Characterising cognition in later life and its relationship with biomarkers of Alzheimer's disease: a study of members of the National Survey of Health and Development (the British 1946 birth cohort)

Alzheimer’s disease (AD) has a long preclinical stage characterised by the accumulation of brain pathology, which is estimated to begin several decades before the onset of symptoms. A significant proportion of older adults harbour such pathology, although many of them may not develop dementia during their lifetimes. Growing evidence suggests that subtle cognitive decline occurs during this preclinical period, but many unanswered questions remain about the nature and timing of changes in different cognitive domains, and associations with life-course predictors. This thesis is based on data from Insight 46, a neuroimaging sub-study of the MRC National Survey of Health and Development (the British 1946 birth cohort). In this population-based sample of 502 adults aged ~70 years, cognitive performance was assessed using standard and novel tests, and associations were investigated between cognition, life-course predictors, genetic risk factors for AD and brain pathologies, with a particular focus on β-amyloid. The key finding was that participants with elevated levels of β-amyloid showed poorer performance across a range of cognitive domains – some of which have received little attention in previous studies – including non-verbal reasoning, intra-individual variability in reaction time, visuomotor integration and memory. Other important results include: independent effects of childhood cognitive ability, educational attainment and adult socioeconomic position on later-life cognition; an association between white matter pathology and slower processing speed; associations between larger whole brain volume and faster performance on several diverse timed measures; and evidence that APOE-ε4 carriers may be advantaged on tests of short-term memory after accounting for the detrimental effect of β-amyloid. These results have implications for the interpretation of cognitive data measured in later life, and for the use of cognitive assessments to detect and track subtle cognitive decline in clinical trials that seek to delay or prevent the onset of AD dementia

Secretory vesicles are preferentially targeted to areas of low molecular SNARE density

Intercellular communication is commonly mediated by the regulated fusion, or exocytosis, of vesicles with the cell surface. SNARE (soluble N-ethymaleimide sensitive factor attachment protein receptor) proteins are the catalytic core of the secretory machinery, driving vesicle and plasma membrane merger. Plasma membrane SNAREs (tSNAREs) are proposed to reside in dense clusters containing many molecules, thus providing a concentrated reservoir to promote membrane fusion. However, biophysical experiments suggest that a small number of SNAREs are sufficient to drive a single fusion event. Here we show, using molecular imaging, that the majority of tSNARE molecules are spatially separated from secretory vesicles. Furthermore, the motilities of the individual tSNAREs are constrained in membrane micro-domains, maintaining a non-random molecular distribution and limiting the maximum number of molecules encountered by secretory vesicles. Together our results provide a new model for the molecular mechanism of regulated exocytosis and demonstrate the exquisite organization of the plasma membrane at the level of individual molecular machines

Secretory Vesicles Are Preferentially Targeted to Areas of Low Molecular SNARE Density

Intercellular communication is commonly mediated by the regulated fusion, or exocytosis, of vesicles with the cell surface. SNARE (soluble N-ethymaleimide sensitive factor attachment protein receptor) proteins are the catalytic core of the secretory machinery, driving vesicle and plasma membrane merger. Plasma membrane SNAREs (tSNAREs) are proposed to reside in dense clusters containing many molecules, thus providing a concentrated reservoir to promote membrane fusion. However, biophysical experiments suggest that a small number of SNAREs are sufficient to drive a single fusion event. Here we show, using molecular imaging, that the majority of tSNARE molecules are spatially separated from secretory vesicles. Furthermore, the motilities of the individual tSNAREs are constrained in membrane micro-domains, maintaining a non-random molecular distribution and limiting the maximum number of molecules encountered by secretory vesicles. Together our results provide a new model for the molecular mechanism of regulated exocytosis and demonstrate the exquisite organization of the plasma membrane at the level of individual molecular machines

A sex-specific microRNA-96/5HT1B Axis influences development of pulmonary hypertension

Rationale: Females are predisposed to pulmonary arterial hypertension (PAH); evidence suggests that serotonin, mutations in the bone morphogenetic protein receptor (BMPR) II gene, and estrogens influence development of PAH. The 5-hydroxytryptamine 1B receptor (5-HT1BR) mediates human pulmonary artery smooth muscle cell (hPASMC) proliferation. Objectives: We aimed to determine whether selected microRNAs (miRNAs) expressed in PASMCs are influenced by sex, BMPR-II mutations, and estrogens, and contribute to PASMC proliferation in PAH. Methods: Expression levels of miRNAs targeting genes related to PAH, estrogen, and serotonin were determined by quantitative RT-PCR in hPASMCs and mouse PASMCs harboring a heterozygous mutation in BMPR-II (BMPR-IIR899X+/− PASMCs). miRNA-96 targets 5-HT1BR and was selected for further investigation. miRNA target validation was confirmed by luciferase reporter assay. Precursor miRNA-96 was transfected into hPASMCs to examine effects on proliferation and 5-HT1BR expression. The effect of a miRNA-96 mimic on the development of hypoxic pulmonary hypertension in mice was also assessed. Measurements and Main Results: miRNA-96 expression was reduced in BMPR-IIR899X+/− PASMCs from female mice and hPASMCs from female patients with PAH; this was associated with increased 5-HT1BR expression and serotonin-mediated proliferation. 5-HT1BR was validated as a target for miRNA-96. Transfection of precursor miRNA-96 into hPASMCs reduced 5-HT1BR expression and inhibited serotonin-induced proliferation. Restoration of miRNA-96 expression in pulmonary arteries in vivo via administration of an miRNA-96 mimic reduced the development of hypoxia-induced pulmonary hypertension in the mouse. Conclusions: Increased 5-HT1BR expression may be a consequence of decreased miRNA-96 expression in female patient PASMCs, and this may contribute to the development of PAH

Augmenting dementia cognitive assessment with instruction-less eye-tracking tests

© 2020 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.Eye-tracking technology is an innovative tool that holds promise for enhancing dementia screening. In this work, we introduce a novel way of extracting salient features directly from the raw eye-tracking data of a mixed sample of dementia patients during a novel instruction-less cognitive test. Our approach is based on self-supervised representation learning where, by training initially a deep neural network to solve a pretext task using well-defined available labels (e.g. recognising distinct cognitive activities in healthy individuals), the network encodes high-level semantic information which is useful for solving other problems of interest (e.g. dementia classification). Inspired by previous work in explainable AI, we use the Layer-wise Relevance Propagation (LRP) technique to describe our network's decisions in differentiating between the distinct cognitive activities. The extent to which eye-tracking features of dementia patients deviate from healthy behaviour is then explored, followed by a comparison between self-supervised and handcrafted representations on discriminating between participants with and without dementia. Our findings not only reveal novel self-supervised learning features that are more sensitive than handcrafted features in detecting performance differences between participants with and without dementia across a variety of tasks, but also validate that instruction-less eye-tracking tests can detect oculomotor biomarkers of dementia-related cognitive dysfunction. This work highlights the contribution of self-supervised representation learning techniques in biomedical applications where the small number of patients, the non-homogenous presentations of the disease and the complexity of the setting can be a challenge using state-of-the-art feature extraction methods.Peer reviewe

Causes of accidental childhood deaths in China in 2010: A systematic review and analysis

Background: Infectious causes of childhood deaths in the world have decreased substantially in the 21st century. This trend has exposed accidental deaths as an increasingly important future challenge. Presently, little is known about the cause structure of accidental childhood deaths in low– and middle–income country (LMIC) settings. In this paper, we aim to establish cause structure for accidental deaths in children aged 0–4 years in China in the year 2010. Methods: In this paper, we explored the database of 208 multi–cause child mortality studies in Chinese that formed a basis for the first published estimate of the causes of child deaths in China (for the year 2008). Only five of those studies identified specific causes of accidental deaths. Because of this, we searched the Chinese medical literature databases CNKI and WanFang for single–cause mortality studies that were focused on accidental deaths. We identified 71 further studies that provided specific causes for accidental deaths. We used epidemiological modeling to estimate the number of accidental child deaths in China in 2010 and to assign those deaths to specific causes. Results: In 2010, we estimated 314 581 deaths in children 0–4 years in China, of which 31 633 (10.1%) were accidental. Accidental deaths contributed 7240 (4.0%) of all deaths in neonatal period, 8838 (10.5%) among all post–neonatal infant deaths, and 15 554 (31.7%) among children with 1–4 years of age. Among four tested models, the most predictive was used to establish the likely cause structure of accidental deaths in China. We estimated that asphyxia caused 9490 (95% confidence interval (CI) 8224–11 072), drowning 5694 (95% CI 5061–6327), traffic accidents 3796 (95% CI 3163–4745), poisoning 3163 (95% CI 2531–3796) and falls 2531 (95% CI 2214–3163) deaths. Based on medians from a few rare studies, we also predict 633 (95% CI 316–1265) deaths to be due to burns and 316 (95% CI 0–633) due to falling objects. Together, these 7 causes explain more than 80% of all accidental deaths when modeling is primarily used, and more than 95% when the analysis is based purely on medians from the 76 available studies. Conclusions: Reduction in global child mortality is a leading political priority and accidental deaths will soon emerge as one of the main challenges. In this paper we provided a detailed breakdown of causes of these deaths in a large middle–income country. We noted that, wherever the share of accidental deaths among all child deaths is increased, drowning is more likely to be the leading cause; asphyxia seems to be equally important in all contexts, while traffic accidents, poisoning and falls are relatively more important in contexts where the overall share of accidents to all child deaths is low

Straight and Divergent Pathways to Cognitive State: Seven Decades of Follow-Up in the British 1946 Birth Cohort

BACKGROUND: Using the British 1946 birth cohort we previously estimated life course paths to the Addenbrooke's Cognitive Examination (ACE-III). OBJECTIVE: We now compared those whose ACE-III scores were expected, worse and better than predicted from the path model on a range of independent variables including clinical ratings of cognitive impairment and neuroimaging measures. METHODS: Predicted ACE-III scores were categorized into three groups: those with Expected (between -1.5 and 1.5 standard deviation; SD); Worse (1.5 SD) scores. Differences in the independent variables were then tested between these three groups. RESULTS: Compared with the Expected group, those in the Worse group showed independent evidence of progressive cognitive impairment: faster memory decline, more self-reported memory difficulties, more functional difficulties, greater likelihood of being independently rated by experienced specialist clinicians as having a progressive cognitive impairment, and a cortical thinning pattern suggestive of preclinical Alzheimer's disease. Those in the Better group showed slower verbal memory decline and absence of independently rated progressive cognitive impairment compared to the Expected group, but no differences in any of the other independent variables including the neuroimaging variables. CONCLUSION: The residual approach shows that life course features can map directly to clinical diagnoses. One future challenge is to translate this into a readily usable algorithm to identify high-risk individuals in preclinical state, when preventive strategies and therapeutic interventions may be most effective

A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes

Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties

Disease duration in autosomal dominant familial Alzheimer disease: A survival analysis.

OBJECTIVE: To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival. METHODS: Symptomatic mutation carriers (201 presenilin 1 [PSEN1] and 55 amyloid precursor protein [APP]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, APOE ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models. The contribution of mutation and family to variance in age at onset and duration was also assessed. RESULTS: Estimated mean survival was 11.6 (10.4-12.9) years and was similar for APP and PSEN1 mutations. Sixty-seven percent of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 6% of the variance in disease duration was explained by mutation specificity and 18% by family membership. Irrespective of gene, survival appeared longer for successive generations and in individuals with atypical presentations. Older age at onset was associated with longer duration within PSEN1 and shorter duration within APP mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within PSEN1. CONCLUSIONS: Survival is influenced by mutation to a much lesser extent than age at onset. Survival time has increased over time and is longer in atypical presentations. These insights may inform the interpretation of disease-modifying therapy trials in ADAD

The seroprevalence of hepatitis C virus infection among children and their mothers attending for dental care in Glasgow, Scotland, United Kingdom

This paper describes a voluntary anonymous survey to investigate the seroprevalence of Hepatitis C (HCV) in children in Glasgow, UK attending a Dental Hospital and the proportion of HCV positive mothers who have a child who is HCV seropositive. The study was undertaken among children and accompanying parents and household contacts attending a general anaesthetic assessment clinic at Glasgow Dental Hospital and School. Children were asked to provide an oral fluid specimen for HCV testing. Accompanying adults were asked to provide demographic data on the child and information on familial risk factors for HCV infection using a standardised questionnaire. Birth mothers were also asked to provide an oral fluid specimen. Specimens and questionnaires were linked by a unique anonymous study number. Between June 2009 and December 2011, samples were collected from 2141 children and 1698 mothers. None of the samples from the children were HCV seropositive but 16 (0.9%, 95% CI 0.6% to 1.5%) of the specimens from mothers were HCV antibody positive. In summary, the prevalence of HCV seropositivity in the birth mothers of the children was similar to that estimated in the general population served by the hospital and showed no evidence of mother-to-child transmission of HCV