Cerebral Glucose Metabolism Research Articles

Sex‐specific decoupling of cerebral blood flow and glucose metabolism in Alzheimer’s disease mouse model

AbstractBackgroundCerebral blood flow (CBF) dysregulation and neurovascular impairment are central to Alzheimer’s disease (AD) etiology1. Even though two‐thirds of the AD patients are women, the sex differences in vascular and metabolic risk factors are still unclear2. Previously, we described sex‐specific CBF trajectories in mouse model of AD3. In the present study, we connect these CBF changes with cerebral glucose metabolism in the same males and females. We quantify the correlation between metabolic rate and vascular flow and identify unique points of divergence across lifespan.MethodWe used 9.4T MRI of APPswe.PSEN1dE9 mice (23 males, 24 females; young 3‐7 months, middle age 7‐15 months, and old 15‐24 months) and B6C3F1/J controls (n=20). We quantified CBF (qCBF) using T1‐weighted mapping and continuous arterial spin labeling (CASL) as previously described3.The glucose uptake rate (ΔR1ρ) was measured using chemical exchange‐sensitive spin lock (CESL) and computed as the difference between the steady state before and after intravenous injection of 2‐Deoxy‐d‐glucose (2DG)4. Region of interests were drawn manually on the cortex and subcortical areas.ResultWe found that AD females, but not AD males had lower cortical glucose metabolism than age‐matched controls, while both AD groups had lower CBF than controls. These differences were not significant in the subcortical regions. The metabolic trajectory during aging was similar between AD males and females (Fig 1A), however, the CBF trajectory of AD males showed a transient increase from young to middle age, while the female group showed an opposite trend (Fig 1B). The sex‐specific divergence between glucose consumption and CBF appeared during middle age. Male AD mice had higher positive correlation between glucose metabolism and CBF in the cortex compared to females (Fig 2A). Additionally, in both AD groups, this correlation was positive in the cortex but not in the subcortical region (Fig 2).ConclusionWhen interpreting metabolic rate of glucose and CBF as AD biomarkers, age, sex and brain region should be taken into consideration.

Does glucose metabolism dissociate from tau deposition in Alzheimer’s disease?

AbstractBackgroundAlzheimer’s disease progression is characterised by accumulation of tau and reductions in cerebral glucose metabolism. However, the spread of tau could be influenced by the presence of amyloid, while changes in cerebral glucose metabolism could be influenced by microglial activation, atrophy, synaptic dysfunction, along with oxidative stress and inflammation. Hence, the association between these biomarkers at a global cortical level remains unclear. Here we sought the establish the global cortical relationship in a novel single subject design.Method380 subjects were recruited from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu) (Table 1). Amyloid status (Aβ+/Aβ‐ ve) and T1‐weghted MRI scans were obtained for all participants. Dynamic PET scans were processed with SPM12 and standard uptake value ratio (SUVR) images were created. Cerebellum grey matter and pons were selected as reference region for [18F]AV1451 and [18F]FDG respectively. Each cognitively impaired SUVR image was compared against the healthy control group using Statistical Parametric Mapping software. We extracted the total number of voxels with increases of [18F]AV1451 and decreases of [18F]FDG compared to the controls; termed ‘global cortical tau load’ and ‘global hypometabolism’ for subsequent analysis.ResultIn this sample of 240 cognitively impaired subjects, in Aβ+ve AD subjects, there was no correlation between global cortical tau load and global hypometabolism. Interestingly, there was minimal correlation in Aβ+ve MCI subjects between global cortical tau and global hypometabolism (r=0.209, p=0.042). There were no significant correlations between global cortical tau load and global hypometabolism in Aβ‐ve cognitively impaired subjects.ConclusionGlucose hypometabolism and tau deposition dissociate at a global level in AD subjects; while in early stages there may be minimal association between these two processes. The dissociation between glucose metabolism and tau deposition in the later stages of AD trajectory suggests that other pathological features including microglial activation, inflammation, and oxidative stress all influence the metabolic decline in AD, perhaps explaining our apparent lack of association later in disease progression. As such, we argue changes in glucose metabolism and tau deposition have distinct trajectories in the context of Alzheimer’s disease and future clinical trials should consider separate evaluation.

Type 2 diabetes mellitus and obesity impact AD‐related pathology through overlapping and independent pathways

AbstractBackgroundIt is proposed that neuronal damage in diabetes is related to hyperglycaemia and insulin resistance, whilst inflammation and subsequent oxidative stress affects cognitive function in obesity. We investigated whether obesity and diabetes present distinct neuropathological features of neurodegeneration.MethodsTo compare amyloid, tau and cerebral glucose metabolism, we processed 1973 available PET scans for 18F‐AV‐45, 18F‐flortaucipir and 18F‐fludeoxyglucose (FDG) from 971 participants with diabetes (n=194), obesity (n=377) and without diabetes or obesity (n=400) from the Alzheimer’s Disease Neuroimaging Initiative dataset. Independent t‐tests and multivariate analysis were used for regions of interest (ROIs) analysis in participant groups with diabetes vs non‐diabetic/non‐obese and obesity vs non‐diabetic/non‐obese. This was conducted across different cognitive subgroups, namely Alzheimer’s disease, mild cognitive impairment or normal cognition. Amyloid positive and negative subjects were evaluated separately. Voxel‐wise analysis using SPM was also conducted for these groups.ResultsFor diabetes, higher amyloid uptake was found in the medial temporal regions in the cognitively normal diabetic group compared to the cognitively normal (non‐diabetic/non‐obese) group. This was also found in the amyloid positive mild cognitively impaired diabetic groups compared to mild cognitively impaired (non‐diabetic/non‐obese) group. Similarly, higher amyloid deposition was seen in the hippocampus of the cognitively normal obese group compared to the cognitively normal (non‐diabetic/non‐obese) group.Additionally, higher tau uptake was found in the whole brain (global brain value), frontal, parietal and occipital lobes for cognitively normal diabetic and obese groups, compared to cognitively normal (non‐diabetic/non‐obese) groups. Higher tau was further found in the temporal lobe and anterior cingulate of AD obesity participants compared to the AD (non‐diabetic/non‐obese) participants.Discrete cerebral glucose metabolic patterns were found in diabetes and obesity. In the diabetic groups, reduced FDG uptake was found in mild cognitively impaired participants (whole brain, frontal, parietal and occipital lobes) and amyloid positive AD participants (occipital lobe) compared to non‐diabetic/non‐obese participants. In contrast, increased FDG uptake was mainly found in amyloid negative obese participants.ConclusionsGlucose hypometabolism in diabetic participants in contrast to hypermetabolism in obese participants implies that different pathological processes of neurodegeneration occur in these two conditions. This suggests that these two conditions require different therapeutic strategies to prevent neurodegeneration.

Cortical diffusivity associates with early neuronal damage

AbstractBackgroundDiffusion weighted imaging can provide a marker a microstructural damage which cannot be detected by conventional structural MRI. Changes in cortical diffusivity may be a value marker of neuronal breakdown, which predates macrostructural damage. We aimed to evaluate the efficacy of cortical diffusivity in predicting the extent of metabolic changes in different stages of Alzheimer’s disease progression.Method90 participants diagnosed with mild to moderate Alzheimer’s disease were recruited at Imperial College London. A median split was conducted to categorise participants into ‘Early’ (MMSE ≥ 25, n = 42) and ‘Late’ stage of AD groups (MMSE < 25, n = 48) to reflect different stages of disease progression. All participants underwent [18F]fluorodeoxyglucose imaging with arterial input, t1‐weighted MRI images and diffusion weighted images were also acquired. Spectral analysis was conducted to calculate the cerebral metabolic rate of glucose (CMRglc). CMRglc and mean diffusivity maps were spatially normalised to MNI space and individualised grey matter object maps were created for all participants. Linear regression was conducted between CMRglc and mean diffusivity maps. Mean diffusivity and CMRglc values within the temporal lobe were extracted to confirm voxelwise results.ResultIn this cohort, voxel‐wise statistics revealed a significant relationship between cortical diffusivity and reduced CMRglc, particularly in our ‘early’ stage AD group. Most notable correlations were located within temporal lobe regions. Regional analysis revealed that increased temporal lobe mean diffusivity was strongly correlated with decreased CMRglc in ‘early’ AD participants (r=‐0.525, p<0.001, 95% CI: ‐0.263 to ‐0.715). We found evidence of a weaker correlation in the ‘late’ AD group between increased diffusivity and CMRglc reductions within the temporal lobe (r=‐0.322, p=0.026, 95% CI: ‐0.042 to ‐0.555).ConclusionCortical mean diffusivity is a valuable predictor of early neuronal damage measured by cerebral glucose metabolism in Alzheimer’s disease. This association was strongest in earlier stages of the disease trajectory, as such, we establish that cortical mean diffusivity as an early biomarker in Alzheimer’s disease which reflects early changes in tissue integrity and cell/organelle breakdown.

Cerebral perfusion and glucose metabolism profiling reveal special phenotypes in the hAPOE3, hAPOE4, Trem2 risk, and doubled risks mice

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia in the United States. Approximately 95% of patients have sporadic Late‐Onset AD (LOAD) which lacks an inheritance pattern. Therefore, identifying phenotypic patterns is critical for understanding disease progression.Among all the genetic markers which being identified as AD risks, and APOE4 confers the strongest one. The GWAS analysis also revealed a LOAD‐associated locus on the gene of TREM2. As the microglial receptor of APOE, the R47H variant on TREM2 increases the AD risk. In this study, how these risk alleles affect the brain phenotypes were assessed by MODEL‐AD.MethodWe established an analytical scheme which elucidates the cerebral perfusion and metabolism profiles across 27 brain regions by using 64Cu‐PTSM and 18F‐FDG PET imaging platform in the mice with wild‐type, humanized APOE3 (hAPOε3/ ε3), humanized APOE4 (hAPOε4/ ε4), TREM2 risk (Trem2R47H/R47H), and doubled risks (hAPOε4/ ε4:Trem2R47H/R47H) alleles.Also, RNA‐seq results from the hemisphere samples were used to conduct the correlation between PET measurements and the gene expression changes from each animal cohort.ResultLongitudinal analysis (4mo animals as reference) revealed aging effects in each cohort. The male hAPOE4 mice and both sexes of Trem2 risk animals had hypo‐perfusion and metabolism, while female hAPOE4 mice showed an uncoupled hyper‐perfusion and hypo‐metabolism phenotype. In the doubled risks mice, perfusion and metabolism showed a mixed regional‐dependent phenotype.Cross‐sectional analysis (wildtype mice as reference) showed the effects of humanized genes. A reduction in glucose metabolism was discovered. Intriguingly, male risks mice also showed reduced in perfusion, while the female mice showed a metabolic uncoupling profile.Cross‐sectional analysis (hAPOE3 mice as reference) showed the effects of risk alleles. An overall reduction in both perfusion and metabolism was discovered in all animal cohorts.To confirm these findings, RNAseq showed the genes involved in cerebral perfusion, glucose transportation, and metabolism regulation were altered, which are consistent with the findings.ConclusionThese data suggest that the new perfusion‐metabolism strategy may help to identify AD‐related patterns. Moreover, they replicate clinical manifestations of subjects with the same variants. Finally, additional studies are needed to elucidate the mechanisms and etiology of this uncoupling phenomenon.

Exploration of visual hallucinations – FDG‐PET associations in DLB and MCI‐LB with and without visual hallucinations

AbstractBackgroundSeveral hypotheses exist regarding the neurologic substrate underlying visual hallucinations (VH) in Dementia with Lewy Bodies (DLB). Studies have suggested an association with regional cerebral hypometabolism in the primary visual or visual association cortices on FDG‐PET. We compared regional cerebral glucose metabolism and posterior cingulate island sign (CIS) ratios in DLB and in Mild Cognitive Impairment with Lewy Bodies (MCI‐LB) participants with (VH+) and without (VH‐) VH.MethodParticipants with clinically probable DLB or MCI‐LB and an FDG‐PET scan were identified from the Mayo ADRC database. Responses on the Visual Hallucinations and Delusions Questionnaire and Neuropsychiatric Inventory were used to assess presence or absence of VH. Standardized uptake value ratios (SUVr) were used to calculate regional cerebral glucose hypometabolism in the primary visual cortex (PVC), lateral occipital cortex (LOC), and whole occipital cortex (WOC). The CIS ratio was defined as posterior cingulate divided by the sum of the precuneus plus cuneus FDG‐PET uptake ratio.ResultTwo cohorts were identified (27 DLB and 18 MCI‐LB, 87% male). Eighteen DLB participants were VH+ and 9 were VH‐, whereas 5 MCI‐LB were VH+ and 13 were VH‐. There were no statistically significant differences in demographic (age, sex, education) and clinical features (MoCA, CDR, presence of other core DLB features, and UPDRS) between VH+ vs VH‐ in those with DLB, and between VH+ vs VH‐ in those with MCI‐LB. Similarly, there were no statistically significant differences in DLB between VH+ vs VH‐ in PVC (1.55±0.14 vs 1.58±0.15), LOC (1.22±0.16 vs 1.28±0.12), WOC (1.29±0.15 vs 1.34±0.11), or CIS ratio (1.16±0.08 vs 1.14±0.10), nor in MCI‐LB between VH+ vs VH‐ in PVC (1.68±0.19 vs 1.58±0.14), LOC (1.40±0.21 vs 1.32±0.14), WOC (1.45±0.20 vs 1.37±0.14), or CIS ratio (1.17±0.08 vs 1.19±0.10) (P>0.05 for all comparisons).ConclusionThese findings do not support a direct correlation between regional cerebral glucose metabolism and VH in DLB or MCI‐LB. Further work in DLB and MCI‐LB with larger numbers is warranted. Other neurologic substrates and mechanisms, such as REM sleep intrusions during wakefulness, neurotransmitter dysfunction, and disruption of functional connectivity across brain regions should be explored as contributors to VH in DLB.

Reproductive health data and its relationship to baseline brain imaging and cognitive measurements in cognitively unimpaired female PSEN1 E280A mutation carriers and non‐carriers from the API ADAD Trial

AbstractBackgroundThe impact of sex steroid hormones on Alzheimer’s disease (AD) remains to be further clarified. Research suggests that shorter reproductive span, late menarcheal age, early menopause, oophorectomies and hysterectomies, are associated with increased dementia risk. We examined reproductive health and its associations with brain imaging and cognitive measurements in unimpaired female Presenilin 1 (PSEN1) E280A mutation carriers and non‐carriers from the Alzheimer’s Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841).MethodA total of 151 cognitively unimpaired 30‐53 year‐old females (101 PSEN1 mutation carriers and 50 non‐carriers) were included. Reproductive health data (i.e., menarcheal age, number of pregnancies, deliveries, miscarriages, and living children) from all participants were examined, as well as the extent to which menarcheal age was related to age‐adjusted baseline 1) cortical amyloid plaque burden (florbetapir PET), 2) Precuneus cerebral glucose metabolism (fluorodeoxyglucose PET), 3) hippocampal volume (3TMRI), and 4) the API ADAD preclinical cognitive composite score, which includes the MMSE Orientation score, CERAD Word List Delayed Recall and Constructional Praxis, Multilingual Naming Test and Raven’s Progressive Matrices subset. We examined associations with the cognitive and brain imaging measures corrected for multiple comparisons (Bonferroni).ResultCarrier and non‐carrier females did not differ on number of pregnancies, deliveries, miscarriages, or living children. Female carriers had a significantly younger menarcheal age than non‐carriers (12.8 ±1.5 versus 13.7±1.6 years, p = 0.007, Bonferroni). Among carrier females, older menarcheal age was associated with lower scores on the Raven’s test (Bonferroni: r = ‒0.28,p =0.035). Menarcheal age was not associated with scores on the cognitive composite or other individual subtests, or with brain imaging measures.ConclusionOur findings suggest reproductive health data did not differ between carrier and non‐carrier females, except for a slightly younger menarcheal age compared to non‐carriers, and that menarcheal age may have a very limited impact on brain pathology and function at preclinical stages of ADAD. Longitudinal studies with larger samples are needed to clarify the extent to which earlier menarcheal age may be related to changes in cognitive function in mutation carrier females transitioning from preclinical to clinical stages.

Investigating changes in fluid biomarkers in early Alzheimer’s disease: design of plasma biomarker analyses and a cerebrospinal fluid sub‐study in the evoke and evoke+ trials of semaglutide versus placebo

AbstractBackgroundSeveral studies have generated data supporting a role for glucagon‐like peptide 1 receptor agonists (GLP‐1RA) in the treatment of Alzheimer’s disease (AD). For example, GLP‐1RAs reduced neuroinflammation and phospho‐tau accumulation, provided neuroprotective effects, and improved cognitive function in animal model studies. In patients with AD, GLP‐1RAs preserved cerebral glucose metabolism, favorably affected cognition and cortical volume, and in post‐hoc analyses of randomized clinical trials in type 2 diabetes, reduced cognitive impairment and dementia risk. The phase 3 evoke and evoke+ trials (NCT04777396 and NCT04777409, respectively) will assess the efficacy and safety of oral semaglutide (a GLP‐1RA) versus placebo in early AD. Here, we describe how fluid biomarkers will be investigated.MethodParticipants in the randomized double‐blind, placebo‐controlled evoke and evoke+ trials (N=1,840 per trial) will be randomized 1:1 to oral semaglutide 14 mg once‐daily or matched placebo for 156 weeks. The primary endpoint is change in Clinical Dementia Rating Scale – Sum of Boxes score from baseline to week 104. In both studies, fluid biomarkers will be measured in plasma (all participants [except those in China]) and cerebrospinal fluid (CSF) (a sub‐set of participants). For plasma biomarkers, blood samples will be collected at baseline (week 0) and weeks 52, 104, and 156. For CSF biomarkers, samples will be collected before randomization and at week 78, aiming for around 210 consenting participants (Figure). In each trial, participants will be stratified by CSF sub‐study participation (yes/no) to ensure 1:1 randomization in the sub‐study population. The range of biomarkers analyzed will encompass markers of AD, neuroinflammation, neurodegeneration, blood–brain barrier integrity, oxidative stress, and vascular health (Table).ResultResults from the plasma biomarker analyses and CSF sub‐study of the evoke and evoke+ trials are expected in 2025.ConclusionThese analyses of the evoke and evoke+ studies will investigate the effects of semaglutide on fluid biomarkers in participants with early AD. The analyses will provide insights into the mechanism of action of semaglutide on neuroinflammation and neurodegeneration (and the relationship between the two) in this population.

Acetylcholinesterase Inhibitor Exerted Neuroprotection Against Trastuzumab‐Induced Chemobrain

AbstractBackgroundChemobrain has recently gained attention as a serious neurobehavioral consequence of chemotherapy in cancer patients. Even well‐recognized among conventional chemotherapeutic agents, trastuzumab (TRZ), an oncogene‐targeted therapy for treating breast cancer, has been shown to intricately caused symptoms of chemobrain elicited by impaired cerebral glucose metabolism and long‐term cognitive function. Noticeably, the inhibition of acetylcholinesterase using donepezil (DPZ), a medication widely used to treat Alzheimer’s disease (AD), possesses several pleiotropic effects including mitochondrial protection and immunomodulation. However, the mechanistic insights regarding the pathophysiology and therapeutic benefit of DPZ have never been holistically determined in a rat model of TRZ‐induced chemobrain.MethodFifteen male Wistar rats were randomized to receive either a 0.9% normal saline solution (Control; n=5) or 4 mg/kg of TRZ via intraperitoneal injection for 7 consecutive days. Then, TRZ‐treated rats were subdivided into 2 groups to receive either drinking water (TRZ, n=5) or 5 mg/kg of DPZ (TRZ+DPZ; n=5) via oral gavage as co‐treatment with TRZ for 7‐day duration. After cessation of the treatment paradigm, cognitive performance was assessed using the novel object location task (NOLT). The brain tissues were obtained for further molecular investigation.ResultTRZ‐treated rats showed impaired long‐term spatial memory as demonstrated by a reduction of preference index in the NOLT (Figure A). Systemic TRZ administration compromised mitochondrial anti‐oxidant capacity (Figure B) and potentiated the activation of mitochondrial‐fission related protein. Furthermore, the upregulation of neuroinflammation was observed in TRZ‐treated rats presented by increased TNF‐α mRNA level (Figure C) and microglial morphological changes into neurotoxic amoeboid‐shaped (Figure D). Additionally. Administration of TRZ triggered the phosphorylation of Tau protein (Figure E) and reduced dendritic spine density in CA1 region (Figure F). Strikingly, co‐administration with DPZ effectively rescued cognitive performance of TRZ‐treated rats by improving mitochondrial anti‐oxidant capacity, reducing mitochondrial fission, mitigating neuroinflammation and microglial polarization, attenuating Tau hyperphosphorylation, and preserving dendritic spine density (Figure A‐F).ConclusionThese findings suggested that DPZ exerted neuroprotective effects against TRZ‐induced chemobrain. Our findings pave the way for parasympathetic activation using DPZ as a therapeutic approach in the prevention of chemobrain in patients who received chemotherapy in the future.

Cell sorting after tracer injection to elucidate allocation of cellular FDG uptake in different cell types and different microglial activation states

AbstractBackground2‐deoxy‐2‐[18F]fluoro‐d‐glucose positron‐emission‐tomography (FDG‐PET) is widely used to study cerebral glucose metabolism. Radiosorting revealed that the FDG‐PET signal is directly influenced by microglial glucose uptake in mouse models and we found similar associations in patients with neurodegenerative diseases. Now, we questioned the allocation of cellular FDG uptake in the rodent brain.MethodSingle cell [18F]FDG uptake as assessed by magnetic activated cell sorting (MACS) was multiplied with published total cell numbers in the mouse brain, i.e. 71e+6 neurons or 7% (≈ 7.6e+6) microglia cells to estimate the overall uptake per cell fraction. Estimated cellular microglial [18F]FDG uptake as assessed by MACS was cross‐validated with observed %‐FDG‐PET reductions after microglia depletion. Interstitial and vessel [18F]FDG was estimated by interstitial compartment volume and assumed equilibrium of non‐phosphorylated extra‐ and intracellular [14C]Deoxyglucose. Synaptic [18F]FDG uptake was estimated via an enriched synaptosome fraction relative to [18F]FDG uptake of whole‐brain homogenate. A microglia proliferation index of 1.3 was assumed for the whole brain in the Aβ mouse model.ResultMicroglia cells accounted for 8.6% of the overall brain [18F]FDG uptake in wild‐type mice and for 29.9% of the overall brain [18F]FDG uptake in PS2APP mice, confirmed by similar alterations after microglia depletion in PET. Synapses contributed to 13.2‐17.1% of the overall brain [18F]FDG uptake whereas interstitial (5.9‐7.7%) and vessel (2.6‐3.4%) [18F]FDG uptake was of minor magnitude. Neuronal and astrocyte cell bodies accounted for <10% of the overall brain [18F]FDG uptake, but a proportion of 42‐55% was not recovered and likely allocated in lost cell processes, oligodendrocytes and other cell types.ConclusionMicroglial FDG uptake alterations are the source of FDG‐PET changes in models of neurodegenerative diseases. Our data should increase the awareness to consider glia cells as key contributors of FDG uptake and the detailed proportions of these cellular contributions in healthy brains and under disease conditions deserve deeper investigation.

Cerebral metabolism of glucose and selected glucose transporters in neurodegenerative diseases

Cerebral glucose metabolism is an issue of researchers’ interest for a long time. Disturbed transport and metabolism of glucose in the brain lead to development of numerous neurological pathologies. Recently, a significant correlation between perturbed cerebral glucose metabolism and development of neurodegenerative diseases has been shown. Glucose, a monosaccharide, is the main source of energy for brain cells. Brain is the organ which is the most sensitive to changes in blood glucose level. Perturbed glucose transport leads to disorders of the central glucose metabolism. Neurodegenerative diseases are defined in the literature as progressive and irreversible degeneration of nerve tissue, causing cell death as a result of degenerative processes. The aim of this article is to discuss the physiology and the role of selected glucose transporters in the development of neurodegenerative diseases: expression of selected GLUT1 and GLUT3 transporters in Alzheimer's and Huntington's diseases. Understanding of the cerebral glucose metabolism may be a crucial factor in fight with central nervous system diseases.

Migraine severity, disability, and duration: Is a good diet quality, high intake of phytochemicals and polyphenols important?

Dietary pattern may be the determinant of migraine prognosis through various mechanisms such as systemic inflammation, vasodilation, cerebral glucose metabolism, and mitochondrial dysfunction.This study was conducted to examine the relationship of the symptoms and signs of migraine with dietary polyphenols and the phytochemical intake and the quality of the diet. Individuals (n = 90), who were admitted to the headache outpatient clinic due to the diagnosis of episodic migraine, underwent physical examination by a neurologist. Migraine characteristics were assessed using the Migraine Disability Assessment Questionnaire and the Visual Analogue Scale. The Healthy Eating Index-2015 (HEI-2015) was used to evaluate the diet quality of individuals, and the Phytochemical Index developed by McCarty was used to determine the dietary intake of phytochemicals. Phenol-Explorer version 3.6 and the USDA Database for the Flavonoid Content of Selected Foods-Release 3.3 were used to calculate the dietary polyphenol intake. Migraine severity was negatively correlated with the intake of phytochemicals and good diet quality (r = -0.37, p = 0.0003; r = -0.37, p = 0.0003, respectively), and with the intake of phenolic components flavanones (r = -0.27, p = 0.01) and lignans (r = -0.27, p = 0.01). With respect to the food groups; migraine severity was found to be inversely correlated with the total phenol intake from olive oil, oil, and fruits (r = -0.26, p = 0.01; r = -0.21, p = 0.04; r = -0.24, p = 0.02, respectively), and the flavonoid intake from olive oil, oil, fruits, and vegetables (r = -0.26, p = 0.01; r = -0.26, p = 0.01; r = -0.35, p = 0.0007; r = -0.22, p = 0.04, respectively). Strikingly, fruit flavanone intake was correlated with low migraine severity (r = -0.39, p = 0.0002), and fruit flavanol intake was correlated with low migraine disability (r = -0.21, p = 0.04). A high-quality diet rich in phytochemicals and polyphenols (especially flavanones and lignans) is associated with low migraine severity. Lower intake of phenols and flavonoids from vegetable oil, olive oil, fruits, and vegetables were associated with more severe migraine attacks. Examination of migraine characteristics and dietary pattern together with phytochemical and polyphenol intake may guide the development of dietary strategies to be used in migraine patients.

Validation of dynamic [18F]FE-PE2I PET for estimation of relative regional cerebral blood flow: a comparison with [15O]H2O PET

BackgroundDopamine transporter (DAT) imaging is used in the diagnostic work-up in suspected parkinsonian syndromes and dementia with Lewy bodies but cannot differentiate between these syndromes, and an extra brain imaging examination of the regional cerebral blood flow (rCBF) or glucose metabolism is often needed for differential diagnosis. The requirement of two different imaging examinations is resource-consuming and inconvenient for the patients. Therefore, imaging of both cortical blood flow and DAT imaging with the same radiotracer would be more convenient and cost-effective. The aim of this study was to test whether relative regional cerebral blood flow (rCBFR) can be measured with the DAT-specific positron emission tomography (PET) tracer [18F]FE-PE2I (FE-PE2I), by validation with cerebral perfusion measured with [15O]H2O PET (H2O).MethodsThe rCBFR was quantified by kinetic modeling for FE-PE2I (R1) and H2O (F). The R1 was calculated using the simplified reference tissue model, and F was calculated with a modified Koopman double-integration method. The linear relationship and intraclass correlation (ICC) between R1 and F were tested in image data derived from 29 patients with recent onset parkinsonism and 30 healthy controls.ResultsThere was a strong linear correlation across all subjects between R1 and F in the frontal, parietal, temporal, cingulate and occipital cortex as well as in the striatum (r ≥ 0.731–0.905, p < 0.001) with a good-to-excellent ICC, ranging from 0.727 to 0.943 (p < 0.001).ConclusionsOur results suggest that FE-PE2I may be used as a proxy for cerebral perfusion, thus potentially serving as a radiotracer for assessment of both DAT availability and rCBFR in one single dynamic scan. This could be valuable in the differential diagnosis of parkinsonian syndromes.Trial registration: EUDRA-CT 2015-003045-26. Registered 23 October 2015 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-003045-26

Increased white matter glycolysis in humans with cerebral small vessel disease.

White matter lesions in cerebral small vessel disease are related to ischemic injury and increase the risk of stroke and cognitive decline. Pathological changes due to cerebral small vessel disease are increasingly recognized outside of discrete lesions, but the metabolic alterations in nonlesional tissue has not been described. Aerobic glycolysis is critical to white matter myelin homeostasis and repair. In this study, we examined cerebral metabolism of glucose and oxygen as well as blood flow in individuals with and without cerebral small vessel disease using multitracer positron emission tomography. We show that glycolysis is relatively elevated in nonlesional white matter in individuals with small vessel disease relative to healthy, age-matched controls. On the other hand, in young healthy individuals, glycolysis is relatively low in areas of white matter susceptible to lesion formation. These results suggest that increased white matter glycolysis is a marker of pathology associated with small vessel disease.

Cerebral 18 F-fluorodeoxyglucose metabolism alteration of reward- and motivation-related regions in groups of different BMI classifications.

This study explored the relationship between BMI and regional cerebral glucose metabolism and explicitly detected regions with significant differences in cerebral metabolism using positron emission tomography (PET)/magnetic resonance imaging in the resting state. Corresponding PET images acquired from 220 participants were sorted into four groups according to Asian BMI standards: underweight, normal weight, overweight, and obesity. Pearson correlation coefficient analysis was performed to assess the association between BMI and standard uptake value. The regional cerebral glucose metabolism was measured in the fasted state. The PET images were analyzed using statistical parameter maps. One-way ANOVA was used to explore differences in the standard uptake value as an indicator of regional cerebral glucose metabolism. This study found that lower cerebral glucose metabolism in reward- and motivation-related regions was accompanied by more severe obesity and that regional cerebral glucose metabolism activities were negatively correlated with BMI. In addition, more severe obesity was accompanied by a larger range of areas with significant differences independent of current dietary status. These findings suggest that the reward and motivation circuits may be a factor regulating energy balance and influencing the degree of obesity.

Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress.

Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD.

Altered Patterns of Brain Glucose Metabolism Involve More Extensive and Discrete Cortical Areas in Treatment-resistant Schizophrenia Patients Compared to Responder Patients and Controls: Results From a Head-to-Head 2-[18F]-FDG-PET Study.

Treatment resistant schizophrenia (TRS) affects almost 30% of patients with schizophrenia and has been considered a different phenotype of the disease. In vivo characterization of brain metabolic patterns associated with treatment response could contribute to elucidate the neurobiological underpinnings of TRS. Here, we used 2-[18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) to provide the first head-to-head comparative analysis of cerebral glucose metabolism in TRS patients compared to schizophrenia responder patients (nTRS), and controls. Additionally, we investigated, for the first time, the differences between clozapine responders (Clz-R) and non-responders (Clz-nR). 53 participants underwent FDG-PET studies (41 patients and 12 controls). Response to conventional antipsychotics and to clozapine was evaluated using a standardized prospective procedure based on PANSS score changes. Maps of relative brain glucose metabolism were processed for voxel-based analysis using Statistical Parametric Mapping software. Restricted areas of significant bilateral relative hypometabolism in the superior frontal gyrus characterized TRS compared to nTRS. Moreover, reduced parietal and frontal metabolism was associated with high PANSS disorganization factor scores in TRS (P < .001 voxel level uncorrected, P < .05 cluster level FWE-corrected). Only TRS compared to controls showed significant bilateral prefrontal relative hypometabolism, more extensive in CLZ-nR than in CLZ-R (P < .05 voxel level FWE-corrected). Relative significant hypermetabolism was observed in the temporo-occipital regions in TRS compared to nTRS and controls. These data indicate that, in TRS patients, altered metabolism involved discrete brain regions not found affected in nTRS, possibly indicating a more severe disrupted functional brain network associated with disorganization symptoms.

Lower brain glucose metabolism in normal ageing is predominantly frontal and temporal: A systematic review and pooled effect size and activation likelihood estimates meta-analyses.

This review provides a qualitative and quantitative analysis of cerebral glucose metabolism in ageing. We undertook a systematic literature review followed by pooled effect size and activation likelihood estimates (ALE) meta-analyses. Studies were retrieved from PubMed following the PRISMA guidelines. After reviewing 635 records, 21 studies with 22 independent samples (n= 911 participants) were included in the pooled effect size analyses. Eight studies with eleven separate samples (n= 713 participants) were included in the ALE analyses. Pooled effect sizes showed significantly lower cerebral metabolic rates of glucose for older versus younger adults for the whole brain, as well as for the frontal, temporal, parietal, and occipital lobes. Among the sub-cortical structures, the caudate showed a lower metabolic rate among older adults. In sub-group analyses controlling for changes in brain volume or partial volume effects, the lower glucose metabolism among older adults in the frontal lobe remained significant, whereas confidence intervals crossed zero for the other lobes and structures. The ALE identified nine clusters of lower glucose metabolism among older adults, ranging from 200 to 2640 mm3 . The two largest clusters were in the left and right inferior frontal and superior temporal gyri and the insula. Clusters were also found in the inferior temporal junction, the anterior cingulate and caudate. Taken together, the results are consistent with research showing less efficient glucose metabolism in the ageing brain. The findings are discussed in the context of theories of cognitive ageing and are compared to those found in neurodegenerative disease.

Cerebral glucose changes after chemotherapy and their relation to long-term cognitive complaints and fatigue

PurposeTo investigate the short-term cerebral metabolic effects of intravenous chemotherapy and their association with long-term fatigue/cognitive complaints.Experimental designUsing [18F]-FDG-PET/CT whole-body scans, we retrospectively quantified relative cerebral glucose metabolism before and after neoadjuvant chemotherapy in a cohort of patients treated for non-metastatic breast cancer (2009-2019). Self-report of cognitive complaints and fatigue were prospectively assessed 7 ± 3 years after therapy. Metabolic changes were estimated with i) robust mixed-effects modelling in regions-of-interest (frontal, parietal, temporal, occipital, and insular cortex) and ii) general-linear modelling of whole-brain voxel-wise outcomes. iii) The association between metabolic changes and self-reported outcomes was evaluated using linear regression-analysis.ResultsOf the 667 screened patients, 263 underwent PET/CT before and after chemotherapy and 183 (48 ± 9 years) met the inclusion criteria. After chemotherapy, decreased frontal and increased parietal and insular metabolism were observed (|ß|>0.273, pFDR <0.008). Separately, additional increased occipital metabolism after epiribucin+ cyclophosphamide (EC) and temporal metabolism after EC+ fluorouracil chemotherapy were observed (ß>0.244, pFDR ≤0.048). Voxel-based analysis (pcluster-FWE <0.001) showed decreased metabolism in the paracingulate gyrus (-3.2 ± 3.9%) and putamen (3.1 ± 4.1%) and increased metabolism in the lateral cortex (L=2.9 ± 3.1%) and pericentral gyri (3.0 ± 4.4%). Except for the central sulcus, the same regions showed changes in EC, but not in FEC patients. Of the 97 self-reported responders, 23% and 27% experienced extreme fatigue and long-term cognitive complaints, respectively, which were not associated with metabolic changes.ConclusionBoth hyper- and hypometabolism were observed after chemotherapy for breast cancer. Combined with earlier findings, this study could support inflammatory mechanisms resulting in relative hypermetabolism, mainly in the parietal/occipital cortices. As early metabolic changes did not precede long-term complaints, further research is necessary to identify vulnerable patients.

Near-Infrared Optical Transducer for Dynamic Imaging of Cerebrospinal Fluid Glucose in Brain Tumor.

Aberrant cerebral glucose metabolism is related to many brain diseases, especially brain tumor. However, it remains challenging to measure the dynamic changes in cerebral glucose. Here, we developed a near-infrared (NIR) optical transducer to sensitively monitor the glucose variations in cerebrospinal fluid in vivo. The transducer consists of an oxygen-sensitive nanoparticle combined with glucose oxidase (GOx), yielding highly sensitive NIR phosphorescence in response to blood glucose change. We demonstrated long-term continuous glucose monitoring by using the NIR transducer. After subcutaneous implantation, the glucose transducer provides a strong luminescence signal that can continuously monitor blood glucose fluctuations for weeks. By using the NIR emission of the transducer, we further observed abnormal dynamic changes in cerebrospinal fluid glucose and quantitatively assessed cerebral glucose uptake rates in transgenic mice bearing brain tumors. This study provides a promising method for the diagnosis of various metabolic diseases with altered glucose metabolism.