Blood Flow Improvement Trial: Design and Enrollment Developing Topics

Background Midlife insulin resistance (IR) has previously been shown to be associated with lower cerebral blood flow (CBF), and is a potentially modifiable risk factor for dementia. The Blood Flow Improvement Trial (BFiT), NCT03117829 , tested a 12 week carbohydrate restricted diet (CRD) and exercise behavioral intervention to reverse IR, and aimed to 1) determine the extent to which improving or normalizing glucose homeostasis improves CBF and cognitive function in individuals with IR, 2) determine whether participants continue to maintain improved or normalized glycemic control for 6 months, and 3) determine changes in the human metabolome as individuals improve or normalize IR and glucose homeostasis through diet and exercise. Method Participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and screened for metabolic risk factor eligibility based on the criteria shown in Table 1. The design involved a 12 week diet and exercise intervention focused on self‐monitoring to promote adherence. Exercise was conducted in a supervised group setting 3 days/week for 50 minutes and participants were instructed to exercise on their own an additional 2 days/week. Participants followed a CRD and monitored their own blood glucose with the goal of achieving and maintaining fasting blood glucose/dL. Participants underwent baseline, 12 week, and 6 month procedures including urine and blood labs/metabolomics, cognitive testing, fitness testing, and blood flow imaging via MRI (Table 2). Result The enrollment goal was 40 participants. 118 individuals were screened for eligibility, and 72.5% of the target enrollment was met; of those participants, nearly 80% completed the 12 week intervention. Of the 23 participants that completed the intervention, mean attendance was 70% for supervised exercise sessions and 81% for weekly behavioral coaching sessions. Figure 1 summarizes screening, enrollment, and procedure completion. Conclusion IR may be a modifiable risk factor for dementia. The BFiT pilot trial was designed to test the feasibility of exercise and CRD to reduce IR and improve brain blood flow in middle‐aged adults. Reasonable enrollment and completion N were achieved. Future analysis will center on barriers to enrollment and adherence, as well as analysis of the primary and secondary outcome measures

Yeast Golden Gate: Standardized Assembly of S. cerevisiae Transcriptional Units

BBF RFC 88 describes a new standard for the assembly of basic Saccharomyces cerevisiae transcriptional units (TUs) consisting of a promoter/5’untranslated region (UTR), open reading frame (ORF), and 3’UTR/terminator. Note that we use the term “promoter” here to refer to both the promoter and the 5’ UTR, which we currently define as a single part. Future iterations of this standard will incorporate subdivision of currently defined parts e.g. into promoter and 5’ UTR. The standard makes use of the type IIS restriction enzyme BsaI to generate standardized and user­‐defined ‘signature overhangs’, thus enabling directional and seamless TU assembly. RFC88 is supported by the Yeast Standardized Collection of Parts for Expression (SCoPE), a repository of subcloned and sequence verified parts compatible with this assembly standard. The Yeast SCoPE is currently populated by a large number of S. cerevisiae promoters and terminators that facilitate expression and characterization of non­‐native ORFs

Older adults at greater risk for Alzheimers disease show stronger associations between sleep apnea severity in REM sleep and verbal memory.

BACKGROUND: Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimers disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. METHODS: Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. RESULTS: Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. CONCLUSION: Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low

Inflammation, tau pathology, and synaptic integrity associated with sleep spindles and memory prior to β-amyloid positivity

STUDY OBJECTIVES: Fast frequency sleep spindles are reduced in aging and Alzheimer's disease (AD), but the mechanisms and functional relevance of these deficits remains unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD. METHODS: Fifty-eight cognitively unimpaired, β-amyloid negative, older adults (mean±SD; 61.4±6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system (CNS) inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13-<16Hz) sleep spindle measures through these AD biomarkers. RESULTS: Glial activation was associated with prefrontal fast frequency sleep spindle expression deficits. While adjusting for sex, APOE ε4 genotype, apnea-hypopnea index (AHI), and time between CSF sampling and sleep study, serial mediation models detected indirect effects of age on fast sleep spindle expression through microglial activation markers and then tau phosphorylation and synaptic degeneration markers. Sleep spindle expression at these electrodes was also associated with overnight memory retention in multiple regression models adjusting for covariates. CONCLUSIONS: These findings point toward microglia dysfunction as associated with tau phosphorylation, synaptic loss, sleep spindle deficits, and memory impairment even prior to β-amyloid positivity, thus offering a promising candidate therapeutic target to arrest cognitive decline associated with aging and AD

Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimers disease.

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimers disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic&nbsp;models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management

Fallacious convergence? Williamson’s real wage comparisons under scrutiny

The idea of manifest real-wage convergence for unskilled workers in the latter half of the nineteenth century stems from an article from 1995 by Jeffrey G. Williamson. That article presented real wage comparisons of unskilled urban workers for seventeen countries. Sweden, along with the rest of Scandinavia, is found to be an influential case in accounting for much of the alleged factor price convergence taking place. This paper takes a closer look at all the three steps that have to be taken in order to establish real wage comparisons, focusing on Sweden in relation to the US and the UK. The most important findings are twofold. First, that the US–Sweden wage gap is considerably smaller for manufacturing than for building workers, and second, that the rate at which Sweden’s real wages approached the American and the British has been grossly overestimated. Swedish real wages did grow rapidly, but not as rapidly as Williamson’s comparison will have us to believe, because his real wage series does not constitute a representative account of the Swedish unskilled real wage experience. It is argued that, as we suffer from a serious paucity of data for narrow and comparable samples of late nineteenth century unskilled workers, resorting to more encompassing wage measures is a more viable option. That also implies a questioning of the American unskilled wage series, which makes considerably slower progress than the wage series for manufacturing workers.Convergence, Real wages, Wage benchmark, Purchasing power parity, Catching up, International comparisons