assess the validity of linear mixed effects models for describing longitudinal changes. Functional assessment and nerve conduction studies were undertaken in 58 ALS patients. Neurophysiological data were collected on four occasions over 12 weeks (baseline, weeks 4, 8 and 12). The NI was calculated for the abductor digiti minimi and ulnar nerve at the wrist. NI declined at a rate of 0.04 per week (S.E. 0.006, p < 0.0001). Patients with bulbar-onset disease had 0.88 greater NI than patients with upper limb-onset disease over the follow-up period (S.E. 0.39, p = 0.03). There were no differences in the rates of decline among patients with different disease phenotypes. Rates of change in NI and functional impairment were weakly correlated (Spearman's p = 0.29, p = 0.03). Linear mixed effects models were appropriate for detailing the longitudinal changes in NI. The present findin...

Protein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateral sclerosis.

Abstract: The major pathological hallmarks of amyotrophic lateral sclerosis (ALS) are neuronal cytoplasmic inclusions (NCIs) and swollen neurites. Superoxide dismutase (SOD)-1-immunopositive NCIs are observed in patients with familial ALS (FALS), and TAR DNA-binding protein 43kDa (TDP-43)-immunopositive NCIs are found in patients with sporadic ALS (SALS). Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins by catalyzing the disulfide interchange reaction, which is the rate-limiting step during protein folding in the luminal space of the endoplasmic reticulum. Post mortem spinal cord specimens from five patients with SALS and one with FALS (I113T), and five normal controls were utilized in this immunohistochemical study. We found PDI-immunopositive swollen neurites and NCIs in the patients with ALS. Furthermore, PDI was colocalized with TDP-43 and SOD1 in NCIs. The accumulation of misfolding proteins may disturb a...

Magnetic resonance spectroscopy of the cervical cord in amyotrophic lateral sclerosis.

Abstract: The objective of this study was to use magnetic resonance spectroscopy (MRS) to compare metabolite ratios in the cervical spinal cord of ALS patients to healthy controls. Fourteen ALS patients and 16 controls were scanned using a 3T scanner. A rectangular voxel (8 × 5 × 35 mm) was placed along the main axis of the cord with the lower limit at the inferior aspect of the C2 vertebral body. MRS was performed with a point-resolved spectroscopy (PRESS) sequence. Water signals were suppressed using a three-pulse chemical shift selective (CHESS) saturation sequence. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and NAA were computed from metabolite peaks. Differences in metabolite ratios between ALS patients and controls were assessed with a Wilcoxon rank-sum test. The relationship of metabolite ratios to clinical measures (ALSFRS-R and FVC) was determined by Pearson correlation. The NAA/Cr and NAA/Myo ratios were reduced by 40% and 38%, respectively, in ALS patients. The r...

Changing incidence and subtypes of ALS in Modena, Italy: A 10-years prospective study.

Abstract: We performed a prospective population-based study to describe the temporal pattern of the incidence and prevalence and the clinical features and phenotypes of ALS in Modena, Italy, from 2000 to 2009. From 2000 onwards, a prospective registry has been collecting all cases of incident ALS among residents in the province of Modena. This source was implemented by cases resulting from the provincial hospitals, and by death certificates. Based on 193 newly diagnosed cases, the crude average annual incidence rate of ALS was 2.9 cases per 100,000 person years (py); adjusted incidence rate was 2.8/100,000. The age-standardized incidence rates increased from 2.6 per 100,000 py in 2000-2004 to 2.9 per 100,000 py in 2005-2009, representing an annual increase of approximately 2% throughout the 10-year period. There was a constant increase in prevalence rates throughout the years of the study (from 5.8/100,000 on 31 December 2000 to 11.2/100,000 on 31 December 2009). Median life time was 29 months for patients diagnosed before the year 2000 and 36 months for patients diagnosed from 1 January 2000 (p < 0.01). Thus, we report incidence rates similar to those reported by recent European population based studies, but we observed an increasing trend over the 10 years of the study. The increasing incidence is not explained by aging of the population, and our study raises the question as to whether local environmental or genetic factors are driving this temporal trend. Along with an increasing incidence, we found an important increase in prevalence and survival probably related to access to mutidisciplinary clinics and improvements in symptomatic care of ALS.

Autonomic dysfunction in the early stage of ALS with bulbar involvement.

Abstract: Our objective was to assess the autonomic function of ALS patients with and without bulbar signs to characterize dysautonomia in ALS disease. Standard autonomic tests and spectral analysis of heart rate variability (HRV), reflecting changes in the sympathovagal balance, were examined in 33 ALS patients (14 with bulbar signs) and 30 controls. Results showed that in the supine position, ALS patients had significantly lower total power and absolute values of high-frequency power indicating a depressed sinus arrhythmia. Patients with bulbar signs showed more marked autonomic alterations at rest. Tilting did not induce the expected increase in low-frequency and decrease in high-frequency power of HRV in all patients. No correlation was found between autonomic tests and clinical parameters. Our findings suggest an early subclinical involvement of the autonomic system in ALS, particularly affecting parasympathetic cardiac control. Patients with prominent bulbar signs show a more severe autonomic dysfunction under resting conditions.

Psychological health in patients with ALS is maintained as physical function declines

Abstract: Although quality of life (QoL) in patients with ALS has been shown to be independent of physical function and to be maintained over time, the status of psychological health over the disease course has not been studied using an ALS-specific instrument. It is also uncertain how three common interventions - antidepressants, percutaneous endoscopic gastrostomy (PEG), and non-invasive ventilatory support (NIPPV) - influence psychological health. We performed a retrospective review of the Negative Emotion subscale (NES) score, a measure of psychological health within the ALS-Specific QoL Instrument. Analysis of 72 patients over three months, and of a subset of 48 over six months, showed stability of psychological health despite a decline in the ALS Functional Rating Scale-Revised to 88.4% of baseline at three months and 82.6% at six months. NES did not change after antidepressants, PEG, or NIPPV, although there was a suggestion of improvement with antidepressants in a subgroup. In conclusion, as with overall QoL, psychological health of ALS patients as measured with an ALS-specific instrument does not decline as physical function is lost. Supports found in a multidisciplinary ALS clinic may influence expectations, facilitate response shift, and stabilize psychological health while masking the independent effects of specific interventions.

Identification of compounds protective against G93A-SOD1 toxicity for the treatment of amyotrophic lateral sclerosis.

Abstract: The underlying cause of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder, remains unknown. However, there is strong evidence that one pathophysiological mechanism, toxic protein misfolding and/or aggregation, may trigger motor neuron dysfunction and loss. Since the clinical and pathological features of sporadic and familial ALS are indistinguishable, all forms of the disease may be better understood and ultimately treated by studying pathogenesis and therapy in models expressing mutant forms of SOD1. We developed a cellular model in which cell death depended on the expression of G93A-SOD1, a mutant form of superoxide dismutase found in familial ALS patients that produces toxic protein aggregates. This cellular model was optimized for high throughput screening to identify protective compounds from a >50,000 member chemical library. Three novel chemical scaffolds were selected for further study following screen implementation, counter-screening and secondary testing, including studies with purchased analogs. All three scaffolds blocked SOD1 aggregation in high content screening assays and data on the optimization and further characterization of these compounds will be reported separately. These data suggest that optimization of these chemicals scaffolds may produce therapeutic candidates for ALS patients.

Uncovering amyotrophic lateral sclerosis phenotypes: Clinical features and long-term follow-up of upper motor neuron-dominant ALS

Abstract: The aim of our study was to analyse the natural history and clinical features of upper motor neuron- dominant (UMN-D) ALS. We studied a large series of sporadic ALS patients admitted in a single referral centre over a 23-year period. UMN-D phenotype was compared with other ALS forms, including classic ALS, flail arm and progressive muscular atrophy. Seven hundred and thirty-four sporadic ALS patients were included of which 163 had UMN-D ALS. The mean age of onset in UMN-D ALS (52 years) was 10 years lower than in classic ALS (61.4 years, p < 0.0001); sex ratio by age groups significantly differed with respect to other phenotypes. The pattern of spread of lower motor neuron signs in UMN-D was characterized by early involvement of upper limb muscles and late impairment of respiratory muscles. Duration of the disease was longer in the UMN-D group (56 months) than in classic ALS (33 months, p < 0.001). The UMN-D phenotype was a strong independent predictor of long survival. In summary, UMN-D ALS showed significant differences in age of onset, sex ratio, pattern of spreading and prognosis with respect to other ALS forms, most probably reflecting biological differences.

Causes and places of death of patients with amyotrophic lateral sclerosis in south-west China.

Abstract: Understanding the causes and places of death of amyotrophic lateral sclerosis (ALS) patients leads to the development of better treatment modalities. The present study aimed to identify the causes and places of death of ALS patients in south-west China. A total of 139 ALS patients (89 males and 50 females) were regularly followed up in the Department of Neurology, West China Hospital of Sichuan University from 2004 to 2010 until their deaths. Information on the causes and places of death was provided by family members, caregivers, or family physicians. Overall, 91 patients (65.5%) died of respiratory failure, 36 patients (25.9%) died of nutritional causes due to dysphagia, five patients (3.6%) met sudden deaths, three patients (2.2%) died of heart related causes, and four patients (2.9%) died of unknown reasons. Of the 139 patients, 114 (82%) died at home. Consistent with reports in the literature, respiratory failure is the leading cause of death in ALS patients. However, unlike in other studies, the second leading cause is nutrition related. Most patients die at home. The inconsistencies of these results with foreign studies may be attributable to economic and cultural differences. The findings have significant implications on the treatment modalities and palliative care for ALS patients in China.

Association between low sniff nasal-inspiratory pressure (SNIP) and sleep disordered breathing in amyotrophic lateral sclerosis: Preliminary results

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that rapidly involves the respiratory system, leading to persistent respiratory insufficiency. Neuromuscular respiratory weakness is also responsible for sleep disordered breathing (SDB), which occurs at an early stage of ALS. Maximal sniff nasal-inspiratory pressure (SNIP) is a sensitive test to early disclose respiratory muscle decline. The aim of this study was to evaluate the role of the SNIP test, compared to FVC, as a marker of SDB in ALS. We studied 31 (18 males) patients with ALS, who were divided into two groups according to the SNIP test value. Ten patients who showed a SNIP value higher than 60 cmH(2)O were considered as group 1. Twenty-one patients exhibited a SNIP lower than 60 cmH(2)O and were included in group 2. Both groups of patients were also investigated with nocturnal sleep study. A linear correlation between lower SNIP value and reduced nocturnal SaO(2) in patients with a SNIP value less than 60 cmH(2)O (n = 21; r = 0.449; p = 0.04) was found. A negative correlation between SNIP and time spent in SaO(2) below 90% (TST90) (n = 21; r = -0.584; p = 0.0054), and between SNIP and oxyhaemoglobin desaturation index (ODI, events/hour) (n = 21; r = -0.458; p = 0.0368) was also established in all the patients of group 2, while, in this group, FVC did not correlate with any nocturnal parameter observed. A positive correlation between SNIP and PaO(2) at baseline of the entire population of patients (n = 31; r = 0.614; p < 0.001) was also seen. In conclusion, the results of this preliminary study show that SNIP < 60 cmH(2)O might be considered an early predictor of SDB in ALS.

Identification of novel FUS mutations in sporadic cases of amyotrophic lateral sclerosis.

Abstract: Mutations in the FUS gene have been recently associated with amyotrophic lateral sclerosis (ALS). While most of the variants have been identified in patients with a family history of the disease, a few mutations were also found in sporadic patients. Considering this, we wanted to evaluate the frequency of mutations in the coding region of the FUS gene in a sporadic ALS (SALS) cohort compared to a control population. We tested 475 SALS cases of European origin and 475 matched controls for coding variations in the 15 exons of the FUS gene. Rare novel variants were identified in a total of five SALS patients: one missense, one deletion, one frameshift, and one nonsense substitution. Two of the four variants are located in the carboxy terminal of the protein where the previously reported variants were mostly clustered. In conclusion, FUS gene mutations are rare in SALS, with four new FUS variants identified in five different SALS cases. These findings will help evaluate the proportion of FUS variation...