Cerebral blood flow and Aβ-amyloid estimates by WARM analysis of [¹¹C]PiB uptake distinguish among and between neurodegenerative disorders and aging

Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [C]Pittsburgh Compound B ([C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including Alzheimer's disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute cerebral blood flow indices (sCBF) from the early accumulation of the tracer in brain tissue. Objective: We tested the hypothesis that a change of cerebral blood flow is correlated with the degree of tracer [C]PiB retention, reflecting dendritic spine pathology and consequent inhibition of brain energy metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer's disease. Methods: Previously reported images of [C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer's Disease (AD), eight subjects with dementia with Lewy bodies (DLB), five patients with frontotemporal lobar degeneration (FTLD), five patients with mild cognitive impairment, and 29 age-matched healthy control subjects (HC)], underwent analysis of PiB delivery and retention by means of WARM for quantitation of [C]PiB's binding potentials (BP) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [C]PiB retention with cerebellum gray matter as reference. Receiver Operating Characteristics (ROC) revealed the power of discrimination among estimates. Results: For AD, the discriminatory power of [C]PiB binding potential (BP) by WARM exceeded the power of SUVR that in turn exceeded the power of sCBF estimates. Differences of [C]PiB binding and sCBF measures between AD and HC both were highly significant (p < 0.001). For all the dementia groups as a whole, sCBF estimates revealed the greatest discrimination between the patient and HC groups. WARM resolves a major issue of amyloid load quantification with [C]PiB in human brain by determining absolute sCBF and amyloid load measures from the same images. The two parameter approach provides key discriminary information in AD for which [C]PiB traditionally is used, as well as for the distinct flow deficits in FTLD, and the marked parietal and occipital lobe flow deficits in DLB. Conclusion: We conclude that WARM yields estimates of two important variables that together discriminate among patients with dementia, including AD, and healthy volunteers, with ROC that are superior to conventional methods of analysis. The distinction between estimates of flow and amyloid load from the same dynamic emission tomograms provides valuable pathogenetic information

Users’ encounter with normative discourses on Facebook:A three-pronged analysis of user agency as power structure, nexus and reception

This study asks whether users’ encounter with normative discourses of lifestyle, consumption, and health on social media such as Facebook gives rise to agency. The theoretical framework draws on reception analysis, for its implied, but central interest in agency that lies at the intersection of texts and audiences. Based on a critique of the “participatory paradigm,” a paradigm that situates the locus of agency in the structural opposition between senders and users, in the norms of rational deliberation or in the figure of the activist, gaps are identified which can be filled by adopting an explicit focus on the socio-cultural practices of ordinary audiences in their encounters with media discourses. The study investigates user agency on seven Facebook groups and pages with the help of a three-pronged perspective based on the notion of the media–audience relationship as (1) power structure, (2) nexus, and (3) reception. The analysis reveals that the structure at play on these Facebook groups and pages does not encourage user agency. However, user agency manifests itself through user interactions and expressive sense-making processes associated with reception. The benefits of such audience agency are a public, collective, and communicative sense-making process and an expansion of the professionally controlled text

Impact of Global Mean Normalization on Regional Glucose Metabolism in the Human Brain

Because the human brain consumes a disproportionate fraction of the resting body’s energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease

Trajectories of Brain Lactate and Re-visited Oxygen-Glucose Index Calculations Do Not Support Elevated Non-oxidative Metabolism of Glucose Across Childhood

Brain growth across childhood is a dynamic process associated with specific energy requirements. A disproportionately higher rate of glucose utilization (CMRglucose) compared with oxygen consumption (CMRO2) was documented in children's brain and suggestive of non-oxidative metabolism of glucose. Several candidate metabolic pathways may explain the CMRglucose-CMRO2 mismatch, and lactate production is considered a major contender. The ~33% excess CMRglucose equals 0.18 μmol glucose/g/min and predicts lactate release of 0.36 μmol/g/min. To validate such scenario, we measured the brain lactate concentration ([Lac]) in 65 children to determine if indeed lactate accumulates and is high enough to (1) account for the glucose consumed in excess of oxygen and (2) support a high rate of lactate efflux from the young brain. Across childhood, brain [Lac] was lower than predicted, and below the range for adult brain. In addition, we re-calculated the CMRglucose-CMRO2 mismatch itself by using updated lumped constant values. The calculated cerebral metabolic rate of lactate indicated a net influx of 0.04 μmol/g/min, or in terms of CMRglucose, of 0.02 μmol glucose/g/min. Accumulation of [Lac] and calculated efflux of lactate from brain are not consistent with the increase in non-oxidative metabolism of glucose. In addition, the value for the lumped constant for [18F]fluorodeoxyglucose has a high impact on calculated CMRglucose and use of updated values alters or eliminates the CMRglucose-CMRO2 mismatch in developing brain. We conclude that the presently-accepted notion of non-oxidative metabolism of glucose during childhood must be revisited and deserves further investigations

A mathematical model of brain glucose homeostasis

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Quantitative estimation of tissue blood flow rate

The rate of blood flow through a tissue (F) is a critical parameter for assessing the functional efficiency of a blood vessel network following angiogenesis. This chapter aims to provide the principles behind the estimation of F, how F relates to other commonly used measures of tissue perfusion, and a practical approach for estimating F in laboratory animals, using small readily diffusible and metabolically inert radio-tracers. The methods described require relatively nonspecialized equipment. However, the analytical descriptions apply equally to complementary techniques involving more sophisticated noninvasive imaging. Two techniques are described for the quantitative estimation of F based on measuring the rate of tissue uptake following intravenous administration of radioactive iodo-antipyrine (or other suitable tracer). The Tissue Equilibration Technique is the classical approach and the Indicator Fractionation Technique, which is simpler to perform, is a practical alternative in many cases. The experimental procedures and analytical methods for both techniques are given, as well as guidelines for choosing the most appropriate method

Quantifying the Link between Anatomical Connectivity, Gray Matter Volume and Regional Cerebral Blood Flow: An Integrative MRI Study

Background In the graph theoretical analysis of anatomical brain connectivity, the white matter connections between regions of the brain are identified and serve as basis for the assessment of regional connectivity profiles, for example, to locate the hubs of the brain. But regions of the brain can be characterised further with respect to their gray matter volume or resting state perfusion. Local anatomical connectivity, gray matter volume and perfusion are traits of each brain region that are likely to be interdependent, however, particular patterns of systematic covariation have not yet been identified. Methodology/Principal Findings We quantified the covariation of these traits by conducting an integrative MRI study on 23 subjects, utilising a combination of Diffusion Tensor Imaging, Arterial Spin Labeling and anatomical imaging. Based on our hypothesis that local connectivity, gray matter volume and perfusion are linked, we correlated these measures and particularly isolated the covariation of connectivity and perfusion by statistically controlling for gray matter volume. We found significant levels of covariation on the group- and regionwise level, particularly in regions of the Default Brain Mode Network. Conclusions/Significance Connectivity and perfusion are systematically linked throughout a number of brain regions, thus we discuss these results as a starting point for further research on the role of homology in the formation of functional connectivity networks and on how structure/function relationships can manifest in the form of such trait interdependency