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Cerebral glucose and oxygen metabolism and blood perfusion play key roles in neuroenergetics and oxidative phosphorylation to produce adenosine triphosphate (ATP) energy molecules in supporting cellular activity and brain function. Their impairments have been linked to numerous brain disorders. This study aimed to develop an in vivo magnetic resonance spectroscopy (MRS) method capable of simultaneously assessing and quantifying the major cerebral metabolic rates of glucose (CMRGlc) and oxygen (CMRO2) consumption, lactate formation (CMRLac), and tricarboxylic acid (TCA) cycle (VTCA); cerebral blood flow (CBF); and oxygen extraction fraction (OEF) via a single dynamic MRS measurement using an interleaved deuterium (2H) and oxygen‐17 (17O) MRS approach. We introduced a single‐loop multifrequency radio‐frequency (RF) surface coil that can be used to acquire proton (1H) magnetic resonance imaging (MRI) or interleaved low‐γ X‐nuclei 2H and 17O MRS. By combining this RF coil with a modified MRS pulse sequence, 17O‐isotope‐labeled oxygen gas inhalation, and intravenous 2H‐isotope‐labeled glucose administration, we demonstrate for the first time the feasibility of simultaneously and quantitatively measuring six important physiological parameters, CMRGlc, CMRO2, CMRLac, VTCA, CBF, and OEF, in rat brains at 16.4 T. The interleaved 2H–17O MRS technique should be readily adapted to image and study cerebral energy metabolism and perfusion in healthy and diseased brains. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are secreted by the adrenal glands and increase in response to stressors (e.g., infection). The brain regulates local GC levels via GC synthesis, regeneration and/or metabolism. Little is known about local GC regulation within discrete brain regions at baseline or in response to stress. We treated male and female C57BL/6J mice at postnatal day 5 (PND5) or PND90 with lipopolysaccharide (LPS; 50 μg/kg bw i.p.) or vehicle and collected blood and brain after 4 h. We microdissected the prefrontal cortex, hippocampus, hypothalamus and amygdala. We measured seven steroids, including corticosterone, via liquid chromatography–tandem mass spectrometry and measured transcripts for key steroidogenic enzymes (Cyp11b1, Hsd11b1, Hsd11b2) via qPCR. At both ages, LPS increased GC levels in blood and all brain regions; however, the increases were much greater at PND90 than at PND5. Interestingly, PND5 corticosterone levels were lower in prefrontal cortex than in blood, but higher in amygdala than in blood. These changes in corticosterone levels align with local changes in steroidogenic enzyme expression, demonstrating robust regional heterogeneity and a possible mechanism for the region‐specific effects of early‐life stress. In contrast, PND90 corticosterone levels were lower in all brain regions than in blood and similar among regions, and steroidogenic enzyme mRNA levels were generally not affected by LPS. Together, these data indicate that local GC levels within discrete brain regions are more heterogeneous at baseline and in response to LPS at PND5 than at PND90, as a result of increased local GC production and metabolism in the neonatal brain. [ABSTRACT FROM AUTHOR]

Nowadays, particularly in countries with high incomes, individual mutations in people affected by genetic epilepsies are identified, and genetic therapies are being developed. In addition, drugs are being screened to directly target specific mutations, and personalised medicine is possible. However, people with epilepsy do not yet benefit from these advances, and many types of epilepsies are medication‐resistant, including Dravet syndrome. Thus, in the meantime, alternative and effective treatment options are needed. There is increasing evidence that metabolic deficits contribute to epileptic seizures and that such metabolic impairments may be amenable to treatment, with metabolic treatment options like the ketogenic diet being employed with some success. However, the brain metabolic alterations that occur in ion channel epilepsies are not well‐understood, nor how these may differ from epilepsies that are of acquired and unknown origins. Here, we provide an overview of studies investigating metabolic alterations in epilepsies caused by mutations in the SCN1A and KCNA1 genes, which are currently the most studied ion channel epilepsies in animal models. The metabolic changes found in these models are likely to contribute to seizures. A metabolic basis of these ion channel epilepsies is supported by human and/or animal studies that show beneficial effects of the ketogenic diet, which may be mediated by the provision of auxiliary brain fuel in the form of ketone bodies. Other potentially more preferred dietary therapies including medium‐chain triglycerides and triheptanoin have also been tested in a limited number of studies, but their efficacies remain to be clearly established. The extent to which brain metabolism is affected in people with Dravet syndrome, KCNA1 epilepsy and the models thereof still requires clarification. This requires more experiments that yield functional insight into metabolism. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Regulating brain iron metabolism and reducing neuronal ferroptosis is proven to be a potential method for treating Alzheimer's disease (AD). However, gastric juice has a pH of 1.1—2.2 where a large number of interfering ions are dissociated from the food, which in turn causes traditional oral iron chelators to be saturated and inactivated. Herein, poly(4‐vinylbenzoic acid) polymer chains were introduced as guided by Fe3+ ion template into the porous network (TpPa‐1) via molecularly imprinted technology to obtain porous iron chelators, COOH@TpPa‐1. The COOH@TpPa‐1 maintains a multiple hydrogen bonding structure to block the channels in the stomach (pH ~1.1—2.2) with a strongly acidic environment, so just a small amount of active sites have been occupied. As COOH@TpPa‐1 enters the colon, the alkaline environment disrupts the original hydrogen‐bonded structure and forms anionic fragments, the bonding affinity for Fe3+ ions was ~4.0 times that in the stomach, and also gave a high selective coefficient 4.2 times higher than that of conventional iron chelators. These designable "on" and "off" states promote the effective enrichment of iron ions within the colon by the porous chelator and produce a favorable therapeutic effect on Alzheimer's symptoms caused by ferroptosis in mice. [ABSTRACT FROM AUTHOR]

The brain is a sensitive organ with numerous essential functions and complex mechanisms. It is secluded and safeguarded from the external environment as part of the central nervous system (CNS), serving as a sanctuary. By regulating their selective and specific absorption, efflux, and metabolism in the brain, the CNS controls brain homeostasis and the transit of endogenous and foreign substances. The mechanism which protects the brain from environmental chemicals, also prevent the entry of therapeutic chemicals to it. The delivery of molecules to the brain is hindered by several major barriers, such as the blood–brain barrier (BBB), blood‐cerebrospinal fluid barrier (BCSFB), and blood‐tumor barrier. BBB is formed by the combination of cerebral endothelial cells, astrocytes, neurons, pericytes and microglia. It is a tight junction of capillary endothelial cells, preventing the diffusion of solute into the brain. BCSFB is the second barrier, located at the choroid plexus, separating the blood from cerebrospinal fluid (CSF). It is comparatively more permeable than BBB. An uneven distribution of microvasculature across the tumor interstitial compromises drug delivery to neoplastic cells of a solid tumor, resulting in spatially inconsistent drug administration. Nasal drug delivery to the brain is a method of drug delivery that tries to deliver therapeutic substances directly from the nasal cavity to the central nervous system including the brain. In this review, besides the role of barriers we have discussed in detail about approaches adapted to deliver drugs to the brain along with mechanisms through nasal route. Further, different commercial formulations, clinical trials and patents have been thoroughly elaborated to date. The findings suggest that the nose‐to‐brain drug delivery method holds promise as an evolving approach, potentially contributing to the specific and targeted delivery of drugs into the brain. [ABSTRACT FROM AUTHOR]

Objective: Avoidant/restrictive food intake disorder (ARFID) is an eating disorder characterized by a severely restrictive diet leading to significant physical and/or psychosocial sequelae. Largely owing to the phenotypic heterogeneity, the underlying pathophysiological mechanisms are relatively unknown. Recently, the communication between microorganisms within the gastrointestinal tract and the brain—the so‐called microbiota‐gut‐brain axis—has been implicated in the pathophysiology of eating disorders. This Spotlight review sought to investigate and conceptualize the possible ways that the microbiota‐gut‐brain axis is involved in ARFID to drive future research in this area. Method: By relating core symptoms of ARFID to gut microbiota and its signaling pathways to the brain, we evaluated how the gut microbiota is potentially involved in the pathophysiology of ARFID. Results: We hypothesized that the restricted type and amount of food intake characteristic of ARFID diminishes gut microbial diversity, including beneficial bacteria and their metabolites capable of signaling to the brain, to modulate biopsychological pathways relevant to ARFID: homeostatic signaling, food reward, interoception, sensory sensitivity, disgust, perseveration, fear‐based learning, and mood. Candidate signaling mechanisms include microbial‐induced effects on inflammation, cortisol, and neurotransmitters such as dopamine and serotonin. Discussion: Through reviewing the extant evidence, we conceptualized a new theoretical framework of ARFID with an emphasis on microbiota‐gut‐brain axis signaling to inform future research. Although more research is necessary to evaluate this theoretical model, the tentative evidence suggests that therapeutics specifically targeting the gut microbiota for the treatment of ARFID symptomatology warrants more investigation. [ABSTRACT FROM AUTHOR]

Cyclic adenosine monophosphate‐response element‐binding protein‐1‐regulated transcription coactivator‐1 (CRTC1), a cytoplasmic coactivator that translocates to the nucleus in response to cAMP, is associated with obesity. We previously reported that CRTC1 deficiency in melanocortin‐4 receptor (MC4R)‐expressing neurons, which regulate appetite and energy metabolism in the brain, causes hyperphagia and obesity under a high‐fat diet (HFD). HFD is preferred for mice, and the dietary fat in HFD is the main factor contributing to its palatability. These findings, along with our previous results, suggest that CRTC1 regulates the appetite for dietary fat. Therefore, in this study, we aimed to investigate the dietary fat intake behavior and energy metabolism of MC4R neuron‐specific CRTC1 knockout mice fed soybean oil or lard. CRTC1 deficiency increased the intake of soybean oil and significantly increased body weight gain. Furthermore, obesity induced by soybean oil intake was partially due to leptin resistance. No significant changes in soybean oil intake were observed between young CRTC1‐deficient and wild‐type mice; however, soybean oil intake increased with age. Moreover, lard intake did not significantly affect the body weight. Overall, our findings highlighted the crucial role of CRTC1 in the regulation of spontaneous dietary fat intake. Furthermore, the role of CRTC1 becomes increasingly significant with age. [ABSTRACT FROM AUTHOR]

Isoflurane is one of the most widely used anesthetic agents in rodent imaging studies. However, the impact of isoflurane on brain metabolism has not been fully characterized to date, primarily due to a scarcity of noninvasive technologies to quantitatively measure the brain's metabolic rate in vivo. In this study, using noncontrast MRI techniques, we dynamically measured cerebral metabolic rate of oxygen (CMRO2) under varying doses of isoflurane anesthesia in mice. Concurrently, systemic parameters of heart and respiration rates were recorded alongside CMRO2. Additionally, electroencephalogram (EEG) recording was used to identify changes in neuronal activities under the same anesthetic regimen employed in the MRI experiments. We found suppression of the CMRO2 by isoflurane in a dose‐dependent manner, concomitant with a diminished high‐frequency EEG activity. The degree of metabolic suppression by isoflurane was strongly correlated with the respiration rate, which offers a potential approach to calibrate CMRO2 measurements. Furthermore, the metabolic level associated with neural responses of the somatosensory and motor cortices in mice was estimated as 308.2 μmol/100 g/min. These findings may facilitate the integration of metabolic parameters into future studies involving animal disease models and anesthesia usage. [ABSTRACT FROM AUTHOR]

Honey bee, Apis mellifera L. (Hymenoptera: Apidae), colonies and individuals respond variably to disturbances. The response depends on perception and interpretation of stimuli requiring both neural modulation and use of energy. In this study, we examined the role of neural modulation and brain metabolism in constitutive and experience‐dependent differences in defensive response. For constitutive differences, we compared brain gene expression in bees from gentle and defensive colonies identified in a standard colony‐level assay. For experience‐dependent changes in defensiveness response, we compared brain gene expression in control bees and bees that responded by sting extension to electric shock in a standardized individual behavioral assay. In both experiments, for neuromodulation, we examined membrane receptor genes for the biogenic amines dopamine (DopR2), octopamine (OA1), and serotonin (5HT2a), as well the gene for the enzyme responsible for serotonin synthesis (THR). For neural metabolism, we examined the expression of two Oxidative Phosphorylation Pathway “OXPHOS” genes (ND51 and ND20‐LIKE). Bees collected from defensive colonies had a significantly lower expression of amine receptor, synthesis gene, and OXPHOS genes. However, bees responding to noxious stimuli (i.e., electric shock) showed greater gene expression for both OXPHOS and neuromodulation genes, except for 5HT2a. We discuss the intriguing intersection of neuromodulation and neural metabolism in defensive response both for constitutive differences, and contrasting experience dependent or adaptive differences. [ABSTRACT FROM AUTHOR]

Cholesterol is a critical molecule in the central nervous system, and imbalances in the synthesis and metabolism of brain cholesterol can result in a range of pathologies, including those related to hyperexcitability. The impact of cholesterol on disorders of epilepsy and developmental and epileptic encephalopathies is an area of growing interest. Cholesterol cannot cross the blood–brain barrier, and thus the brain synthesizes and metabolizes its own pool of cholesterol. The primary metabolic enzyme for brain cholesterol is cholesterol 24‐hydroxylase (CH24H), which metabolizes cholesterol into 24S‐hydroxycholesterol (24HC). Dysregulation of CH24H and 24HC can affect neuronal excitability through a range of mechanisms. 24HC is a positive allosteric modulator of N‐methyl‐D‐aspartate (NMDA) receptors and can increase glutamate release via tumor necrosis factor‐α‐dependent pathways. Increasing cholesterol metabolism can lead to dysfunction of excitatory amino acid transporter 2 and impair glutamate reuptake. Finally, overstimulation of NMDA receptors can further activate metabolism of cholesterol, leading to a vicious cycle of overactivation. All of these mechanisms increase extracellular glutamate and can lead to hyperexcitability. For these reasons, the cholesterol pathway represents a new potential mechanistic target for antiseizure medications. CH24H inhibition has been shown to decrease seizure behavior and improve survival in multiple animal models of epilepsy and could be a promising new mechanism of action for the treatment of neuronal hyperexcitability and developmental and epileptic encephalopathies. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injuries (TBIs) are one of the leading causes of death or long‐term disability around the world. As a result of improvements in supportive care, patients are surviving more severe insults with more pronounced dependency on their families, hospitals, and long‐term care facilities. The introduction of brain tissue oxygenation (PbtO2) monitoring aims to recognize episodes of reduced cerebral perfusion with and without associated increased intracranial pressure (ICP). Aim: The aim of this review is to determine the impact of PbtO2 on the Glasgow Outcome Scale/Glasgow Outcome Scale Extended (GOS/GOSE) in patients with moderate to severe TBI. Study Design: Systematic review with narrative and meta‐analysis. All original research in which adult patients undergoing PbtO2 were compared with a control group of traditional ICP/cerebral perfusion pressure (CPP) monitoring. Both randomized controlled trials and observational studies were included in this review. Methods: Databases were searched in September 2022. The primary outcome of the review was the impact of PbtO2 monitoring on GOS/GOSE, while secondary outcomes were mortality and length of stay (LOS) in the intensive care unit (ICU). Results: Seven studies with a combined number of 770 patients were included in the review. These patients were adults ≥16 years of age. Only two of the studies included found a statistically significant association between PbtO2 monitoring and improved long‐term neurological outcomes in patients with TBI (p =.01, p <.01). A meta‐analysis of the secondary outcomes identified an associated reduction of mortality in favour of the group treated with PbtO2 monitoring (p <.0001). Results from studies examining LOS in ICU have demonstrated an associated increase of LOS in ICU in patients treated with PbtO2‐guided therapy. Conclusion: From the studies included in this review, only two found a statistically significant association between PbtO2 monitoring and long‐term outcomes. It is unclear whether PbtO2 goal‐directed therapy has a positive impact on the long‐term neurological functions and mortality of patients suffering from TBI. A multicentre randomized controlled trial may provide further evidence, but not necessarily conclusive. Relevance to Clinical Practice: Further research is warranted to determine the efficacy of the introduction of this new monitoring system to guide local policy change. [ABSTRACT FROM AUTHOR]

A significant fraction of the popular inbred C57Bl/6J mice show structural and biochemical features of the congenital portosystemic shunt (PSS). How this hepatic abnormality affects physiological and behavioural parameters has not been explored in detail. Here, we confirmed the frequent occurrence of the PSS in C57Bl/6J mice by three different methods. We screened a cohort of 119 C57Bl/6J mice for total bile acids (TBA) in plasma, identified 11 animals (9.2%) with high TBA (>11 µm; 171.1 ± 76.8 µm), and confirmed PSS presence in that subset by magnetic resonance angiography and 1H‐magnetic resonance spectroscopy of brain metabolites in the hippocampal area. In addition to the high glutamine and low myo‐inositol levels, we detected lower levels of several neurotransmitters and metabolites in the hippocampus, higher brain weight and volume, as well as enhanced brain glucose utilisation in the PSS mice. We also observed differences in peripheral organ weights, haematological cell counts and clinical chemistry parameters in C57Bl/6J mice with and without PSS. Animals with PSS were slightly hyperlocomotive, had better balance on the rotarod, showed altered gait properties, and displayed attenuated fear memory in the fear conditioning test. Furthermore, we revealed a significant alteration of the pharmacokinetic profile of diazepam in C57Bl/6J mice with PSS. Our data support previous reports of hepatic disturbances and demonstrate an altered neurobiological phenotype in C57Bl/6J mice with PSS. Such congenital differences between inbred C57Bl/6J littermates may significantly distort experimental outcomes of pharmacological, behavioural and genetic studies. Key points: A significant proportion of C57Bl/6J mice, an inbred strain popular in preclinical research, have congenital portosystemic shunts (PSS) that allow venous blood to enter systemic circulation bypassing the liver.In this study, we extended existing knowledge of PSS consequences, particularly with respect to the effects on brain structure and function.We demonstrated that C57Bl/6J mice with PSS differ from their normal counterparts in brain size and contents of several neuroactive substances, as well as in peripheral organ weights, rate of glucose utilisation, blood cell counts and blood clinical chemistry parameters.C57Bl/6J mice with PSS showed altered locomotor behaviour, performed worse in a memory test and had abnormal blood pharmacokinetics of a benzodiazepine drug after a single administration.PSS presence may significantly complicate the interpretation of experiments in C57Bl/6J mice; therefore, we propose that before their use in biomedical studies, these mice should be screened with a simple blood test. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well‐known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient‐induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. METHODS: Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock‐in (APPSAA) mice using two‐photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. RESULTS: NiMA is inhibited in APPSAA mice before other defects are detected in these Aβ‐producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. DISCUSSION: NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA mice, and may represent an early stage in human AD. Highlights: Amyloid beta blocks communication between lysosomes and mitochondria in vivo.Nutrient‐induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock‐in (APPSAA/+) mice.NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice.Pharmacological interventions can rescue AD‐related NiMA disruption in vivo. [ABSTRACT FROM AUTHOR]

Hypoxic‐ischemic encephalopathy (HIE) is a common neurological syndrome in newborns with high mortality and morbidity. Therapeutic hypothermia (TH), which is standard of care for HIE, mitigates brain injury by suppressing anaerobic metabolism. However, more than 40% of HIE neonates have a poor outcome, even after TH. This study aims to provide metabolic biomarkers for predicting the outcomes of hypoxia‐ischemia (HI) after TH using hyperpolarized [1‐13C] pyruvate magnetic resonance spectroscopy. Postnatal day 10 (P10) mice with HI underwent TH at 1 h and were scanned at 6–8 h (P10), 24 h (P11), 7 days (P17), and 21 days (P31) post‐HI on a 14.1‐T NMR spectrometer. The metabolic images were collected, and the conversion rate from pyruvate to lactate and the ratio of lactate to pyruvate in the injured left hemisphere (kPL(L) and Lac/Pyr(L), respectively) were calculated at each timepoint. The outcomes of TH were determined by the assessments of brain injury on T2‐weighted images and behavioral tests at later timepoint. kPL(L) and Lac/Pyr(L) over time between the good‐outcome and poor‐outcome groups and across timepoints within groups were analyzed. We found significant differences in temporal trends of kPL(L) and Lac/Pyr(L) between groups. In the good‐outcome group, kPL(L) increased until P31 with a significantly higher value at P31 compared with that at P10, while the level of Lac/Pyr(L) at P31 was notably higher than those at all other timepoints. In the poor‐outcome group, kPL(L) and Lac/Pyr(L) increased within 24 h. The kPL(L) value at P11 was considerably higher compared with P10. Discrete temporal changes of kPL(L) and Lac/Pyr(L) after TH between the good‐outcome and poor‐outcome groups were seen as early as 24 h after HI, reflecting various TH effects on brain anaerobic metabolism, which may provide insights for early screening for response to TH. [ABSTRACT FROM AUTHOR]

Phosphorus (31P) magnetic resonance spectroscopic imaging (MRSI) can serve as a critical tool for more direct quantification of brain energy metabolism, tissue pH, and cell membrane turnover. However, the low concentration of 31P metabolites in biological tissue may result in low signal‐to‐noise ratio (SNR) in 31P MRS images. In this work, we present an innovative design and construction of a 31P radiofrequency coil for whole‐brain MRSI at 7 T. Our coil builds on current literature in ultra‐high field 31P coil design and offers complete coverage of the brain, including the cerebellum and brainstem. The coil consists of an actively detunable volume transmit (Tx) resonator and a custom 24‐channel receive (Rx) array. The volume Tx resonator is a 16‐rung high‐pass birdcage coil. The Rx coil consists of a 24‐element phased array composed of catered loop shapes and sizes built onto a custom, close‐fitting, head‐shaped housing. The Rx array was designed to provide complete coverage of the head, while minimizing mutual coupling. The Rx configuration had a mean S11 reflection coefficient better than −20 decibels (dB) when the coil was loaded with a human head. The mean mutual coupling (S21) among Rx elements, when loaded with a human head, was −16 dB. In phantom imaging, the phased array produced a central SNR that was 4.4‐fold higher than the corresponding central SNR when operating the 31P birdcage as a transceiver. The peripheral SNR was 12‐fold higher when applying the optimized phased array. In vivo 3D 31P MRSI experiments produced high‐quality spectra in the cerebrum gray and white matter, as well as in the cerebellum. Characteristic phosphorus metabolites related to adenosine triphosphate metabolism and cell membrane turnover were distinguishable across all brain regions. In summary, our results demonstrate the potential of our novel coil for accurate, whole‐brain 31P metabolite quantification. [ABSTRACT FROM AUTHOR]

Key points There is evidence that aerobic exercise improves brain health. Benefits may be modulated by acute physiological responses to exercise, but this has not been well characterized in older or cognitively impaired adults. The randomized controlled trial ‘AEROBIC’ (NCT04299308) enrolled 60 older adults who were cognitively healthy (n = 30) or cognitively impaired (n = 30) to characterize the acute brain responses to moderate [45–55% heart rate reserve (HRR)] and higher (65–75% HRR) intensity acute exercise. Each participant received two fluorodeoxyglucose positron emission tomography (FDG‐PET) scans, one at rest and one following acute exercise. Change in cerebral glucose metabolism from rest to exercise was the primary outcome. Blood biomarker responses were also characterized as secondary outcomes. Whole grey matter FDG‐PET standardized uptake value ratio (SUVR) differed between exercise (1.045 ± 0.082) and rest (0.985 ± 0.077) across subjects [Diff = −0.060, t(58) = 13.8, P < 0.001] regardless of diagnosis. Exercise increased lactate area under the curve (AUC) [F(1,56) = 161.99, P < 0.001] more in the higher intensity group [mean difference (MD) = 97.0 ± 50.8] than the moderate intensity group (MD = 40.3 ± 27.5; t = −5.252, P < 0.001). Change in lactate AUC and FDG‐PET SUVR correlated significantly (R2 = 0.179, P < 0.001). Acute exercise decreased whole grey matter cerebral glucose metabolism. This effect tracked with the systemic lactate response, suggesting that lactate may serve as a key brain fuel during exercise. Direct measurements of brain lactate metabolism in response to exercise are warranted. Acute exercise is associated with a drop in global brain glucose metabolism in both cognitively healthy older adults and those with Alzheimer's disease. Blood lactate levels increase following acute exercise. Change in brain metabolism tracks with blood lactate, suggesting it may be an important brain fuel. Acute exercise stimulates changes in brain‐derived neurotrophic factor and other blood biomarkers. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) have identified hundreds of common variants associated with alcohol consumption. In contrast, genetic studies of alcohol consumption that use rare variants are still in their early stages. No prior studies of alcohol consumption have examined whether common and rare variants implicate the same genes and molecular networks, leaving open the possibility that the two approaches might identify distinct biology. Methods: To address this knowledge gap, we used publicly available alcohol consumption GWAS summary statistics (GSCAN, N = 666,978) and whole exome sequencing data (Genebass, N = 393,099) to identify a set of common and rare variants for alcohol consumption. We used gene‐based analysis to implicate genes from common and rare variant analyses, which we then propagated onto a shared molecular network using a network colocalization procedure. Results: Gene‐based analysis of each dataset implicated 294 (common variants) and 35 (rare variants) genes, including ethanol metabolizing genes ADH1B and ADH1C, which were identified by both analyses, and ANKRD12, GIGYF1, KIF21B, and STK31, which were identified in only the rare variant analysis, but have been associated with other neuropsychiatric traits. Network colocalization revealed significant network overlap between the genes identified via common and rare variants. The shared network identified gene families that function in alcohol metabolism, including ADH, ALDH, CYP, and UGT. Seventy‐one of the genes in the shared network were previously implicated in neuropsychiatric or substance use disorders but not alcohol‐related behaviors (e.g. EXOC2, EPM2A, and CACNG4). Differential gene expression analysis showed enrichment in the liver and several brain regions. Conclusions: Genes implicated by network colocalization identify shared biology relevant to alcohol consumption, which also underlie neuropsychiatric traits and substance use disorders that are comorbid with alcohol use, providing a more holistic understanding of two disparate sources of genetic information. [ABSTRACT FROM AUTHOR]

D‐Glyceraldehyde, a reactive aldehyde metabolite of fructose and glucose, is neurotoxic in vitro by forming advanced glycation end products (AGEs) with neuronal proteins. In Alzheimer's disease brains, glyceraldehyde‐containing AGEs have been detected intracellularly and in extracellular plaques. However, little information exists on how the brain handles D‐glyceraldehyde metabolically or if glyceraldehyde crosses the blood–brain barrier from the circulation into the brain. We injected [U‐13C]‐D‐glyceraldehyde intravenously into awake mice and analyzed extracts of serum and brain by 13C nuclear magnetic resonance spectroscopy. 13C‐Labeling of brain lactate and glutamate indicated passage of D‐glyceraldehyde from blood to brain and glycolytic and oxidative D‐glyceraldehyde metabolism in brain cells. 13C‐Labeling of serum glucose and lactate through hepatic metabolism of [U‐13C]‐D‐glyceraldehyde could not explain the formation of 13C‐labeled lactate and glutamate in the brain. Cerebral glyceraldehyde dehydrogenase and reductase activities, leading to the formation of D‐glycerate and glycerol, respectively, were 0.27–0.28 nmol/mg/min; triokinase, which phosphorylates D‐glyceraldehyde to D‐glyceraldehyde‐3‐phosphate, has been demonstrated previously at low levels. Thus, D‐glyceraldehyde metabolism toward glycolysis could proceed both through D‐glycerate, glycerol, and D‐glyceraldehyde‐3‐phosphate. The aldehyde group of D‐glyceraldehyde was overwhelmingly hydrated into a diol in aqueous solution, but the diol dehydration rate greatly exceeded glyceraldehyde metabolism and did not restrict it. We conclude that (1) D‐glyceraldehyde crosses the blood–brain barrier, and so blood‐borne glyceraldehyde could contribute to AGE formation in the brain, (2) glyceraldehyde is taken up and metabolized by brain cells. Metabolism thus constitutes a detoxification mechanism for this reactive aldehyde, a mechanism that may be compromised in disease states. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) imaging studies in laboratory animals are almost always performed under isoflurane anesthesia to ensure that the subject stays still during the image acquisition. Isoflurane is effective, safe, and easy to use, and it is generally assumed to not have an impact on the imaging results. Motivated by marked differences observed in the brain uptake and metabolism of the PET tracer 3‐[18F]fluoro‐4‐aminopyridine [(18F]3F4AP) between human and nonhuman primate studies, this study investigates the possible effect of isoflurane on this process. Mice received [18F]3F4AP injection while awake or under anesthesia and the tracer brain uptake and metabolism was compared between groups. A separate group of mice received the known cytochrome P450 2E1 inhibitor disulfiram prior to tracer administration. Isoflurane was found to largely abolish tracer metabolism in mice (74.8 ± 1.6 vs. 17.7 ± 1.7% plasma parent fraction, % PF) resulting in a 4.0‐fold higher brain uptake in anesthetized mice at 35 min post‐radiotracer administration. Similar to anesthetized mice, animals that received disulfiram showed reduced metabolism (50.0 ± 6.9% PF) and a 2.2‐fold higher brain signal than control mice. The higher brain uptake and lower metabolism of [18F]3F4AP observed in anesthetized mice compared to awake mice are attributed to isoflurane's interference in the CYP2E1‐mediated breakdown of the tracer, which was confirmed by reproducing the effect upon treatment with the known CYP2E1 inhibitor disulfiram. These findings underscore the critical need to examine the effect of isoflurane in PET imaging studies before translating tracers to humans that will be scanned without anesthesia. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the feasibility of downfield MR spectroscopic imaging (DF‐MRSI) in the human brain at 7T. Methods: A 7T DF‐MRSI pulse sequence was implemented based on the previously described methodology at 3T, with 3D phase‐encoding, 13‾31‾$$ 1\overline{3}3\overline{1} $$ spectral‐spatial excitation, and frequency selective refocusing. Data were pre‐processed followed by analysis using the "LCModel" software package, and metabolite maps created from the LCModel results. Total scan time, including brain MRI and a water‐reference MRSI, was 24 min. The sequence was tested in 10 normal volunteers. Estimated metabolite levels and uncertainty values (Cramer Rao lower bounds, CRLBs) for nine downfield peaks were compared between seven different brain regions, anterior cingulate cortex (ACC), centrum semiovale (CSO), corpus callosum (CC), cerebellar vermis (CV), dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC), and thalamus (Thal). Results: DF peaks were relatively uniformly distributed throughout the brain, with only a small number of peaks showing any significant regional variations. Most DF peaks had average CRLB<25% in most brain regions. Average SNR values were higher for the brain regions ACC and DLPFC (˜7 ± 0.95, mean ± SD) while in a range of 3.4–6.0 for other brain regions. Average linewidth (FWHM) values were greater than 35 Hz in the ACC, CV, and Thal, and 22 Hz in CC, CSO, DLPFC, and PCC. Conclusion: High‐field DF‐MRSI is able to spatially map exchangeable protons in the human brain at high resolution and with near whole‐brain coverage in acceptable scan times, and in the future may be used to study metabolism of brain tumors or other neuropathological disorders. [ABSTRACT FROM AUTHOR]

Objective: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. Methods: We included 30 patients with PSP‐Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F‐florzolotau positron emission tomography. Myo‐inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. Results: The levels of myo‐inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo‐inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. Interpretation: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo‐inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247–261 [ABSTRACT FROM AUTHOR]

INTRODUCTION: Brain glucose hypometabolism is a preclinical feature of Alzheimer's disease (AD). Dietary omega‐3 fatty acids promote brain glucose metabolism, but clinical research is incipient. Circulating omega‐3s objectively reflect their dietary intake. METHODS: This was a cross‐sectional study in 320 cognitively unimpaired participants at increased risk of AD dementia. Using lipidomics, we determined blood docosahexaenoic (DHA) and alpha‐linolenic (ALA) acid levels (omega‐3s from marine and plant origin, respectively). We assessed brain glucose metabolism using [18‐F]‐fluorodeoxyglucose (FDG) positron emission tomography (PET). RESULTS: Blood ALA directly related to FDG uptake in brain areas known to be affected in AD. Stronger associations were observed in apolipoprotein E ε4 carriers and homozygotes. For DHA, significant direct associations were restricted to amyloid beta–positive tau‐positive participants. DISCUSSION: Blood omega‐3 directly relate to preserved glucose metabolism in AD‐vulnerable brain regions in individuals at increased risk of AD dementia. This adds to the benefits of omega‐3 supplementation in the preclinical stage of AD dementia. Highlights: Blood omega‐3s were related to brain glucose uptake in participants at risk of Alzheimer's disease (AD) dementia.Complementary associations were observed for omega‐3 from marine and plant sources.Foods rich in omega‐3 might be useful in early features of AD. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) is a complex neuropsychiatric disorder widely recognized for its impaired bioenergy utilization. The astrocyte‐neuron lactate shuttle (ANLS) plays a critical role in brain energy supply. Recent studies have revealed abnormal lactate metabolism in SCZ, which is associated with mitochondrial dysfunction, tissue hypoxia, gastric acid retention, oxidative stress, neuroinflammation, abnormal brain iron metabolism, cerebral white matter hypermetabolic activity, and genetic susceptibility. Furthermore, astrocytes, neurons, and glutamate abnormalities are prevalent in SCZ with abnormal lactate metabolism, which are essential components for maintaining ANLS in the brain. Therefore, an in‐depth study of the pathophysiological mechanisms of ANLS in SCZ with abnormal lactate metabolism will contribute to a better understanding of the pathogenesis of SCZ and provide new ideas and approaches for the diagnosis and treatment of SCZ. [ABSTRACT FROM AUTHOR]

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research. [ABSTRACT FROM AUTHOR]

This Preface introduces the Special Issue entitled, “Energy Substrates and Microbiome Govern Brain Bioenergetics and Cognitive Function with Aging”, which is comprised of manuscripts contributed by invited speakers and program/organizing committee members who participated in the 14th International Conference on Brain Energy Metabolism (ICBEM) held on October 24–27, 2022 in Santa Fe, New Mexico, USA. The conference covered the latest developments in research related to neuronal energetics, emerging roles for glycogen in higher brain functions, the impact of dietary intervention on aging, memory, and Alzheimer's disease, roles of the microbiome in gut-brain signaling, astrocyte-neuron interactions related to cognition and memory, novel roles for mitochondria and their metabolites, and metabolic neuroimaging in aging and neurodegeneration. The special issue contains 25 manuscripts on these topics plus three tributes to outstanding scientists who have made important contributions to brain energy metabolism and participated in numerous ICBEM conferences. In addition, two of the manuscripts describe important directions and the rationale for future research in many thematic areas covered by the conference. [ABSTRACT FROM AUTHOR]

Brain fuel (specifically, glucose) supply and metabolism are well-established to be limiting factors for cognitive performance, with the largest body of data being for hippocampally mediated tasks. Consistent with this, disease states such as Alzheimer's disease and insulin-resistant diabetes, that impair cognitive metabolism, impair cognition with this being shown again most prominently for hippocampally mediated processes. In addition to glucose supplied from the blood, brain oxidative metabolism can use local glycogen stores (within astrocytes) as a fuel source via conversion to lactate; both lactate and glycogen have been shown to be important contributors to regulation of cognitive metabolism. Insulin has been shown to be a key regulator of hippocampal cognitive and metabolic processes; in the periphery, insulin facilitates glycogen synthesis and storage, but the impact on brain glycogen is unclear. Furthermore, the impact of diet-induced diabetes on hippocampal glycogen levels and/or metabolism is unknown. Here, we show that in rats with high-fat diet-induced diabetes, hippocampal glycogen is reduced and is less responsive to acute intrahippocampal administration of insulin, which significantly reduces glycogen in the hippocampi of control animals: Our data suggest that impaired fuel availability from glycogen may be a contributing factor to the cognitive impairment seen in disease states that include central insulin resistance. [ABSTRACT FROM AUTHOR]

The metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply. Glucose is considered an obligate fuel for supporting brain metabolism. Although alternative fuels are often available, the extent of their contribution to central carbon metabolism remains debated. Differential fuel metabolism likely depends on cell type, location, and activity state, complicating its study. While biosensors provide excellent spatial and temporal information, they are limited to observations of only a few metabolites. On the other hand, mass spectrometry is rich in chemical information, but traditionally relies on cell culture or homogenized tissue samples. Here, we use mass spectrometry imaging (MALDI-MSI) to focus on the fuel metabolism of the dentate granule cell (DGC) layer in murine hippocampal slices. Using stable isotopes, we explore labeling dynamics at baseline, as well as in response to brief stimulation or fuel competition. We find that at rest, glucose is the predominant fuel metabolized through glycolysis, with little to no measurable contribution from glycerol or fructose. However, lactate/pyruvate, β-hydroxybutyrate (βHB), octanoate, and glutamine can contribute to TCA metabolism to varying degrees. In response to brief depolarization with 50 mM KCl, glucose metabolism was preferentially increased relative to the metabolism of alternative fuels. With an increased supply of alternative fuels, both lactate/pyruvate and βHB can outcompete glucose for TCA cycle entry. While lactate/pyruvate modestly reduced glucose contribution to glycolysis, βHB caused little change in glycolysis. This approach achieves broad metabolite coverage from a spatially defined region of physiological tissue, in which metabolic states are rapidly preserved following experimental manipulation. Using this powerful methodology, we investigated metabolism within the dentate gyrus not only at rest, but also in response to the energetic demand of activation, and in states of fuel competition. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is a key sensor of energy balance playing important roles in the balancing of anabolic and catabolic activities. The high energy demands of the brain and its limited capacity to store energy indicate that AMPK may play a significant role in brain metabolism. Here, we activated AMPK in guinea pig cortical tissue slices, both directly with A769662 and PF 06409577 and indirectly with AICAR and metformin. We studied the resultant metabolism of [1-13C]glucose and [1,2-13C]acetate using NMR spectroscopy. We found distinct activator concentrationdependent effects on metabolism, which ranged from decreased metabolic pool sizes at EC50 activator concentrations with no expected stimulation in glycolytic flux to increased aerobic glycolysis and decreased pyruvate metabolism with certain activators. Further, activation with direct versus indirect activators produced distinct metabolic outcomes at both low (EC50) and higher (EC50× 10) concentrations. Specific direct activation of β1-containing AMPK isoforms with PF 06409577 resulted in increased Krebs cycle activity, restoring pyruvate metabolism while A769662 increased lactate and alanine production, as well as labelling of citrate and glutamine. These results reveal a complex metabolic response to AMPK activators in brain beyond increased aerobic glycolysis and indicate that further research is warranted into their concentration- and mechanism-dependent impact. [ABSTRACT FROM AUTHOR]

This is a tribute to Sebastián Cerdán, a brilliant and innovative NMR spectroscopist whose studies contributed greatly to the fundamental information to the understanding of brain metabolism, particularly in regard to multinuclear magnetic resonance spectroscopy (MRS) techniques. Sebastián Cerdán sadly passed away in May 2022. He was a wonderful mentor and colleague who will be greatly missed. [ABSTRACT FROM AUTHOR]

This is a tribute to John Edmond, professor emeritus of biological chemistry in the David Geffen School of Medicine at UCLA, a renowned neurochemist who had a leadership role in founding the ICBEM meeting series in 1993. John was known for his very warm and engaging personality and his innovative approaches to studying the developing brain and auditory system. He was a brilliant scientist and a fun and delightful person. Without John Edmond's enthusiasm and contributions, we would not have the biennial ICBEM meetings which as noted by Dienel et al. “have had a high impact on conceptual and experimental advances” … “in the energetics and metabolism underlying neural functions”… and “on promoting collaborative interactions among neuroscientists.” Sadly, John Edmond passed away on February 18, 2022, following a cerebral hemorrhage. He will be greatly missed by his colleagues and friends. [ABSTRACT FROM AUTHOR]

Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non-metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n-GSDs). n-GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late-onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n-GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease. [ABSTRACT FROM AUTHOR]

Genetically encoded fluorescent biosensors provide an attractive means of measuring chemical changes in single cells on fast timescales (milliseconds to seconds). While their most prominent application has been in tracking neural activity and neurotransmitter release, there has been growing interest in developing and deploying new versions of these tools to study brain metabolism. However, the careful use of these tools and the interpretation of the data they provide remain challenging. Many biosensors are subject to interferences that can alter sensor responses within a single cell or between cells, producing ambiguous results. This presents a challenge for quantitation and for our ability to accurately interpret sensor responses. This review describes current methods of sensor quantitation, with a focus on cellular interferences that commonly affect sensor performance, ways to avoid false inferences, and recent advances in sensor optimization to make them more robust. [ABSTRACT FROM AUTHOR]

The brain requires large quantities of energy to sustain its functions. At the same time, the brain is isolated from the rest of the body, forcing this organ to develop strategies to control and fulfill its own energy needs. Likely based on these constraints, several brain-specific mechanisms emerged during evolution. For example, metabolically specialized cells are present in the brain, where intercellular metabolic cycles are organized to separate workload and optimize the use of energy. To orchestrate these strategies across time and space, several signaling pathways control the metabolism of brain cells. One of such controlling systems is the endocannabinoid system, whose main signaling hub in the brain is the type-1 cannabinoid (CB1) receptor. CB1 receptors govern a plethora of different processes in the brain, including cognitive function, emotional responses, or feeding behaviors. Classically, the mechanisms of action of CB1 receptors on brain function had been explained by its direct targeting of neuronal synaptic function. However, new discoveries have challenged this view. In this review, we will present and discuss recent data about how a small fraction of CB1 receptors associated to mitochondrial membranes (mtCB1), are able to exert a powerful control on brain functions and behavior. mtCB1 receptors impair mitochondrial functions both in neurons and astrocytes. In the latter cells, this effect is linked to an impairment of astrocyte glycolytic function, resulting in specific behavioral outputs. Finally, we will discuss the potential implications of (mt)CB1 expression on oligodendrocytes and microglia metabolic functions, with the aim to encourage interdisciplinary approaches to better understand the role of (mt)CB1 receptors in brain function and behavior. [ABSTRACT FROM AUTHOR]

Leif Hertz, M.D., D.Sc. (honōris causā) (1930–2018), was one of the original and noteworthy participants in the International Conference on Brain Energy Metabolism (ICBEM) series since its inception in 1993. The biennial ICBEM conferences are organized by neuroscientists interested in energetics and metabolism underlying neural functions; they have had a high impact on conceptual and experimental advances in these fields and on promoting collaborative interactions among neuroscientists. Leif made major contributions to ICBEM discussions and understanding of metabolic and signaling characteristics of astrocytes and their roles in brain function. His studies ranged from uptake of K+ from extracellular fluid and its stimulation of astrocytic respiration, identification, and regulation of enzymes specifically or preferentially expressed in astrocytes in the glutamate–glutamine cycle of excitatory neurotransmission, a requirement for astrocytic glycogenolysis for fueling K+ uptake, involvement of glycogen in memory consolidation in the chick, and pharmacology of astrocytes. This tribute to Leif Hertz highlights his major discoveries, the high impact of his work on astrocyte–neuron interactions, and his unparalleled influence on understanding the cellular basis of brain energy metabolism. His work over six decades has helped integrate the roles of astrocytes into neurotransmission where oxidative and glycogenolytic metabolism during neurotransmitter glutamate turnover are key aspects of astrocytic energetics. Leif recognized that brain astrocytic metabolism is greatly underestimated unless the volume fraction of astrocytes is taken into account. Adjustment for pathway rates expressed per gram tissue for volume fraction indicates that astrocytes have much higher oxidative rates than neurons and astrocytic glycogen concentrations and glycogenolytic rates during sensory stimulation in vivo are similar to those in resting and exercising muscle, respectively. These novel insights are typical of Leif's astute contributions to the energy metabolism field, and his publications have identified unresolved topics that provide the neuroscience community with challenges and opportunities for future research. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a complex chronic metabolic disorder characterized by hyperglycemia because of insulin resistance. Diabetes with chronic hyperglycemia may alter brain metabolism, including brain glucose and neurotransmitter levels; however, detailed, longitudinal studies of metabolic alterations in T2D are lacking. To shed insight, here, we characterized the consequences of poorly controlled hyperglycemia on neurochemical profiles that reflect metabolic alterations of the brain in both humans and animal models of T2D. Using in vivo 1 H magnetic resonance spectroscopy, we quantified 12 metabolites cross-sectionally in T2D patients and 20 metabolites longitudinally in T2D db/db mice versus db+ controls. We found significantly elevated brain glucose (91%, p< 0.001), taurine (22%, p= 0.02), glucose+taurine (56%, p< 0.001), myo-inositol (12%, p= 0.02), and choline-containing compounds (10%, p= 0.01) in T2D patients versus age- and sex-matched controls, findings consistent with measures in T2D db/db versus control db+ littermates. In mice, hippocampal and striatal neurochemical alterations in brain glucose, ascorbate, creatine, phosphocreatine, γ-aminobutyric acid, glutamate, glutamine, glutathione, glycerophosphorylcholine, lactate, myo-inositol, and taurine persisted in db/db mice with chronic disease progression from 16 to 48 weeks of age, which were distinct from control db+ mice. Overall, our study demonstrates the utility of 1 H magnetic resonance spectroscopy as a non-invasive tool for characterizing and monitoring brain metabolic changes with T2D progression. [ABSTRACT FROM AUTHOR]

Objectives: Mild cognitive impairment presenting with an amnestic syndrome (aMCI) and amyloid positivity is considered due to AD. Many subjects, however, can show an overall very slow progression relevant for differential diagnosis, prognosis, and treatment. This study assessed PET biomarkers, including brain glucose metabolism, tau, and amyloid load, in a series of comparable aMCI at baseline, clinically evaluated at follow‐up. Methods: We included 72 aMCI subjects from Geneva Memory Center (N = 31) and ADNI cohorts (N = 41), selected based on available FDG‐PET, tau‐PET, amyloid‐PET, and clinical follow‐up (2.3 years ± 1.2). A data‐driven algorithm classified brain metabolic patterns into subtypes that were then compared for clinical and PET biomarker measures and cognitive decline. Voxel‐wise comparisons were performed both with FDG‐PET and tau‐PET data. Results: The algorithm classified three metabolic subtypes, namely "Hippocampal‐sparing with cortical hypometabolism" (Type1; N = 27), "Hippocampal and cortical hypometabolism" (Type 2; N = 23), and "Medial temporal hypometabolism" (Type 3; N = 22). Amyloid positivity and tau accumulation in the medial temporal and neocortical regions characterized Type 1 and Type 2, whereas Type 3 showed no significant tau pathology, variable amyloid positivity, and stability at follow‐up. All tau‐positive patients, independently of the FDG‐based subtype, showed faster cognitive decline. Interpretation: aMCI subjects can differ in metabolic patterns, tau and amyloid pathology, and clinical progression. Here, we complemented with PET tau biomarker the specific brain hypometabolic patterns at the individual level in the prodromal phase, contributing to the patient's classification. Tau PET is the most accurate biomarker in supporting or excluding the AD diagnosis in aMCI across metabolic subtypes and also predicting the risk of decline. [ABSTRACT FROM AUTHOR]

Functional MRI (fMRI) and MRS (fMRS) can be used to noninvasively map cerebral activation and metabolism. Recently, hyperpolarized 13C spectroscopy and metabolic imaging have provided an alternative approach to assess metabolism. In this study, we combined 1H fMRI and hyperpolarized [1‐13C]pyruvate MRS to compare cerebral blood oxygenation level‐dependent (BOLD) response and real‐time cerebral metabolism, as assessed with lactate and bicarbonate labelling, during nicotine stimulation. Simultaneous 1H fMRI (multislice gradient echo echo‐planar imaging) and 13C spectroscopic (single slice pulse‐acquire) data were collected in urethane‐anaesthetized female Sprague–Dawley rats (n = 12) at 9.4 T. Animals received an intravenous (i.v.) injection of either nicotine (stimulus; 88 μg/kg, n = 7, or 300 μg/kg, n = 5) or 0.9% saline (matching volume), followed by hyperpolarized [1‐13C]pyruvate injection 60 s later. Three hours later, a second injection was administered: the animals that had previously received saline were injected with nicotine and vice versa, both followed by another hyperpolarized [1‐13C]pyruvate i.v. injection 60 s later. The low‐dose (88 μg/kg) nicotine injection led to a 12% ± 4% (n = 7, t‐test, p ~ 0.0006 (t‐value −5.8, degrees of freedom 6), Wilcoxon p ~ 0.0078 (test statistic 0)) increase in BOLD signal. At the same time, an increase in 13C‐bicarbonate signal was seen in four out of six animals. Bicarbonate‐to‐total carbon ratios were 0.010 ± 0.004 and 0.018 ± 0.010 (n = 6, t‐test, p ~ 0.03 (t‐value −2.3, degrees of freedom 5), Wilcoxon p ~ 0.08 (test statistic 3)) for saline and nicotine experiments, respectively. No increase in the lactate signal was seen; lactate‐to‐total carbon was 0.16 ± 0.02 after both injections. The high (300 μg/kg) nicotine dose (n = 5) caused highly variable BOLD and metabolic responses, possibly due to the apparent respiratory distress. Simultaneous detection of 1H fMRI and hyperpolarized 13C‐MRS is feasible. A comparison of metabolic response between control and stimulated states showed differences in bicarbonate signal, implying that the hyperpolarization technique could offer complimentary information on brain activation. [ABSTRACT FROM AUTHOR]

Depression is a serious public health problem, and adolescence is an 'age of risk' for the onset of Major Depressive Disorder. Recently, we and others have proposed neuroimmune network models that highlight bidirectional communication between the brain and the immune system in both mental and physical health, including depression. These models draw on research indicating that the cellular actors (particularly monocytes) and signaling molecules (particularly cytokines) that orchestrate inflammation in the periphery can directly modulate the structure and function of the brain. In the brain, inflammatory activity heightens sensitivity to threats in the cortico‐amygdala circuit, lowers sensitivity to rewards in the cortico‐striatal circuit, and alters executive control and emotion regulation in the prefrontal cortex. When dysregulated, and particularly under conditions of chronic stress, inflammation can generate feelings of dysphoria, distress, and anhedonia. This is proposed to initiate unhealthy, self‐medicating behaviors (e.g. substance use, poor diet) to manage the dysphoria, which further heighten inflammation. Over time, dysregulation in these brain circuits and the inflammatory response may compound each other to form a positive feedback loop, whereby dysregulation in one organ system exacerbates the other. We and others suggest that this neuroimmune dysregulation is a dynamic joint vulnerability for depression, particularly during adolescence. We have three goals for the present paper. First, we extend neuroimmune network models of mental and physical health to generate a developmental framework of risk for the onset of depression during adolescence. Second, we examine how a neuroimmune network perspective can help explain the high rates of comorbidity between depression and other psychiatric disorders across development, and multimorbidity between depression and stress‐related medical illnesses. Finally, we consider how identifying neuroimmune pathways to depression can facilitate a 'next generation' of behavioral and biological interventions that target neuroimmune signaling to treat, and ideally prevent, depression in youth and adolescents. [ABSTRACT FROM AUTHOR]

Background: Cognitive reserve (CR) is the mismatch between preserved cognition and neuropathological damage. Amyloidopathy in Parkinson's disease (PD) could be associated with faster progression to dementia, but the putative protective effect of CR is unknown. Objectives: To evaluate the effect of CR on β‐amyloid burden and brain metabolism in non‐demented PD subjects. Methods: Participants with PD (n = 53) underwent a clinical evaluation, [18F]‐fluorodeoxyglucose and [18F]‐flutemetamol positron emission tomography magnetic resonances, and were classified according to CR. The metabolic pattern of 16 controls was compared to PD subjects. Results: The PD subjects showed hypometabolism mainly in the bilateral posterior cortex. Superior‐CR subjects (n = 22) exhibited better cognitive performance, increased amyloid burden, and higher metabolism in several right hemisphere areas compared to low‐medium‐CR subjects (n = 31). Conclusions: Higher CR in non‐demented PD is associated with better cognitive performance, which might reduce vulnerability to the effect of β‐amyloid. Whether superior CR leads to protection against metabolic deterioration, and predominantly right hemisphere involvement, deserves further exploration. [ABSTRACT FROM AUTHOR]

Background: Late‐onset depression (LOD) is defined as primary depression that first manifests after the age of 65. Luteolin (LUT) is a natural flavonoid that has shown promising antidepressant effects and improvement in neurological function in previous studies. Aims: In this study, we utilized UPLC–MS/MS non‐targeted metabolomics techniques, along with molecular docking technology and experimental validation, to explore the mechanism of LUT in treating LOD from a metabolomics perspective. Results: The behavioral results of our study demonstrate that LUT significantly ameliorated anxiety and depression‐like behaviors while enhancing cognitive function in LOD rats. Metabolomic analysis revealed that the effects of LUT on LOD rats were primarily mediated through the glycerophospholipid metabolic pathway in the hippocampus and prefrontal cortex. The levels of key lipid metabolites, phosphatidylserine (PS), phosphatidylcholine (PC), and phosphatidylethanolamine (PE), in the glycerophospholipid metabolic pathway were significantly altered by LUT treatment, with PC and PE showing significant correlations with behavioral indices. Molecular docking analysis indicated that LUT had strong binding activity with phosphatidylserine synthase 1 (PTDSS1), phosphatidylserine synthase 2 (PTDSS2), and phosphatidylserine decarboxylase (PISD), which are involved in the transformation and synthesis of PC, PE, and PS. Lastly, our study explored the reasons for the opposing trends of PC, PE, and PS in the hippocampus and prefrontal cortex from the perspective of autophagy, which may be attributable to the bidirectional regulation of autophagy in distinct brain regions. Conclusions: Our results revealed significant alterations in the glycerophospholipid metabolism pathways in both the hippocampus and prefrontal cortex of LOD rats. Moreover, LUT appears to regulate autophagy disorders by specifically modulating glycerophospholipid metabolism in different brain regions of LOD rats, consequently alleviating depression‐like behavior in these animals. [ABSTRACT FROM AUTHOR]

The goal of this study was to investigate the origin of brain lactate (Lac) signal in the healthy anesthetized rat after injection of hyperpolarized (HP) [1‐13C]pyruvate (Pyr). Dynamic two‐dimensional spiral chemical shift imaging with flow‐sensitizing gradients revealed reduction in both vascular and brain Pyr, while no significant dependence on the level of flow suppression was detected for Lac. These results support the hypothesis that the HP metabolites predominantly reside in different compartments in the brain (i.e., Pyr in the blood and Lac in the parenchyma). Data from high‐resolution metabolic imaging of [1‐13C]Pyr further demonstrated that Lac detected in the brain was not from contributions of vascular signal attributable to partial volume effects. Additionally, metabolite distributions and kinetics measured with dynamic imaging after injection of HP [1‐13C]Lac were similar to Pyr data when Pyr was used as the substrate. These data do not support the hypothesis that Lac observed in the brain after Pyr injection was generated in other organs and then transported across the blood–brain barrier (BBB). Together, the presented results provide further evidence that even in healthy anesthetized rats, the transport of HP Pyr across the BBB is sufficiently fast to permit detection of its metabolic conversion to Lac within the brain. [ABSTRACT FROM AUTHOR]

Recent thermodynamic modelling indicates that maintaining the brain tissue ratio of O2 to CO2 (abbreviated tissue O2/CO2) is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. This provides a novel perspective for understanding physiological responses under different conditions in terms of preserving tissue O2/CO2. To enable estimation of tissue O2/CO2 in the human brain, a detailed mathematical model of O2 and CO2 transport was developed, and applied to reported physiological responses to different challenges, asking: how well is tissue O2/CO2 preserved? Reported experimental results for increased neural activity, hypercapnia and hypoxia due to high altitude are consistent with preserving tissue O2/CO2. The results highlight two physiological mechanisms that control tissue O2/CO2: cerebral blood flow, which modulates tissue O2; and ventilation rate, which modulates tissue CO2. The hypoxia modelling focused on humans at high altitude, including acclimatized lowlanders and Tibetan and Andean adapted populations, with a primary finding that decreasing CO2 by increasing ventilation rate is more effective for preserving tissue O2/CO2 than increasing blood haemoglobin content to maintain O2 delivery to tissue. This work focused on the function served by particular physiological responses, and the underlying mechanisms require further investigation. The modelling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions. Key points: Thermodynamic modelling indicates that preserving the O2/CO2 ratio in brain tissue is critical for preserving the entropy change available from oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism.A detailed model of O2 and CO2 transport was developed to allow estimation of the tissue O2/CO2 ratio in the human brain in different physiological states.Reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity are consistent with maintaining brain tissue O2/CO2 ratio.The hypoxia modelling of high‐altitude acclimatization and adaptation in humans demonstrates the critical role of reducing CO2 with increased ventilation for preserving tissue O2/CO2.Preservation of tissue O2/CO2 provides a novel perspective for understanding the function of observed physiological responses under different conditions in terms of preserving brain energy metabolism, although the mechanisms underlying these functions are not well understood. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of dementia. A genome‐wide association study has shown that several AD risk genes are involved in lipid metabolism. Additionally, epidemiological studies have indicated that the levels of several lipid species are altered in the AD brain. Therefore, lipid metabolism is likely changed in the AD brain, and these alterations might be associated with an exacerbation of AD pathology. Oligodendrocytes are glial cells that produce the myelin sheath, which is a lipid‐rich insulator. Dysfunctions of the myelin sheath have been linked to white matter abnormalities observed in the AD brain. Here, we review the lipid composition and metabolism in the brain and myelin and the association between lipidic alterations and AD pathology. We also present the abnormalities in oligodendrocyte lineage cells and white matter observed in AD. Additionally, we discuss metabolic disorders, including obesity, as AD risk factors and the effects of obesity and dietary intake of lipids on the brain. [ABSTRACT FROM AUTHOR]

Work by many groups demonstrate links between peripheral markers of inflammation and symptoms of depression. Here, Nusslock and colleagues present an update to their neuroimmune network model to incorporate a developmental lens. They propose that specific neural circuits may be responsible for causing heightened inflammation. One principal circuit includes the amygdala and prefrontal cortex and is proposed to be involved in threat detection. Thus, heightened threat sensitivity resulting from early life stress is suggested to cause increases in inflammatory signaling. Second, the authors suggest that reward circuits, including the striatum, may be targets of increased inflammation leading to symptoms of anhedonia. In this commentary, I add context to the model proposed by Nusslock et al., suggesting that taking a learning perspective and considering additional circuits, including the hippocampus and midline structures may be necessary to more fully account for the phenomena described by the authors. [ABSTRACT FROM AUTHOR]

WenDanTang (WDT) is a Chinese herbal formula used to treat various diseases, including neurodegenerative diseases. However, the neuroprotective metabolic pathways and the components involved in this process are not fully understood. In this study, we examined the neuroprotective metabolic pathways of WDT in rat brains using cerebrospinal fluid metabolomics and ultra‐high‐performance liquid chromatography–high‐resolution mass spectrometry. Twelve rats were randomly divided into a WDT (administrated with WDT solution) and a control group. The ultra‐high‐performance liquid chromatography technique was used to explore the components of the WDT solution and cerebrospinal fluid, and secondary mass spectra of cerebrospinal fluid were used to identify possible brain‐incorporating components after WDT. The results of the differential metabolism analysis showed that eight metabolites were typically altered (all p < 0.05). By comparing the secondary mass spectra of the cerebrospinal fluid of rats and WDT solution, two possible brain‐incorporating components of WDT, stachydrine and α‐methoxyphenylacetic acid, were identified. The data also suggested that WDT affects nucleotide metabolism, glutathione metabolism, and B‐vitamin metabolic pathways, the central differential metabolic pathways. These data suggest that WDT protects neurons through its active components, such as stachydrine, and regulates biochemical metabolism to affect the brain's energy metabolism and antioxidant capacity. [ABSTRACT FROM AUTHOR]

Objective: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD. Methods: The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [11C]PiB and [18F]florzolotau, respectively. Myo‐inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography. Results: Myo‐inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo‐inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo‐inositol and lactate levels were positively associated with the Clinical Dementia Rating sum‐of‐boxes scores (p < 0.05). Significant correlations were noted between myo‐inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05). Interpretation: We found high myo‐inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo‐inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2024;95:104–115 [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have reported that hearing loss (HL) is associated with dementia, although the mechanistic underpinnings remain elusive. This study aimed to evaluate the changes in brain metabolism in patients with HL and different types of dementia. Methods: Patients with cognitive impairment (CI) and HL treated at the university‐based memory clinic from May 2016 to October 2021 were included. In total, 108 patients with CI and HL prospectively underwent audiometry, neuropsychological test, magnetic resonance imaging, and 18F‐fluorodeoxyglucose positron emission tomography. Twenty‐seven individuals without cognitive impairment and hearing loss were enrolled as a control group. Multivariable regression was performed to evaluate brain regions correlated with each pathology type after adjusting for confounding factors. Results: Multivariable regression analyses revealed that Alzheimer's disease‐related CI (ADCI) was associated with hypometabolic changes in the right superior temporal gyrus (STG), right middle temporal gyrus (MTG), and bilateral medial temporal lobe. Lewy body disease‐related CI (LBDCI) and vascular CI were associated with hypermetabolic and hypometabolic changes in the ascending auditory pathway, respectively. In the pure ADCI group, the degree of HL was positively associated with abnormal increase of brain metabolism in the right MTG, whereas it was negatively associated with decreased brain metabolism in the right STG in the pure LBDCI group. Conclusion: Each dementia type is associated with distinct changes in brain metabolism in patients with HL. [ABSTRACT FROM AUTHOR]

Summary: Over the last decades, neuroimaging has become a substantial component of insomnia research. While theoretical underpinnings of different studies vary just like methodological choices and the experimental design, it is suggested that major features of insomnia disorder rely on the impaired function, structure, metabolism and connectivity of brain areas involved in sleep generation, emotion regulation, self‐processing/‐awareness and attentional orientation. However, neuroimaging research on insomnia often suffers from small sample sizes, heterogeneous methodology and a lack of replicability. With respect to these issues, the field needs to address the questions: (1a) how sufficiently large sample sizes can be accumulated within a reasonable economic framework; (1b) how effect sizes in insomnia‐related paradigms can be amplified; (2a) how a higher degree of standardisation and transparency in methodology can be provided; and (2b) how an adequate amount of flexibility/complexity in study design can be maintained. On condition that methodological consistency and a certain degree of adaptability are given, pooled data/large cohort analyses can be considered to be one way to answer these questions. Regarding experimental single‐centre trials, it might be helpful to focus on insomnia‐related transdiagnostic concepts. In doing so, expectable effect sizes (in between‐subjects designs) can be increased by: (a) comparing groups that are truly distinct regarding the variables examined in a concept‐specific paradigm; and (b) facilitated, intensified and precise elicitation of a target symptom. [ABSTRACT FROM AUTHOR]

The brain is quite sensitive to changes in energy supply because of its high energetic demand. Even small changes in energy metabolism may be the basis of impaired brain function, leading to the occurrence and development of cerebral ischemia/reperfusion (I/R) injury. Abundant evidence supports that metabolic defects of brain energy during the post‐reperfusion period, especially low glucose oxidative metabolism and elevated glycolysis levels, which play a crucial role in cerebral I/R pathophysiology. Whereas research on brain energy metabolism dysfunction under the background of cerebral I/R mainly focuses on neurons, the research on the complexity of microglia energy metabolism in cerebral I/R is just emerging. As resident immune cells of the central nervous system, microglia activate rapidly and then transform into an M1 or M2 phenotype to correspond to changes in brain homeostasis during cerebral I/R injury. M1 microglia release proinflammatory factors to promote neuroinflammation, while M2 microglia play a neuroprotective role by secreting anti‐inflammatory factors. The abnormal brain microenvironment promotes the metabolic reprogramming of microglia, which further affects the polarization state of microglia and disrupts the dynamic equilibrium of M1/M2, resulting in the aggravation of cerebral I/R injury. Increasing evidence suggests that metabolic reprogramming is a key driver of microglial inflammation. For example, M1 microglia preferentially produce energy through glycolysis, while M2 microglia provide energy primarily through oxidative phosphorylation. In this review, we highlight the emerging significance of regulating microglial energy metabolism in cerebral I/R injury. [ABSTRACT FROM AUTHOR]

Astrocytes are essential players in development and functions, being particularly relevant as regulators of brain energy metabolism, ionic homeostasis and synaptic transmission. They are also the major source of l‐serine in the brain, which is synthesized from the glycolytic intermediate 3‐phosphoglycerate through the phosphorylated pathway. l‐Serine is the precursor of the two main co‐agonists of the N‐methyl‐d‐aspartate receptor, glycine and d‐serine. Strikingly, dysfunctions in both l‐ and d‐serine metabolism are associated with neurological and psychiatric disorders. Here, we exploited a differentiation protocol, based on the generation of human mature astrocytes from neural stem cells, and investigated the modification of the proteomic and metabolomic profile during the differentiation process. We show that differentiated astrocytes are more similar to mature rather than to reactive ones, and that axogenesis and pyrimidine metabolism increase up to 30 days along with the folate cycle and sphingolipid metabolism. Consistent with the proliferation and cellular maturation processes that are taking place, also the intracellular levels of l‐serine, glycine, threonine, l‐ and d‐aspartate (which level is unexpectedly higher than that of d‐serine) show the same biosynthetic time course. A significant utilization of l‐serine from the medium is apparent while glycine is first consumed and then released with a peak at 30 days, parallel to its intracellular level. These results underline how metabolism changes during astrocyte differentiation, highlight that d‐serine synthesis is restricted in differentiated astrocytes and provide a valuable model for developing potential novel therapeutic approaches to address brain diseases, especially the ones related to serine metabolism alterations. [ABSTRACT FROM AUTHOR]