Blood Glucose Levels and Genetic Factors as Predictors of Neurocognitive Outcomes

Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive cognitive decline, is becoming increasingly prevalent as the population ages. There is no effective treatment for AD, so manipulating modifiable risk factors before clinical symptoms of dementia develop may be the most effective course to prevent, delay, or modify the course of AD. Type II diabetes mellitus (DM), characterized by hyperglycemia and insulin resistance, affects over a quarter of older adults and has been linked with AD, cognitive decline, and brain atrophy. Because DM is preventable and treatable, it represents an intervention target for AD. This dissertation investigated the association between glucose levels and three outcomes – performance on a battery of cognitive tests over time, time to symptom onset of mild cognitive impairment (MCI) or dementia, and cortical thickness in AD-signature regions (i.e., entorhinal cortex, inferior temporal gyrus, parahippocampal gyrus pars triangularis, precuneus, superior frontal and parietal gyri, supramarginal gyrus, and temporal pole). Additionally, it investigated how two genes – apolipoprotein E (APOE) and translocase of the outer mitochondrial membrane (TOMM) 40 – may modify the relationship between glucose and these outcomes. Both the APOE ε4 allele and the TOMM40 very long/very long (VL/VL) genotype (versus the short/short (S/S) genotype) have been associated with increased risk of dementia, cognitive decline, and brain atrophy, and some evidence suggests that these genetic factors may further increase the risk in individuals with DM. This research was conducted using data from the BIOCARD Study (n=349), which enrolled primarily middle-aged individuals, three-quarters of whom had a first-degree relative with dementia. The goal of the study was to examine the early signs and symptoms of AD in a high-risk cohort. For this dissertation, baseline blood glucose level, which was ascertained from a blood draw in a clinical exam, was the primary predictor and was available for 333 participants. APOE and TOMM40 genotypes were also determined from blood samples. Age of MCI or dementia symptom onset was determined through consensus diagnosis. At annual visits, participants completed a neuropsychological test battery, and at baseline and bi-annually, participants completed magnetic resonance imaging (MRI) scans. The first paper in this study used linear mixed effects models (LMMs) and generalized estimating equation (GEE) models to investigate the association between glucose and cognitive performance over time. We used confirmatory factor analysis (CFA) to create one factor based on performance on tests of executive function (the executive function factor) and one factor based on performance on tests of memory (the memory factor). We found that higher baseline glucose was associated with greater decline on the executive function factor score in both LMMs (B=-0.005; 95% CI -0.008, -0.001) and GEE models (B=-0.004; 95% CI -0.007, -0.001) that controlled for age, sex, race, education, depression, and medical conditions (i.e., cardiovascular conditions, hypertension, hypercholesterolemia, traumatic brain injury (TBI)). Interaction analyses using LMMs found that higher glucose was associated with significant decline in executive function score in ε4 carriers (B=-0.013; 95% CI -0.020, -0.006), but not in non-carriers (B=-0.002, 95% CI -0.006, 0.002). In LMMs, higher glucose was also associated with poorer memory factor score over time in subjects with the S/S genotype (B=-0.013; 95% CI -0.024, -0.002), versus the VL/VL genotype (B=0.004; 95% CI -0.003, 0.010). The second paper in this study used Cox proportional hazard models to investigate the association between baseline blood glucose level and time to MCI or dementia symptom onset, as well as the association between the interaction of APOE and glucose and TOMM40 and glucose and time to symptom onset. We did not find an association between glucose level and time to symptom onset; additionally, we did not find that APOE or TOMM40 modified this relationship. In the final paper, linear regression analyses showed that glucose level was associated with reduced cortical thickness in the parahippocampal gyrus (B=-0.002; 95% CI -0.003, -0.0001) and temporal pole (B=-0.002; 95% CI -0.003, -0.0002) in a fully-adjusted model. Additionally, higher glucose levels were associated with thinner measures of the superior parietal gyri (B=-0.001; 95% CI -0.002, 0.0005 vs. B=0.0007; 95% CI 3.05e-6, 0.001) and temporal pole (B=-0.004; 95% CI -0.008, -0.0009 vs. B=-0.0003; 95% CI -0.002, 0.001) in ε4 allele carriers versus non-carriers. This evidence suggests that even in middle-aged, cognitively healthy samples, higher levels of glucose, even in those without DM, can negatively impact cognitive performance and cortical thickness. Maintaining normal blood glucose levels may be important in middle age for reducing risk of cognitive decline, AD, and brain atrophy

Subjective Sleep Quality as it Relates to Cognitive and Physical Function in Spinal Muscular Atrophy Patients

Sleep quality and its association with cognition has been widely studied in some neurodegenerative diseases, but less is known about this association in spinal muscular atrophy (SMA). In adult SMA (n = 21) patients and age-matched controls (n = 23), we assessed subjectively measured sleep quality and daytime somnolence. Cognition was assessed with a multi-domain neuropsychological battery. Further, we investigated the association between clinical functional scores and sleep questionnaire scores. Among SMA patients, better motor and limb function was associated with better subjective sleep quality (p's < 0.05). Clinicians should consider sleep quality in patient care and future studies are needed to better understand these relationships

Constraints on aerosol nitrate photolysis as a potential source of HONO and NO_x

The concentration of nitrogen oxides (NO_x) plays a central role in controlling air quality. On a global scale, the primary sink of NO_x is oxidation to form HNO_3. Gas-phase HNO_3 photolyses slowly with a lifetime in the troposphere of 10 days or more. However, several recent studies examining HONO chemistry have proposed that particle-phase HNO_3 undergoes photolysis 10–300 times more rapidly than gas-phase HNO_3. We present here constraints on the rate of particle-phase HNO_3 photolysis based on observations of NO_x and HNO_3 collected over the Yellow Sea during the KORUS-AQ study in summer 2016. The fastest proposed photolysis rates are inconsistent with the observed NO_x to HNO_3 ratios. Negligible to moderate enhancements of the HNO_3 photolysis rate in particles, 1–30 times faster than in the gas phase, are most consistent with the observations. Small or moderate enhancement of particle-phase HNO_3 photolysis would not significantly affect the HNO_3 budget but could help explain observations of HONO and NO_x in highly aged air

Constraints on aerosol nitrate photolysis as a potential source of HONO and NOx, Environmental Science and Technology

The concentration of nitrogen oxides (NOx) plays a central role in controlling air quality. On a global scale, the primary sink of NOx is oxidation to form HNO3. Gas-phase HNO3 photolyses slowly with a lifetime in the troposphere of 10 days or more. However, several recent studies examining HONO chemistry have proposed that particle-phase HNO3 undergoes photolysis 10–300 times more rapidly than gas-phase HNO3. We present here constraints on the rate of particle-phase HNO3 photolysis based on observations of NOx and HNO3 collected over the Yellow Sea during the KORUS-AQ study in summer 2016. The fastest proposed photolysis rates are inconsistent with the observed NOx to HNO3 ratios. Negligible to moderate enhancements of the HNO3 photolysis rate in particles, 1–30 times faster than in the gas phase, are most consistent with the observations. Small or moderate enhancement of particle-phase HNO3 photolysis would not significantly affect the HNO3 budget but could help explain observations of HONO and NOx in highly aged air

Constraints on aerosol nitrate photolysis as a potential source of HONO and NO_x

The concentration of nitrogen oxides (NO_x) plays a central role in controlling air quality. On a global scale, the primary sink of NO_x is oxidation to form HNO_3. Gas-phase HNO_3 photolyses slowly with a lifetime in the troposphere of 10 days or more. However, several recent studies examining HONO chemistry have proposed that particle-phase HNO_3 undergoes photolysis 10–300 times more rapidly than gas-phase HNO_3. We present here constraints on the rate of particle-phase HNO_3 photolysis based on observations of NO_x and HNO_3 collected over the Yellow Sea during the KORUS-AQ study in summer 2016. The fastest proposed photolysis rates are inconsistent with the observed NO_x to HNO_3 ratios. Negligible to moderate enhancements of the HNO_3 photolysis rate in particles, 1–30 times faster than in the gas phase, are most consistent with the observations. Small or moderate enhancement of particle-phase HNO_3 photolysis would not significantly affect the HNO_3 budget but could help explain observations of HONO and NO_x in highly aged air

A three arm cluster randomised controlled trial to test the effectiveness and cost-effectiveness of the SMART work & life intervention for reducing daily sitting time in office workers : study protocol

Background:Office-based workers typically spend 70-85% of working hours, and a large proportion of leisure time, sitting. High levels of sitting have been linked to poor health. There is a need for fully powered randomised controlled trials (RCTs) with long-term follow-up to test the effectiveness of interventions to reduce sitting. This paper describes the methodology of a three-arm cluster RCT designed to determine the effectiveness and cost-effectiveness of the SMART Work &amp; Life intervention, delivered with and without a height-adjustable desk, for reducing daily sitting. Methods/Design:A three-arm cluster RCT of 33 clusters (660 council workers) will be conducted in three areas in England (Leicester; Manchester; Liverpool). Office groups (clusters) will be randomised to the SMART Work &amp; Life intervention delivered with (group 1) or without (group 2) a height-adjustable desk or a control group (group 3). SMART Work &amp; Life includes organisational (e.g., management buy-in, provision/support for standing meetings), environmental (e.g., relocating waste bins, printers), and group/individual (education, action planning, goal setting, addressing barriers, coaching, self-monitoring, social support) level behaviour change strategies, with strategies driven by workplace champions. Baseline, 3, 12 and 24 month measures will be taken. Objectively measured daily sitting time (activPAL3). objectively measured sitting, standing, stepping, prolonged sitting and moderate-to-vigorous physical activity time and number of steps at work and daily; objectively measured sleep (wrist accelerometry). Adiposity, blood pressure, fasting glucose, glycated haemoglobin, cholesterol (total, HDL, LDL) and triglycerides will be assessed from capillary blood samples. Questionnaires will examine dietary intake, fatigue, musculoskeletal issues, job performance and satisfaction, work engagement, occupational and general fatigue, stress, presenteeism, anxiety and depression and sickness absence (organisational records). Quality of life and resources used (e.g. GP visits, outpatient attendances) will also be assessed. We will conduct a full process evaluation and cost-effectiveness analysis. Discussion:The results of this RCT will 1) help to understand how effective an important simple, yet relatively expensive environmental change is for reducing sitting, 2) provide evidence on changing behaviour across all waking hours, and 3) provide evidence for policy guidelines around population and workplace health and well-being. Trial registration: ISRCTN11618007 . Registered on 21 January 2018

Examining the generalizability of research findings from archival data

This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability—for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples

Delaktig i det lilla : Barn i behov av särskilt stöd och deras möjlighet till delaktighet i förskola och förskoleklass

Syftet med denna studie är att bidra med kunskap om huruvida barn i behov av särskilt stöd är delaktiga i olika förskolor/förskoleklasser. Arbetet vilar på forskningsfrågorna: Hur beskriver pedagogerna innebörden av delaktighet? Vilka metoder beskriver pedagogerna att de använder sig av vid arbete med barn i behov av särskilt stöd? Arbetar pedagogerna utifrån ett kategoriskt eller relationellt perspektiv? Denna studie baseras på en kvalitativ studie i form av intervjuer. Vi valde att använda oss av halvstrukturerade intervjufrågor för att skapa möjlighet till följdfrågor. Den utvalda metoden grundar sig i att vi ville ta reda på förskollärares beskrivningar och erfarenheter relaterade till studiens syfte. Vi valde att intervjua fem förskollärare där alla arbeta på olika förskolor/förskoleklasser. Den teoretiska utgångspunkten som vår studie baseras på är det sociokulturella perspektivet. En utvald analysmodell framtagen för att synliggöra det kategoriska och relationella perspektivet har haft stor betydelse vid arbetet med att analysera resultatet. Studiens resultat framhåller att delaktighet är svårt för pedagogerna att klargöra. Flera av pedagogerna beskriver att delaktighet är när barnen får vara med, ett aktivt deltagande i olika sammanhang. Något som saknades i pedagogernas svar är begreppet delaktighet i relation till social tillhörighet. Vår tolkning utifrån pedagogernas beskrivning är att två av fem arbetar ur ett relationellt perspektiv. Avslutningsvis kan vi konstatera att pedagogerna bör reflektera över innebörden av ordet delaktighet och förhållningssättets betydelse för barnen och omgivningen.