Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Motion perception in glaucoma

PURPOSE. This study was performed to investigate motion perception in patients with glaucoma. METHODS. A random dot motion test was used to measure three aspects of central motion perception: minimum displacement threshold (Dmin), maximum displacement threshold (Dmax), and coherence threshold (signal to noise). Motion perception was assessed in 15 patients with primary open-angle glaucoma, 23 low-risk patients in whom glaucoma was suspected, and 24 age-matched normal subjects. RESULTS. Central motion perception was significantly impaired in patients with glaucoma; in particular, the Dmin was nearly twice that for the normal subjects (glaucoma mean, -0.27 +/- 0.24 log minutes of arc; normal mean, -0.56 +/- 0.13 log minutes of arc; F = 21.79, P < 0.001). Furthermore, Dmin values fell outside the normal range in 10 of the 15 patients with glaucoma, despite normal visual acuity and normal foveal perimetric thresholds. Coherence thresholds and Dmax did not discriminate between patients with glaucoma and normal subjects. Dmin was not correlated with any indices of perimetric sensitivity, and none of the tests of motion perception showed any abnormalities in patients in whom glaucoma was suspected. CONCLUSIONS. Central motion perception can be affected in glaucoma and may reflect preferential damage to larger retinal ganglion cells. Future work will measure Dmin in a larger population of patients with suspected glaucoma and those with glaucoma, and investigate peripheral motion perception in glaucoma

Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS

To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development. In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations. For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect

Validation of Serum Neurofilaments as Prognostic & Potential Pharmacodynamic Biomarkers for ALS

Objective. Identify preferred neurofilament assays, and clinically validate serum NfL and pNfH as prognostic and potential pharmacodynamic biomarkers relevant to ALS therapy development. Methods. Prospective, multi-center, longitudinal observational study of patients with ALS (n=229), primary lateral sclerosis (PLS, n=20) and progressive muscular atrophy (PMA, n=11). Biological specimens were collected, processed and stored according to strict standard operating procedures (SOPs) 1. Neurofilament assays were performed in a blinded manner by independent contract research organizations (CROs). Results. For serum NfL and pNfH measured using the Simoa assay, missing data (i.e. both technical replicates below the lower limit of detection (LLD) was not encountered. For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ~4% and ~10% of serum samples respectively. Mean coefficients of variation (CVs) for pNfH in serum and CSF were ~4-5% and ~2-3% respectively in all assays. Baseline NfL concentration, but not pNfH, predicted the future ALSFRS-R slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ~8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. Conclusions. Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, have potential utility as pharmacodynamic biomarkers of treatment effect