Summary C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is ...often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain.
Summary Background Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a ...particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. Methods We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995–2012), the Netherlands (2006–12), Italy (1995–2004), Scotland (1989–98), and England (2002–09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. Findings We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r2 =0·95, Ireland r2 =0·99, Italy r2 =0·95, the Netherlands r2 =0·99, and Scotland r2 =0·97; overall r2 =0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5–5·0), with similar estimates for men (4·6, 4·3–4·9) and women (5·0, 4·5–5·5). Interpretation A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues. Funding UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme).
Summary Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 ...years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS–frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries. Methods We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10−7 Findings After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10−6 ; odds ratio OR 1·39, 95% CI 1·21–1·59) and rs2814707 (p=3·32×10−6 ; 1·38, 1·20–1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10−10 ; OR 1·22, 95% CI 1·15–1·30) and rs2814707 (p=4·72×10−10 ; 1·22, 1·15–1·30) were associated with ALS. Interpretation We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS–frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS–frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene. Funding ALS Therapy Alliance, the Angel Fund, the Medical Research Council, the Motor Neurone Disease Association of Great Britain and Northern Ireland, the Wellcome Trust, and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network (DeNDRoN).
A rating scale to measure anxiety in dementia sufferers was developed and evaluated in a sample of 51 inpatients and 32 day-hospital patients. Anxiety scores were not related to sex, age, ...accommodation or DSM-IV diagnosis of the type of dementia. However, both subjects with physical illnesses and subjects with insight into their memory problems had significantly higher anxiety scores.The kappa values for inter-rater reliability ranged from 0.51 to 1 and for test-retest reliability from 0.53 to 1, which indicates moderate to good reliability.The overall agreement on individual items ranged from 82-100% (inter-rater) and 84-100% (test-retest).The professionals working in the care of the elderly and carer groups felt that the scale was comprehensive and all the items in the scale were important, thereby confirming that it has good content validity. The scale significantly correlated with other anxiety scales and also with independent ratings both by a consultant psychiatrist and also nursing staff, indicating good concurrent validity. Anxiety scores were significantly higher in dementia patients who fulfilled modified DSM-IV criteria for anxiety and clinical diagnosis of anxiety disorder.This showed evidence of good criterion validity. Factor analysis showed five factors, including all items of the scale. Scores of 11 and above on the scale indicated significant clinical anxiety. Overall, the scale had good reliability and validity. It should be a useful clinical and research instrument for assessing anxiety in dementia sufferers.
Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method ...for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800–4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.
This article presents an analysis and the resulting limits on light dark matter inelastically scattering off of electrons, and on dark photon and axionlike particle absorption, using a ...second-generation SuperCDMS high-voltage eV-resolution detector. The 0.93 g Si detector achieved a 3 eV phonon energy resolution; for a detector bias of 100 V, this corresponds to a charge resolution of 3% of a single electron-hole pair. The energy spectrum is reported from a blind analysis with 1.2 g-days of exposure acquired in an above-ground laboratory. With charge carrier trapping and impact ionization effects incorporated into the dark matter signal models, the dark matter-electron cross section σe is constrained for dark matter masses from 0.5 to 104 MeV / c2; in the mass range from 1.2 to 50 eV / c2 the dark photon kinetic mixing parameter ϵ and the axioelectric coupling constant gae are constrained. The minimum 90% confidence-level upper limits within the above-mentioned mass ranges are σe = 8.7 × 10−34 cm2, ϵ = 3.3 × 10−14, and gae = 1.0 × 10−9.
There is little evidence to indicate how far psychiatric day hospitals for older people can identify and address the needs of older people who attend. The current practice of Care Programme Approach ...(CPA) in which multidisciplinary team members, patients and their families meet, may provide a suitable forum for needs to be discussed and interventions planned and implemented. One hundred and twelve new day hospital patients over a period of one year were randomly allocated to an experimental group in which the Camberwell Assessment of Need for the Elderly (CANE). Assessment reports were fed back to day hospital staff but not to the control group in which routine practice was maintained. Similar follow-up assessments were performed after three months in the day hospital or at the time of discharge. At follow-up, both the experimental and control groups had over 60% of their initial unmet needs being adequately met. In both groups, the Health of the Nation Outcome Scales 65+ scores and number of unmet needs were reduced indicating an improvement for both groups. However, there were no significant differences in outcome at follow-up between the experimental and control groups. Day hospitals for older people with mental health problems appear effective in identifying and meeting needs. The feedback from CANE made no difference in terms of outcome.
We report on several features in the energy spectrum from an ultralow-noise germanium detector operated deep underground. By implementing a new technique able to reject surface events, a number of ...cosmogenic peaks can be observed for the first time. We discuss an irreducible excess of bulklike events below 3 keV in ionization energy. These could be caused by unknown backgrounds, but also dark matter interactions consistent with DAMA/LIBRA. It is not yet possible to determine their origin. Improved constraints are placed on a cosmological origin for the DAMA/LIBRA effect.
Fifteen months of cumulative CoGeNT data are examined for indications of an annual modulation, a predicted signature of weakly interacting massive particle (WIMP) interactions. Presently available ...data support the presence of a modulated component of unknown origin, with parameters prima facie compatible with a galactic halo composed of light-mass WIMPs. Unoptimized estimators yield a statistical significance for a modulation of ∼2.8σ, limited by the short exposure.
We report the result of a blinded search for weakly interacting massive particles (WIMPs) using the majority of the SuperCDMS Soudan data set. With an exposure of 1690 kg d, a single candidate event ...is observed, consistent with expected backgrounds. This analysis (combined with previous Ge results) sets an upper limit on the spin-independent WIMP-nucleon cross section of 1.4×10^{-44} (1.0×10^{-44}) cm^{2} at 46 GeV/c^{2}. These results set the strongest limits for WIMP-germanium-nucleus interactions for masses >12 GeV/c^{2}.
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