The role of peripheral inflammatory insults in Alzheimer's disease: a review and research roadmap.

Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer's disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e.

Neurons require glucose uptake and glycolysis in vivo.

Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons.

Impact of COVID-19 on the Onset and Progression of Alzheimer's Disease and Related Dementias: A Roadmap for Future Research.

COVID-19 causes lasting neurological symptoms in some survivors. Like other infections, COVID-19 may increase risk of cognitive impairment. This perspective highlights four knowledge gaps about COVID-19 that need to be filled to avoid this possible health issue.

Non-Invasive Differentiation of M1 and M2 Activation in Macrophages Using Hyperpolarized C MRS of Pyruvate and DHA at 1.47 Tesla.

Macrophage activation, first generalized to the M1/M2 dichotomy, is a complex and central process of the innate immune response. Simply, M1 describes the classical proinflammatory activation, leading to tissue damage, and M2 the alternative activation promoting tissue repair. Given the central role of macrophages in multiple diseases, the ability to noninvasively differentiate between M1 and M2 activation states would be highly valuable for monitoring disease progression and therapeutic responses.

ELISA detection of SARS-CoV-2 antibodies in saliva.

To facilitate containment of the COVID-19 pandemic currently active in the United States and across the world, options for easy, non-invasive antibody testing are required. Here we have adapted a commercially available, serum-based enzyme-linked immunosorbent assay (ELISA) for use with saliva samples, achieving 84.2% sensitivity and 100% specificity in a set of 149 clinical samples.

Imaging Brain Metabolism Using Hyperpolarized C Magnetic Resonance Spectroscopy.

Aberrant metabolism is a key factor in many neurological disorders. The ability to measure such metabolic impairment could lead to improved detection of disease progression, and development and monitoring of new therapeutic approaches. Hyperpolarized C magnetic resonance spectroscopy (MRS) is a developing imaging technique that enables non-invasive measurement of enzymatic activity in real time in living organisms.

First hyperpolarized [2-C]pyruvate MR studies of human brain metabolism.

We developed methods for the preparation of hyperpolarized (HP) sterile [2-C]pyruvate to test its feasibility in first-ever human NMR studies following FDA-IND & IRB approval. Spectral results using this MR stable-isotope imaging approach demonstrated the feasibility of investigating human cerebral energy metabolism by measuring the dynamic conversion of HP [2-C]pyruvate to [2-C]lactate and [5-C]glutamate in the brain of four healthy volunteers. Metabolite kinetics, signal-to-noise (SNR) and area-under-curve (AUC) ratios, and calculated [2-C]pyruvate to [2-C]lactate conversion rates (k) were measured and showed similar but not identical inter-subject values.

Hyperpolarized C magnetic resonance spectroscopy detects toxin-induced neuroinflammation in mice.

Lipopolysaccharide (LPS) is a commonly used agent for induction of neuroinflammation in preclinical studies. Upon injection, LPS causes activation of microglia and astrocytes, whose metabolism alters to favor glycolysis. Assessing in vivo neuroinflammation and its modulation following therapy remains challenging, and new noninvasive methods allowing for longitudinal monitoring would be highly valuable.

Assessing the effect of hypoxia on cardiac metabolism using hyperpolarized C magnetic resonance spectroscopy.

Hypoxia plays a role in many diseases and can have a wide range of effects on cardiac metabolism depending on the extent of the hypoxic insult. Noninvasive imaging methods could shed valuable light on the metabolic effects of hypoxia on the heart in vivo. Hyperpolarized carbon-13 magnetic resonance spectroscopy (HP C MRS) in particular is an exciting technique for imaging metabolism that could provide such information.

In vivo investigation of hyperpolarized [1,3-C]acetoacetate as a metabolic probe in normal brain and in glioma.

Dysregulation in NAD/NADH levels is associated with increased cell division and elevated levels of reactive oxygen species in rapidly proliferating cancer cells. Conversion of the ketone body acetoacetate (AcAc) to β-hydroxybutyrate (β-HB) by the mitochondrial enzyme β-hydroxybutyrate dehydrogenase (BDH) depends upon NADH availability. The β-HB-to-AcAc ratio is therefore expected to reflect mitochondrial redox.

Simultaneous in vivo assessment of cardiac and hepatic metabolism in the diabetic rat using hyperpolarized MRS.

Understanding and assessing diabetic metabolism is vital for monitoring disease progression and improving treatment of patients. In vivo assessments, using MRI and MRS, provide non-invasive and accurate measurements, and the development of hyperpolarized C spectroscopy in particular has been demonstrated to provide valuable metabolic data in real time. Until now, studies have focussed on individual organs.

Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation.

Key Points: Adaptation to hypoxia makes the heart more oxygen efficient, by metabolising more glucose. In contrast, type 2 diabetes makes the heart metabolise more fatty acids. Diabetes increases the chances of the heart being exposed to hypoxia, but whether the diabetic heart can adapt and respond is unknown.

Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study.

Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function.

Hyperpolarized butyrate: a metabolic probe of short chain fatty acid metabolism in the heart.

Purpose: Butyrate, a short chain fatty acid, was studied as a novel hyperpolarized substrate for use in dynamic nuclear polarization enhanced magnetic resonance spectroscopy experiments, to define the pathways of short chain fatty acid and ketone body metabolism in real time.

Methods: Butyrate was polarized via the dynamic nuclear polarization process and subsequently dissolved to generate an injectable metabolic substrate. Metabolism was initially assessed in the isolated perfused rat heart, followed by evaluation in the in vivo rat heart.

In vivo alterations in cardiac metabolism and function in the spontaneously hypertensive rat heart.

Aims: The aim of this work was to use hyperpolarized carbon-13 ((13)C) magnetic resonance (MR) spectroscopy and cine MR imaging (MRI) to assess in vivo cardiac metabolism and function in the 15-week-old spontaneously hypertensive rat (SHR) heart. At this time point, the SHR displays hypertension and concentric hypertrophy. One of the cellular adaptations to hypertrophy is a reduction in β-oxidation, and it has previously been shown that in response to hypertrophy the SHR heart switches to a glycolytic/glucose-oxidative phenotype.