Tau Kinetics in Alzheimer\u27s Disease

The Cytoskeletal Protein Tau is Implicated in the Pathogenesis of Alzheimer\u27s Disease Which is Characterized by Intra-Neuronal Neurofibrillary Tangles Containing Abnormally Phosphorylated Insoluble Tau. Levels of Soluble Tau Are Elevated in the Brain, the CSF, and the Plasma of Patients with Alzheimer\u27s Disease. to Better Understand the Causes of These Elevated Levels of Tau, We Propose a Three-Compartment Kinetic Model (Brain, CSF, and Plasma). the Model Assumes that the Synthesis of Tau Follows Zero-Order Kinetics (Uncorrelated with Compartmental Tau Levels) and that the Release, Absorption, and Clearance of Tau is Governed by First-Order Kinetics (Linearly Related to Compartmental Tau Levels). Tau that is Synthesized in the Brain Compartment Can Be Released into the Interstitial Fluid, Catabolized, or Retained in Neurofibrillary Tangles. Tau Released into the Interstitial Fluid Can Mix with the CSF and Eventually Drain to the Plasma Compartment. However, Losses of Tau in the Drainage Pathways May Be Significant. the Kinetic Model Estimates Half-Life of Tau in Each Compartment (552 H in the Brain, 9.9 H in the CSF, and 10 H in the Plasma). the Kinetic Model Predicts that an Increase in the Neuronal Tau Synthesis Rate or a Decrease in Tau Catabolism Rate Best Accounts for Observed Increases in Tau Levels in the Brain, CSF, and Plasma Found in Alzheimer\u27s Disease. Furthermore, the Model Predicts that Increases in Brain Half-Life of Tau in Alzheimer\u27s Disease Should Be Attributed to Decreased Tau Catabolism and Not to Increased Tau Synthesis. Most Clearance of Tau in the Neuron Occurs through Catabolism Rather Than Release to the CSF Compartment. Additional Experimental Data Would Make Ascertainment of the Model Parameters More Precise

Classification of Rest and Active Periods in Actigraphy Data using PCA

In this paper we highlight a clustering algorithm for the purpose of identifying sleep and wake periods directly from actigraphy signals. The paper makes use of statistical Principal Component Analysis to identify periods of rest and activity. The aim of the proposed methodology is to develop a quick and efficient method to determine the sleep duration of an individual. In addition, a robust method that can identify sleep periods in the accelerometer data when duration, time of day varies by individual. A selected group of 10 individual\u27s sensor data consisting of actigraphy from an accelerometer (3-axis), near body temperature, and lux sensors from a single GENEActiv watch worn on the non-dominant hand. The actigraphy of each individual was collected 24 hours a day for a period spanning 80 days. We highlight that a simple data preprocessing stage followed with a 2 phase clustering method provides results that align with previously validated methodologies

The Perilipin Homologue, Lipid Storage Droplet 2, Regulates Sleep Homeostasis and Prevents Learning Impairments Following Sleep Loss

Starvation, which is common in the wild, appears to initiate a genetic program that allows fruitflies to remain awake without the sleepiness and cognitive impairments that typically follow sleep deprivation

Comparative sequence analysis and tissue localization of members of the SLC6 family of transporters in adult Drosophila melanogaster

SUMMARY The SLC6 family comprises proteins that move extracellular neurotransmitters, amino acids and osmolytes across the plasma membrane into the cytosol. In mammals, deletion of SLC6 family members has dramatic physiologic consequences, but in the model organism Drosophila melanogaster, little is known about this family of proteins. Therefore, in this study we carried out an initial analysis of 21 known or putative SLC6 family members from the Drosophila genome. Protein sequences from these genes segregated into either well-defined subfamilies, including the novel insect amino acid transporter subfamily, or into a group of weakly related sequences not affiliated with a recognized subfamily. Reverse transcription-polymerase chain reaction analysis and in situ hybridization showed that seven of these genes are expressed in the CNS. In situ hybridization revealed that two previously cloned SLC6 members, the serotonin and dopamine transporters, were localized to presumptive presynaptic neurons that previously immunolabelled for these transmitters. RNA for CG1732 (the putative GABA transporter) and CG15088 (a member of the novel insect amino acid transporter family) was localized in cells likely to be subtypes of glia, while RNA for CG5226, CG10804 (both members of the orphan neurotransmitter transporter subfamily) and CG5549 (a putative glycine transporter) were expressed broadly throughout the cellular cortex of the CNS. Eight of the 21 sequences were localized outside the CNS in the alimentary canal, Malpighian tubules and reproductive organs. Localization for six sequences was not found or not attempted in the adult fly. We used the Drosophila ortholog of the mammalian vesicular monoamine transporter 2, CG33528, to independently identify monoaminergic neurons in the adult fly. RNA for CG33528 was detected in a limited number of cells in the central brain and in a beaded stripe at the base of the photoreceptors in the position of glia, but not in the photoreceptors themselves. The SLC6 localization observations in conjunction with likely substrates based on phylogenetic inferences are a first step in defining the role of Na/Cl-dependent transporters in Drosophila physiology

Excessive Daytime Sleepiness Is Associated with Changes in Salivary Inflammatory Genes Transcripts

Excessive daytime sleepiness (EDS) is a ubiquitous problem that affects public health and safety. A test that can reliably identify individuals that suffer from EDS is needed. In contrast to other methods, salivary biomarkers are an objective, inexpensive, and noninvasive method to identify individuals with inadequate sleep. Although we have previously shown that inflammatory genes are elevated in saliva samples taken from sleep deprived individuals, it is unclear if inflammatory genes will be elevated in clinical populations with EDS. In this study, salivary samples from individuals with sleep apnea were evaluated using the Taqman low density inflammation array. Transcript levels for 3 genes, including prostaglandin-endoperoxide synthase 2 (PTGS2), were elevated in patients with sleep apnea. Interestingly, PTGS2 was also elevated in patients with EDS but who did not have sleep apnea. These data demonstrate the feasibility of using salivary transcript levels to identify individuals that self-report excessive daytime sleepiness

MODELING SLEEP AND WAKE BOUTS IN DROSOPHILA MELANOGASTER

Adequate sleep restores vital processes required for health and well-being; but the function and regulation of sleep is not well understood. Unfortunately, a definition of adequate sleep is unclear. On an hours-long timescale, consolidated and cycling sleep results in better health and performance outcomes. At shorter timescales, older studies report conflicting results regarding the relationship between sleep and wake bout durations. One approach to this problem has been to simply analyze the distribution of bout durations. While informative, this method eliminates the time relationship between bouts, which may be important. Here, we develop a model that describes the relationship between sleep and wake bout durations using the model organism, Drosophila melanogaster, which exhibits behavioral and molecular homology to human sleep. We present an exploratory analysis of the data to gain a better understanding of the sleep bout duration distribution by considering a broader range of potential distributions than considered in previous studies. We use the results of the distribution analysis to develop a model for sleep bout durations in the fly based upon their past sleep and wake history and find that this relationship should not be ignored

The acyl-CoA Synthetase, pudgy, Promotes Sleep and Is Required for the Homeostatic Response to Sleep Deprivation

The regulation of sleep and the response to sleep deprivation rely on multiple biochemical pathways. A critical connection is the link between sleep and metabolism. Metabolic changes can disrupt sleep, and conversely decreased sleep can alter the metabolic environment. There is building evidence that lipid metabolism, in particular, is a critical part of mounting the homeostatic response to sleep deprivation. We have evaluated an acyl-CoA synthetase, pudgy (pdgy), for its role in sleep and response to sleep deprivation. When pdgy transcript levels are decreased through transposable element disruption of the gene, mutant flies showed lower total sleep times and increased sleep fragmentation at night compared to genetic controls. Consistent with disrupted sleep, mutant flies had a decreased lifespan compared to controls. pdgy disrupted fatty acid handling as pdgy mutants showed increased sensitivity to starvation and exhibited lower fat stores. Moreover, the response to sleep deprivation is reduced when compared to a control flies. When we decreased the transcript levels for pdgy using RNAi, the response to sleep deprivation was decreased compared to background controls. In addition, when the pdgy transcription is rescued throughout the fly, the response to sleep deprivation is restored. These data demonstrate that the regulation and function of acyl-CoA synthetase plays a critical role in regulating sleep and the response to sleep deprivation. Endocrine and metabolic signals that alter transcript levels of pdgy impact sleep regulation or interfere with the homeostatic response to sleep deprivation

Foraging Alters Resilience/Vulnerability to Sleep Disruption and Starvation in Drosophila

Recent human studies suggest that genetic polymorphisms allow an individual to maintain optimal cognitive functioning during sleep deprivation. If such polymorphisms were not associated with additional costs, selective pressures would allow these alleles to spread through the population such that an evolutionary alternative to sleep would emerge. To determine whether there are indeed costs associated with resiliency to sleep loss, we challenged natural allelic variants of the foraging gene (for) with either sleep deprivation or starvation. Flies with high levels of Protein Kinase G (PKG) (forR) do not display deficits in short-term memory following 12 h of sleep deprivation. However, short-term memory is significantly disrupted when forR flies are starved overnight. In contrast, flies with low levels of PKG (fors, fors2) show substantial deficits in short-term memory following sleep deprivation but retain their ability to learn after 12 h of starvation. We found that forR phenotypes could be largely recapitulated in fors flies by selectively increasing the level of PKG in the α/ß lobes of the mushroom bodies, a structure known to regulate both sleep and memory. Together, these data indicate that whereas the expression of for may appear to provide resilience in one environmental context, it may confer an unexpected vulnerability in other situations. Understanding how these tradeoffs confer resilience or vulnerability to specific environmental challenges may provide additional clues as to why an evolutionary alternative to sleep has not emerged

A Kinetic Model for Blood Biomarker Levels after Mild Traumatic Brain Injury

Traumatic brain injury (TBI) imposes a significant economic and social burden. The diagnosis and prognosis of mild TBI, also called concussion, is challenging. Concussions are common among contact sport athletes. After a blow to the head, it is often difficult to determine who has had a concussion, who should be withheld from play, if a concussed athlete is ready to return to the field, and which concussed athlete will develop a post-concussion syndrome. Biomarkers can be detected in the cerebrospinal fluid and blood after traumatic brain injury and their levels may have prognostic value. Despite significant investigation, questions remain as to the trajectories of blood biomarker levels over time after mild TBI. Modeling the kinetic behavior of these biomarkers could be informative. We propose a one-compartment kinetic model for S100B, UCH-L1, NF-L, GFAP, and tau biomarker levels after mild TBI based on accepted pharmacokinetic models for oral drug absorption. We approximated model parameters using previously published studies. Since parameter estimates were approximate, we did uncertainty and sensitivity analyses. Using estimated kinetic parameters for each biomarker, we applied the model to an available post-concussion biomarker dataset of UCH-L1, GFAP, tau, and NF-L biomarkers levels. We have demonstrated the feasibility of modeling blood biomarker levels after mild TBI with a one compartment kinetic model. More work is needed to better establish model parameters and to understand the implications of the model for diagnostic use of these blood biomarkers for mild TBI

Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice