Capturing alterations of intracellular-extracellular lactate distribution in the brain using diffusion-weighted MR spectroscopy in vivo.

While the intracellular-extracellular distribution of lactate has been suggested to play a critical role in the healthy and diseased brain, tools are lacking to noninvasively probe lactate in intracellular and extracellular spaces. Here, we show that, by measuring the diffusion of lactate with diffusion-weighted magnetic resonance (MR) spectroscopy in vivo and comparing it to the diffusion of purely intracellular metabolites, noninvasive quantification of extracellular and intracellular lactate fractions becomes possible. More specifically, we detect alterations of lactate diffusion in the APP/PS1 mouse model of Alzheimer's disease. Data modeling allows quantifying decreased extracellular lactate fraction in APP/PS1 mice as compared to controls, which is quantitatively confirmed with implanted enzyme-microelectrodes. The capability of diffusion-weighted MR spectroscopy to quantify extracellular-intracellular lactate fractions opens a window into brain metabolism, including in Alzheimer's disease.

Neurochemical Anatomy of Cushing's Syndrome.

The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.

Coupling motor evoked potentials and brain [18F]FDG-PET in Amyotrophic Lateral Sclerosis: preliminary findings on disease severity.

BACKGROUND: The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation. OBJECTIVE: To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and [18F]FDG-PET measures of neural dysfunction. METHODS: We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and [18F]FDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For [18F]FDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC). RESULTS: Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the [18F]FDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC. CONCLUSION: This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.

The impact of six-week dihydrogen-pyrroloquinoline quinone supplementation on mitochondrial biomarkers, brain metabolism, and cognition in elderly individuals with mild cognitive impairment: a randomized controlled trial.

OBJECTIVES: To assess the impact of medium-term supplementation with dihydrogen and pyrroloquinoline quinone (PQQ) on mitochondrial biomarkers, brain metabolism, and cognition in elderly individuals diagnosed with mild cognitive impairment. DESIGN: A parallel-group, randomized, placebo-controlled, double-blind experimental design, maintaining a 1:1 allocation ratio between the experimental group (receiving the dihydrogen-producing minerals and PQQ) and the control group (receiving the placebo) throughout the trial. SETTING AND PARTICIPANTS: Thirty-four elderly individuals with mild cognitive impairment (mean age 71.9 ± 3.8 years; 28 females) voluntarily provided written consent to participate in this trial. Participants were assigned in a double-blind parallel-group design to receive either a dihydrogen-PQQ mixture (Alpha Hope®, CalerieLife, Irvine, CA) or placebo twice daily for a 6-week intervention period. METHODS: The primary endpoint was the change in serum brain-derived neurotrophic factor (BDNF) from baseline to the 6-week follow-up; secondary outcomes included cognitive function indices, specific metabolites in brain tissue, brain oxygenation, and the prevalence and severity of side effects. Interaction effects (time vs. intervention) were evaluated using two-way ANOVA with repeated measures and Friedman's 2-way ANOVA by ranks, for normally distributed data with homogeneous variances and non-homogeneous variances, respectively. RESULTS: Dihydrogen-PQQ resulted in a significant elevation in serum BDNF levels at the six-week follow-up (P = 0.01); conversely, no changes in BDNF levels were observed in the placebo group throughout the study duration (P = 0.27). A non-significant trend in the impact of interventions on BDNF levels was observed (treatment vs. time interaction, P = 0.14), suggesting a tendency for dihydrogen-PQQ to upregulate BDNF levels compared to the placebo. A significant interaction effect was observed for the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores in the orientation domain (P = 0.03), indicating the superiority of dihydrogen-PQQ over placebo in enhancing this cognitive aspect. Cerebral oxygenation saturation exhibited a significant increase following the administration of the dihydrogen-PQQ mixture, from 48.4 ± 7.2% at baseline to 52.8 ± 6.6% at 6-week post-administration (P = 0.005). In addition, brain N-acetyl aspartate levels significantly increased at seven out of thirteen locations post-intervention in participants receiving the mixture (P ≤ 0.05). CONCLUSIONS: Despite the limited number of participants included in the study for interpreting clinical parameters, the dihydrogen-PQQ mixture blend shows promise as a potential dietary intervention for enhancing mental orientation and brain metabolism in individuals with age-related mild cognitive decline.

Effect of reducing isoflurane level on glucosamine uptake in the mouse brain during magnetic resonance imaging studies.

Anesthesia is often required during magnetic resonance imaging (MRI) examinations in animal studies. Anesthetic drugs differ in their capacity to interfere with homeostatic mechanisms responsible for glucose metabolism in the brain, which may create a constraint in the study design. Recent studies suggest that the chemical exchange saturation transfer (CEST) MRI scanning technique can detect localized metabolic changes in rodent brains induced by the uptake of glucose or its analogs; however, most of these studies do not account for the impact of anesthesia type on the brain metabolism. Herein, we aimed to evaluate the effect of reduced isoflurane levels on the preclinical imaging of glucosamine (GlcN) uptake in healthy mouse brains to establish optimal conditions for future brain imaging studies using the CEST MRI technique. The commonly used anesthesia protocol for longitudinal MRI examinations using 1.5% isoflurane level was compared to that using a mixture of low isoflurane (0.8%) level combined with midazolam (2 mg/kg, SC). Magnetization transfer ratio asymmetry (MTRasym) and area under the curve (AUC) analyses were used to characterize GlcN signals in the brain. The results indicated that mice injected with GlcN and anesthetized with 1.5% isoflurane exhibited low and insignificant changes in the MTRasym and AUC signals in the frontal cortex, whereas mice administered with 0.8% isoflurane combined with midazolam demonstrated a significant increase in these signals in the frontal cortex. This study highlights the diverse GlcN metabolic changes observed in mouse brains under variable levels of isoflurane anesthesia using the CEST MRI method. The results suggest that it is feasible to maintain anesthesia with low-dose isoflurane by integrating midazolam, which may enable the investigation of GlcN uptake in the brain. Thus, reducing isoflurane levels may support studies into mouse brain metabolism using the CEST MRI method and should be considered in future studies.

Effect of HHFNC therapy on organ oxygenation and brain metabolism in neonates receiving exchange transfusion.

Background: Exchange transfusion therapy is a complex and invasive procedure with a high risk coefficient. This method involves replacing the entire blood of a child with fresh blood with double circulating blood volume in a short period, typically in 1-2 h. This procedure can cause the body's internal environment to be unstable, which can put newborns under a lot of stress. This stress can lead to many, including abnormal laboratory biochemical examination, low or high blood pressure, and apnea. There is also the possibility of secondary infection and, in severe cases, cardiac arrest. This study investigated the effects of Humidified high-flow nasal cannula (HHFNC) ventilation on hemodynamic stability and oxygenation during exchange transfusion in neonates. Furthermore, the effects on brain metabolism and salivary cortisol during exchange transfusion were also analyzed. Methods: In this study, the control group consisted of 45 cases of children who underwent simple blood exchange between 1 May 2017, and 31 December 2019 control group. The observation group consisted of 33 cases of children who underwent blood exchange under HHFNC support between 1 January 2020, and 30 April 2022. The study compared various physiological parameters between the control and the observation group. These included blood gas analysis, pulmonary artery pressure, ejection fraction, invasive mean arterial pressure, heart rate, cerebral oxygenation, intestinal oxygenation, renal oxygenation, and duration of blood exchange. Furthermore, the study also compared the changes in brain metabolic and salivary cortisol indicators between the two groups of children. Results: The results did not reveal any significant difference in PH, PaO2, and duration of blood exchange between the control and the observation group. However, the observation group's invasive mean arterial pressure, ejection fraction, cerebral oxygenation, intestinal oxygenation, and renal oxygenation were higher than those of the control group. Furthermore, compared with the control group, the pulmonary artery pressure, heart rate, and PaCO2 were lower in the observation group. There was a statistically significant difference between the two groups of children in the relevant clinical indicators (total bilirubin, hemoglobin, SPO2, etc.) after exchange transfusion. After 1 h of blood exchange and after blood exchange, the salivary cortisol levels of the observation group were lower than the control group. The difference was statistically significant. The NAA/Cho and Cho/Cr values of the two groups of children were also significantly different. Conclusion: During blood exchange, unstable hemodynamics substantially impact organ oxygenation. The results of this study suggest that HHFNC and specific ventilation pressure support can improve the respiratory rate and help maintain blood flow stability and organ oxygenation. This technique can also reduce adverse reactions caused by blood exchange, minimizing patient stress and reducing the impact on brain metabolism.

Synaptic signaling modeled by functional connectivity predicts metabolic demands of the human brain.

PURPOSE: The human brain is characterized by interacting large-scale functional networks fueled by glucose metabolism. Since former studies could not sufficiently clarify how these functional connections shape glucose metabolism, we aimed to provide a neurophysiologically-based approach. METHODS: 51 healthy volunteers underwent simultaneous PET/MRI to obtain BOLD functional connectivity and [18F]FDG glucose metabolism. These multimodal imaging proxies of fMRI and PET were combined in a whole-brain extension of metabolic connectivity mapping. Specifically, functional connectivity of all brain regions were used as input to explain glucose metabolism of a given target region. This enabled the modeling of postsynaptic energy demands by incoming signals from distinct brain regions. RESULTS: Functional connectivity input explained a substantial part of metabolic demands but with pronounced regional variations (34 - 76%). During cognitive task performance this multimodal association revealed a shift to higher network integration compared to resting state. In healthy aging, a dedifferentiation (decreased segregated/modular structure of the brain) of brain networks during rest was observed. Furthermore, by including data from mRNA maps, [11C]UCB-J synaptic density and aerobic glycolysis (oxygen-to-glucose index from PET data), we show that whole-brain functional input reflects non-oxidative, on-demand metabolism of synaptic signaling. The metabolically-derived directionality of functional inputs further marked them as top-down predictions. In addition, the approach uncovered formerly hidden networks with superior efficiency through metabolically informed network partitioning. CONCLUSIONS: Applying multimodal imaging, we decipher a crucial part of the metabolic and neurophysiological basis of functional connections in the brain as interregional on-demand synaptic signaling fueled by anaerobic metabolism. The observed task- and age-related effects indicate promising future applications to characterize human brain function and clinical alterations.

Shaping down syndrome brain cognitive and molecular changes due to aging using adult animals from the Ts66Yah murine model.

Down syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy of Homo sapiens chromosome 21 (HSA21). The increased dosage of genes on HSA21 is associated with early neurodevelopmental changes and subsequently at adult age with the development of Alzheimer-like cognitive decline. However, the molecular mechanisms promoting brain pathology along aging are still missing. The novel Ts66Yah model represents an evolution of the Ts65Dn, used in characterizing the progression of brain degeneration, and it manifest phenotypes closer to human DS condition. In this study we performed a longitudinal analysis (3-9 months) of adult Ts66Yah mice. Our data support the behavioural alterations occurring in Ts66Yah mice at older age with improvement in the detection of spatial memory defects and also a new anxiety-related phenotype. The evaluation of hippocampal molecular pathways in Ts66Yah mice, as effect of age, demonstrate the aberrant regulation of redox balance, proteostasis, stress response, metabolic pathways, programmed cell death and synaptic plasticity. Intriguingly, the genotype-driven changes observed in those pathways occur early promoting altered brain development and the onset of a condition of premature aging. In turn, aging may account for the subsequent hippocampal deterioration that fall in characteristic neuropathological features. Besides, the analysis of sex influence in the alteration of hippocampal mechanisms demonstrate only a mild effect. Overall, data collected in Ts66Yah provide novel and consolidated insights, concerning trisomy-driven processes that contribute to brain pathology in conjunction with aging. This, in turn, aids in bridging the existing gap in comprehending the intricate nature of DS phenotypes.

Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors.

Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.

Evidence for a role of the basolateral amygdala in regulating regional metabolism in the stressed brain.

The brain regulates every physiological process in the body, including metabolism. Studies investigating brain metabolism have shown that stress can alter major metabolic processes, and that these processes can vary between regions. However, no study has investigated how metabolic pathways may be altered by stressor perception, or whether stress-responsive brain regions can also regulate metabolism. The basolateral amygdala (BLA), a region important for stress and fear, has reciprocal connections to regions responsible for metabolic regulation. In this study, we investigated how BLA influences regional metabolic profiles within the hippocampus (HPC) and medial prefrontal cortex (mPFC), regions involved in regulating the stress response and stress perception, using optogenetics in male C57BL/6 mice during footshock presentation in a yoked shuttlebox paradigm based on controllable (ES) and uncontrollable (IS) stress. RNA extracted from HPC and mPFC were loaded into NanoString® Mouse Neuroinflammation Panels, which also provides a broad view of metabolic processes, for compilation of gene expression profiles. Results showed differential regulation of carbohydrate and lipid metabolism, and insulin signaling gene expression pathways in HPC and mPFC following ES and IS, and that these differences were altered in response to optogenetic excitation or inhibition of the BLA. These findings demonstrate for the first time that individual brain regions can utilize metabolites in a way that are unique to their needs and function in response to a stressor, and that vary based on stressor controllability and influence by BLA.

Neuroprotective effects of lactate and ketone bodies in acute brain injury.

The goal of neurocritical care is to prevent and reverse the pathologic cascades of secondary brain injury by optimizing cerebral blood flow, oxygen supply and substrate delivery. While glucose is an essential energetic substrate for the brain, we frequently observe a strong decrease in glucose delivery and/or a glucose metabolic dysregulation following acute brain injury. In parallel, during the last decades, lactate and ketone bodies have been identified as potential alternative fuels to provide energy to the brain, both under physiological conditions and in case of glucose shortage. They are now viewed as integral parts of brain metabolism. In addition to their energetic role, experimental evidence also supports their neuroprotective properties after acute brain injury, regulating in particular intracranial pressure control, decreasing ischemic volume, and leading to an improvement in cognitive functions as well as survival. In this review, we present preclinical and clinical evidence exploring the mechanisms underlying their neuroprotective effects and identify research priorities for promoting lactate and ketone bodies use in brain injury.

Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study.

Introduction: Type C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by 1H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites. Methods: The bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. 1H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/µm2) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy). Results: The characteristic 1H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity-Callaghan's model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema. Discussion: dMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.

Brain metabolism response to intrahospital transfers in neurocritical ill patients and the impact of microdialysis probe location.

Intrahospital transfer (IHT), a routine in the management of neurocritical patients requiring imaging or interventions, might affect brain metabolism. Studies about IHT effects using microdialysis (MD) have produced conflicting results. In these studies, only the most damaged hemisphere was monitored, and those may not reflect the impact of IHT on overall brain metabolism, nor do they address differences between the hemispheres. Herein we aimed to quantify the effect of IHT on brain metabolism by monitoring both hemispheres with bilateral MD. In this study, 27 patients with severe brain injury (10 traumatic brain injury and 17 subarachnoid hemorrhage patients) were included, with a total of 67 IHT. Glucose, glycerol, pyruvate and lactate were measured by MD in both hemispheres for 10 h pre- and post-IHT. Alterations in metabolite levels after IHT were observed on both hemispheres; although these changes were more marked in hemisphere A (most damaged) than B (less damaged). Our results suggest that brain metabolism is altered after an IHT of neurocritical ill patients particularly but not limited to the damaged hemisphere. Bilateral monitorization may be more sensitive than unilateral monitorization for detecting metabolic disturbances not directly related to the course of the disease.

Mapping brain metabolism, connectivity and neurotransmitters topography in early and late onset dementia with lewy bodies.

INTRODUCTION: Early-onset dementia with Lewy bodies (EO-DLB) is associated with rapid cognitive decline and severe neuropsychiatric symptoms at onset. METHODS: Using FDG-PET imaging for 62 patients (21 EO-DLB, 41 LO (late-onset)-DLB), we explored brain hypometabolism, and metabolic connectivity in the whole-brain network and resting-state networks (RSNs). We also evaluated the spatial association between brain hypometabolism and neurotransmitter pathways topography. RESULTS: Direct comparisons between the two clinical subgroups showed that EO-DLB was characterized by a lower metabolism in posterior cingulate/precuneus and occipital cortex. Metabolic connectivity analysis revealed significant alterations in posterior regions in both EO-DLB and LO-DLB. The EO-DLB, however, showed more severe loss of connectivity between occipital and parietal nodes and hyperconnectivity between frontal and cerebellar nodes. Spatial topography association analysis indicated significant correlations between neurotransmitter maps (i.e. acetylcholine, GABA, serotonin, dopamine) and brain hypometabolism in both EO and LO-DLB, with significantly higher metabolic correlation in the presynaptic serotonergic system for EO-DLB, supporting its major dysfunction. CONCLUSIONS: Our study revealed greater brain hypometabolism and loss of connectivity in posterior brain region in EO- than LO-DLB. Serotonergic mapping emerges as a relevant factor for further investigation addressing clinical differences between DLB subtypes.

Metabolite transport across central nervous system barriers.

Metabolomic analysis of cerebrospinal fluid (CSF) is used to improve diagnostics and pathophysiological understanding of neurological diseases. Alterations in CSF metabolite levels can partly be attributed to changes in brain metabolism, but relevant transport processes influencing CSF metabolite concentrations should be considered. The entry of molecules including metabolites into the central nervous system (CNS), is tightly controlled by the blood-brain, blood-CSF, and blood-spinal cord barriers, where aquaporins and membrane-bound carrier proteins regulate influx and efflux via passive and active transport processes. This report therefore provides reference for future CSF metabolomic work, by providing a detailed summary of the current knowledge on the location and function of the involved transporters and routing of metabolites from blood to CSF and from CSF to blood.

Non-invasive assessment of stimulation-specific changes in cerebral glucose metabolism with functional PET.

PURPOSE: Functional positron emission tomography (fPET) with [18F]FDG allows quantification of stimulation-induced changes in glucose metabolism independent of neurovascular coupling. However, the gold standard for quantification requires invasive arterial blood sampling, limiting its widespread use. Here, we introduce a novel fPET method without the need for an input function. METHODS: We validated the approach using two datasets (DS). For DS1, 52 volunteers (23.2 ± 3.3 years, 24 females) performed Tetris® during a [18F]FDG fPET scan (bolus + constant infusion). For DS2, 18 participants (24.2 ± 4.3 years, 8 females) performed an eyes-open/finger tapping task (constant infusion). Task-specific changes in metabolism were assessed with the general linear model (GLM) and cerebral metabolic rate of glucose (CMRGlu) was quantified with the Patlak plot as reference. We then estimated simplified outcome parameters, including GLM beta values and percent signal change (%SC), and compared them, region and whole-brain-wise. RESULTS: We observed higher agreement with the reference for DS1 than DS2. Both DS resulted in strong correlations between regional task-specific beta estimates and CMRGlu (r = 0.763…0.912). %SC of beta values exhibited strong agreement with %SC of CMRGlu (r = 0.909…0.999). Average activation maps showed a high spatial similarity between CMRGlu and beta estimates (Dice = 0.870…0.979) as well as %SC (Dice = 0.932…0.997), respectively. CONCLUSION: The non-invasive method reliably estimates task-specific changes in glucose metabolism without blood sampling. This streamlines fPET, albeit with the trade-off of being unable to quantify baseline metabolism. The simplification enhances its applicability in research and clinical settings.

Evidence of brain metabolism redistribution from neocortex to primitive brain structures in early acute COVID-19 respiratory syndrome.

BACKGROUND: Neuropsychiatric sequelae of COVID-19 have been widely documented in patients with severe neurological symptoms during the chronic or subacute phase of the disease. However, it remains unclear whether subclinical changes in brain metabolism can occur early in the acute phase of the disease. The aim of this study was to identify and quantify changes in brain metabolism in patients hospitalized for acute respiratory syndrome due to COVID-19 with no or mild neurological symptoms. RESULTS: Twenty-three non-intubated patients (13 women; mean age 55.5 ± 12.1 years) hospitalized with positive nasopharyngeal swab test (RT-PCR) for COVID-19, requiring supplemental oxygen and no or mild neurological symptoms were studied. Serum C-reactive protein measured at admission ranged from 6.43 to 189.0 mg/L (mean: 96.9 ± 54.2 mg/L). The mean supplemental oxygen demand was 2.9 ± 1.4 L/min. [18F]FDG PET/CT images were acquired with a median of 12 (4-20) days of symptoms. After visual interpretation of the images, semiquantitative analysis of [18F]FDG uptake in multiple brain regions was evaluated using dedicated software and the standard deviation (SD) of brain uptake in each region was automatically calculated in comparison with reference values of a normal database. Evolutionarily ancient structures showed positive SD mean values of [18F]FDG uptake. Lenticular nuclei were bilaterally hypermetabolic (> 2 SD) in 21/23 (91.3%) patients, and thalamus in 16/23 (69.6%), bilaterally in 11/23 (47.8%). About half of patients showed hypermetabolism in brainstems, 40% in hippocampi, and 30% in cerebellums. In contrast, neocortical regions (frontal, parietal, temporal and occipital lobes) presented negative SD mean values of [18F]FDG uptake and hypometabolism (< 2 SD) was observed in up to a third of patients. Associations were found between hypoxia, inflammation, coagulation markers, and [18F]FDG uptake in various brain structures. CONCLUSIONS: Brain metabolism is clearly affected during the acute phase of COVID-19 respiratory syndrome in neurologically asymptomatic or oligosymptomatic patients. The most frequent finding is marked hypermetabolism in evolutionary ancient structures such as lenticular nucleus and thalami. Neocortical metabolism was reduced in up to one third of patients, suggesting a redistribution of brain metabolism from the neocortex to evolutionary ancient brain structures in these patients.

Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.

BACKGROUND: We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI). OBJECTIVE: To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril. METHODS: Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study. RESULTS: MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group. CONCLUSION: Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.

Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.

The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.

Distinct changes in brain metabolism in patients with dementia and hearing loss.

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 18 F-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.