bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022–12–11
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Consumption and Metabolism of Extracellular Pyruvate by Cultured Rat Brain Astrocytes.
  2. The Role of Ketogenic Metabolic Therapy on the Brain in Serious Mental Illness: A Review.
  3. Induced pluripotent stem cell-derived cells model brain microvascular endothelial cell glucose metabolism.
  4. Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.
  5. Fatty acid-binding proteins 3 and 5 are involved in the initiation of mitochondrial damage in ischemic neurons.
  6. The mammalian purine salvage pathway as an exploitable route for cerebral bioenergetic support after brain injury.
  7. Analysis of the time-dependent changes of phospholipids in the brain regions of a mouse model of Alzheimer's disease.
  8. Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.
  9. PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy.
  10. A New Deuterium Labeled Compound [2,3,4,6,6'-2 H5 ]-D-Glucose for Deuterium Magnetic Resonance Metabolic Imaging.
  11. Vitamin B12 deficiency induces glucose intolerance, delays peak insulin levels and promotes ketogenesis in female rats.
  12. Modeling digestion, absorption, and ketogenesis after administration of tricaprilin formulations to humans.
  13. A study of brain glucose metabolism in obsessive-compulsive disorder patients.
  14. The role of nutrients in human neurodevelopment and their potential to prevent neurodevelopmental adversity.
  15. The sex-specific metabolic signature of C57BL/6NRj mice during aging.
  16. Brain metabolic correlates of Locus Coeruleus degeneration in Alzheimer's disease: a multimodal neuroimaging study.
  17. The roles of NADPH and isocitrate dehydrogenase in cochlear mitochondrial antioxidant defense and aging.
  18. Glucose-to-lactate ratio and neurodevelopment in infants with hypoxic-ischemic encephalopathy: an observational study.
  19. A pilot study assessing sphingolipids and glycolipids dysmetabolism in idiopathic normal pressure hydrocephalus.
  20. Does the ketogenic ratio matter when using ketogenic diet therapy in pediatric epilepsy?
  21. How do different parts of brain white matter develop after birth in humans?
  1. Neurochem Res. 2022 Dec 10.
    Consumption and Metabolism of Extracellular Pyruvate by Cultured Rat Brain Astrocytes.
    Nadine Denker, Antonia R Harders, Christian Arend, Ralf Dringen.
      Brain astrocytes are considered as glycolytic cell type, but these cells also produce ATP via mitochondrial oxidative phosphorylation. Exposure of cultured primary astrocytes in a glucose-free medium to extracellular substrates that are known to be metabolised by mitochondrial pathways, including pyruvate, lactate, beta-hydroxybutyrate, alanine and acetate, revealed that among the substrates investigated extracellular pyruvate was most efficiently consumed by astrocytes. Extracellular pyruvate was consumed by the cells almost proportional to time over hours in a concentration-dependent manner with apparent Michaelis-Menten kinetics [Km = 0.6 ± 0.1 mM, Vmax = 5.1 ± 0.8 nmol/(min × mg protein)]. The astrocytic consumption of pyruvate was strongly impaired in the presence of the monocarboxylate transporter 1 (MCT1) inhibitor AR-C155858 or by application of a 10-times excess of the MCT1 substrates lactate or beta-hydroxybutyrate. Pyruvate consumption by viable astrocytes was inhibited in the presence of UK5099, an inhibitor of the mitochondrial pyruvate carrier, or after application of the respiratory chain inhibitor antimycin A. In contrast, the mitochondrial uncoupler BAM15 strongly accelerated cellular pyruvate consumption. Lactate and alanine accounted after 3 h of incubation with pyruvate for around 60% and 10%, respectively, of the pyruvate consumed by the cells. These results demonstrate that consumption of extracellular pyruvate by astrocytes involves uptake via MCT1 and that the velocity of pyruvate consumption is strongly modified by substances that affect the entry of pyruvate into mitochondria or the activity of mitochondrial respiration.
    Keywords:  Astrocytes; MCT1; Metabolism; Mitochondria; Pyruvate carrier; Transport
    DOI:  https://doi.org/10.1007/s11064-022-03831-6
  2. J Psychiatr Brain Sci. 2022 ;pii: e220009. [Epub ahead of print]7(5):
    The Role of Ketogenic Metabolic Therapy on the Brain in Serious Mental Illness: A Review.
    Shebani Sethi, Judith M Ford.
      In search of interventions targeting brain dysfunction and underlying cognitive impairment in schizophrenia, we look at the brain and beyond to the potential role of dysfunctional systemic metabolism on neural network instability and insulin resistance in serious mental illness. We note that disrupted insulin and cerebral glucose metabolism are seen even in medication-naïve first-episode schizophrenia, suggesting that people with schizophrenia are at risk for Type 2 diabetes and cardiovascular disease, resulting in a shortened life span. Although glucose is the brain's default fuel, ketones are a more efficient fuel for the brain. We highlight evidence that a ketogenic diet can improve both the metabolic and neural stability profiles. Specifically, a ketogenic diet improves mitochondrial metabolism, neurotransmitter function, oxidative stress/inflammation, while also increasing neural network stability and cognitive function. To reverse the neurodegenerative process, increasing the brain's access to ketone bodies may be needed. We describe evidence that metabolic, neuroprotective, and neurochemical benefits of a ketogenic diet potentially provide symptomatic relief to people with schizophrenia while also improving their cardiovascular or metabolic health. We review evidence for KD side effects and note that although high in fat it improves various cardiovascular and metabolic risk markers in overweight/obese individuals. We conclude by calling for controlled clinical trials to confirm or refute the findings from anecdotal and case reports to address the potential beneficial effects of the ketogenic diet in people with serious mental illness.
    Keywords:  bipolar disorder; functional connectivity; insulin resistance; metabolic psychiatry; metabolism; neural network stability; psychotic symptoms; schizophrenia
    DOI:  https://doi.org/10.20900/jpbs.20220009
  3. Fluids Barriers CNS. 2022 Dec 09. 19(1): 98
    Induced pluripotent stem cell-derived cells model brain microvascular endothelial cell glucose metabolism.
    Callie M Weber, Bilal Moiz, Sophia M Zic, Viviana Alpízar Vargas, Andrew Li, Alisa Morss Clyne.
      Glucose transport from the blood into the brain is tightly regulated by brain microvascular endothelial cells (BMEC), which also use glucose as their primary energy source. To study how BMEC glucose transport contributes to cerebral glucose hypometabolism in diseases such as Alzheimer's disease, it is essential to understand how these cells metabolize glucose. Human primary BMEC (hpBMEC) can be used for BMEC metabolism studies; however, they have poor barrier function and may not recapitulate in vivo BMEC function. iPSC-derived BMEC-like cells (hiBMEC) are readily available and have good barrier function but may have an underlying epithelial signature. In this study, we examined differences between hpBMEC and hiBMEC glucose metabolism using a combination of dynamic metabolic measurements, metabolic mass spectrometry, RNA sequencing, and Western blots. hiBMEC had decreased glycolytic flux relative to hpBMEC, and the overall metabolomes and metabolic enzyme levels were different between the two cell types. However, hpBMEC and hiBMEC had similar glucose metabolism, including nearly identical glucose labeled fractions of glycolytic and TCA cycle metabolites. Treatment with astrocyte conditioned media and high glucose increased glycolysis in both hpBMEC and hiBMEC, though hpBMEC decreased glycolysis in response to fluvastatin while hiBMEC did not. Together, these results suggest that hiBMEC can be used to model cerebral vascular glucose metabolism, which expands their use beyond barrier models.
    Keywords:  Brain microvascular endothelial cells; Glucose metabolism; Induced pluripotent stem cells
    DOI:  https://doi.org/10.1186/s12987-022-00395-z
  4. Alzheimers Dement. 2022 Dec 08.
    Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.
    Nutrition, Metabolism and Dementia PIA, Alzheimer's Association ISTAART
      Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.
    DOI:  https://doi.org/10.1002/alz.12845
  5. Redox Biol. 2022 Nov 26. pii: S2213-2317(22)00319-6. [Epub ahead of print]59 102547
    Fatty acid-binding proteins 3 and 5 are involved in the initiation of mitochondrial damage in ischemic neurons.
    Qingyun Guo, Ichiro Kawahata, An Cheng, Haoyang Wang, Wenbin Jia, Hiroshi Yoshino, Kohji Fukunaga.
      We have previously shown that a fatty acid-binding protein7 (FABP7) inhibitor ameliorates cerebral ischemia-reperfusion injury in mice, suggesting an association between FABPs and ischemic neuronal injury. However, the precise role of FABPs in ischemic neuronal injury remains unclear. In this study, we investigated the role of FABPs in ischemia-reperfusion neuronal injury. FABP3, FABP5, and FABP7 were upregulated in the ischemic penumbra regions in mice. However, only FABP3 and FABP5 were expressed in injured neurons. Furthermore, FABP3 and FABP5 accumulated in the mitochondria of ischemic neurons. Overexpressing either FABP3 or FABP5 aggravated the reduced mitochondrial membrane potential and induced cell death in human neuroblastoma SH-SY5Y cells during oxidative stress. This damage was mediated by the formation of BAX-containing pores in the mitochondrial membrane. Moreover, FABP5 mediates lipid peroxidation and generates toxic by-products (i.e., 4-HNE) in SH-SY5Y cells. HY11-08 (HY08), a novel FABP3 and 5 inhibitor that does not act on FABP7, significantly reduced cerebral infarct volume and blocked FABP3/5-induced mitochondrial damage, including lipid peroxidation and BAX-related apoptotic signaling. Thus, FABP3 and FABP5 are key players in triggering mitochondrial damage in ischemic neurons. In addition, the novel FABP inhibitor, HY08, may be a potential neuroprotective treatment for ischemic stroke.
    Keywords:  4-HNE; BAX; Fatty acid-binding proteins; Ischemic stroke; Mitochondria damage
    DOI:  https://doi.org/10.1016/j.redox.2022.102547
  6. Neuropharmacology. 2022 Dec 06. pii: S0028-3908(22)00429-4. [Epub ahead of print] 109370
    The mammalian purine salvage pathway as an exploitable route for cerebral bioenergetic support after brain injury.
    Philipp Gessner, Jenni Lum, Bruno G Frenguelli.
      Purine-based molecules play ancient, fundamental, and evolutionarily-conserved roles across life on Earth, ranging from their presence in DNA and RNA, and in the universal energy currency, ATP. In mammals, the two primary routes for the synthesis of the adenine nucleotides ATP, ADP and AMP, and, as a consequence, the major bioactive metabolite adenosine, are the de novo purine biosynthesis (DNPB) pathway, and the purine salvage pathway (PSP). Of the two, the PSP dominates in both the mammalian brain and heart. This is because the PSP utilizes the breakdown products of ATP, occasioned by the high energy demands of these organs, to rapidly regenerate adenine nucleotides. This resynthesis route, while efficient and energetically favourable, leaves these organs vulnerable to loss of salvageable metabolites, with the potential for protracted depletion of the means to synthesize ATP, and the ability to deploy neuro- and cardioprotective adenosine. Having previously shown that hippocampal cellular ATP and adenosine release can be increased by supplying substrates for the PSP (d-ribose and adenine), we now explore the expression of DNPB and PSP enzymes in hippocampal neurons and astrocytes based on available transcriptomic data. We find that key enzymes of the PSP are expressed at higher levels than those in the DNPB pathway, and that PSP enzymes are expressed at higher levels in neurons than in astrocytes. These data reflect the importance of the PSP in the mammalian brain and imply that pharmacological targeting of the PSP may be particularly beneficial to neurons at times of metabolic stress.
    Keywords:  ATP; Adenine; Adenosine; Astrocytes; Ischemia; Neurons; Purine metabolism; Purine salvage pathway; Ribose; Stroke; Traumatic brain injury; de novo purine biosynthesis
    DOI:  https://doi.org/10.1016/j.neuropharm.2022.109370
  7. Brain Res. 2022 Dec 05. pii: S0006-8993(22)00421-8. [Epub ahead of print] 148197
    Analysis of the time-dependent changes of phospholipids in the brain regions of a mouse model of Alzheimer's disease.
    Md Ahsanul Haque, Naoki Omori, Abdullah Md Sheikh, Shozo Yano, Harumi Osago, Shingo Mitaki, Abul Kalam Azad, Hiromichi Sakai, Makoto Michikawa, Atsushi Nagai.
      Phospholipid levels are reported to be decreased in Alzheimer's disease (AD). For a better understanding, we investigated the time-dependent changes of phospholipids species in a mouse model of AD. The levels of phospholipids in the hippocampus and prefrontal cortex of wild-type and APP-Tg (J20) mice were measured by LC-ESI-MS/MS. Compared to wild-type, total phosphatidylcholine (PC), phosphatidylethanolamine (PE), and lysophosphatidylcholine (LPC) were Increased at 3 months but decreased at 6 months in the cortex of J20 mice. Total lysophosphatidylethanolamine (LPE) was decreased both at 3 and 6 months. PC was decreased and LPC was increased at 6 months, resulting in an increased LPC/PC ratio in the hippocampus of J20 mice. At species levels, PCA analysis could discriminate wild-type and J20 based on PC and LPC distribution at 6 months. At 6 months, several highly abundant PC including PC (16:0/16:0), PC (16:0/18:0), PC (16:0/18:1), and PC (18:0/18:1) were decreased in the cortex and hippocampus of J20. Conversely, LPC species including LPC 16:0, LPC 18:1, and LPC 20:4 were increased especially in the hippocampal area. Increased activation of phospholipid-metabolizing enzyme cPLA2 was seen in the hippocampus and cortex of J20 mice at 9 months. On the other hand, ROS levels started to increase as early as 3 months. Compared to 3 months, ROS levels were higher at 6 months in J20 mice. Thus, we demonstrated here a time- and area-dependent alteration of phospholipid composition during the early stage of AD, which could be important in understanding the pathological process.
    Keywords:  Alzheimer’s disease; LC-MS/MS; Phosphatidylcholine; Phosphatidylethanolamine; Reactive oxygen species; phospholipase A(2)
    DOI:  https://doi.org/10.1016/j.brainres.2022.148197
  8. Orphanet J Rare Dis. 2022 Dec 05. 17(1): 423
    Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.
    Emily Shelkowitz, Russell P Saneto, Walla Al-Hertani, Charlotte M A Lubout, Nicholas V Stence, Mark S Brown, Patrick Long, Diana Walleigh, Julie A Nelson, Francisco E Perez, Dennis W W Shaw, Emma J Michl, Johan L K Van Hove.
       BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction.
    AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate.
    METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS).
    RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable.
    CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.
    Keywords:  Benzoate; Epilepsy; Glycine; Ketogenic diet; Magnetic resonance spectroscopy; Nonketotic hyperglycinemia
    DOI:  https://doi.org/10.1186/s13023-022-02581-6
  9. iScience. 2022 Dec 22. 25(12): 105612
    PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy.
    Keiko Morita, Mariko Wada, Kohta Nakatani, Yuki Matsumoto, Nahoki Hayashi, Ikuko Yamahata, Kotone Mitsunari, Nagi Mukae, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Michiko Shirane.
      Dyslipidemia including the accumulation of cholesteryl esters (CEs) in the brain is associated with neurological disorders, although the underlying mechanism has been unclear. PDZD8, a Rab7 effector protein, transfers lipids between endoplasmic reticulum (ER) and Rab7-positive organelles and thereby promotes endolysosome maturation and contributes to the maintenance of neuronal integrity. Here we show that CEs accumulate in the brain of PDZD8-deficient mice as a result of impaired lipophagy. This CE accumulation was not affected by diet, implicating a defect in intracellular lipid metabolism. Whereas cholesterol synthesis appeared normal, degradation of lipid droplets (LDs) was defective, in the brain of PDZD8-deficient mice. PDZD8 may mediate the exchange of cholesterol and phosphatidylserine between ER and Rab7-positive organelles to promote the fusion of CE-containing LDs with lysosomes for their degradation. Our results thus suggest that PDZD8 promotes clearance of CEs from the brain by lipophagy, with this role of PDZD8 likely contributing to brain function.
    Keywords:  Biological sciences; Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.105612
  10. NMR Biomed. 2022 Dec 07. e4890
    A New Deuterium Labeled Compound [2,3,4,6,6'-2 H5 ]-D-Glucose for Deuterium Magnetic Resonance Metabolic Imaging.
    Chao Zou, Yingheng Ruan, Huanxi Li, Qian Wan, Feng Du, Jiawen Yuan, Qikai Qin, Garth J Thompson, Xiaojun Yang, Ye Li, Xin Liu, Hairong Zheng.
      Deuterium (2 H) magnetic resonance imaging is an emerging approach for noninvasively studying glucose metabolism in vivo, which is important for understanding pathogenesis and monitoring the progression of many diseases such as tumors, diabetes, and neurodegenerative diseases. However, the synthesis of 2 H-labeled glucose is costly due to the expensive raw substrates and the requirements for extreme reaction conditions, making the 2 H-labeled glucose rather expensive and unaffordable for clinic use. In this study, we present a new deuterated compound [2,3,4,6,6'-2 H5 ]-D-glucose with approximately 10-fold reduction in production costs. The synthesis route uses cheaper raw substrate methyl-α-D-glucopyranoside, relies on mild reaction conditions (80°C), and has higher deuterium labeling efficiency. Magnetic resonance spectroscopy (MRS) and mass spectroscopy experiments confirmed the successful deuterium labeling in the compound. Animal studies demonstrated that the substrate could describe the glycolytic metabolism in a glioma rat model by quantifying the downstream metabolites through 2 H-MRS at ultra-high field system. Comparison on the glucose metabolism characteristics have been carried out between the [2,3,4,6,6'-2 H5 ]-D-Glucose and the commercial [6,6'-2 H2 ]-D-Glucose in the animal studies. This cost-effective compound will help facilitate the clinical translation of deuterium magnetic resonance imaging, and enable this powerful metabolic imaging modality to be widely used in both pre-clinical/clinical research and applications.
    DOI:  https://doi.org/10.1002/nbm.4890
  11. J Endocrinol. 2022 Dec 01. pii: JOE-22-0158. [Epub ahead of print]
    Vitamin B12 deficiency induces glucose intolerance, delays peak insulin levels and promotes ketogenesis in female rats.
    Elliott Neal, Vinod Kumar, Karin Borges, James Sm Cuffe.
      Vitamin B12 (B12) deficiency is common among individuals with diabetes mellitus but it is unknown if B12 deficiency contributes to impaired glucose homeostasis in this disorder. Female Sprague-Dawley rats were assigned to a control or B12 deficient diet for 4 weeks. Intraperitoneal glucose tolerance tests were performed after 25 days and blood and liver samples were collected for metabolic profiling. B12 deficiency resulted in a prediabetic-like phenotype characterised by glucose intolerance, a delayed peak in plasma insulin levels following a glucose challenge and increased ketogenesis. We attributed increased ketogenesis to reduced liver anaplerosis, which limited availability of the TCA cycle intermediates citrate and succinate. This was associated with increased Mut mRNA levels and citrate synthase activity and lower succinyl-CoA availability. One carbon metabolite levels were altered in plasma and the liver, which was linked to reduced methylation capacity, altered amino acid levels and elevated Slc7a5 mRNA expression. Plasma folate and biotin levels were reduced, as were the majority of B vitamins in the liver. Changes in these B12-dependent processes and reduced B vitamin amounts likely contributed to deficits in glucose handling. Our findings highlight that B12 deficiency may promote the development of metabolic disorders like diabetes mellitus and emphasise the importance of adequate B12 intake for metabolic health.
    DOI:  https://doi.org/10.1530/JOE-22-0158
  12. Eur J Pharm Biopharm. 2022 Dec 02. pii: S0939-6411(22)00281-8. [Epub ahead of print]
    Modeling digestion, absorption, and ketogenesis after administration of tricaprilin formulations to humans.
    Zhuoxuan Li, Gisela Ramirez, Rushi Tang, Cheong Kin Xian Paul, Murali Nair, Samuel Henderson, Bruce Morimoto, Julie Liu, Thomas Kaasgaard, Benjamin Boyd, Matthias G Wacker.
      At present, tricaprilin is used as a ketogenic source for the management of mild to moderate Alzheimer's disease. After administration of the medium-chain triglyceride, tricaprilin is hydrolyzed to octanoic acid and further metabolized to ketones, acting as an alternative energy substrate for the brain. In this investigation, we developed a physiologically based biopharmaceutics model simulating in vivo processes following the peroral administration of tricaprilin. The model includes multiple data sources to establish a partially verified framework for the simulation of plasma profiles. The input parameters were identified based on existing literature data and in vitro digestion studies. Model validation was conducted using the outcome of a phase I clinical trial. A partial parameter sensitivity analysis elucidated various influences on the plasma ketone levels that are mainly responsible for the therapeutic effects of tricaprilin. Based on our findings, we concluded that dispersibility and lipolysis of tricaprilin together with the gastric emptying patterns are limiting ketogenesis, while other steps such as the conversion of octanoic acid to ketone bodies play a minor role only.
    Keywords:  Alzheimer’s disease; in vitro lipid digestion; ketogenesis; medium-chain triglycerides MCTs; physiologically based pharmacokinetic (PBPK) modeling; tricaprilin
    DOI:  https://doi.org/10.1016/j.ejpb.2022.11.022
  13. Ann Palliat Med. 2022 Nov;11(11): 3503-3512
    A study of brain glucose metabolism in obsessive-compulsive disorder patients.
    Xuejiao Hou, Hong Wang, Minfeng Cheng, Jihui Yue.
       BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic neural psychological condition. Its pathogenesis is not yet completely understood. This current research used fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging to examine the changes in brain glucose metabolism in patients with OCD during the course of treatment, and analyzed its relationship with clinical efficacy.
    METHODS: A total of 23 patients with OCD were enrolled and divided into case group 1, consisting of patients who received no drug treatment or those who recently stopped drug treatment for more than five half-life periods (OCD1 group, N=10), and case group 2, consisting of patients who were receiving drug treatment before enrollment (OCD2 group, N=13). Ten healthy volunteers were selected as controls. All patients and healthy controls were subjected to head PET-computed tomography (CT) examination. Seven patients in case group 2 underwent scanning again after 3 months of drug treatment, namely, case group 3 (OCD3 group, N=7). Statistical Parametric Mapping (SPM) 8 software was used to analyze the PET-CT results.
    RESULTS: OCD patients had abnormally enhanced glucose metabolism in the medium orbito-frontal region of the brain, and abnormally reduced glucose metabolism in brain areas including the insula, caudate nucleus, and middle temporal gyrus. No changes in brain glucose metabolism related to curative effect was found.
    CONCLUSIONS: In OCD patients, abnormal brain function may not only be limited to the usual cortico-striato-thalamo-cortical (CSTC) loop model, but may involve a wide range of brain regions simultaneously.
    Keywords:  Obsessive-compulsive disorder (OCD); brain glucose metabolism; changes before and after drug therapy
    DOI:  https://doi.org/10.21037/apm-22-1161
  14. Front Nutr. 2022 ;9 992120
    The role of nutrients in human neurodevelopment and their potential to prevent neurodevelopmental adversity.
    Sarah Heland, Neville Fields, Stacey Joan Ellery, Michael Fahey, Kirsten Rebecca Palmer.
      Nutritional deficits or excesses affect a huge proportion of pregnant women worldwide. Maternal nutrition has a significant influence on the fetal environment and can dramatically impact fetal brain development. This paper reviews current nutritional supplements that can be used to optimise fetal neurodevelopment and prevent neurodevelopmental morbidities, including folate, iodine, vitamin B12, iron, and vitamin D. Interestingly, while correcting nutritional deficits can prevent neurodevelopmental adversity, overcorrecting them can in some cases be detrimental, so care needs to be taken when recommending supplementation in pregnancy. The potential benefits of using nutrition to prevent neurodiversity is shown by promising nutraceuticals, sulforaphane and creatine, both currently under investigation. They have the potential to promote improved neurodevelopmental outcomes through mitigation of pathological processes, including hypoxia, inflammation, and oxidative stress. Neurodevelopment is a complex process and whilst the role of micronutrients and macronutrients on the developing fetal brain is not completely understood, this review highlights the key findings thus far.
    Keywords:  fetal development; neurodevelopment; neurodevelopment adversity; nutraceuticals; nutrition; pregnancy; prenatal nutrition
    DOI:  https://doi.org/10.3389/fnut.2022.992120
  15. Sci Rep. 2022 Dec 06. 12(1): 21050
    The sex-specific metabolic signature of C57BL/6NRj mice during aging.
    Doruntina Bresilla, Hansjoerg Habisch, Iva Pritišanac, Kim Zarse, Warisara Parichatikanond, Michael Ristow, Tobias Madl, Corina T Madreiter-Sokolowski.
      Due to intact reactive oxygen species homeostasis and glucose metabolism, C57BL/6NRj mice are especially suitable to study cellular alterations in metabolism. We applied Nuclear Magnetic resonance spectroscopy to analyze five different tissues of this mouse strain during aging and included female and male mice aged 3, 6, 12, and 24 months. Metabolite signatures allowed separation between the age groups in all tissues, and we identified the most prominently changing metabolites in female and male tissues. A refined analysis of individual metabolite levels during aging revealed an early onset of age-related changes at 6 months, sex-specific differences in the liver, and a biphasic pattern for various metabolites in the brain, heart, liver, and lung. In contrast, a linear decrease of amino acids was apparent in muscle tissues. Based on these results, we assume that age-related metabolic alterations happen at a comparably early aging state and are potentially associated with a metabolic switch. Moreover, identified differences between female and male tissues stress the importance of distinguishing between sexes when studying age-related changes and developing new treatment approaches. Besides, metabolomic features seem to be highly dependent on the genetic background of mouse strains.
    DOI:  https://doi.org/10.1038/s41598-022-25396-8
  16. Neurobiol Aging. 2022 Nov 10. pii: S0197-4580(22)00232-9. [Epub ahead of print]122 12-21
    Brain metabolic correlates of Locus Coeruleus degeneration in Alzheimer's disease: a multimodal neuroimaging study.
    Gayane Aghakhanyan, Alessandro Galgani, Andrea Vergallo, Francesco Lombardo, Nicola Martini, Filippo Baldacci, Gloria Tognoni, Andrea Leo, Federica Guidoccio, Gabriele Siciliano, Francesco Fornai, Nicola Pavese, Duccio Volterrani, Filippo S Giorgi.
      Locus Coeruleus (LC) degeneration occurs early in Alzheimer's disease (AD) and this could affect several brain regions innervated by LC noradrenergic axon terminals, as these bear neuroprotective effects and modulate neurovascular coupling/neuronal activity. We used LC-sensitive Magnetic Resonance imaging (MRI) sequences enabling LC integrity quantification, and [18F]Fluorodeoxyglucose (FDG) PET, to investigate the association of LC-MRI changes with brain glucose metabolism in cognitively impaired patients (30 amnesticMCI and 13 demented ones). Fifteen cognitively intact age-matched controls (HCs) were submitted only to LC-MRI for comparison with patients. Voxel-wise regression analyses of [18F]FDG images were conducted using the LC-MRI parameters signal intensity (LCCR) and LC-belonging voxels (LCVOX). Both LCCR and LCVOX were significantly lower in patients compared to HCs, and were directly associated with [18F]FDG uptake in fronto-parietal cortical areas, mainly involving the left hemisphere (p < 0.001, kE > 100). These results suggest a possible association between LC degeneration and cortical hypometabolism in degenerative cognitive impairment with a prevalent left-hemispheric vulnerability, and that LC degeneration might be linked to large-scale functional network alteration in AD pathology.
    Keywords:  Alzheimer's disease; Locus Coeruleus; Locus Coeruleus Integrity; Magnetic Resonance imaging; [18F]Fluorodeoxyglucose Positron Emission Tomography
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.11.002
  17. Hear Res. 2022 Nov 24. pii: S0378-5955(22)00227-1. [Epub ahead of print]427 108659
    The roles of NADPH and isocitrate dehydrogenase in cochlear mitochondrial antioxidant defense and aging.
    Karessa White, Shinichi Someya.
      Hearing loss is the third most prevalent chronic health condition affecting older adults. Age-related hearing loss affects one in three adults over 65 years of age and is caused by both extrinsic and intrinsic factors, including genetics, aging, and exposure to noise and toxins. All cells possess antioxidant defense systems that play an important role in protecting cells against these factors. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) serves as a co-factor for antioxidant enzymes such as glutathione reductase and thioredoxin reductase and is produced by glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, isocitrate dehydrogenase 1 (IDH1) or malic enzyme 1 in the cytosol, while in the mitochondria, NADPH is generated from mitochondrial transhydrogenase, glutamate dehydrogenase, malic enzyme 3 or IDH2. There are three isoforms of IDH: cytosolic IDH1, and mitochondrial IDH2 and IDH3. Of these, IDH2 is thought to be the major supplier of NADPH to the mitochondrial antioxidant defense system. The NADP+/NADPH and NAD+/NADH couples are essential for maintaining a large array of biological processes, including cellular redox state, and energy metabolism, mitochondrial function. A growing body of evidence indicates that mitochondrial dysfunction contributes to age-related structural or functional changes of cochlear sensory hair cells and neurons, leading to hearing impairments. In this review, we describe the current understanding of the roles of NADPH and IDHs in cochlear mitochondrial antioxidant defense and aging.
    Keywords:  antioxidant defense; cochlea; inner ear; isocitrate dehydrogenase; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1016/j.heares.2022.108659
  18. Eur J Pediatr. 2022 Dec 09.
    Glucose-to-lactate ratio and neurodevelopment in infants with hypoxic-ischemic encephalopathy: an observational study.
    Alfonso Galderisi, Mattia Tordin, Agnese Suppiej, Elisa Cainelli, Eugenio Baraldi, Daniele Trevisanuto.
      We aimed to assess the glucose and lactate kinetics during therapeutic hypothermia (TH) in infants with hypoxic-ischemic encephalopathy and its relationship with longitudinal neurodevelopment. We measured glucose and lactate concentrations before TH and on days 2 and 3 in infants with mild, moderate, and severe hypoxic-ischemic encephalopathy (HIE). Neurodevelopment was assessed at 2 years. Participants were grouped according to the neurodevelopmental outcome into favorable (FO) or unfavorable (UFO). Eighty-eight infants were evaluated at follow-up, 34 for the FO and 54 for the UFO group. Severe hypo- (< 2.6 mmol/L) and hyperglycemia (> 10 mmol/L) occurred in 18% and 36% from the FO and UFO groups, respectively. Glucose-to-lactate ratio on day 1 was the strongest predictor of unfavorable metabolic outcome (OR 3.27 [Formula: see text] 1.81, p = 0.032) when adjusted for other clinical and metabolic variables, including Sarnat score.
    CONCLUSION: Glucose-to-lactate ratio on day 1 may represent a new risk marker for infants with HIE undergoing TH.
    WHAT IS KNOWN: • Glucose and lactate are key metabolic fuels during neonatal hypoglycemia. This suggests that their concentrations may influence the neurodevelopmental outcome of neonates experiencing hypoxic-hischemic encephalopathy (HIE).
    WHAT IS NEW: • We describe the relative availbility of glucose and lactate before and during theraputic hypothermia in neonates with HIE.
    Keywords:  Glucose-to-lactate ratio; Hypoxic-ischemic encephalopathy; Therapeutic hypothermia
    DOI:  https://doi.org/10.1007/s00431-022-04694-3
  19. Biochem Biophys Res Commun. 2022 Nov 29. pii: S0006-291X(22)01648-5. [Epub ahead of print]639 84-90
    A pilot study assessing sphingolipids and glycolipids dysmetabolism in idiopathic normal pressure hydrocephalus.
    Tatsuro Mutoh, Yoshiki Niimi, Shinji Ito, Hisako Akiyama, Ryoichi Shiroki, Yoshio Hirabayashi, Kiyotaka Hoshinaga.
      Idiopathic normal pressure hydrocephalus usually exhibits triad of symptoms including gait disturbance, urinary incontinence, and dementia with ventriculomegaly. Currently, its pathogenesis remains to be fully elucidated. To provide a better understanding of this order, we examined whether dysmetabolism of sphingolipids as major lipid components in the brain present in cerebrospinal fluid (CSF) of the patients. Here, we measured various sphingolipidsincluding ceramide and sphingomyelin and glycolipids by electrospray ionization-tandem mass spectrometry in the cerebrospinal fluid of 19 consecutive idiopathic normal pressure hydrocephalus patients, 49 Parkinson's disease patients, and 17 neurologically normal controls. The data showed that there was a significant and specific reduction of all galactosylceramide subspecies levels in idiopathic normal pressure hydrocephalus patients compared with other groups, whereas ceramide and sphingomyelin levels as well as other neutral glycolipids such as glucosylceramide and lactosylceramide were similar in both disease states. Multiple regression analysis of sex and age did not show any correlation with galactosylceramide levels. We also examined whether MMSE scores are correlated with sphingolipid levels in iNPH patients. A specific subspecies of sphingomyelin (d18:1/18:0) only exhibited a statistically significant negative correlation (p = 0.0473, R = -0.4604) with MMSE scores but no other sphingolipids in iNPH patients. These data strongly suggest that myelin-rich galactosylceramide metabolism is severely impaired in idiopathic normal pressure hydrocephalus patients and might serve as the basis of biomarker for this disorder.
    Keywords:  Ceramide; Galactosylceramide; Idiopathic normal pressure hydrocephalus; Parkinson's disease; Sphingolipids; Sphingomyelin
    DOI:  https://doi.org/10.1016/j.bbrc.2022.11.091
  20. Epilepsia. 2022 Dec 05.
    Does the ketogenic ratio matter when using ketogenic diet therapy in pediatric epilepsy?
    Suvasini Sharma, Robyn Whitney, Eric H Kossoff, Rajesh RamachandranNair.
      The ketogenic diet (KD) is a widely used therapeutic option for individuals with medically refractory epilepsy. As the diet's name implies, ketosis is a historically important component of the diet, but it is not well understood how important ketosis is for seizure control. The ketogenic ratio is defined as the ratio of fat to carbohydrate plus protein by weight in the diet (grams). Traditionally, the classic KD contains a 4:1 ratio, and a very high proportion of fat in the diet. The classic KD, with its high proportion of fat and limited carbohydrate intake can be restrictive for patients with epilepsy. Recently, there is experience with use of lower ketogenic ratios and less restrictive diets such as the modified Atkins diet and the low glycemic index treatment. In this narrative review, we examine the role of ketosis and ketogenic ratios in determining the efficacy of the ketogenic diet in children with epilepsy.
    Keywords:  Drug resistant epilepsy; beta hydroxybutyrate; ketone bodies; low glycemic index treatment; low ratio diets; modified Atkins diet
    DOI:  https://doi.org/10.1111/epi.17476
  21. Neuron. 2022 Dec 07. pii: S0896-6273(22)01034-0. [Epub ahead of print]110(23): 3860-3863
    How do different parts of brain white matter develop after birth in humans?
    Sarah Genon, Stephanie J Forkel.
      Understanding human white matter development is vital to characterize typical brain organization and developmental neurocognitive disorders. In this issue of Neuron, Nazeri and colleagues1 identify different parts of white matter in the neonatal brain and show their maturational trajectories in line with microstructural feature development.
    DOI:  https://doi.org/10.1016/j.neuron.2022.11.011
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