bims-medebr 2021-12-19 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2021‒12‒19
fourteen papers selected by
Regina F. Fernández
Johns Hopkins University

Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress.
Lipids and brain inflammation in APOE4-associated dementia.
Presynaptic Mitochondrial Volume and Packing Density Scale with Presynaptic Power Demand.
ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway.
Bioactive lipids and their metabolism: new therapeutic opportunities for Parkinson's disease.
Beneficial Effects on Brain Micro-Environment by Caloric Restriction in Alleviating Neurodegenerative Diseases and Brain Aging.
A metabolic biomarker for early stage of Parkinson's disease in patients and animal models.
Rethinking the necessity of low glucose intervention for cerebral ischemia/reperfusion injury.
The Influence of Maternal Metabolic State and Nutrition on Offspring Neurobehavioral Development: A Focus on Preclinical Models.
Hypothalamic inflammation in metabolic disorders and aging.
Characterising the dynamics of cerebral metabolic dysfunction following traumatic brain injury: A microdialysis study in 619 patients.
Critical role of mitochondrial aldehyde dehydrogenase 2 in acrolein sequestering in rat spinal cord injury.
Hypothermia selectively protects the anterior forebrain mesocircuit during global cerebral ischemia.
Neurometabolite Changes in Hyperthyroid Patients Before and After Antithyroid Treatment: An in vivo 1H MRS Study.

Acta Pharmacol Sin. 2021 May 02.

Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress.

An Cheng, Yi-Fei Wang, Yasuharu Shinoda, Ichiro Kawahata, Tetsunori Yamamoto, Wen-Bin Jia, Hanae Yamamoto, Tomohiro Mizobata, Yasushi Kawata, Kohji Fukunaga.

  We previously show that fatty acid-binding protein 3 (FABP3) triggers α-synuclein (Syn) accumulation and induces dopamine neuronal cell death in Parkinson disease mouse model. But the role of fatty acid-binding protein 7 (FABP7) in the brain remains unclear. In this study we investigated whether FABP7 was involved in synucleinopathies. We showed that FABP7 was co-localized and formed a complex with Syn in Syn-transfected U251 human glioblastoma cells, and treatment with arachidonic acid (100 M) significantly promoted FABP7-induced Syn aggregation, which was associated with cell death. We demonstrated that synthetic FABP7 ligand 6 displayed a high affinity against FABP7 with Kd value of 209 nM assessed in 8-anilinonaphthalene-1-sulfonic acid (ANS) assay; ligand 6 improved U251 cell survival via disrupting the FABP7-Syn interaction. We showed that activation of phospholipase A2 (PLA2) by psychosine (10 M) triggered oligomerization of endogenous Syn and FABP7, and induced cell death in both KG-1C human oligodendroglia cells and oligodendrocyte precursor cells (OPCs). FABP7 ligand 6 (1 M) significantly decreased Syn oligomerization and aggregation thereby prevented KG-1C and OPC cell death. This study demonstrates that FABP7 triggers α-synuclein oligomerization through oxidative stress, while FABP7 ligand 6 can inhibit FABP7-induced Syn oligomerization and aggregation, thereby rescuing glial cells and oligodendrocytes from cell death.

Keywords:  arachidonic acid; cell death; fatty acid binding protein 7; psychosine; synucleinopathies; α-synuclein oligomerization

DOI:  https://doi.org/10.1038/s41401-021-00675-8
Curr Opin Lipidol. 2021 Dec 13.

Lipids and brain inflammation in APOE4-associated dementia.

Marlon V Duro, Brandon Ebright, Hussein N Yassine.

PURPOSE OF REVIEW: To highlight recent developments in studying mechanisms by which the apolipoprotein E4 (APOE4) allele affects the metabolism of brain lipids and predisposes the brain to inflammation and Alzheimer's disease (AD) dementia.RECENT FINDINGS: APOE4 activates Ca2+ dependent phospholipase A2 (cPLA2) leading to changes in arachidonic acid (AA), eicosapentaenoic acid and docosahexaenoic acid signaling cascades in the brain. Among these changes, the increased conversion of AA to eicosanoids associates with sustained and unresolved chronic brain inflammation. The effects of APOE4 on the brain differ by age, disease stage, nutritional status and can be uncovered by brain imaging studies of brain fatty acid uptake. Reducing cPLA2 expression in the dementia brain presents a viable strategy that awaits to be tested.
SUMMARY: Fatty acid brain imaging techniques can clarify how changes to brain polyunsaturated fatty acid metabolism during the various phases of AD and guide the development of small molecules to mitigate brain inflammation.

DOI: https://doi.org/10.1097/MOL.0000000000000801
J Neurosci. 2021 Dec 10. pii: JN-RM-1236-21. [Epub ahead of print]

Presynaptic Mitochondrial Volume and Packing Density Scale with Presynaptic Power Demand.

Karlis A Justs, Zhongmin Lu, Amit K Chouhan, Jolanta A Borycz, Zhiyuan Lu, Ian A Meinertzhagen, Gregory T Macleod.

Stable neural function requires an energy supply that can meet the intense episodic power demands of neuronal activity. Neurons have presumably optimized the volume of their bioenergetic machinery to ensure these power demands are met, but the relationship between presynaptic power demands and the volume available to the bioenergetic machinery has never been quantified. Here we estimated the power demands of six motor nerve terminals in female Drosophila larvae through direct measurements of neurotransmitter release and Ca2+ entry, and via theoretical estimates of Na+ entry and power demands at rest. Electron microscopy revealed that terminals with the highest power demands contained the greatest volume of mitochondria, indicating that mitochondria are allocated according to presynaptic power demands. In addition, terminals with the greatest power demand-to-volume ratio (∼66 nmol·min-1·μL-1) harbor the largest mitochondria packed at the greatest density. If we assume sequential and complete oxidation of glucose by glycolysis and oxidative phosphorylation, then these mitochondria are required to produce ATP at a rate of 52 nmol·min-1·μL-1 at rest, rising to 963 during activity. Glycolysis would contribute ATP at 0.24 nmol·min-1·μL-1 of cytosol at rest, rising to 4.36 during activity. These data provide a quantitative framework for presynaptic bioenergetics in situ, and reveal that, beyond an immediate capacity to accelerate ATP output from glycolysis and oxidative phosphorylation, over longer time periods presynaptic terminals optimize mitochondrial volume and density to meet power demand.Significance StatementThe remarkable energy demands of the brain are supported by the complete oxidation of its fuel but debate continues regarding a division of labor between glycolysis and oxidative phosphorylation across different cell types. Here we exploit the neuromuscular synapse, a model for studying neurophysiology, to elucidate fundamental aspects of neuronal energy metabolism that ultimately constrain rates of neural processing. We quantified energy production rates required to sustain activity at individual nerve terminals and compared these with the volume capable of oxidative phosphorylation (mitochondria) and glycolysis (cytosol). We find strong support for oxidative phosphorylation playing a primary role in presynaptic terminals and provide the first in vivo estimates of energy production rates per unit volume of presynaptic mitochondria and cytosol.

DOI: https://doi.org/10.1523/JNEUROSCI.1236-21.2021
Brain Res Bull. 2021 Dec 09. pii: S0361-9230(21)00340-3. [Epub ahead of print]

ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway.

Hengjiang Guo, Yan Jiang, Zhiqing Gu, Lulu Ren, Change Zhu, Shenghua Yu, Rong Wei.

  The imbalance of mitochondrial dynamics plays an important role in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Zinc-finger protein 36 (ZFP36) has been documented to have neuroprotective effects, however, whether ZFP36 is involved in the regulation of neuronal survival during cerebral I/R injury remains unknown. In this study, we found that the transcriptional and translational levels of ZFP36 were increased in immortalized hippocampal HT22 neuronal cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ZFP36 gene silencing exacerbated OGD/R-induced dynamin-related protein 1 (DRP1) activity, mitochondrial fragmentation, oxidative stress and neuronal apoptosis, whereas ZFP36 overexpression exhibited the opposite effects. Besides, we found that NADPH oxidase 4 (NOX4) was upregulated by OGD/R, and NOX4 inhibition remarkably attenuated OGD/R-instigated DRP1 activity, mitochondrial fragmentation and neuronal apoptosis. Further study demonstrated that ZFP36 targeted NOX4 mRNA directly by binding to the AU-rich elements (AREs) in the NOX4 3'-untranslated regions (3'-UTR) and inhibited NOX4 expression. Taken together, our data indicate that ZFP36 protects against OGD/R-induced neuronal injury by inhibiting NOX4-mediated DRP1 activation and excessive mitochondrial fission. Pharmacological targeting of ZFP36 to suppress excessive mitochondrial fission may provide new therapeutic strategies in the treatment of cerebral I/R injury.

Keywords:  DRP1; ZFP36; mitochondrial dysfunction; mitochondrial fission; neuronal apoptosis

DOI:  https://doi.org/10.1016/j.brainresbull.2021.12.003
Eur J Neurosci. 2021 Dec 13.

Bioactive lipids and their metabolism: new therapeutic opportunities for Parkinson's disease.

Wenjing Shen, Li Jiang, Jingyi Zhao, Haili Wang, Meng Hu, Lanlan Chen, Yingzhu Chen.

  Parkinson's disease (PD) is a neurological disorder characterized by motor dysfunction, which can also be associated with non-motor symptoms. Its pathogenesis is thought to stem from a loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies containing aggregated α-synuclein. Recent works suggested that lipids might play a pivotal role in the pathophysiology of PD. In particular, the so-called "bioactive" lipids whose changes in the concentration may lead to functional consequences and affect many pathophysiological processes, including neuroinflammation, are closely related to PD in terms of symptoms, disease progression, and incidence. This study aimed to explore the molecular metabolism and physiological functions of bioactive lipids, such as fatty acids (mainly unsaturated fatty acids), eicosanoids, endocannabinoids, oxysterols, representative sphingolipids, diacylglycerols, and lysophosphatidic acid, in the development of PD. The knowledge of bioactive lipids in PD gained through preclinical and clinical studies is expected to improve the understanding of disease pathogenesis and provide novel therapeutic avenues.

Keywords:  Eicosanoids; endocannabinoids; oxysterols; sphingolipids; unsaturated fatty acids

DOI:  https://doi.org/10.1111/ejn.15566
Front Physiol. 2021 ;12 715443

Beneficial Effects on Brain Micro-Environment by Caloric Restriction in Alleviating Neurodegenerative Diseases and Brain Aging.

Li Zhang, Huachong Xu, Ning Ding, Xue Li, Xiaoyin Chen, Zhuangfei Chen.

  Aging and neurodegenerative diseases are frequently associated with the disruption of the extracellular microenvironment, which includes mesenchyme and body fluid components. Caloric restriction (CR) has been recognized as a lifestyle intervention that can improve long-term health. In addition to preventing metabolic disorders, CR has been shown to improve brain health owing to its enhancing effect on cognitive functions or retarding effect on the progression of neurodegenerative diseases. This article summarizes current findings regarding the neuroprotective effects of CR, which include the modulation of metabolism, autophagy, oxidative stress, and neuroinflammation. This review may offer future perspectives for brain aging interventions.

Keywords:  brain aging; cognitive functions; extracellular microenvironment; metabolic homeostasis; neuroinflammation

DOI:  https://doi.org/10.3389/fphys.2021.715443
J Clin Invest. 2021 Dec 16. pii: e146400. [Epub ahead of print]

A metabolic biomarker for early stage of Parkinson's disease in patients and animal models.

David Mallet, Thibault Dufourd, Mélina Decourt, Carole Carcenac, Paola Bossù, Laure Verlin, Pierre-Olivier Fernagut, Marianne Benoit-Marand, Gianfranco Spalletta, Emmanuel L Barbier, Sebastien Carnicella, Véronique Sgambato, Florence Fauvelle, Sabrina Boulet.

  BACKGROUND: Care management of Parkinson's disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detecting PD therefore represents a key step for developing therapies able to delay or slow down its progression.METHODS: We investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.
RESULTS: Our translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects.
CONCLUSION: From our translational study which included three animal models and three de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis and may possibly predict early PD development, before motor symptoms appearance.FUNDINGS. ANR, DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes.

Keywords:  Diagnostics; Metabolism; Neuroscience; Parkinson disease

DOI:  https://doi.org/10.1172/JCI146400
Neural Regen Res. 2022 Jul;17(7): 1397-1403

Rethinking the necessity of low glucose intervention for cerebral ischemia/reperfusion injury.

Jiahua Xie, Farooqahmed S Kittur, P Andy Li, Chiu-Yueh Hung.

  Glucose is the essential and almost exclusive metabolic fuel for the brain. Ischemic stroke caused by a blockage in one or more cerebral arteries quickly leads to a lack of regional cerebral blood supply resulting in severe glucose deprivation with subsequent induction of cellular homeostasis disturbance and eventual neuronal death. To make up ischemia-mediated adenosine 5'-triphosphate depletion, glucose in the ischemic penumbra area rapidly enters anaerobic metabolism to produce glycolytic adenosine 5'-triphosphate for cell survival. It appears that an increase in glucose in the ischemic brain would exert favorable effects. This notion is supported by in vitro studies, but generally denied by most in vivo studies. Clinical studies to manage increased blood glucose levels after stroke also failed to show any benefits or even brought out harmful effects while elevated admission blood glucose concentrations frequently correlated with poor outcomes. Surprisingly, strict glycaemic control in clinical practice also failed to yield any beneficial outcome. These controversial results from glucose management studies during the past three decades remain a challenging question of whether glucose intervention is needed for ischemic stroke care. This review provides a brief overview of the roles of cerebral glucose under normal and ischemic conditions and the results of managing glucose levels in non-diabetic patients. Moreover, the relationship between blood glucose and cerebral glucose during the ischemia/reperfusion processes and the potential benefits of low glucose supplements for non-diabetic patients are discussed.

Keywords:  blood glucose; blood-brain barrier; cerebral glucose; glucose intervention; glucose transporter; glycosylation; induced hyperglycemia; ischemic penumbra; ischemic stroke; non-diabetic patients

DOI:  https://doi.org/10.4103/1673-5374.330592
Biol Psychiatry Cogn Neurosci Neuroimaging. 2021 Dec 13. pii: S2451-9022(21)00342-6. [Epub ahead of print]

The Influence of Maternal Metabolic State and Nutrition on Offspring Neurobehavioral Development: A Focus on Preclinical Models.

A J Mitchell, Geoffrey A Dunn, Elinor L Sullivan.

  The prevalence of both obesity and neurodevelopmental disorders have increased substantially over the last several decades. Early environmental factors including maternal nutrition and metabolic state during gestation influence offspring neurodevelopment. Both human and preclinical models demonstrate a link between poor maternal nutrition, altered metabolic state, and risk for behavioral abnormalities in offspring. This review aims to highlight evidence from the current literature connecting maternal nutrition and the associated metabolic changes with neural and behavioral outcomes in the offspring, as well as identify possible mechanisms underlying these neurodevelopmental outcomes. Due to the highly correlated nature of poor nutrition and obesity in humans, preclinical animal models are important in distinguishing the unique effects of maternal nutrition and metabolic state on offspring brain development. We use a translational lens to highlight results from preclinical animal models of maternal obesogenic diet related to alterations in behavioral and neurodevelopmental outcomes in offspring. Specifically, we aim to highlight results that resemble behavioral phenotypes described in the diagnostic criteria of neurodevelopmental conditions in humans. Finally, we examine the pro-inflammatory nature of maternal obesity and consumption of a high-fat diet as a mechanism for neurodevelopmental alterations that may alter offspring behavior later in life. It is important that future studies examine potential therapeutic interventions and prevention strategies to interrupt the transgenerational transmission of disease. Given the tremendous risk to the next generation, changes need to be made to ensure all pregnant people have access to nutritious food and are informed about the optimal diet for their developing child.

Keywords:  Animal models; Maternal Obesity; Neurodevelopmental Disorders; Neuroinflammation; Nutrition; Western-Style Diet

DOI:  https://doi.org/10.1016/j.bpsc.2021.11.014
Cell Mol Life Sci. 2021 Dec 15.

Hypothalamic inflammation in metabolic disorders and aging.

Anup Bhusal, Md Habibur Rahman, Kyoungho Suk.

  The hypothalamus is a critical brain region for the regulation of energy homeostasis. Over the years, studies on energy metabolism primarily focused on the neuronal component of the hypothalamus. Studies have recently uncovered the vital role of glial cells as an additional player in energy balance regulation. However, their inflammatory activation under metabolic stress condition contributes to various metabolic diseases. The recruitment of monocytes and macrophages in the hypothalamus helps sustain such inflammation and worsens the disease state. Neurons were found to actively participate in hypothalamic inflammatory response by transmitting signals to the surrounding non-neuronal cells. This activation of different cell types in the hypothalamus leads to chronic, low-grade inflammation, impairing energy balance and contributing to defective feeding habits, thermogenesis, and insulin and leptin signaling, eventually leading to metabolic disorders (i.e., diabetes, obesity, and hypertension). The hypothalamus is also responsible for the causation of systemic aging under metabolic stress. A better understanding of the multiple factors contributing to hypothalamic inflammation, the role of the different hypothalamic cells, and their crosstalks may help identify new therapeutic targets. In this review, we focus on the role of glial cells in establishing a cause-effect relationship between hypothalamic inflammation and the development of metabolic diseases. We also cover the role of other cell types and discuss the possibilities and challenges of targeting hypothalamic inflammation as a valid therapeutic approach.

Keywords:  Aging; Diabetes; Hypertension; Hypothalamus; Inflammation; Obesity

DOI:  https://doi.org/10.1007/s00018-021-04019-x
PLoS One. 2021 ;16(12): e0260291

Characterising the dynamics of cerebral metabolic dysfunction following traumatic brain injury: A microdialysis study in 619 patients.

Mathew R Guilfoyle, Adel Helmy, Joseph Donnelly, Matthew G Stovell, Ivan Timofeev, John D Pickard, Marek Czosnyka, Peter Smielewski, David K Menon, Keri L H Carpenter, Peter J Hutchinson.

Traumatic brain injury (TBI) is a major cause of death and disability, particularly amongst young people. Current intensive care management of TBI patients is targeted at maintaining normal brain physiology and preventing secondary injury. Microdialysis is an invasive monitor that permits real-time assessment of derangements in cerebral metabolism and responses to treatment. We examined the prognostic value of microdialysis parameters, and the inter-relationships with other neuromonitoring modalities to identify interventions that improve metabolism. This was an analysis of prospective data in 619 adult TBI patients requiring intensive care treatment and invasive neuromonitoring at a tertiary UK neurosciences unit. Patients had continuous measurement of intracranial pressure (ICP), arterial blood pressure (ABP), brain tissue oxygenation (PbtO2), and cerebral metabolism and were managed according to a standardized therapeutic protocol. Microdialysate was assayed hourly for metabolites including glucose, pyruvate, and lactate. Cerebral perfusion pressure (CPP) and cerebral autoregulation (PRx) were derived from the ICP and ABP. Outcome was assessed with the Glasgow Outcome Score (GOS) at 6 months. Relationships between monitoring variables was examined with generalized additive mixed models (GAMM). Lactate/Pyruvate Ratio (LPR) over the first 3 to 7 days following injury was elevated amongst patients with poor outcome and was an independent predictor of ordinal GOS (p<0.05). Significant non-linear associations were observed between LPR and cerebral glucose, CPP, and PRx (p<0.001 to p<0.05). GAMM models suggested improved cerebral metabolism (i.e. reduced LPR with CPP >70mmHg, PRx <0.1, PbtO2 >18mmHg, and brain glucose >1mM. Deranged cerebral metabolism is an important determinant of patient outcome following TBI. Variations in cerebral perfusion, oxygenation and glucose supply are associated with changes in cerebral LPR and suggest therapeutic interventions to improve cerebral metabolism. Future prospective studies are required to determine the efficacy of these strategies.

DOI: https://doi.org/10.1371/journal.pone.0260291
Neural Regen Res. 2022 Jul;17(7): 1505-1511

Critical role of mitochondrial aldehyde dehydrogenase 2 in acrolein sequestering in rat spinal cord injury.

Seth A Herr, Liangqin Shi, Thomas Gianaris, Yucheng Jiao, Siyuan Sun, Nick Race, Scott Shapiro, Riyi Shi.

  Lipid peroxidation-derived aldehydes, such as acrolein, the most reactive aldehyde, have emerged as key culprits in sustaining post-spinal cord injury (SCI) secondary pathologies leading to functional loss. Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2 (ALDH2), a key oxidoreductase and powerful endogenous anti-aldehyde machinery, is likely important for protecting neurons from aldehydes-mediated degeneration. Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator (Alda-1), we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2. Over an acute 2 day period post injury, we found that ALDH2 expression was significantly lowered post-SCI, but not so in rats given Alda-1. This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction, which was revealed in co-immunoprecipitation experiments. We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord, and reduced cyst pathology. In addition, Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI. Finally, ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure. It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims. All animal work was approved by Purdue Animal Care and Use Committee (approval No. 1111000095) on January 1, 2021.

Keywords:  acrolein; acrolein-lysine adduct; alda-1; enzymatic catalyst; lipid peroxidation; mitochondrial aldehyde dehydrogenase-2; neurotrauma; oxidative stress; reactive aldehydes; spinal cord contusion

DOI:  https://doi.org/10.4103/1673-5374.330613
Neural Regen Res. 2022 Jul;17(7): 1512-1517

Hypothermia selectively protects the anterior forebrain mesocircuit during global cerebral ischemia.

Xiao-Hua Wang, Wei Jiang, Si-Yuan Zhang, Bin-Bin Nie, Yi Zheng, Feng Yan, Jian-Feng Lei, Tian-Long Wang.

  Hypothermia is an important protective strategy against global cerebral ischemia following cardiac arrest. However, the mechanisms of hypothermia underlying the changes in different regions and connections of the brain have not been fully elucidated. This study aims to identify the metabolic nodes and connection integrity of specific brain regions in rats with global cerebral ischemia that are most affected by hypothermia treatment. 18F-fluorodeoxyglucose positron emission tomography was used to quantitatively determine glucose metabolism in different brain regions in a rat model of global cerebral ischemia established at 31-33°C. Diffusion tensor imaging was also used to reconstruct and explore the brain connections involved. The results showed that, compared with the model rats established at 37-37.5°C, the rat models of global cerebral ischemia established at 31-33°C had smaller hypometabolic regions in the thalamus and primary sensory areas and sustained no obvious thalamic injury. Hypothermia selectively preserved the integrity of the anterior forebrain mesocircuit, exhibiting protective effects on the brain during the global cerebral ischemia. The study was approved by the Institutional Animal Care and Use Committee at Capital Medical University (approval No. XW-AD318-97-019) on December 15, 2019.

Keywords:  anterior forebrain mesocircuit; cardiac arrest; corpus callosum; global cerebral ischemia; hypometabolic areas; hypothermia; magnetic resonance imaging; positron emission tomography; prefrontal cortex; rats; thalamus

DOI:  https://doi.org/10.4103/1673-5374.330616
Front Hum Neurosci. 2021 ;15 739917

Neurometabolite Changes in Hyperthyroid Patients Before and After Antithyroid Treatment: An in vivo 1H MRS Study.

Mukesh Kumar, Sadhana Singh, Poonam Rana, Pawan Kumar, Tarun Sekhri, Ratnesh Kanwar, Maria D'Souza, Subash Khushu.

  Purpose: Patients with hyperthyroidism have frequent neuropsychiatric symptoms such as lack of attention, concentration, poor memory, impaired executive functions, depression, and anxiety. These neurocognitive impairments such as memory, attention, and executive functions appear to be associated with dysfunction in brain regions. This study was conducted to investigate the metabolic changes in the brain subcortical regions, i.e., posterior parietal cortex and dorsolateral prefrontal cortex (DLPFC), in patients with hyperthyroidism before and after antithyroid treatment using proton magnetic resonance spectroscopy (1H MRS). Materials and Methods: We collected neuropsychological and 1H MRS data from posterior parietal cortex and DLPFC, in both control (N = 30) and hyperthyroid (N = 30) patients. In addition, follow-up data were available for 19 patients treated with carbimazole for 30 weeks. The relative ratios of the neurometabolites were calculated using the Linear Combination Model (LCModel). Analysis of co-variance using Bonferroni correction was performed between healthy controls and hyperthyroid patients, and a paired t-test was applied in patients at baseline and follow-up. Spearman's rank-order correlation was used to analyze bivariate associations between thyroid hormone levels and metabolite ratios, and the partial correlation analysis was performed between neuropsychological scores and metabolite ratios, with age and sex as covariates, in the patients before and after treatment. Results: Our results revealed a significant decrease in choline/creatine [glycerophosphocholine (GPC) + phosphocholine (PCh)/creatine (tCr)] in both the posterior parietal cortex and DLPFC in hyperthyroid patients, and these changes were reversible after antithyroid treatment. The posterior parietal cortex also showed significantly reduced glutamate/creatine (Glu/tCr), (glutamate + glutamine)/creatine (Glx/tCr), and increased glutathione/creatine (GSH/tCr) ratios in the hyperthyroid patients over control subjects. In DLPFC, only (N-acetyl aspartate + N-acetyl aspartyl-glutamate)/creatine (NAA + NAAG)/tCr was increased in the hyperthyroid patients. After antithyroid treatment, (GPC + PCh)/tCr increased, and Glx/tCr decreased in both brain regions in the patients at follow-up. Gln/tCr in the posterior parietal cortex was decreased in patients at follow-up. Interestingly, (GPC + PCh)/tCr in DLPFC showed a significantly inverse correlation with free tri-iodothyronine (fT3) in hyperthyroid patients at baseline, whereas NAA/tCr showed positive correlations with fT3 and free thyroxine (fT4) in hyperthyroid patients before and after antithyroid treatment, in the posterior parietal cortex. In DLPFC, only (NAA + NAAG)/tCr showed positive correlations with fT3 and fT4 in the patients before treatment. Conclusion: The overall findings suggest that all the brain metabolite changes were not completely reversed in the hyperthyroid patients after antithyroid treatment, even after achieving euthyroidism.

Keywords:  dorsolateral prefrontal cortex; hyperthyroidism; magnetic resonance spectroscopy; neurometabolites; posterior parietal cortex

DOI:  https://doi.org/10.3389/fnhum.2021.739917