Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition

Introduction Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage. Methods Plasma and cerebrospinal fluid (CSF) neurofilament light (NFL) were related to neuropsychological performance among Vanderbilt Memory & Aging Project participants (plasma n = 333, 73 ± 7 years; CSF n = 149, 72 ± 6 years) ranging from normal cognition (NC) to mild cognitive impairment (MCI). Models adjusted for age, sex, race/ethnicity, education, apolipoprotein E ε4 carriership, and Framingham Stroke Risk Profile. Results Plasma NFL was related to all domains (P values ≤ .008) except processing speed (P values ≥ .09). CSF NFL was related to memory and language (P values ≤ .04). Interactions with cognitive diagnosis revealed widespread plasma associations, particularly in MCI participants, which were further supported in head-to-head comparison models. Discussion Plasma and CSF NFL (reflecting neuroaxonal injury) relate to cognition among non-demented older adults albeit with small to medium effects. Plasma NFL shows particular promise as an accessible biomarker with relevance to cognition in MCI

Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences

INTRODUCTION: While Alzheimer’s disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages. METHODS: Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n = 18, 75 ± 8 years), moderate (n = 89 72 ± 7 years), and severe subtypes (n = 18, 78 ± 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-ε4 status, CSF biomarkers of amyloid beta (Aβ), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models. RESULTS: Stages differed at baseline on APOE-ε4 status (early middle = late), phosphorylated and total tau (early = middle < late; p-values < 0.05), and neurogranin concentrations (early = middle < late; p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late; p-values < 0.03). DISCUSSION: Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets

Ipl1/aurora kinase suppresses S-CDK-driven spindle formation during prophase I to ensure chromosome integrity during meiosis

Cells coordinate spindle formation with DNA repair and morphological modifications to chromosomes prior to their segregation to prevent cell division with damaged chromosomes. Here we uncover a novel and unexpected role for Aurora kinase in preventing the formation of spindles by Clb5-CDK (S-CDK) during meiotic prophase I and when the DDR is active in budding yeast. This is critical since S-CDK is essential for replication during premeiotic S-phase as well as double-strand break induction that facilitates meiotic recombination and, ultimately, chromosome segregation. Furthermore, we find that depletion of Cdc5 polo kinase activity delays spindle formation in DDR-arrested cells and that ectopic expression of Cdc5 in prophase I enhances spindle formation, when Ipl1 is depleted. Our findings establish a new paradigm for Aurora kinase function in both negative and positive regulation of spindle dynamics

Lower Left Ventricular Ejection Fraction Relates to Cerebrospinal Fluid Biomarker Evidence of Neurodegeneration in Older Adults

BACKGROUND: Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer's disease (AD) pathology and neurodegeneration. OBJECTIVE: This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. METHODS: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognitive (NC), mild cognitive impairment (MCI)). RESULTS: Higher LVEF related to decreased CSF Aβ42 levels (β= -6.50, p = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p = 0.004) and p-tau levels (p = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= -9.74, p = 0.01) and p-tau in the NC (β= -1.41, p = 0.003) but not MCI participants (p-values>0.13). CONCLUSIONS: Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life

Engaging with community researchers for exposure science: lessons learned from a pesticide biomonitoring study

A major challenge in biomonitoring studies with members of the general public is ensuring their continued involvement throughout the necessary length of the research. The paper presents evidence on the use of community researchers, recruited from local study areas, as a mechanism for ensuring effective recruitment and retention of farmer and resident participants for a pesticides biomonitoring study. The evidence presented suggests that community researchers' abilities to build and sustain trusting relationships with participants enhanced the rigour of the study as a result of their on-the-ground responsiveness and flexibility resulting in data collection beyond targets expected

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Interleaved Parton Showers and Tuning Prospects

General-purpose Monte Carlo event generators have become important tools in particle physics, allowing the simulation of exclusive hadronic final states. In this article we examine the Pythia 8 generator, in particular focusing on its parton-shower algorithms. Some relevant new additions to the code are introduced, that should allow for a better description of data. We also implement and compare with 2 to 3 real-emission QCD matrix elements, to check how well the shower algorithm fills the phase space away from the soft and collinear regions. A tuning of the generator to Tevatron data is performed for two PDF sets and the impact of first new LHC data is examined

Optical Magnetometry

Some of the most sensitive methods of measuring magnetic fields utilize interactions of resonant light with atomic vapor. Recent developments in this vibrant field are improving magnetometers in many traditional areas such as measurement of geomagnetic anomalies and magnetic fields in space, and are opening the door to new ones, including, dynamical measurements of bio-magnetic fields, detection of nuclear magnetic resonance (NMR), magnetic-resonance imaging (MRI), inertial-rotation sensing, magnetic microscopy with cold atoms, and tests of fundamental symmetries of Nature.Comment: 11 pages; 4 figures; submitted to Nature Physic

Identifying the physical features of marina infrastructure associated with the presence of non-native species in the UK

Marine invasive non-native species (NNS) are one of the greatest threats to global marine biodiversity, causing significant economic and social impacts. Marinas are increasingly recognised as key reservoirs for invasive NNS. They provide submersed artificial habitat that unintentionally supports the establishment of NNS introduced from visiting recreational vessels. While ballast water and shipping vectors have been well documented, the role of recreational vessels in spreading NNS has been relatively poorly studied. Identification of the main physical features found within marinas, which relate to the presence of NNS, is important to inform the development of effective biosecurity measures and prevent further spread. Towards this aim, physical features that could influence the presence of NNS were assessed for marinas throughout the UK in July 2013. Thirty-three marine and brackish NNS have been recorded in UK marinas, and of the 88 marinas studied in detail, 83 contained between 1 and 13 NNS. Significant differences in freshwater input, marina entrance width and seawall length were associated with the presence of NNS. Additionally, questionnaires were distributed to marina managers and recreational vessel owners to understand current biosecurity practices and attitudes to recreational vessel biosecurity. The main barriers to biosecurity compliance were cited as cost and time. Further work identifying easily distinguished features of marinas could be used as a proxy to assess risk of invasion. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00227-016-2941-8) contains supplementary material, which is available to authorized users

Development of a Mesoamerican intra-genepool genetic map for quantitative trait loci detection in a drought tolerant × susceptible common bean (Phaseolus vulgaris L.) cross

Drought is a major constraint to common bean (Phaseolus vulgaris L.) production, especially in developing countries where irrigation for the crop is infrequent. The Mesoamerican genepool is the most widely grown subdivision of common beans that include small red, small cream and black seeded varieties. The objective of this study was to develop a reliable genetic map for a Mesoamerican × Mesoamerican drought tolerant × susceptible cross and to use this map to analyze the inheritance of yield traits under drought and fully irrigated conditions over 3 years of experiments. The source of drought tolerance used in the cross was the cream-seeded advanced line BAT477 crossed with the small red variety DOR364 and the population was made up of recombinant inbred lines in the F5 generation. Quantitative trait loci were detected by composite interval mapping for the traits of overall seed yield, yield per day, 100 seed weight, days to flowering and days to maturity for each field environment consisting of two treatments (irrigated and rainfed) and lattice design experiments with three repetitions for a total of six environments. The genetic map based on amplified fragment length polymorphism and random amplified polymorphic DNA markers was anchored with 60 simple sequence repeat (SSR) markers and had a total map length of 1,087.5 cM across 11 linkage groups covering the whole common bean genome with saturation of one marker every 5.9 cM. Gaps for the genetic map existed on linkage groups b03, b09 and b11 but overall there were only nine gaps larger than 15 cM. All traits were inherited quantitatively, with the greatest number for seed weight followed by yield per day, yield per se, days to flowering and days to maturity. The relevance of these results for breeding common beans is discussed in particular in the light of crop improvement for drought tolerance in the Mesoamerican genepool