The resting brain is fuelled by glucose with a small release of lactate. During exercise, the brain switches to extracting lactate from blood and this increases brain carbohydrate uptake in great excess to that of oxygen. The fate of this excess carbohydrate uptake is unknown. Studies investigating the fate of brain carbohydrate uptake use brief periods of brain activation and so it is possible that the dissociation between brain glucose and oxygen metabolism is temporal and not material. In 13 healthy humans, we induced sustained increases in brain carbohydrate uptake via 2 h of mixed-intensity cycling exercise and hypothesized that lactate accumulation in the cerebrospinal fluid would account for some of this excess carbohydrate uptake. Exercise shifted the brain from releasing to extracting lactate (p = 0.034), causing an excess uptake of 14.3 ± 3.7 mmol of carbohydrate over 2 h of exercise. Although CSF glucose remained perfectly stable (3.0 ± 0.2 vs 3.0 ± 0.1 mmol/L; p = 1.0), CSF lactate concentration doubled (1.1 ± 0.05 vs 2.2 ± 0.3 mmol/L; p < 0.0001) and was correlated to cerebral lactate uptake (r = 0.68, p = 0.015). This accumulation of lactate in CSF represents a 15% increase in carbohydrate-based ATP availability, but accounts for only 6% of the unexplained carbohydrate extracted by the brain during exercise.

Chemotherapy-induced cognitive impairment is increasingly recognized in leukemia survivors. Its underlying neurobiologic correlations remain unclear. This study investigated voxel-based alterations in brain glucose metabolism after chemotherapy using high-resolution [18F]FDG PET/CT. Methods: This retrospective study included 100 adults with leukemia, both newly diagnosed and relapsed, who underwent [18F]FDG PET/CT brain imaging. Patients were grouped by chemotherapy exposure: recent (≤1 y), prior (>1 y), and none (chemotherapy-naïve controls). Brain metabolism was quantified using MIM software and normalized to reference regions. Statistical analysis included t tests and ANOVA, adjusted for age and sex. Results: Among 100 patients (49 recent, 22 prior, and 29 control), chemotherapy-exposed individuals showed significant metabolic alterations compared with controls. Decreased uptake was found in the posterior cingulate gyrus (1.33 vs. 1.36; P = 0.04), anterior orbital gyrus (1.05 vs. 1.11; P = 0.05), and thalami (1.19 vs. 1.24; P = 0.05). In patients aged 55 y or older, reduced metabolism was observed in the Rolandic operculum (1.12 vs. 1.19; P < 0.001) and inferior frontal gyrus (1.16 vs. 1.19; P = 0.05). Recent chemotherapy recipients showed increased metabolism in the fusiform gyrus (1.34 vs. 1.27; P = 0.04) and insula, whereas long-term survivors did not. Intrathecal chemotherapy was linked to reduced thalamic metabolism (1.11 vs. 1.15; P = 0.02). Conclusion: Chemotherapy is associated with voxel-based brain metabolic alterations, particularly in areas governing cognition and emotion. Effects are more pronounced in older adults and those receiving intrathecal treatment. These findings support research into metabolic imaging biomarkers for early detection and intervention in chemotherapy-induced cognitive impairment.

Directly compare the brain glucose patterns seen with [F-18] fluorodeoxyglucose (FDG) positron emission tomography (PET) between 2 genetically determined forms of Alzheimer's disease: Down syndrome (DS) and autosomal dominant Alzheimer's disease (ADAD). Cross-sectional analyses of FDG were performed in individuals with DS (n = 76) from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS), ADAD (n = 297), and neurotypical familial controls (n = 188) from the Dominantly Inherited Alzheimer Network (DIAN). Within-group linear regression models and generalized additive models were performed for select regional FDG uptake measures (isthmus cingulate and inferior parietal, precuneus, middle temporal gyrus, and precentral gyrus). Age, sex, apolipoprotein (APOE) ε4 carrier status, and cortical amyloid burden were included within these analyses. Even 20 years before expected onset of clinical symptoms, FDG uptake was lower for DS compared to neurotypical familial controls (p < 0.01). ADAD baseline FDG was similar to neurotypical familial controls until 7 years before expected symptom onset. Both symptomatic individuals with DS and ADAD had lower FDG compared to neurotypical familial controls (p < 0.01). A higher amyloid burden was associated with lower FDG for both genetic forms, with similar rates of decline in FDG uptake for DS and ADAD who were amyloid positive. Brain glucose metabolism is substantially lower for people with DS, even in individuals who are cognitively stable. The patterns of FDG decline are distinct in these 2 genetically determined forms of AD. The diagnostic utility of FDG-PET is specific to the genetic form of AD. ANN NEUROL 2025;98:1237-1248.

Restoration of glucose metabolic homeostasis for treating CNS diseases: mechanistic insights and potential clinical prospect.

BackgroundKetamine has attracted clinical interest for its therapeutic potential, but prolonged exposure raises concerns about dependence and its long-term effects on brain metabolism.Materials and MethodsMale mice received daily intraperitoneal injections of ketamine (30 mg/kg) for 28 days. Brain glucose metabolism was evaluated using [18F]FDG positron emission tomography at 1 h, 1 week, and 1 month post-injection. Expression levels of glucose transporters (GLUT1), glycolytic enzymes (PKM2, HK1), NMDA receptor subunits (NR2B), and apoptotic markers (caspase-3) were analyzed by Western blotting and RT-PCR.ResultsFDG-PET imaging suggested a biphasic metabolic pattern, with an increase in uptake at 1 h and 1 week, followed by a significant reduction by 1 month, returning toward baseline levels. GLUT1 mRNA expression gradually increased, although protein levels did not show a clear parallel change. PKM2 and HK1 remained largely unchanged. At 1 month, NR2B and caspase-3 transcripts were elevated, while protein-level changes were less evident, suggesting possible transcriptional regulation of stress-related pathways.DiscussionThese findings demonstrate that ketamine induces dynamic alterations in brain glucose metabolism accompanied by molecular adaptations. The early hypermetabolic response may reflect acute excitatory effects, whereas longer exposure could engage compensatory or stress-associated mechanisms. Metabolic imaging may provide a useful, non-invasive approach to better understand ketamine’s temporal effects and support long-term safety monitoring.

Targeting glycolysis and maintaining glucose homeostasis for treating perioperative neurocognitive disorder: a narrative review.

Dementia with Lewy bodies (DLB) and Parkinson disease (PD), especially when associated with REM sleep behavior disorder (RBD), represent partially overlapping phenotypes of overt α-synucleinopathies. We aimed to investigate overlapping and discrepant features between DLB with RBD (DLBRBD), PD with RBD (PDRBD), and PD without RBD (PD) patients. This was a cross-sectional study where consecutive patients with de novo PD, de novo PDRBD, and de novo DLBRBD underwent a full neuropsychological battery to study cognitive impairment, brain [18F]FDG PET as a marker of brain glucose metabolism, and [123I]FP-CIT SPECT as a marker of nigrostriatal dopaminergic functioning. Diagnosis was performed following current criteria, confirmed by evidence of dopaminergic deficit on [123I]FP-CIT SPECT and by at least 2 years of clinical follow-up. We recruited 31 de novo PD (mean age 71.8 ± 6.2; 38.7% females), 32 de novo PDRBD (mean age 72.6 ± 6, 28% females), and 30 de novo DLBRBD (mean age 78 ± 5.4; 40% females). Compared with de novo PD and de novo PDRBD, de novo DLBRBD patients were older, and had a lower education and significantly poorer cognitive performance (p < 0.001), especially involving attention, executive, and visuospatial functions. De novo DLBRBD patients showed significant reduced glucose metabolism involving the bilateral precuneus, bilateral cuneus, right angular gyrus, right posterior cingulate cortex, and right fusiform gyrus. Dopaminergic function was significantly worst in de novo PD, with a significantly lower [123I]FP-CIT binding in the least affected hemisphere (LAH) putamen (p = 0.042), LAH caudate (p = 0.027), and most affected hemisphere (MAH) putamen (p = 0.046) compared with de novo PDRBD patients, which was significantly lower also compared with de novo DLBRBD patients (p = 0.03). De novo DLBRBD had a lower binding compared with de novo PDRBD patients (p = 0.021) in the LAH caudate. The putamen/caudate ratio in the MAH was significantly lower in de novo PD compared with de novo PDRBD patients (p < 0.001) and in de novo PDRBD compared with de novo DLBRBD patients (p = 0.002). This study emphasizes how DLB with RBD and PD without RBD represent opposite ends of the neuronal α-synucleinopathy spectrum. The study highlights both overlapping and divergent clinical and neuroimaging features, with PD with RBD patients displaying an intermediate profile.

BackgroundCerebrospinal fluid (CSF) metabolomics offers an opportunity to investigate in vivo biological pathways impacted in the human brain by Alzheimer's disease (AD). While impairments in brain glucose metabolism and lipid homeostasis are implicated in AD, the underlying metabolic pathways remain unclear. Genotype information can also be leveraged to study associations between CSF metabolites and AD genetic risk.ObjectiveTo evaluate how CSF metabolomic profiles and genetic risk are associated with AD pathology as reflected by established CSF biomarkers (Aβ, P-Tau, and T-Tau).MethodsWe collected CSF mass spectrometry measurements of 678 metabolites and 4865 unnamed compounds, as well as genome-wide genotype data from 487 individuals in the Amsterdam Dementia cohort. Polygenic risk scores (PRS) for AD were calculated. Elastic net regression models were used to predict AD biomarker levels with CSF metabolites, and pathway enrichment analysis was performed to assess the metabolic pathways involved.Results98 CSF metabolites were found to be significantly correlated with P-Tau or T-Tau, but none with Aβ CSF levels. Elastic net regression models identified 42 and 34 metabolites predicting P-Tau and T-Tau, respectively, including novel associations with Anserine and Fucose. Pathway enrichment analysis implicated Pentose and Glucuronate Interconversions, Glycerophospholipid Metabolism, and ABC Transporters in AD pathology. PRS analysis highlighted four CSF phosphatidylcholines significantly associated with AD genetic risk.ConclusionsCSF metabolites demonstrate a lack of Aβ levels associations, contrasting with multiple significant findings for P-Tau and T-Tau. Novel associations with Anserine and Fucose may provide new insights into metabolic pathways impacted by AD pathology.

ABSTRACTDeuterium metabolic imaging (DMI) allows non‐invasive dynamic in vivo assessment of transport, uptake and metabolism of deuterated molecules. To date, DMI experiments in humans have involved ingestion of glucose‐d2 ([6,6’‐2H₂]glucose), where labelling of the sixth carbon facilitates 2H‐label transfer to pyruvate, then to lactate (Lac) via lactate dehydrogenase, or to glutamate and glutamine (Glx) via the tricarboxylic acid cycle. There are advantages to using glucose‐d7 ([1,2,3,4,5,6,6’‐2H₇]glucose) for DMI as this should yield larger signals from glucose and downstream metabolites, including deuterated water (HDO). Here, we evaluated DMI at 7 T following glucose‐d7 ingestion for monitoring glucose metabolism in the human brain. Results were compared to measurements using the same protocol but with oral glucose‐d2. Fifteen healthy volunteers participated in the study, which involved initial measurements at natural abundance, followed by 90 min of acquisition after ingestion of 0.75 g/kg glucose‐d7 (7 participants) or glucose‐d2 (8 participants). A visual stimulus was applied for 10 participants. Larger 2H signals were measured following glucose‐d7 ingestion, and whole‐brain signal ratios at times of 100 to 120 min after glucose‐d7 or glucose‐d2 ingestion for HDO, Glx and lactate (with potential contamination from lipid signals) were 1.8 ± 0.3, 1.7 ± 0.3 and 1.6 ± 0.3, respectively. At natural abundance, the SNR of the HDO signal in the CSI data was 14 ± 1. For both isotopologues, the glucose signal peaked ~80 min after ingestion, while Glx, lactate + lipid and HDO signals increased throughout the measurement period. Estimated cerebral concentrations of HDO were larger for glucose‐d7, but similar concentrations were found for glucose, Glx and lactate. No significant difference in signal or concentration between visually stimulated and unstimulated participants was found. These findings suggest that glucose‐d7 with DMI can facilitate non‐invasive in vivo assessment of metabolism in the human brain, with wide applications in experimental medicine and disease.

ABSTRACTSocioeconomic status is a multifaceted construct that plays a prominent role in shaping our environment. This study investigated the associations between family income, education level, and brain glucose metabolism in middle‐aged males. We retrospectively analysed data of healthy males who underwent a health check‐up programme including (1) brain 18F‐fluorodeoxyglucose positron emission tomography, (2) anthropometric measurements, (3) survey of family income and education level and (4) measures of stress, anxiety and depression. Bayesian hierarchical modelling was used to evaluate the relationships between SES variables and regional standardized uptake value ratios (SUVRs). A total of 233 healthy males were included in this study. Family income was positively correlated with education level. Higher family income was associated with increased glucose metabolism in the caudate, putamen, anterior cingulate, hippocampus and amygdala. In contrast, education level showed no significant association with regional brain metabolism in either ROI‐based or full‐volume analyses. In conclusion, family income, and education level show differential associations with brain glucose metabolism in middle‐aged males. Family income is associated with elevated brain glucose metabolism in regions involved in reward processing and stress regulation, suggesting a potential link between current socioeconomic resources and neural activity. However, these findings are cross‐sectional and must be interpreted as associative rather than causal. Education level does not show a significant association with brain glucose metabolism.

Objective: To investigate whether nacre extract improves insulin sensitivity, brain glucose metabolism, and cognitive function in diabetic mice. Methods: Diabetic KK-Ay mice ( n =5/group) were fed a standard diet or diets supplemented with nacre extract (125 or 250 mg/kg) for 13 weeks. Metabolic status was assessed by measuring fasting glucose and insulin levels, HOMA-IR, glucose tolerance, and insulin tolerance. The expression of IRS-1, IRS-2, and GLUT4 in the brain was analyzed by qPCR, Western blotting, and immunohistochemistry. Cognitive and anxiety-like behaviors were evaluated using the Y-maze, novel object recognition, Barnes maze, and open field tests. Results: Nacre extract significantly reduced fasting glucose and insulin levels, improved HOMA-IR, and enhanced glucose and insulin tolerance ( P &lt;0.05) in diabetic mice. It also restored GLUT4 expression and significantly upregulated SIRT1 and BDNF. Behavioral assessments showed significant improvements in memory and reduced anxiety-like behaviors. Conclusions: Nacre extract enhances insulin sensitivity, improves brain glucose metabolism, and alleviates cognitive and emotional dysfunction in diabetic mice. Further studies are warranted to verify the exact molecular mechanisms and efficacy of nacre extract in diabetes-associated metabolic and neurocognitive dysfunction.

18F]FDG-PET provides insights into the liver-brain axis and confirms SUVgluc as a surrogate for MRGlu in a mouse model of liver fibrosis.

Neurodegenerative diseases (NDs) pose a significant public health concern due to their association with cognitive impairment and disrupted brain glucose metabolism. Cyanidin 3-O-β-galactoside (Cy3Gal), an anthocyanin from black chokeberry, exerted neuroprotective effects by modulating brain energy metabolism. This study aims to investigate its absorption, tissue distribution, and metabolic profile. Following a single-dose administration (gavage, 300mg/kg) to male Sprague-Dawley rats, Cy3Gal reached a peak plasma concentration of 2967.29 ± 556.71ng/mL within 0.25h. Pharmacokinetic analysis revealed a short half-life (0.77 ± 0.05h) and high clearance rate (101.84 ± 23.90 L/h/kg), suggesting a fast distribution and elimination. Twenty metabolites were identified in plasma, including methylated, glucuronidated, and sulfated forms, with varying distribution across rat tissues. Notably, this is the first study to demonstrate that Cy3Gal and its methylated metabolites (peonidin 3-O-galactoside [Peo3Gal]) can cross the blood-brain barrier, which provided strong evidence for the neuroprotective effects. Peo3Gal showed superior protection against high glucose-induced injury compared to Cy3Gal. Additionally, in vitro fermentation with rat gut microbiota uncovered three Cy3Gal-derived metabolites, suggesting microbial involvement in its transformation. Overall, these findings provide critical insights into Cy3Gal's bioavailability and brain accessibility, supporting its potential as a dietary neuroprotective agent.

Lactobacillales derived from traditional Xizang dairy products improve insomnia and restore neurotransmitter-metabolic profiles via gut microbiota in PCPA-induced mice.

Serum bile acids associated with brain hypometabolism in patients across the Alzheimer's disease continuum.

ObjectiveFreezing of gait (FOG) is a common gait disorder in the advanced stages of Parkinson’s disease (PD), closely associated with impaired balance and executive function. This study aimed to investigate specific changes in brain glucose metabolism in FOG patients using 18F-FDG PET. Deep learning methods were utilized to offer valuable perspectives for identifying FOG.MethodsEighteen PD patients with FOG(PD-FOG), 11 patients without FOG (PD-NFOG) and 17 healthy controls (HC) were recruited. All participants underwent 18F-FDG PET imaging, and group comparisons were employed, to identify regions with significant differences in glucose metabolism. 3D convolutional neural network (3D CNN), as well as traditional machine learning models, were constructed for the automatic identification of the FOG type.ResultsPET imaging analysis showed that the differences between the PD-FOG group and the PD-NFOG group were mainly located in the frontal lobe, parietal lobe and cingulate gyrus. The 3D CNN achieved diagnostic accuracies of 90.09% for distinguishing PD and 95.40% for FOG, surpassing other machine learning models. The 3D CNN achieved the smallest mean squared error (MSE), amounting to 48.01, in the prediction of Freezing of Gait Questionnaire (FOG-Q) scores.ConclusionSpecific glucose metabolism patterns in PD-FOG mainly covered the frontoparietal network (FPN). The integration of 18F-FDG PET imaging with deep learning methods effectively differentiated patients with FOG. The 3D CNN exhibited a high diagnosis accuracy level, providing reliable imaging and artificial intelligence support for PD with FOG.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12883-025-04468-y.

Omega-3 fatty acids (OM) have been employed as adjunctive therapy in patients with schizophrenia, but their potential as a preventive strategy remains unclear. This study aims to evaluate whether dietary OM supplementation during pregnancy may prevent schizophrenia-like deficits in a maternal immune stimulation (MIS) model. Pregnant Wistar rats were injected with PolyI:C (i.e. MIS) or Saline on gestational day 15. They were fed with OM-enriched chow, either from MIS until delivery (OM7) or throughout gestation (OM21). Two control groups (Saline-naïve & MIS-naïve) were maintained on standard chow. In adulthood, offspring were assessed through tests for locomotion, anxiety and short- and long-term memory (STM, LTM). Brain glucose metabolism and structural in vivo neuroimaging studies were performed using PET and MRI techniques. OM7/OM21 treatments prevented the hyperlocomotion in MIS-offspring while STM deficits were only improved by OM7. Both OM7/OM21 treatments prevented certain metabolic and volumetric changes in the cortex, as well as the enlargement of the ventricles. Additionally, OM21 protected WM integrity in MIS-offspring. Altogether, our study highlights the potential of prenatal OM dietary supplementation to ameliorate some of the SCZ-like deficits observed in the MIS model.

Disclosure: M. Mirabelli: None. F.S. Brunetti: None. E. Chiefari: None. D.P. Foti: None. A. Brunetti: None.Background: Growing evidence links tau-related neurodegeneration, a hallmark of Alzheimer's disease (AD) and other tauopathies, to insulin resistance (IR). However, the molecular mechanisms underlying this association remain unclear. The chromatin factor HMGA1, a key regulator of the insulin receptor and glucose metabolism genes, has been implicated in IR and diabetes when defective. A known genetic variant, HMGA1 rs146052672, disrupts HMGA1 protein production. This study investigates whether HMGA1 deficiency contributes to tauopathy development and its intersection with IR. Methods: We used human and mouse neuronal cell models to perform immunoblotting, protein-DNA interaction assays, chromatin immunoprecipitation, and reporter gene analyses. In Hmga1 knockout mice, we examined tau immunoreactivity, behavioral phenotypes, and brain glucose metabolism. We also conducted a case-control study involving 69 patients with AD or non-AD tauopathies and 200 age-matched controls to assess the clinical and molecular impact of the HMGA1 rs146052672 variant. Results: In vitro, HMGA1 bound to the tau promoter and repressed tau gene transcription. Reduced HMGA1 levels in neuronal cells and primary mouse neurons led to increased tau mRNA and protein, along with oxidative stress and reactive oxygen species (ROS) accumulation. In Hmga1 knockout mouse brains, we observed increased tau expression, hyperphosphorylation, and toxic tau aggregation, alongside reduced insulin receptor levels and impaired glucose uptake. These molecular and metabolic alterations were associated with behavioral deficits similar to those in classic tauopathy models and clinical features of human AD and non-AD tauopathies. In the case-control study, the HMGA1 rs146052672 variant was four times more prevalent in tauopathy patients than in controls. Carriers had significantly higher levels of total and phosphorylated tau in cerebrospinal fluid, faster disease progression, worse treatment outcomes, and more severe IR. Conclusion: These findings suggest that HMGA1 deficiency drives both IR and the pathological overproduction and aggregation of tau, establishing a mechanistic link between metabolic dysfunction and neurodegeneration. HMGA1 may thus represent a central player in the pathogenesis of both IR and tauopathy, making it a promising target for predicting and developing therapeutic strategies for these diseases.Presentation: Monday, July 14, 2025

FDG-PET brain glucose hypometabolism predicts Alzheimer's disease progression pathways in cognitively normal adults: A longitudinal competing risks modeling

A growing body of evidence shows significant sex differences in Alzheimer's Disease (AD) epidemiology, clinical presentation, and pathology burden; however, sex differences in neuroimaging biomarkers remain underexplored, prompting recent calls to action for more targeted research in this field. We analyzed static brain positron emission tomography (PET) imaging with 2-[18F] fluoro-2-deoxy-D-glucose (FDG) from 247 elderly individuals with AD dementia, including 151 women and 96 men. Voxel-based analysis was used to detect reductions in FDG uptake in each sex relative to a publicly shared normative database and to identify sex differences in FDG uptake within the AD cohort. Both sexes exhibited glucose hypometabolism in AD-vulnerable regions, including the parieto-temporal cortex, posterior cingulate, hippocampus, parahippocampal gyrus, and frontal lobes (PFWE ≤ 0.001 in women and ≤ 0.013 in men). Sex differences in regional FDG uptake were observed in both directions, with greater hypometabolism in limbic and frontal regions in women (PFWE ≤ 0.023) and in parietal cortices in men (PFWE ≤ 0.008). The sex-specific distribution of hypometabolism, with more pronounced anterior involvement in women and posterior involvement in men, aligns with known differences in brain reserve and hormone-sensitive regions. This pattern suggests that neurophysiological and neuroendocrine aging may contribute to AD neuropathology in a sex-dependent manner. Recognizing these variations could refine diagnostic approaches and inform the development of sex-specific therapeutic strategies.