Cortical Glucose Research Articles

Explaining recovery from coma with multimodal neuroimaging

The aim of this prospective, observational cohort study was to investigate and assess diverse neuroimaging biomarkers to predict patients’ neurological recovery after coma. 32 patients (18–76 years, M = 44.8, SD = 17.7) with disorders of consciousness participated in the study. Multimodal neuroimaging data acquired during the patient’s hospitalization were used to derive cortical glucose metabolism (18F-fluorodeoxyglucose positron emission tomography/computed tomography), and structural (diffusion-weighted imaging) and functional connectivity (resting-state functional MRI) indices. The recovery outcome was defined as a continuous composite score constructed from a multivariate neurobehavioral recovery assessment administered upon the discharge from the hospital. Fractional anisotropy-based white matter integrity in the anterior forebrain mesocircuit (r = 0.72, p < .001, 95% CI: 0.87, 0.45), and the functional connectivity between the antagonistic default mode and dorsal attention resting-state networks (r = − 0.74, p < 0.001, 95% CI: − 0.46, − 0.88) strongly correlated with the recovery outcome. The association between the posterior glucose metabolism and the recovery outcome was moderate (r = 0.38, p = 0.040, 95% CI: 0.66, 0.02). Structural (adjusted R2 = 0.84, p = 0.003) or functional connectivity biomarker (adjusted R2 = 0.85, p = 0.001), but not their combination, significantly improved the model fit to predict the recovery compared solely to bedside neurobehavioral evaluation (adjusted R2 = 0.75). The present study elucidates an important role of specific MRI-derived structural and functional connectivity biomarkers in diagnosis and prognosis of recovery after coma and has implications for clinical care of patients with severe brain injury.

Associations of CSF BACE1 with amyloid pathology, neurodegeneration, and cognition in Alzheimer's disease.

Β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) is a crucial protease in the production of amyloid-β (Aβ) in Alzheimer's disease (AD) patients. However, the side effects observed in clinical trials of BACE1 inhibitors, including reduction in brain volume and cognitive worsening, suggest that the exact role of BACE1 in AD pathology is not fully understood. To further investigate this, we examined cerebrospinal fluid (CSF) levels of BACE1 and its cleaved product sAPPβ that reflects BACE1 activity in the China Aging and Neurodegenerative Disorder Initiative cohort. We found significant correlations between CSF BACE1 or sAPPβ levels and CSF Aβ40, Aβ42, and Aβ42/Aβ40 ratio, but not with amyloid deposition detected by 18F-Florbetapir PET. Additionally, CSF BACE1 and sAPPβ levels were positively associated with cortical thickness in multiple brain regions, and higher levels of sAPPβ were linked to increased cortical glucose metabolism in frontal and supramarginal areas. Interestingly, individuals with higher baseline levels of CSF BACE1 exhibited slower rates of brain volume reduction and cognitive worsening over time. This suggests that increased levels and activity of BACE1 may not be the determining factor for amyloid deposition, but instead, may be associated with increased neuronal activity and potentially providing protection against neurodegeneration in AD.

Abstract 1801: Rewiring of cortical glucose metabolism fuels human brain cancer growth

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth. Citation Format: Andrew J. Scott, Anjali Mittal, Baharan Meghdadi, Sravya Palavalasa, Abhinav Achreja, Alexandra O'Brien, Ayesha Kothari, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Donna M. Edwards, Vijay Tarnal, Nathan Qi, Theodore S. Lawrence, Sriram Venneti, Nathalie Y. Agar, Costas A. Lyssiotis, Wajd N. Al-Holou, Deepak Nagrath, Daniel R. Wahl. Rewiring of cortical glucose metabolism fuels human brain cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1801.

Coupling Between Human Brain Cortical Thickness and Glucose Metabolism from Regional to Connective Level: A Positron Emission Tomography/Magnetic Resonance Imaging Study.

Background: Balance between brain structure and function is implicated in aging and many brain disorders. This study aimed to investigate the coupling between brain structure and function using 18F-fludeoxyglucose positron emission tomography (PET)/magnetic resonance imaging (MRI). Methods: One hundred thirty-eight subjects who underwent brain 18F-FDG PET/MRI were recruited. The structural and functional coupling at the regional level was explored by calculating within-subject Spearman's correlation between glucose metabolism (GluM) and cortical thickness (CTh) across the cortex for each subject, which was then correlated with age to explore its physiological effects. Then, subjects were divided into groups of middle-aged and young adults and older adults (OAs); structural connectivity (SC) based on CTh and functional connectivity (FC) based on GluM were constructed for the two groups, respectively, followed by exploring the connective-level structural and functional coupling on SC and FC matrices. The global and local efficiency values of the brain SC and FC were also evaluated. Results: Of the subjects, 97.83% exhibited a significant negative correlation between regional CTh and GluM (r = -0.24 to -0.71, p < 0.05, FDR correction), and this CTh-GluM correlation was negatively correlated with age (R = -0.35, p < 0.001). For connectivity matrices, many regions showed positive correlation between SC and FC, especially in the OA group. Besides, FC exhibited denser connections than SC, resulting in both higher global and local efficiency, but lower global efficiency when the network size was corrected. Conclusions: This study found couplings between CTh and GluM at both regional and connective levels, which reflected the aging progress, and might provide new insight into brain disorders. Impact statement The intricate interplay between brain structures and functions plays a pivotal role in unraveling the complexities inherent in the aging process and the pathogenesis of neurological disorders. This study revealed that 97.83% subjects showed negative correlation between the brain's regional cortical thickness and glucose metabolism, while at the connective level, many regions showed positive correlations between structural and functional connectivity. The observed coupling at the regional and connective levels reflected physiological progress, such as aging, and provides insights into the brain mechanisms and potential implications for the diagnosis and treatment of brain disorders.

Striatal Amyloid deposition in sporadic Alzheimer’s Disease

AbstractBackgroundIt has been shown that disorders associated with early‐life alterations in amyloid production or processing such as in autosomal dominant Alzheimer’s disease (AD) and down syndrome‐associated dementia have a different pattern of Aβ deposition, with early striatal accumulation, as compared to sporadic late‐onset cases, in which striatal deposition has been suggested to be a marker of late and advanced amyloidosis. It is not clear, however, if the pattern of amyloid accumulation is related to any other factors or if it has any impact on brain metabolism. We aimed to determine if there are any clinical or demographic predictors of striatal tau accumulation in sporadic AD and whether its presence affects the subjects´ brain metabolism.MethodSubjects that underwent positron emission tomography (PET) scans with 18F‐FDG and 11C‐PIB were analyzed retrospectively. Only those with clinical diagnosis of AD and mild cognitive impairment (MCI) due to AD were considered for the analysis. Visual analyses were performed to exclude subjects without cortical amyloid accumulation. Mean values from cortical volumes of interest (VOIs) and striatum were obtained. Amyloid deposition was correlated with age and disease duration via Pearson’s correlations. Amyloid deposition was also correlated to brain metabolism as assessed by FDG PET.Result150 subjects were included in this study. Neither age nor disease duration was correlated with striatal amyloid accumulation. Subjects with striatal Pib accumulation showed higher cortical amyloid burden. Moreover, higher striatal amyloid burden was positively correlated with higher frontal amyloid burden specifically. Amyloid burden in the striatum did not seem to have an impact on the glucose metabolism in the striatum itself. However, variations in cortical glucose metabolism could be observed. A higher striatal amyloid burden was correlated with cortical glucose hypometabolism, specifically in the precuneus and temporal areas (Figure 1).ConclusionThere seems to be a stage of sporadic Alzheimer’s disease in which amyloid accumulates in the striatum. This, in turn, appears to have an impact on brain functioning. Whether this has a real impact on cognitive performance remains to be elucidated.

The cortical glucose metabolism signatures of cognitive resilience in amyloid positive cognitively unimpaired elderly adults

AbstractBackgroundβ‐amyloid (Aβ) positive (A+) cognitively unimpaired (CU) individuals who maintain normal cognitive function at follow‐up may have good cognitive resilience (CR). A+/CU Individuals with high CR may have hypermetabolism. In this study, we explored the cortical glucose metabolism features of CR in A+/CU elderly adults.MethodWe analyzed 855 ADNI participants with Aβ PET (18F‐florbetapir (FBP) or 18F‐florbetaben (FBB)), CSF p‐Tau181, 18F‐fluorodeoxyglucose (FDG) PET and longitudinal residual hippocampal volume (rHCV) and cognitive assessments. A+/T+/N+ were defined as AD summary cortical standardized uptake value ratio (SUVR) for FBP ≥1.11 or FBB ≥1.08, CSF p‐Tau≥23pg/ml, and rHCV≤‐0.67 respectively. We compared intensity‐ and spatial‐normalized FDG SUVR images between 96 A‐/T‐/N‐/CU individuals (Reference group) and 68 A+/CU individuals who maintained CU at follow‐up regardless of T+ or N+ (CR group). Cortical regions with higher FDG SUVR in the CR group were identified as the CR_metaROI. Baseline CR_metaROI FDG‐SUVRs were compared between different stages of AD. Finally, we determined whether CR_metaROI FDG‐SUVR can modulate the association of Aβ PET and CSF p‐Tau with longitudinal changes of cognition, controlling for age, sex, and education.ResultCR_metaROI was primarily located in the precentral and postcentral regions (Fig. 1). AD dementia patients had lower CR_metaROI FDG SUVRs than the CU (standardized β (βstd) = ‐0.326[95% confidence interval (ci): ‐0.534, ‐0.119], p = 0.002) and MCI (βstd = ‐0.303[95%ci: ‐0.496, ‐0.111], p = 0.002) groups (Fig. 2A), and A+/CU group had higher (βstd = 0.605[95%ci: 0.352, 0.859], p&lt;0.001) CR_metaROI FDG SUVRs than the A‐/CU group (Fig. 2B). A‐/T+ and A+/T‐ individuals had lower (βstd = ‐0.248[95%ci: ‐0.4474, ‐0.022], p = 0.031) and higher (βstd = 0.305[95%ci: 0.093, 0.516], p = 0.005) CR_metaROI FDG SUVRs than the A‐/T‐ group respectively (Fig. 2C). The A+/T‐/N+ group had higher (βstd = 0.466[95%ci: 0.153, 0.779], p = 0.004) CR_metaROI FDG SUVRs than the A‐/T‐/N‐group (Fig. 2D). Moreover, higher baseline metaROI FDG‐SUVRs were associated with slower rates of decline in memory, executive function and preclinical Alzheimer cognitive composite scores upon the same levels of Aβ PET (Fig. 3A‐C) and CSF p‐Tau (Fig. 3D‐F).ConclusionWe identified a metabolism signature of CR in A+/CU elderly adults. These findings may provide novel insights into understanding the hypermetabolism patterns of CR in aging people.

Renal Cortical Glucose Uptake Is Decreased in Insulin Resistance and Correlates Inversely With Serum Free-fatty Acids.

Studies on human renal metabolism are scanty. Nowadays, functional imaging allows the characterization of renal metabolism in a noninvasive manner. We have recently demonstrated that fluorodeoxyglucose F18 (18F FDG) positron emission tomography can be used to analyze renal glucose uptake (GU) rates, and that the renal cortex is an insulin-sensitive tissue. To confirm that renal GU is decreased in people with obesity and to test whether circulating metabolites are related to renal GU. Eighteen people with obesity and 18 nonobese controls were studied with [18F]FDG positron emission tomography during insulin clamp. Renal scans were obtained ∼60 minutes after [18F]FDG injection. Renal GU was measured using fractional uptake rate and after correcting for residual intratubular [18F]FDG. Circulating metabolites were measured using high-throughput proton nuclear magnetic resonance metabolomics. Cortical GU was higher in healthy nonobese controls compared with people with obesity (4.7 [3.4-5.6] vs 3.1 [2.2-4.3], P = .004, respectively), and it associated positively with the degree of insulin sensitivity (M value) (r = 0.42, P = .01). Moreover, cortical GU was inversely associated with circulating β-OH-butyrate (r = -0.58, P = .009), acetoacetate (r = -0.48, P = .008), citrate (r = -0.44, P = .01), and free fatty acids (r = -0.68, P < .0001), even when accounting for the M value. On the contrary, medullary GU was not associated with any clinical parameters. These data confirm differences in renal cortical GU between people with obesity and healthy nonobese controls. Moreover, the negative correlations between renal cortex GU and free fatty acids, ketone bodies, and citrate are suggestive of substrate competition in the renal cortex.

Objective sleep was longitudinally associated with brain amyloid burden in mild cognitive impairment.

Understanding the longitudinal association of objective sleep and physical activity with brain amyloid burden and cortical glucose metabolism has critical clinical and public health implications for dementia prevention in later life. We enrolled 118 individuals aged ≥65 years with mild cognitive impairment, who were followed up on from August 2015 to September 2019. All participants continuously wore an accelerometer sensor for 7 consecutive days every 3 months and received annual 11 C-Pittsburgh compound-B and 18 F-fluorodeoxyglucose positron emission tomography (PET). Sleep and physical activity parameters were assessed using accelerometer sensor data andPET imaging was quantified using a standardized uptake-value ratio. Fifty-seven participants (48.3%) completed a lifestyle factor assessment and PET imaging over the 3-year period. A linear mixed-effects model was applied to examine the longitudinal association of sleep and physical activity parameters with PET imaging over the 3-year period, controlling for potential confounders. Sleep efficiency was inversely associated with amyloid uptake in the frontal lobe. Although sleep duration was positively associated with global amyloid uptake, particularly in the frontal lobe, their impact was extremely small. However, physical activity parameters were not significantly associated with the 11 C-Pittsburgh compound-B-uptake. Furthermore, sleep and physical activity parameters were not significantly associated with cortical glucose metabolism. Lower sleep efficiency could be an early symptom of greater brain amyloid burden at the mild cognitive impairment stage. Therefore, the assessment of sleep may be useful for identifying individuals at higher risk for brain amyloid burden. Future longer term observational studies are required to confirm these findings.

Comparison of Brain Amyloid Deposition and Cortical Glucose Metabolism Between Clinic- and Community-Based Cohort.

The differences in positron emission tomography (PET) imaging among older adults with mild cognitive impairment (MCI), according to the recruitment source, remain unclear. To investigate the differences in brain amyloid deposition and cortical glucose metabolism according to recruitment source among older adults with MCI. Participants in the clinic-based MCI cohort, who were referred to Oita University Hospital for cognitive decline, consisted of 90 adults with MCI. The community-based MCI cohort, which participated in a prospective cohort study, consisted of 118 adults with MCI. Participants underwent cognitive function evaluation, 11C-Pittsburgh compound B (PiB)-PET, and 18F-fluorodeoxyglucose (FDG)-PET. The prevalence of amyloid positivity and mean PiB and FDG uptake values were compared between the cohorts. Moreover, a voxel-by-voxel group study was performed to determine the areas with significant differences between the clinic- and community-based MCI cohorts. The prevalence of amyloid positivity and mean PiB uptake value in the clinic-based MCI cohort were significantly higher than those in the community-based MCI cohort (p < 0.001 and p < 0.001, respectively). The mean FDG uptake value in the clinic-based MCI cohort was significantly lower than that in the community-based MCI cohort (p < 0.001). SPM 8 analysis showed significantly increased PiB uptake in the precuneus and parietotemporal lobe and significantly decreased FDG uptake in the posterior cingulate in the clinic-based MCI cohort compared to the community-based MCI cohort. The prevalence and severity of amyloid pathology in older adults with MCI varied depending on the recruitment source.

Co-twin design in brain imaging-review on biomarkers of Alzheimer's disease.

Twin samples allow to conduct a quasi-experimental co-twin case-control approach that can control for genetic and environmental confounding in brain-cognition associations, being more informative on causality compared with studies in unrelated individuals. We conducted a review of studies that have utilized discordant co-twin design to investigate the associations of brain imaging markers of Alzheimer's disease and cognition. Inclusion criteria encompassed twin pairs discordant for cognition or Alzheimer's disease imaging markers and reporting of within-twin pair comparison on the association between cognition and brain measures. Our PubMed search (2022 April 23, updated 2023 March 9) resulted in 18 studies matching these criteria. Alzheimer's disease imaging markers have been addressed only by few studies, most with small sample size. Structural magnetic resonance imaging studies have indicated greater hippocampal volume and thicker cortex in co-twins with better cognitive performance compared with their co-twins with poorer cognitive performance. No studies have looked at cortical surface area. Positron emission tomography imaging studies have suggested that lower cortical glucose metabolism rate and higher cortical neuroinflammation, amyloid, and tau accumulations are related to poorer episodic memory in within-twin pair comparisons. Thus far, only cross-sectional within-twin pair associations of cortical amyloid and hippocampal volume with cognition have been replicated.

Functional Correlates of Microglial and Astrocytic Activity in Symptomatic Sporadic Alzheimer’s Disease: A CSF/18F-FDG-PET Study

Glial and microglial cells contribute to brain glucose consumption and could actively participate in shaping patterns of brain hypometabolism. Here, we aimed to investigate the association between 18F-fluorodeoxyglucose (18F-FDG) uptake and markers of microglial and astrocytic activity in a cohort of patients with Alzheimer's Disease (AD). We dosed cerebrospinal fluid (CSF) levels of soluble Triggering Receptor Expressed on Myeloid cells (sTREM2), Glial Fibrillary Acidic Protein (GFAP), a marker of reactive astrogliosis, and β-S100, a calcium-binding protein associated with a neurotoxic astrocytic profile. No associations were found between sTREM-2 and 18F-FDG uptake. Instead, 18F-FDG uptake was associated negatively with CSF β-S100 in the left supramarginal gyrus, inferior parietal lobe and middle temporal gyrus (Brodmann Areas (BA) 21 and 40). Increased β-S100 levels could negatively regulate neuronal activity in the temporo-parietal cortex to prevent damage associated with AD hyperactivity, or rather they could reflect neurotoxic astrocytic activation contributing to AD progression in key strategic areas. We also identified a trend of positive association of 18F-FDG uptake with CSF GFAP in the right fronto-medial and precentral gyri (BA 6, 9 and 11), which has been reported in early AD and could either be persisting as an epiphenomenon tied to disease progression or be specifically aimed at preserving functions in the frontal cortex. Overall, CSF markers of astrogliosis seem to correlate with cortical glucose uptake in symptomatic sporadic AD, highlighting the role of astrocytes in shaping regional hypometabolism and possibly clinical presentation.

Cortical Thickness and Brain Glucose Metabolism in Healthy Aging.

We aimed to determine the effect of demographic factors on cortical thickness and brain glucose metabolism in healthy aging subjects. The following tests were performed on 71 subjects with normal cognition: neurological examination, 3-tesla magnetic resonance imaging, 18F-fluorodeoxyglucose positron-emission tomography, and neuropsychological tests. Cortical thickness and brain metabolism were measured using vertex- and voxelwise analyses, respectively. General linear models (GLMs) were used to determine the effects of age, sex, and education on cortical thickness and brain glucose metabolism. The effects of mean lobar cortical thickness and mean lobar metabolism on neuropsychological test scores were evaluated using GLMs after controlling for age, sex, and education. The intracranial volume (ICV) was further included as a predictor or covariate for the cortical thickness analyses. Age was negatively correlated with the mean cortical thickness in all lobes (frontal and parietal lobes, p=0.001; temporal and occipital lobes, p<0.001) and with the mean temporal metabolism (p=0.005). Education was not associated with cortical thickness or brain metabolism in any lobe. Male subjects had a lower mean parietal metabolism than did female subjects (p<0.001), while their mean cortical thicknesses were comparable. ICV was positively correlated with mean cortical thickness in the frontal (p=0.016), temporal (p=0.009), and occipital (p=0.007) lobes. The mean lobar cortical thickness was not associated with cognition scores, while the mean temporal metabolism was positively correlated with verbal memory test scores. Age and sex affect cortical thickness and brain glucose metabolism in different ways. Demographic factors must therefore be considered in analyses of cortical thickness and brain metabolism.

Evaluation of renal glucose uptake with [18F]FDG-PET: Methodological advancements and metabolic outcomes

Background/purposeStudying renal glucose metabolism non-invasively in humans is an unmet need. Positron emission tomography (PET) is the current gold standard for measuring regional tissue glucose uptake rates, but the most widely used glucose analog ([18F]FDG) is not a good substrate for sodium-glucose cotransporters (SGLTs). As a consequence, [18F]FDG spills over into the urine and [18F]FDG-PET considerably underestimates published rates of whole renal glucose uptake obtained using the arterial-venous difference technique. Our aim was to assess whether [18F]FDG-PET can be used in the study of renal glucose metabolism in humans. MethodsWe measured individual [18F]FDG radioactivity in the urine and estimated intraluminal [18F]FDG radioactivity concentration; these values were used to correct renal [18F]FDG-PET data acquired ∼90 min from tracer injection under fasting conditions and during an insulin clamp in 9 lean and 16 obese subjects. ResultsWe found that the corrected glucose uptake is consistently higher in the medulla than cortex and that both cortical and medullary glucose uptake are higher in lean than obese participants under both fasting and insulinized conditions. Moreover, cortical but not medullary glucose uptake is increased from the fasting to the insulinized condition. ConclusionThe data show for the first time that [18F]FDG-PET can still provide relevant physiological information on regional renal glucose uptake on the condition that [18F]FDG uptake is corrected for tubular radioactivity.

Brain morphometric and metabolic changes in Subjective Cognitive Decline individuals

AbstractBackgroundSubjective cognitive decline (SCD) is defined as a memory complaint in individuals without an objective measure of cognitive impairment. In this study, we investigated the morphometric and metabolic brain changes in individuals presenting with SCD.MethodAge and sex matched structural MRI and [18F]FDG PET images from SCD and CU (n = 101, per group) were extracted from the ADNI database. We built general linear models corrected for multiple comparisons with 10,000 Monte‐Carlo simulations to verify differences in cortical thickness between groups, using age as a covariate (Freesurfer’s v7.1.1). Metabolic analysis was performed using voxel‐wise general linear models comparing the SUVR of the FDG signal, correcting for age and APOE4 allele carrying status, using the MINC toolkit and the R statistical program.ResultSCD and CU groups presented similar age, sex, years of education, CSF AD‐related protein levels (amyloid beta 1‐42, p‐tau and tau), and Clinical Dementia Rating – Sum of Boxes score (Table 1). Compared to CU individuals, SCD subjects showed increased cortical thickness in the right hemisphere rostral middle frontal gyrus (Figure 1), while glucose metabolism was increased in the right medial temporal lobe, including the hippocampus, and right occipital cortex (Figure 2).ConclusionIndividuals with SCD present cortical hypertrophy in the rostral middle frontal gyrus and glucose hypermetabolism in the medial temporal lobe and occipital cortex, all in the right hemisphere. Previous studies suggest that these areas play a role in personality and humor, and may be altering self‐perception of cognitive decline. At the biological level, given the high concentration of astrocytes in these areas, such changes may suggest a scenario of astrocyte reactivity. More specifically, astrocyte hypertrophy may account for increased cortical thickness and glucose uptake. In summary, we provide neuroimaging evidence of structural and functional changes in individuals with SCD, suggesting early astrocyte reactivity.

Longitudinal changes in brain glucose metabolism, astrocyte biomarkers and behavior in an APP/PS1 rat model

AbstractBackgroundImaging and fluid biomarkers have helped to reconceptualize Alzheimer’s Disease (AD) as a continuum. However, the biological interpretation of each AD biomarker remains under investigation. In this context, animal models that mimic the AD dynamic biomarkers cascade model present high translational value and can be used to refine our interpretation of biomarker findings. In light of this, we longitudinally evaluated [18F]FDG‐PET imaging, cerebrospinal fluid (CSF) glial and immune biomarkers, and behavior in the TgF344‐AD rat, a model harboring human APP/PS1 mutations.MethodsTgF344‐AD rats and wild‐type littermates were longitudinally evaluated at 3, 6, 9, and 12 months of age. Rats underwent [18F]FDG‐microPET scans, behavioral tasks (Y‐maze and novel objective recognition) and CSF samplings. The [18F]FDG SUVr was calculated with pons as the reference region. CSF glial and immune markers were measured by multiplex ELISA. A cross‐sectional cohort was used to measure cortical glutamate uptake (ex‐vivo slices) at the same time points. Further examination of astrocyte proteins immunocontent was conducted at 9 months of age.ResultsAt 3, 6 and 12 months, no changes in [18F]FDG metabolism were found. At 9 months of age, we identified a significant cortical hypermetabolism in the TgF344‐AD and a decline in alternance during the Y‐maze task. CSF GFAP levels were elevated at 6 and 9 months of age, while CSF S100B was decreased at 9 months of age. Additionally, the cortical and hippocampal glutamate uptake and GFAP cortical immunocontent were increased at 9 and 12 months of age. The recognition memory and CSF inflammatory markers (sTREM2, IL‐6, TNF‐α, IL‐10) were not altered in any of the ages evaluated.ConclusionOur results suggest that the TgF344‐AD rat model is suitable for studying astrocytic adaptations during early stages of amyloidosis in the rat brain. These adaptations include cortical glucose hypermetabolism, fluid biomarker evidence of reactive astrogliosis, and spatial memory impairment with concurrent abnormalities in astrocyte glutamate uptake in the cortex and hippocampus. Due to the critical role of astrocytes in brain glucose handling, our findings suggest that astrocyte reactivity could be driving glucose hypermetabolism and memory impairment early in the disease course.

GFAP expression levels are associated with brain glucose metabolism in a rat model of Alzheimer’s disease

AbstractBackgroundGlial Fibrillary Acidic Protein (GFAP) is an intermediate filament expressed almost exclusively in astrocytes, and it is usually overexpressed in reactive astrocytes. We have previously shown that astrocytes play a critical role in brain energy metabolism and are significant contributors to the [18F]FDG‐PET signal. The cortex is majorly composed of glial cells, whereas the cerebellum is predominantly composed of neurons. In light of this, whether GFAP levels in the brain tissue are associated with [18F]FDG‐PET signal remains unknown. Thus, we aimed to investigate the associations between cortical and cerebellar GFAP levels with brain glucose metabolism in a rat model of Alzheimer’s disease.MethodsBrain metabolism of ten‐month‐old TgF344‐AD (n=8) and wild‐type (WT,n=6) rats was assessed with [18F]FDG‐PET. Then, GFAP RNA levels were quantified in the frontal cortex (CXF), temporoparietal cortex (CXTP), and cerebellum (CB) using qRT‐PCR. The [18F]FDG‐PET standardized uptake ratio (SUVr) was calculated using pons as the reference region. T‐tests were used to assess the differences between groups in GFAP RNA expression levels and regional brain [18F]FDG‐PET. Comparisons were conducted using t‐statistical analyses at voxel level (RMINC). Differences were considered statistically significant at p&lt;0.05 (t&gt;2).ResultsNo differences between groups were found in the whole brain FDG metabolism or regions of interest (CXF, CXTP, and CB;t(13)&lt;2). At the voxel level, we identified small cortical hypermetabolic clusters in the TgF344‐AD rats (t(13)=5.55, local maxima). The GFAP RNA was increased in the CXTP of TgF344‐AD rats (p=0.001). No significant differences were found between groups in GFAP RNA levels in other brain regions evaluated. Interestingly, we found positive correlations between [18F]FDG‐PET metabolism and the GFAP RNA expression in the CXTP (local maxima, t(13)=8.33;Fig.1a) and CXF (local maxima, t(13)=4.82;Fig.1b). By contrast, [18F]FDG metabolism did not associate with GFAP RNA expression levels in the CB (t(13)&lt;2;Fig.1c).ConclusionGFAP RNA levels were increased in the CXTP of TgF344‐AD rats, which may indicate early astrocyte reactivity. GFAP RNA expression was associated with [18F]FDG metabolism only in cortical regions, suggesting that astrocytes may have major roles in cortical glucose uptake, but not in cerebellum.

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.

Metabolic assessment of cerebral palsy with normal clinical MRI using 18F-FDG PET imaging: A preliminary report.

To explore the cerebral metabolic patterns of cerebral palsy (CP) patients without structural abnormalities by brain magnetic resonance imaging (MRI) scans, we evaluated 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG PET) imaging features in patients. Thirty-one children with CP [Gross Motor Function Classification System (GMFCS) levels II-V] showing no structural abnormalities by MRI were enrolled in this study. Regional glucose metabolic activity values were calculated using Scenium software and compared between the right and left cerebral hemispheres. These comparisons revealed asymmetric metabolic reductions in the central region, cerebellum, frontal lobe, and parietal lobe (p < 0.01). We next determined whether averaged brain metabolic activity values in different brain regions correlated with GMFCS levels. The metabolic activity values of basal ganglia, left temporal lobe, and cerebellum correlated negatively with GMFCS scores (all p < 0.05). This method was applied to the left cerebellum, which showed higher metabolic activity values than those in the right cerebellum in most patients (83.8%), and these values also correlated negatively with GMFCS scores (Spearman's r = −0.36, p = 0.01). Differential cortical glucose metabolism by 18F-FDG PET, may help to distinguish between different CP diagnoses that are not detected by MRI.

Effect of S-Nitrosylation of RIP3 Induced by Cerebral Ischemia on its Downstream Signaling Pathway

ObjectivesOur preliminary experiments indicate that receptor-interacting protein 3 (RIP3) is S-nitrosylated and contributes to its autophosphorylation (activation) after 3 h of rat brain ischemia/reperfusion mediated by activation of the N-methyl-D-aspartate receptor (NMDAR)-dependent neuronal NO synthase (nNOS) and is involved in the process of neuronal injury. Here, we will to demonstrate whether S-nitrosylation of RIP3 facilitates the activation of the downstream signaling pathway and finally exacerbates ischemic neuron death. Materials and methodsAdult male Sprague-Dawley rat transient brain ischemia/reperfusion and cortical neurons oxygen and glucose deprivation (OGD)/reoxygenation models were performed. The hippocampal CA1 regions or cultured cells were homogenized and the cytosolic fraction were collected as tissue samples. Coimmunoprecipitation and western blot analysis were carried out for detecting phosphorylation of RIP1 and mixed lineage kinase-like domains (MLKL) and the Cleaved-Caspase8 (Cl-Caspase8). The activities of Glycogen phosphorylase (PYGL), Glutamate-ammonia ligase (GLUL) and Glutamate dehydrogenase (GLUD1) were detected with ultraviolet absorption method. ResultsThis study showed that active RIP3 could phosphorylate RIP1 and MLKL through its kinase activity, promote the conversion of Caspase8 to active Cl-Caspase8, enhance the activities of PYGL, GLUL and GLUD1, and finally aggravate neuronal injury in cerebral ischemia/reperfusion. The inhibition of RIP3 S-nitrosylation inhibited the phosphorylation of RIP1 and MLKL, inhibited the activities of Caspase8, PYGL, GLUL, and GLUD1, and alleviated neuronal damage in cerebral ischemia/reperfusion. ConclusionsS-nitrosylation of RIP3 increased RIP1 and MLKL phosphorylation levels, Cl-Caspase8 content and PYGL, GLUL and GLUD1 activities and aggravated neuronal damage during cerebral ischemia/reperfusion and regulating the S-nitrosylation of RIP3 and its downstream signaling pathway might be a therapeutic target for stroke.

Clinicopathologic Factors Associated With Reversion to Normal Cognition in Patients With Mild Cognitive Impairment.

To identify clinicopathologic factors contributing to mild cognitive impairment (MCI) reversion to normal cognition. We analyzed 3 longitudinal cohorts in this study: the Mayo Clinic Study of Aging (MCSA), the Religious Orders Study and Memory and Aging Project (ROSMAP), and the National Alzheimer's Coordinating Center (NACC). Demographic characteristics and clinical outcomes were compared between patients with MCI with or without an experience of reversion to normal cognition (referred to as reverters and nonreverters, respectively). We also compared longitudinal changes in cortical thickness, glucose metabolism, and amyloid and tau load in a subcohort of reverters and nonreverters in MCSA with MRI or PET imaging information from multiple visits. We identified 164 (56.4%) individuals in MCSA, 508 (66.8%) individuals in ROSMAP, and 280 (34.1%) individuals in NACC who experienced MCI reversion to normal cognition. Cox proportional hazards regression models showed that MCI reverters had an increased chance of being cognitively normal at the last visit in MCSA (HR 3.31, 95% CI 2.14-5.12), ROSMAP (HR 3.72, 95% CI 2.50-5.56), and NACC (HR 9.29, 95% CI 6.45-13.40) and a reduced risk of progression to dementia (HR 0.12, 95% CI 0.05-0.29 in MCSA; HR 0.41, 95% CI 0.32-0.53 in ROSMAP; and HR 0.29, 95% CI 0.21-0.40 in NACC). Compared with MCI nonreverters, reverters had better-preserved cortical thickness (β = 0.082, p <0.001) and glucose metabolism (β = 0.119, p = 0.001) and lower levels of amyloid, albeit statistically nonsignificant (β = -0.172, p = 0.090). However, no difference in tau load was found between reverters and nonreverters (β = 0.073, p = 0.24). MCI reversion to normal cognition is likely attributed to better-preserved cortical structure and glucose metabolism.