scholarly journals 2181 Age-related change in 5-HT6 receptor availability in healthy male volunteers measured with 11C-GSK215083 PET

2018 ◽  
Vol 2 (S1) ◽  
pp. 3-4
Author(s):  
Rajiv Radhakrishnan ◽  
Nabeel Nabulsi ◽  
Edward Gaiser ◽  
Jean-Dominique Gallezot ◽  
Shannan Henry ◽  
...  
Keyword(s):  
Negative Correlation ◽  
Serotonin Receptor ◽  
Brain Regions ◽  
Healthy Male ◽  
Time Activity ◽  
Age Related ◽  
Study Population ◽  
Cortical Regions ◽  
Age Range

OBJECTIVES/SPECIFIC AIMS: The serotonin receptor 6 (5-HT6) is a potential therapeutic target given its distribution in brain regions that are important in depression, anxiety, and cognition. This study sought to investigate the effects of age on 5-HT6 receptor availability using 11C GSK215083, a PET ligand with affinity for 5-HT6 in the striatum and 5-HT2A in the cortex. METHODS/STUDY POPULATION: In total, 28 healthy male subjects (age range: 23–52 years) were scanned with 11C-GSK215083 on the HR+PET scanner. Time-activity curves in regions-of-interest were fitted with multilinear analysis-1 method. Binding potentials (BPND) were calculated using cerebellum as the reference region and corrected for partial volume effects. RESULTS/ANTICIPATED RESULTS: In 5-HT6 rich areas, regional 11C-GSK215083 displayed a negative correlation between BPND and age in the caudate (r=−0.41, p=0.03) (14% change per decade), and putamen (r=−0.30, p=0.04) (11% change per decade), but not in the ventral striatum and pallidum. Negative correlation with age was also seen in cortical regions (r=−0.41, p=0.03) (7% change per decade), consistent with the literature on 5-HT2A availability. DISCUSSION/SIGNIFICANCE OF IMPACT: This is the first in vivo study in humans to examine the effect of age on 5-HT6 receptor availability. The study demonstrated a significant age-related decline in 5-HT6 availability (BPND) in the caudate and putamen.

scholarly journals PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2289
Author(s):  
Naresh Damuka ◽  
Paul Czoty ◽  
Ashley Davis ◽  
Michael Nader ◽  
Susan Nader ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Neurological Disorders ◽  
Healthy Male ◽  
Time Activity ◽  
Positron Emission ◽  
Pet Ct ◽  
Scan Data ◽  
The Brain ◽  
Human Primate

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

Brain anatomy and ageing in non-demented adults with Down's syndrome: an in vivo MRI study

2009 ◽  
Vol 40 (4) ◽  
pp. 611-619 ◽  
Author(s):  
F. Beacher ◽  
E. Daly ◽  
A. Simmons ◽  
V. Prasher ◽  
R. Morris ◽  
...  
Keyword(s):  
Down's Syndrome ◽  
Down’S Syndrome ◽  
Brain Regions ◽  
Accelerated Ageing ◽  
Brain Anatomy ◽  
Parietal Lobes ◽  
Age Related ◽  
Brain Ageing ◽  
Mri Study

BackgroundPeople with Down's syndrome (DS) are at high risk for developing dementia in middle age. The biological basis for this is unknown. It has been proposed that non-demented adults with DS may undergo accelerated brain ageing.MethodWe used volumetric magnetic resonance imaging (MRI) and manual tracing to compare brain anatomy and ageing in 39 non-demented adults with DS and 42 healthy controls.ResultsIndividuals with DS had significant differences in brain anatomy. Furthermore, individuals with DS had a significantly greater age-related reduction in volume of frontal, temporal and parietal lobes, and a significantly greater age-related increase in volume of peripheral cerebrospinal fluid (CSF).ConclusionsNon-demented adults with DS have differences in brain anatomy and ‘accelerated’ ageing of some brain regions. This may increase their risk for age-related cognitive decline and Alzheimer's disease (AD).

MAPPING IN VITRO AND IN VIVO DERIVED CYP2C9 AND CYP2C19 ONTOGENY FUNCTIONS: A CRITICAL COMPARISON BETWEEN VARIOUS ONTOGENY MODELS

2015 ◽  
Vol 101 (1) ◽  
pp. e1.38-e1 ◽  
Author(s):  
Farzaneh Salem ◽  
Trevor Johnson ◽  
Amin Rostami-Hodjegan
Keyword(s):  
Literature Review ◽  
Microsomal Protein ◽  
Critical Comparison ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Physiologically Based ◽  
Age Range ◽  
Best Fit

In vivo derived ontogeny profiles for CYP1A2 and CYP3A4, show improved clearance (CL) predictions within a paediatric physiologically based pharmacokinetic (p-PBPK) model1. The aim of this study is to derive ontogeny functions (OF) for CYP2C9 and CYP2C19 based on age related CL data on ibuprofen and pantoprazole & lansoprazole, respectively.A literature review was undertaken to collect age related CL data for these probes, the values were deconvoluted back to intrinsic CL values (per mg of liver microsomal protein) as described previously. The 'best-fit' algorithm for ratio of paediatric to mean adult intrinsic CL with age was determined in Graphpad Prism5 to obtain in vivo OF for CYP2C9 and CYP2C19. These were compared for performance with previously established ‘in vitro' OF in Simcyp Paediatric simulator (v14) using validation datasets.CYP2C9 and CYP2C19 enzyme activities showed an increase with age to values higher than adults by ages 2 and 1 month respectively, maximum values were reached at 1.5 years and 6 months, respectively before declining to typical adult levels by around 25 years.The CYP2C9 in vivo derived OF led to improved predictions of diclofenac and S-Warfarin CL compared to in vitro derived OF across the age range. For CYP2C19 there is a dearth of suitable validation compounds due to lack of clinical data with a possibility of using omeprazole or voriconazole. The reasons for discrepancy between in vitro and in vivo derived OF require further investigation.

scholarly journals Age-related change in task-evoked amygdala-prefrontal circuitry: a multiverse approach with an accelerated longitudinal cohort aged 4-22 years

2021 ◽  
Author(s):  
Paul Alexander Bloom ◽  
Michelle VanTieghem ◽  
Laurel Gabard-Durnam ◽  
Dylan G Gee ◽  
Jessica Flannery ◽  
...  
Keyword(s):  
Los Angeles ◽  
Separation Anxiety ◽  
Developmental Change ◽  
Longitudinal Design ◽  
Brain Regions ◽  
Cross Sectional ◽  
Functional Changes ◽  
Age Related ◽  
Age Range ◽  
Amygdala Reactivity

There has been considerable interest in the development of the amygdala and its connections with medial prefrontal cortex (mPFC) given the central role of these brain regions in emotional processes. While several studies have suggested that this circuitry exhibits functional changes across the first two decades of life, they have typically employed cross-sectional designs, and findings have been mixed. Additionally, analytic choices may contribute to discrepancies across studies. Here we used an accelerated longitudinal design to examine task-evoked changes in amygdala-mPFC circuitry from 4-22 years of age (N=98; 183 total scans; 1-3 scans per participant). Participants were recruited from the greater Los Angeles area, and completed an event-related emotional face (fear, neutral) task designed to be appropriate for the wide age range. 'Multiverse' analyses examined the robustness of our findings to fMRI analysis choices. 2808 parallel analyses varying in preprocessing and modeling choices found evidence for average age-related decreases in amygdala reactivity to faces. Greater amygdala reactivity at younger ages was attributable to elevated responses during the first few trials relative to later trials. Within-participant changes in amygdala reactivity with age could not be differentiated from between-participant differences, however. Across analysis decision points, we did not find consistent evidence of age-related change in amygdala-mPFC connectivity through generalized psychophysiological interaction (gPPI) or beta-series correlation (BSC) methods. We also did not find evidence for associations between separation anxiety behaviors and amygdala reactivity or amygdala-mPFC connectivity. Within the context of this faces task and age range, age-related changes in amygdala reactivity were more robust to processing pipeline than were task-evoked functional connectivity measures, particularly those using gPPI. These findings highlight both the challenges in estimating developmental change in longitudinal cohorts and the value of multiverse approaches in developmental neuroimaging for assessing robustness of results.

HOW DOES THE IN VIVO BILIARY ELIMINATION OF DRUGS CHANGE WITH AGE? EVIDENCE FROM CLINICAL DATA USING A SYSTEMS PHARMACOLOGY APPROACH

2015 ◽  
Vol 101 (1) ◽  
pp. e1.34-e1
Author(s):  
Trevor Johnson ◽  
Karen Rowland-Yeo ◽  
Masoud Jamei ◽  
Amin Rostami-Hodjegan
Keyword(s):  
Clinical Data ◽  
Biliary Excretion ◽  
Pharmacokinetic Model ◽  
Systems Pharmacology ◽  
Biliary Elimination ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Canalicular Transporters ◽  
Age Range

There is little information on the development of biliary drug elimination (BE) with age. The aims of this study were to collate literature data on the pharmacokinetics of biliary excreted drugs used in paediatrics and to apply a Physiologically Based Pharmacokinetic model to predict their systemic clearance (CLiv) across this age range.Drug parameters for azithromycin, ceftriaxone and digoxin were collated from the literature and validated against adult clinical data in Simcyp (V14R1). The change in CLiv with age was simulated in the paediatric model and compared to the observed data; the ontogeny function associated with BE was optimised in order to recover the age-related CLiv.For azithromycin (79% BE) a fraction of adult biliary excretion activity of 15% had to be assumed to be able to predict accurately the CL of the drug in neonates (24 to 28 weeks GA) whilst 100% activity was apparent by 7 months. For ceftriaxone (51% BE) full biliary excretion activity appeared to be present at full term birth. Finally, for digoxin (25% BE), a fraction of adult biliary excretion activity of 10% had to be assumed to predict the CL of the drug at birth whilst 100% activity was present by The ontogeny of BE for all three drugs appears to be rapid and reach adult levels at birth or in the first few months of postnatal age. More research is required in this area particularly on the ontogeny of specific canalicular transporters in humans.

scholarly journals Central amygdala circuits modulate food consumption through a positive valence mechanism

2017 ◽  
Author(s):  
Amelia M. Douglass ◽  
Hakan Kucukdereli ◽  
Marion Ponserre ◽  
Milica Markovic ◽  
Jan Gründemann ◽  
...  
Keyword(s):  
Food Consumption ◽  
Positive Reinforcement ◽  
Serotonin Receptor ◽  
Brain Regions ◽  
Central Nucleus ◽  
Dopamine System ◽  
Mesolimbic Dopamine System ◽  
Neuronal Mechanisms ◽  
Positive Valence

SummaryThe complex behaviors underlying the pursuit and consumption of rewards are integral to an organism’s survival. The hypothalamus and mesolimbic dopamine system are key mediators of these behaviors, yet regulation of appetitive and consummatory behaviors outside of these regions is not well understood. The central nucleus of the amygdala (CeA) is implicated in feeding and reward behavior, but the specific neural players and circuit mechanisms that positively regulate these behaviors remain unclear. Here, we define the neuronal mechanisms by which the CeA promotes consumption of food. We show, using in vivo activity manipulations and Ca2+ imaging, that CeA GABAergic neurons expressing the serotonin receptor 2a (Htr2a) modulate food consumption in multiple contexts, promote positive reinforcement and are active in vivo during eating. We demonstrate using electrophysiology, anatomical tracing methods and in vivo optogenetics that both intra-CeA and long-range circuit mechanisms underlie these functional effects. Finally, we show that CeAHtr2a neurons are poised to regulate food consumption through inputs from feeding-relevant brain regions. Our study highlights a mechanism by which defined CeA neural circuits positively regulate food consumption.

scholarly journals Adolescent tuning of association cortex in human structural brain networks

2017 ◽  
Author(s):  
František Váša ◽  
Jakob Seidlitz ◽  
Rafael Romero-Garcia ◽  
Kirstie J. Whitaker ◽  
Gideon Rosenthal ◽  
...  
Keyword(s):  
Sharp Decrease ◽  
Brain Regions ◽  
Brain Network ◽  
Association Cortex ◽  
Structural Correlation ◽  
Age Related ◽  
Cortical Regions ◽  
Structural Networks ◽  
The Brain ◽  
Age Related Changes

AbstractMotivated by prior data on local cortical shrinkage and intracortical myelination, we predicted age-related changes in topological organisation of cortical structural networks during adolescence. We estimated structural correlation from magnetic resonance imaging measures of cortical thickness at 308 regions in a sample of N=297 healthy participants, aged 14-24 years. We used a novel sliding-window analysis to measure age-related changes in network attributes globally, locally and in the context of several community partitions of the network. We found that the strength of structural correlation generally decreased as a function of age. Association cortical regions demonstrated a sharp decrease in nodal degree (hubness) from 14 years, reaching a minimum at approximately 19 years, and then levelling off or even slightly increasing until 24 years. Greater and more prolonged age-related changes in degree of cortical regions within the brain network were associated with faster rates of adolescent cortical myelination and shrinkage. The brain regions that demonstrated the greatest age-related changes were concentrated within prefrontal modules. We conclude that human adolescence is associated with biologically plausible changes in structural imaging markers of brain network organization, consistent with the concept of tuning or consolidating anatomical connectivity between frontal cortex and the rest of the connectome.

Ontogeny of gastric H(+)-K(+)-ATPase in suckling rabbits

1990 ◽  
Vol 259 (6) ◽  
pp. G913-G921 ◽  
Author(s):  
J. M. Crothers ◽  
W. W. Reenstra ◽  
J. G. Forte
Keyword(s):  
Microsomal Fraction ◽  
Apical Membrane ◽  
Specific Activity ◽  
Oxyntic Cell ◽  
Age Related ◽  
Nitrophenyl Phosphate ◽  
Weaning Age ◽  
Age Range ◽  
Hydrolysis Of

Gastric mucosal homogenates were prepared from resting and stimulated stomachs of rabbits, age 3-57 days postnatal, and fractionated by differential centrifugation. Total H(+)-K(+)-adenosinetriphosphatase (ATPase) (assayed as K(+)-dependent ouabain-insensitive hydrolysis of p-nitrophenyl phosphate) was low in the first 3 wk but rapidly accumulated between days 20 and 43. Specific activity rose eightfold from day 3 to a typically adult level of 2 mumol.mg-1.h-1 by day 43. The microsomal fraction (P3) was subfractionated on sucrose gradients (20, 27, and 33% steps or 10-40% continuous gradient). H(+)-K(+)-ATPase from P3 of resting stomachs was distributed bimodally on the continuous gradients, with activity mainly in the denser peak (or on the 33% sucrose step) before day 20, but accumulating mainly in the lighter peak (or in the lighter step-gradient fractions) after day 20. Throughout the age range tested, in vivo stimulation with histamine just before removal of the stomach caused a loss of most H(+)-K(+)-ATPase from P3 and an increase in H(+)-K(+)-ATPase in a lower-speed fraction P1. Thus, even in the 1st postnatal wk, when H(+)-K(+)-ATPase is low, most of the enzyme occurs in cells with histamine H2 receptors and all the intracellular mechanisms for fusion of oxyntic cell tubulovesicles (enriched in P3) with the apical membrane (enriched in P1). These studies delineate a 3-wk period of sharply accelerated synthesis of H(+)-K(+)-ATPase before weaning. Age-related changes in distribution of H(+)-K(+)-ATPase among microsomal density subfractions suggest maturational changes either in the intracellular partitioning of the enzyme or in properties of the membranes containing the enzyme.

scholarly journals The Emerging Role of Neuropeptides in Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Yanan Zheng ◽  
Linlin Zhang ◽  
Junxia Xie ◽  
Limin Shi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Age Related ◽  
Pituitary Adenylate Cyclase ◽  
New Strategy

Parkinson’s disease (PD), the second most common age-related neurodegenerative disease, results from the loss of dopamine neurons in the substantia nigra. This disease is characterized by cardinal non-motor and motor symptoms. Several studies have demonstrated that neuropeptides, such as ghrelin, neuropeptide Y, pituitary adenylate cyclase-activating polypeptide, substance P, and neurotensin, are related to the onset of PD. This review mainly describes the changes in these neuropeptides and their receptors in the substantia nigra-striatum system as well as the other PD-related brain regions. Based on several in vitro and in vivo studies, most neuropeptides play a significant neuroprotective role in PD by preventing caspase-3 activation, decreasing mitochondrial-related oxidative stress, increasing mitochondrial biogenesis, inhibiting microglial activation, and anti-autophagic activity. Thus, neuropeptides may provide a new strategy for PD therapy.

scholarly journals The Evaluation of Creative Ideas in Older and Younger Adults

2020 ◽  
Vol 34 (1) ◽  
pp. 19-34
Author(s):  
Evgeniya Yu. Privodnova ◽  
Nina V. Volf ◽  
Gennady G. Knyazev
Keyword(s):  
Older Adults ◽  
Successful Aging ◽  
Creative Thinking ◽  
Peak Frequency ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Cingulate Gyrus ◽  
Age Related ◽  
Age Range ◽  
Alpha Peak

Abstract. The ability to solve problems of divergent type is one of the most intact functions in successful aging. However, neurophysiologic mechanisms that support the efficiency of creative thinking remain largely unknown. This study was aimed to investigate age-related difference in localized induced electroencephalogram (EEG) changes during creative idea evaluation stage of divergent problem-solving (Alternate Uses Task), using standardized low-resolution brain electromagnetic tomography. Younger (45 women, 44 men, Mage = 22.1 years, age range: 18–30 years) and older adults (46 women, 43 men, Mage = 64.9 years, age range: 55–75 years) participated in the study. Higher synchronization in individually adjusted theta frequency band [from (individual alpha peak frequency −6 Hz) to (individual alpha peak frequency −4 Hz)] in anterior areas with the maximum values in anterior cingulate gyrus was revealed in older as compared with younger participants by group contrast. Higher desynchronization in wide beta range [from (individual alpha peak frequency +2 Hz) to 30 Hz] was localized in posterior brain regions with the highest values in posterior cingulate gyrus, precuneus, and parietal lobule in older adults. Induced beta 2 synchronization was positively correlated with originality (as measured by the mean frequency of ideas) in younger and years of education in older subjects. Based on the data, it was supposed that controlling the decision-making processes is more important for older adults while maintenance of the internal image of elements’ recombination may play essential role for younger subjects.

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