RESUMO
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (â¼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as â¼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
Assuntos
Esclerose Lateral Amiotrófica/genética , Cromossomos Humanos Par 17/genética , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Humanos , PrognósticoRESUMO
This article reports the severity and profile of neuropsychological impairment on a prevalent cohort of patients with a clinical diagnosis of either multiple system atrophy (n=372) or progressive supranuclear palsy (n=311) from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort. The Dementia Rating Scale and Frontal Assessment Battery were used to assess global cognition and executive dysfunction. For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group. In the former, impairment in a single cognitive domain was observed in 40%, with the same number showing impairment in multiple domains, while in the latter the figures were 28.6 and 13.5%, respectively. On the Frontal Assessment Battery, impairment was observed in 62.0% of patients with progressive supranuclear palsy and 31.8% of those with multiple system atrophy. Although the progressive supranuclear palsy group performed worse overall, the cognitive profiles of the two groups on the Dementia Rating Scale subscales were identical, with the main impairment of the Initiation and Perseveration subscale. The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy). Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment. The rate of impairment in those with a confirmed pathological diagnosis was comparable to that of the sample as a whole. These results demonstrate, in the largest prospectively recruited cohort of patients with progressive supranuclear palsy and multiple system atrophy studied to date, the existence of a cognitive profile similar to that previously reported in idiopathic Parkinson's disease. The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.
Assuntos
Transtornos Cognitivos/complicações , Atrofia de Múltiplos Sistemas/complicações , Paralisia Supranuclear Progressiva/complicações , Fatores Etários , Idoso , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/patologia , Atrofia de Múltiplos Sistemas/psicologia , Testes Neuropsicológicos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/psicologiaRESUMO
In this study, we investigated whether diffusion tensor MRI (DTI) could detect progressive corticospinal tract degeneration in amyotrophic lateral sclerosis (ALS) and whether changes in diffusion variables reflected clinical deterioration. Twenty-three ALS patients and 25 healthy volunteers underwent whole brain DTI. Patients and a subset (n = 12) of controls returned for a second scan. Clinical measures of disease severity were assessed in the ALS group. Changes in fractional anisotropy (FA) and mean diffusivity (MD) were measured along the corticospinal tract using a region of interest approach. Adequate DTI data were available in 11 ALS patients and 11 controls at two time points. FA and MD differed significantly between ALS patients and controls at both time points, but neither changed significantly over time, while global measures of disease severity in patients increased with time. Although we confirmed that DTI detects corticospinal tract damage in ALS, there were no significant changes in diffusion measures over time. The sensitivity of DTI may be improved by advanced data analysis techniques, although the high dropout rate suggests that use of MRI as a biomarker in ALS may be restricted to earlier stages of disease.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Adulto , Idoso , Imagem de Difusão por Ressonância Magnética/tendências , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tratos Piramidais/metabolismo , Tratos Piramidais/patologiaRESUMO
Paraoxonase polymorphisms have been associated with amyotrophic lateral sclerosis (ALS). Paraoxonases are detoxifying enzymes involved in the metabolism of organophosphates. We tested the hypothesis that genetic variation within paraoxonase genes would interact with the environmental exposure to paraoxonase substrates. We used population density in the location of residence of ALS patients as a surrogate marker for environmental exposure. Paraoxonase genotypes at previously associated single nucleotide polymorphisms rs662, rs854560, rs6954345, and rs11981433 were studied in 98 patients from the South East England ALS population-based register. A case-only analysis was carried out and median population density was used to categorize patients into rural or urban environments. We found a significant interaction with population density for marker rs854560 (L55M) in ALS.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Arildialquilfosfatase/genética , Polimorfismo de Nucleotídeo Único , Densidade Demográfica , Inglaterra , Meio Ambiente , Genótipo , Haplótipos , Humanos , Modelos Estatísticos , População RuralRESUMO
Amyotrophic lateral sclerosis is a neurodegenerative disease of largely unknown cause, predominantly affecting upper and lower motor neurons. A recent study in Italy suggested an increased incidence of ALS among professional Italian soccer players. We report a cluster of three amateur league soccer players who were friends from the same part of southern England, and developed ALS simultaneously. This might suggest that keen amateur soccer players are also at risk.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Futebol , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/fisiopatologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neurônios Motores/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Futebol/lesõesRESUMO
A retrospective review was carried out on the influence of pre-procedure respiratory assessment on survival of patients with amyotrophic lateral sclerosis (ALS) requiring nutritional support with either a gastrostomy or a nasogastric feeding tube. Over a five-year period 98 patients (49 male, 49 female; median age 61 years, range 26-86 years) with ALS were referred for enteral feeding with either radiological inserted gastrostomy (RIG), percutaneous endoscopic gastrostomy (PEG) or nasogastric tube (NG). Case notes review was performed to record patient age, sex, pre-procedure respiratory assessment, method of enteral feeding and survival post-procedure. Kaplan-Meier survival curves were constructed for each group, with Cox regression analyses performed in order to establish the effect of each variable on outcome. Median survival (with 95% confidence intervals) following RIG, PEG and NG was 6.31 months (4.58-8.04 months), 7.13 months (4.81-9.45 months) and 0.95 months (0.00-2.77 months), respectively. The survival advantage between RIG and PEG was not statistically significant (p = 0.50), but for NG versus RIG and PEG groups combined, there was a significant difference (p = 0.03). For patients with normal overnight oximetry, median survival was 8.54 months (3.88-13.21 months), compared to 4.80 months (1.20-8.39 months) in the abnormal oximetry group (p = 0.03; relative risk 1.97). It is concluded that RIG and PEG are equivalent in terms of post-procedure survival. Abnormal oximetry prior to the procedure is a significant indicator of post-procedure survival.