KSU Symphony Orchestra

SKU School of Music presents KSU Symphony Orchestra.https://digitalcommons.kennesaw.edu/musicprograms/1144/thumbnail.jp

Changes in Adiposity and Cerebrospinal Fluid Biomarkers Following a Modified Mediterranean Ketogenic Diet in Older Adults at Risk for Alzheimer's Disease

Background: Ketogenic diets have been used to treat both obesity and neurological disorders, including epilepsy and more recently Alzheimer's disease (AD), likely due to favorable effects on both central and peripheral metabolism. Improvements in body composition have also been reported; however, it is unclear if diet-induced changes in adiposity are related to improvements in AD and related neuropathology. Purpose: We examined the effects of a Modified Mediterranean Ketogenic (MMK) diet vs. an American Heart Association (AHA) diet on body weight, body composition, and body fat distribution and their association with cerebrospinal fluid (CSF) biomarkers in older adults at risk for AD. Methods: Twenty adults (mean age: 64.3 ± 6.3 years, 35% Black, 75% female) were randomly assigned to a crossover trial starting with either the MMK or AHA diet for 6 weeks, followed by a 6-week washout and then the opposite diet for 6 weeks. At baseline and after each diet adiposity was assessed by dual-energy x-ray absorptiometry and CSF biomarkers were measured. Linear mixed effect models were used to examine the effect of diet on adiposity. Spearman correlations were examined to assess associations between adiposity and CSF biomarkers. Results: At baseline there was a high prevalence of overweight/obesity and central adiposity, and higher visceral fat and lower peripheral fat were associated with an adverse CSF biomarker profile. The MMK and AHA diets led to similar improvements in body composition and body fat distribution. Significant correlations were found between changes in adiposity and changes in CSF biomarkers (r's = 0.63-0.92, p's < 0.05), with notable differences by diet. Decreases in body fat on the MMK diet were related to changes in Aβ biomarkers, whereas decreases in body fat on the AHA diet were related to changes in tau biomarkers and cholinesterase activity. Interestingly, increases in CSF Aβ on the MMK diet occurred in those with less fat loss. Conclusion: An MMK diet leads to favorable changes in body composition, body fat distribution, and CSF biomarkers. Our data suggest that modest weight loss that maximizes visceral fat loss and preserves peripheral fat, may have the greatest impact on brain health. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT02984540]

Small extracellular vesicles in plasma reveal molecular effects of modified Mediterranean-ketogenic diet in participants with mild cognitive impairment

Extracellular vesicles (EV) have emerged as a less-invasive nano-tool for discovering biomarkers of Alzheimer’s disease and related dementia. Here, we analyzed different neuron-enriched EV from plasma to predict response and molecular mechanisms of ketogenic diet’s efficacy in mild cognitive impairment participants. The study was a randomized crossover design in which cognitively normal and mild cognitive impairment participants consumed a modified Mediterranean-ketogenic diet (MMKD) or American Heart Association diet (AHAD) for six weeks, followed by other diet after washout. L1 cell adhesion molecule (L1CAM), synaptophysin, and neural cell adhesion molecule (NCAM) surface markers were used to enrich for neuron-secreted small EV (sEVL1CAM, sEVSYP, and sEVNCAM). For the first time, we have presented multiple evidences, including immunogold labeling/Transmission electron microscopy, CD63 (clusters of differentiation 63)-ELISA based assay, confocal microscopy fluorescent images, and flow cytometry data confirming the presence of L1CAM on the surface of sEVL1CAM, validating purity and relative abundance of sEVL1CAM in the plasma. Cargo analysis of sEVL1CAM showed that MMKD intervention reduces amyloid beta 1-42 (50.3%, p = 0.011), p181-tau (34.9%, p = 0.033) and neurofilament light (54.2%, p = 0.020) in mild cognitive impairment participants. Moreover, sEVL1CAM showed better sensitivity compared to CSF in analyzing increased glutamate (6 folds, p &amp;lt; 0.0001) from mild cognitive impairment participants following MMKD intervention. sEVL1CAM characterization also suggested that MMKD differentially targets the expression of various glutamate receptors - glutamate receptor ionotropic NMDA1 (GRIN1), glutamate receptor ionotropic NMDA2A (GRIN2A), glutamate receptor ionotropic NMDA2B (GRIN2B) and glutamate receptor ionotropic AMPA type subunit 1 (GRIA1). Importantly, these sEVL1CAM measures strongly correlated with corresponding clinical CSF biomarkers (neurogranin, amyloid beta 1-42, neurofilament light, and tau). Furthermore, sEVL1CAM were loaded with less advanced-glycation endproducts and exhibited anti-inflammatory activity following MMKD intervention. Most importantly, the expression of monocarboxylate transporter 2 on the surface of sEVL1CAM predicted the amyloid beta 1-42 response to MMKD intervention (Area under the curve = 0.87, p = 0.0044) and offered a novel screening tool to identify participants responsive to this dietary intervention. Finally, sEVL1CAM, sEVSYP, and sEVNCAM showed significantly high concordance in analyzing amyloid beta 1-42 (Pearson correlation coefficient ≥ 0.63, p &amp;lt; 0.01) and neurofilament light (Pearson correlation coefficient ≥ 0.49, p &amp;lt; 0.05). Together, sEV in plasma offers promise in assessing the efficacy of dietary/therapeutic intervention against mild cognitive impairment/Alzheimer’s disease

Blood-Based Bioenergetic Profiling Reflects Differences in Brain Bioenergetics and Metabolism

Blood-based bioenergetic profiling provides a minimally invasive assessment of mitochondrial health shown to be related to key features of aging. Previous studies show that blood cells recapitulate mitochondrial alterations in the central nervous system under pathological conditions, including the development of Alzheimer’s disease. In this study of nonhuman primates, we focus on mitochondrial function and bioenergetic capacity assessed by the respirometric profiling of monocytes, platelets, and frontal cortex mitochondria. Our data indicate that differences in the maximal respiratory capacity of brain mitochondria are reflected by CD14+ monocyte maximal respiratory capacity and platelet and monocyte bioenergetic health index. A subset of nonhuman primates also underwent [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to assess brain glucose metabolism. Our results indicate that platelet respiratory capacity positively correlates to measures of glucose metabolism in multiple brain regions. Altogether, the results of this study provide early evidence that blood-based bioenergetic profiling is related to brain mitochondrial metabolism. While these measures cannot substitute for direct measures of brain metabolism, provided by measures such as FDG-PET, they may have utility as a metabolic biomarker and screening tool to identify individuals exhibiting systemic bioenergetic decline who may therefore be at risk for the development of neurodegenerative diseases

Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis

<p>Abstract</p> <p>Background</p> <p>Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in "sporadic form"-meaning their disease is not associated with a family history of the disease. To date, the genetic factors of the sporadic form of ALS are poorly understood.</p> <p>Methods</p> <p>We proposed a two-stage approach based on seventeen biological plausible models to search for two-locus combinations that have significant joint effects to the disease in a genome-wide association study (GWAS). We used a two-stage strategy to reduce the computational burden associated with performing an exhaustive two-locus search across the genome. In the first stage, all SNPs were screened using a single-marker test. In the second stage, all pairs made from the 1000 SNPs with the lowest p-values from the first stage were evaluated under each of the 17 two-locus models.</p> <p>Results</p> <p>we performed the two-stage approach on a GWAS data set of sporadic ALS from the SNP Database at the NINDS Human Genetics Resource Center DNA and Cell Line Repository <url>http://ccr.coriell.org/ninds/</url>. Our two-locus analysis showed that two two-locus combinations--rs4363506 (SNP1) and rs3733242 (SNP2), and rs4363506 and rs16984239 (SNP3) -- were significantly associated with sporadic ALS. After adjusting for multiple tests and multiple models, the combination of SNP1 and SNP2 had a p-value of 0.032 under the Dom∩Dom epistatic model; SNP1 and SNP3 had a p-value of 0.042 under the Dom × Dom multiplicative model.</p> <p>Conclusion</p> <p>The proposed two-stage analytical method can be used to search for joint effects of genes in GWAS. The two-stage strategy decreased the computational time and the multiple testing burdens associated with GWAS. We have also observed that the loci identified by our two-stage strategy can not be detected by single-locus tests.</p

Donald Davidson and moral realism

My thesis is that Donald Davidson's approaches in philosophy of mind, philosophy of language, semantics, and metaphysics provide the basis for an attractive version of moral realism. To show the philosophical interest of this thesis, I first contend that Davidson's approaches are themselves attractive or at least plausible. Davidson's fundamental views imply externalism about the content of mental attitudes and utterances, as well as a modest holism about the attitudes; furthermore, they entail an anti-sceptical argument concluding that coherence is an adequate test of truth, and that there can be no alternative conceptual schemes. Moral realism must account for the practical nature of moral beliefs, as well as showing that moral beliefs justified by coherence can be true. I contend that the holism of the attitudes accounts for the practical nature of moral belief. Finally, the general anti-sceptical and anti-relativist arguments work together to defeat scepticism about coherent moral beliefs.Philosoph

Architecture-Induced Microphase Separation in Nonfrustrated A–B–C Triblock Copolymers

The extent of block microphase separation in nonfrustrated A–B–C triblock copolymers forming a “three-domain, four-layer” lamellar morphology is examined. Specifically, the extent of separation between the B and C blocks is probed, for the case where the B and C blocks are sufficiently compatible that they would not be microphase-separated if they were connected as a diblock. However, attachment of the A block, and consequent localization of the A–B block junction to the A–B lamellar interface, induces extensive separation between the B and C blocks. This separation is revealed both through the small-angle X-ray scattering pattern in the melt, and by distinct glass transitions observed in the solid state for the B block at low B–C segregation strengths, and for both the B and C blocks at higher segregation strengths. The particular polymers studied here have polyethylene as the A block; except for the most weakly segregated triblock, upon cooling from the melt, crystallization of the polyethylene block is confined within the lamellar structure established in the melt, with the polyethylene crystals stacking orthogonally to the microdomain lamellae

Regular Mixing Thermodynamics of Hydrogenated Styrene–Isoprene Block–Random Copolymers

Random copolymerization of A and B monomers represents a versatile method to tune interaction strengths between polymers, as A<i>r</i>B random copolymers will exhibit a smaller effective Flory interaction parameter χ (or interaction energy density <i>X</i>) upon mixing with A or B homopolymers than upon mixing A and B homopolymers with each other, and the A<i>r</i>B composition can be tuned continuously. This approach can also be used to tune the segregation strength in A–A<i>r</i>B “block–random” copolymers. Simple models of polymer mixing thermodynamics suggest that the effective interaction energy density in such block–random copolymers should follow <i>X</i>_{A–A<i>r</i>B} = <i>f</i>_B²<i>X</i>_A–B, but this prediction has not been tested quantitatively. The present work systematically assesses the validity of this rule for thermally stable hydrogenated derivatives of styrene–isoprene block copolymers, through measurements of the order–disorder transition (ODT) temperature on near-symmetric diblock and diblock–random copolymers of varying composition and suitable molecular weight (M). Both hydrogenated derivatives wherein the styrene aromaticity is retained, and derivatives wherein the styrene units are saturated to vinylcyclohexane, are examined, and both are found to closely obey the <i>X</i>_{A–A<i>r</i>B} = <i>f</i>_B²<i>X</i>_A–B prediction, thereby confirming the utility of this simple relationship in designing block copolymers with targeted interaction strengths using only these two common monomers. The reduction in <i>X</i>_{A–A<i>r</i>B} over <i>X</i>_A–B permits the synthesis of polymers having much larger <i>M</i> and domain spacing <i>d</i> while maintaining a thermally accessible ODT; measured domain spacings are found to closely follow the expected scaling, <i>d</i> ∼ <i>X</i>^1/6<i>M</i>^2/3