Cerebral Metabolic Rate For Glucose Research Articles

Selection of the optimal intensity normalization region for FDG-PET studies of normal aging and Alzheimer\u2019s disease

The primary method for measuring brain metabolism in humans is positron emission tomography (PET) imaging using the tracer 18F-fluorodeoxyglucose (FDG). Standardized uptake value ratios (SUVR) are commonly calculated from FDG-PET images to examine intra- and inter-subject effects. Various reference regions are used in the literature of FDG-PET studies of normal aging, making comparison between studies difficult. Our primary objective was to determine the optimal SUVR reference region in the context of healthy aging, using partial volume effect (PVE) and non-PVE corrected data. We calculated quantitative cerebral metabolic rates of glucose (CMRg) from PVE-corrected and non-corrected images from young and older adults. We also investigated regional atrophy using magnetic resonance (MR) images. FreeSurfer 6.0 atlases were used to explore possible reference regions of interest (ROI). Multiple regression was used to predict CMRg data, in each FreeSurfer ROI, with age and sex as predictors. Age had the least effect in predicting CMRg for PVE corrected data in the pons (r2 = 2.83 × 10−3, p = 0.67). For non-PVE corrected data age also had the least effect in predicting CMRg in the pons (r2 = 3.12 × 10−3, p = 0.67). We compared the effects of using the whole brain or the pons as a reference region in PVE corrected data in two regions susceptible to hypometabolism in Alzheimer’s disease, the posterior cingulate and precuneus. Using the whole brain as a reference region resulted in non-significant group differences in the posterior cingulate while there were significant differences between all three groups in the precuneus (all p < 0.004). When using the pons as a reference region there was significant differences between all groups for both the posterior cingulate and the precuneus (all p < 0.001). Therefore, the use of the pons as a reference region is more sensitive to hypometabism changes associated with Alzheimer’s disease than the whole brain.

Fully Integrated PET/MR Imaging for the Assessment of the Relationship Between Functional Connectivity and Glucose Metabolic Rate.

In the past, determination of absolute values of cerebral metabolic rate of glucose (CMRGlc) in clinical routine was rarely carried out due to the invasive nature of arterial sampling. With the advent of combined PET/MR imaging technology, CMRGlc values can be obtained non-invasively, thereby providing the opportunity to take advantage of fully quantitative data in clinical routine. However, CMRGlc values display high physiological variability, presumably due to fluctuations in the intrinsic activity of the brain at rest. To reduce CMRGlc variability associated with these fluctuations, the objective of this study was to determine whether functional connectivity measures derived from resting-state fMRI (rs-fMRI) could be used to correct for these fluctuations in intrinsic brain activity. Methods: We studied 10 healthy volunteers who underwent a test-retest dynamic [18F]FDG-PET study using a fully integrated PET/MR system (Siemens Biograph mMR). To validate the non-invasive derivation of an image-derived input function based on combined analysis of PET and MR data, arterial blood samples were obtained. Using the arterial input function (AIF), parametric images representing CMRGlc were determined using the Patlak graphical approach. Both directed functional connectivity (dFC) and undirected functional connectivity (uFC) were determined between nodes in six major networks (Default mode network, Salience, L/R Executive, Attention, and Sensory-motor network) using either a bivariate-correlation (R coefficient) or a Multi-Variate AutoRegressive (MVAR) model. In addition, the performance of a regional connectivity measure, the fractional amplitude of low frequency fluctuations (fALFF), was also investigated. Results: The average intrasubject variability for CMRGlc values between test and retest was determined as (14 ±8%) with an average inter-subject variability of 25% at test and 15% at retest. The average CMRGlc value (umol/100 g/min) across all networks was 39 ±10 at test and increased slightly to 43 ±6 at retest. The R, MVAR and fALFF coefficients showed relatively large test-retest variability in comparison to the inter-subjects variability, resulting in poor reliability (intraclass correlation in the range of 0.11–0.65). More importantly, no significant relationship was found between the R coefficients (for uFC), MVAR coefficients (for dFC) or fALFF and corresponding CMRGlc values for any of the six major networks. Discussion: Measurement of functional connectivity within established brain networks did not provide a means to decrease the inter- or intrasubject variability of CMRGlc values. As such, our results indicate that connectivity measured derived from rs-fMRI acquired contemporaneously with PET imaging are not suited for correction of CMRGlc variability associated with intrinsic fluctuations of resting-state brain activity. Thus, given the observed substantial inter- and intrasubject variability of CMRGlc values, the relevance of absolute quantification for clinical routine is presently uncertain.

Cerebral glucose metabolism and Cerebral blood flow in thyroid dysfunction: An Activation Likelihood Estimation Meta-analysis

Thyroid dysfunction is frequently associated with functional disturbances of the brain. We performed a meta-analysis of previous positron emission tomography and single-photon emission computed tomography studies using a coordinate-based technique of activation-likelihood estimation (ALE) to investigate the potential background of neuropsychiatric complications in patients with hypo- and hyperthyroidism. We performed a systematic search of MEDLINE and EMBASE for English-language publications using the keywords of “positron emission tomography”, “single-photon emission computed tomography”, and “thyroid”. The software GingerALE ver 2.3.6 was used to transform all reported coordinates into stereotactic Montreal Neurological Institute space. A threshold of uncorrected p < 0.001 (minimum volume of 200 mm3) was applied to the resulting ALE map using cerebral metabolic rate of glucose (CMRglu), and cerebral blood flow (CBF). Six studies were eligible for inclusion in the study; 4 studies of cerebral metabolic rate of CMRglu, and 2 studies of CBF. In hypothyroidism, significant decreases in CMRglu were identified in 3 clusters including left anterior cingulate, right inferior occipital gyrus, and right cuneus. In hyperthyroidism, a significant decrease in CMRglu was identified in right superior frontal gyrus. In hypothyroidism, a significant decrease in CBF was observed in left postcentral gyrus. In conclusion, several brain regions showed altered CMRglu and CBF in patients with thyroid dysfunction compared with euthyroid controls. These findings might account for underlying mechanisms of thyroid hormones on psychological and physiological effects on brain.

Mild Hyperthermia Aggravates Glucose Metabolic Consequences in Repetitive Concussion

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability around the world. Mild TBI (mTBI) makes up approximately 80% of reported cases and often results in transient psychological abnormalities and cognitive disruption. At-risk populations for mTBI include athletes and other active individuals who may sustain repetitive concussive injury during periods of exercise and exertion when core temperatures are elevated. Previous studies have emphasized the impact that increased brain temperature has on adverse neurological outcomes. A lack of diagnostic tools to assess concussive mTBI limits the ability to effectively identify the post-concussive period during which the brain is uniquely susceptible to damage upon sustaining additional injury. Studies have suggested that a temporal window of increased vulnerability that exists corresponds to a period of injury-induced depression of cerebral glucose metabolism. In the current study, we sought to evaluate the relationship between repetitive concussion, local cerebral glucose metabolism, and brain temperature using the Marmarou weight drop model to generate mTBI. Animals were injured three consecutive times over a period of 7 days while exposed to either normothermic or hyperthermic temperatures for 15 min prior to and 1 h post each injury. A 14C-2-deoxy-d-glucose (2DG) autoradiography was used to measure local cerebral metabolic rate of glucose (lCMRGlc) in 10 diverse brain regions across nine bregma levels 8 days after the initial insult. We found that repetitive mTBI significantly decreased glucose utilization bilaterally in several cortical areas, such as the cingulate, visual, motor, and retrosplenial cortices, as well as in subcortical areas, including the caudate putamen and striatum, compared to sham control animals. lCMRGlc was significant in both normothermic and hyperthermic repetitive mTBI animals relative to the sham group, but to a greater degree when exposed to hyperthermic conditions. Taken together, we report significant injury-induced glucose hypometabolism after repetitive concussion in the brain, and additionally highlight the importance of temperature management in the acute period after brain injury.

Imaging mitochondrial complex I activation during a vibrotactile stimulation: A PET study using [18F]BCPP-EF in the conscious monkey brain

In order to evaluate the capability of 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF), a novel positron emission tomography (PET) probe for mitochondrial complex I (MC-I) activity, to assess neuronal activation, an activation PET study was conducted in the conscious monkey brain with a continuous unilateral vibrotactile stimulation. PET scans with [15O]H2O, [18F]BCPP-EF, or 2-deoxy-2-[18F]fluoroglucose ([18F]FDG) were conducted under: (1) resting conditions; (2) a continuous vibration stimulation; (3) a continuous vibration stimulation after 15-min pre-vibration; and (4) a continuous vibration stimulation after 30-min pre-vibration. The contralateral/ipsilateral ratio (CIR) in the somatosensory cortex showed significant increases in the uptake of [15O]H2O, [18F]BCPP-EF, and [18F]FDG with the vibration stimulation. The longer pre-vibration duration induced significantly lower CIR in regional cerebral blood flow (rCBF) measured using [15O]H2O, whereas it did not affect the CIR in [18F]BCPP-EF or the regional cerebral metabolic rate of glucose (rCMRglc) measured using [18F]FDG 30–60 min after the injection. These results suggest that the [18F]BCPP-EF response in the later phase of scans was not influenced by the increase in rCBF, indicating the capability of [18F]BCPP-EF to detect acute changes in MC-I activity induced by neuronal activation. However, the metabolic shift from glycolysis to oxidation was not observed under the stimulation used here.

Magnetic resonance spectroscopy in Parkinson’s disease

Introduction. Modern neuroimaging methods allow to evaluate in vivo biochemical processes in the brain. Such methods include magnetic resonance spectroscopy (MRS) and positron emission tomography (PET). While PET is the “golden standard” in assessing the brain functional state and is widely used in neurodegenerative diseases, the diagnostic value of MRS remains undefined due to the inconsistency of the results obtained in different studies. At the same time, MRC allows obtaining information on the content of many metabolites in living tissues, including N-acetyl aspartate (NAA), which is considered to be a surrogate marker of neuronal integrity, choline (Cho), associated with membrane metabolism, Cr - energy metabolism, etc. The aim of this study is to compare MRS and PET data in patients with Parkinson’s disease (PD).Materials and methods. Twenty-six patients with PD stages I to III according to the Hoehn and Yahr Scale and age-matching control group of neurologically and cognitively intact people were examined. All patients underwent neurological examination, a multivoxel MRS of the supraventricular region, including white and gray matter, and PET with 18F-fluorodeoxyglucose (FDG) to assess cerebral metabolic rate of glucose (CMRglu).Results. Decrease of NAA/Cr and NAA/Cho in the white matter in the left hemisphere was revealed in PD group compared to control, with the NAA/Cr ratio negatively correlating with the stage of the disease of the Hoehn and Yahr Scale. The NAA content in the white matter and the cingulate cortex positively correlated with CMRglu in Brodmann fields 5–7, 8–10, 22, 23, 46. At the same time, Cho/Cr ratio negatively correlated with CMRglu in the cortical areas associated with the development of cognitive impairment in PD (Brodman areas 9, 10, 39, 47).

Positron Emission Tomography After Ischemic Brain Injury: Current Challenges and Future Developments.

Positron emission tomography (PET) is widely used in clinical and animal studies, along with the development of diverse tracers. The biochemical characteristics of PET tracers may help uncover the pathophysiological consequences of cardiac arrest (CA) and ischemic stroke, which include cerebral ischemia and reperfusion, depletion of oxygen and glucose, and neuroinflammation. PubMed was searched for studies of the application of PET for "cardiac arrest," "ischemic stroke," and "targeted temperature management." Available studies were included and classified according to the biochemical properties involved and metabolic processes of PET tracers, and were summarized. The mechanisms of ischemic brain injuries were investigated by PET with various tracers to elucidate the pathological process from the initial decrease of cerebral blood flow (CBF) to the subsequent abnormalities in energy and oxygen metabolism, to the monitoring of inflammation. In general, the trends of cerebral blood flow and oxygen metabolism after ischemic attack are not unidirectional but closely related to the time point of injury and recovery. Glucose metabolism after injury showed significant differences in different brain regions whereas global cerebral metabolic rate of glucose (CMRglc) declined. PET monitoring of neuroinflammation shows comparable efficacy to immunostaining. The technology of PET targeting in brain metabolism and the development of tracers provide new tools to track and evaluate the brain's pathological changes after ischemic brain injury. Despite no existing evidence for an available PET-based prediction method, discoveries of new tracers are expected to provide more possibilities for the whole field.

Transcranial Direct Current Stimulation for Online Gamers.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that applies a weak electric current to the scalp to modulate neuronal membrane potentials. Compared to other brain stimulation methods, tDCS is relatively safe, simple, and inexpensive to administer. Since excessive online gaming can negatively affect mental health and daily functioning, developing treatment options for gamers is necessary. Although tDCS over the dorsolateral prefrontal cortex (DLPFC) has demonstrated promising results for various addictions, it has not been tested in gamers. This paper describes a protocol and a feasibility study for applying repeated tDCS over the DLPFC and neuroimaging to examine the underlying neural correlates in gamers. At baseline, individuals who play online games report average weekly hours spent on games, complete questionnaires on addiction symptoms and self-control, and undergo brain 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET). The tDCS protocol consists of 12 sessions over the DLPFC for 4 weeks (anode F3/cathode F4, 2 mA for 30 min per session). Then, a follow-up is conducted using the same protocol as the baseline. Individuals who do not play online games receive only baseline FDG-PET scans without tDCS. Changes of clinical characteristics and asymmetry of regional cerebral metabolic rate of glucose (rCMRglu) in the DLPFC are examined in gamers. In addition, asymmetry of rCMRglu is compared between gamers and non-gamers at baseline. In our experiment, 15 gamers received tDCS sessions and completed baseline and follow-up scans. Ten non-gamers underwent FDG-PET scans at the baseline. The tDCS reduced addiction symptoms, time spent on games, and increased self-control. Moreover, abnormal asymmetry of rCMRglu in the DLPFC at baseline was alleviated after tDCS. The current protocol may be useful for assessing treatment efficacy of tDCS and its underlying brain changes in gamers. Further randomized sham-controlled studies are warranted. Moreover, the protocol can be applied to other neurological and psychiatric disorders.

Diverging roles of the anterior insula in trauma-exposed individuals vulnerable or resilient to posttraumatic stress disorder

Distinct brain alterations in response to traumatic events may render trauma-exposed individuals either resilient or vulnerable to posttraumatic stress disorder (PTSD). This study compared regional cerebral metabolic rate of glucose (rCMRglu) among trauma-exposed individuals with current PTSD (PTSD group, n = 61), those without current PTSD (Resilience/Recovery group, n = 26), and trauma-unexposed controls (Control group, n = 54). All participants underwent brain [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans. Voxel-wise group differences in rCMRglu among the three groups were evaluated. Associations between rCMRglu and both PTSD severity and resilience were examined. The rCMRglu in the right anterior insula and adjacent prefrontal and striatal areas was lower in the PTSD group, while higher in the Resilience/Recovery group, compared to the Control group. In addition, the lower glucose metabolism of these areas was associated with higher severity and less improvement in PTSD symptoms in the PTSD group, while the higher levels of rCMRglu were correlated with stronger resilience in the Resilience/Recovery group. This study suggests distinct roles of the anterior insula in response to trauma between the PTSD and Resilience/Recovery groups. Heightened rCMRglu in the anterior insular regions may reflect an underlying mechanism of resilience against traumatic stress, while reduced rCMRglu may indicate vulnerability to PTSD.

Hippocampal Neurochemical Profile and Glucose Transport Kinetics in Patients With Type 1 Diabetes.

Longstanding type 1 diabetes (T1D) may lead to alterations in hippocampal neurochemical profile. Upregulation of hippocampal glucose transport as a result of recurrent exposure to hypoglycemia may preserve cognitive function during future hypoglycemia in subjects with T1D and impaired awareness of hypoglycemia (IAH). The effect of T1D on hippocampal neurochemical profile and glucose transport is unknown. To test the hypothesis that hippocampal neurochemical composition is altered in T1D and glucose transport is upregulated in T1D with IAH. Hippocampal neurochemical profile was measured with single-voxel magnetic resonance spectroscopy at 3T during euglycemia in 18 healthy controls (HC), 10 T1D with IAH, and 12 T1D with normal awareness to hypoglycemia (NAH). Additionally, 12 HC, 8 T1D-IAH, and 6 T1D-NAH were scanned during hyperglycemia to assess hippocampal glucose transport with metabolic modeling. University medical center. Concentrations of hippocampal neurochemicals measured during euglycemia and ratios of maximal transport rate to cerebral metabolic rate of glucose (Tmax/CMRGlc), derived from magnetic resonance spectroscopy-measured hippocampal glucose as a function of plasma glucose. Comparison of hippocampal neurochemical profile revealed no group differences (HC, T1D, T1D-IAH, and T1D-NAH). The ratio Tmax/CMRGlc was not significantly different between the groups, T1D-IAH (1.58 ± 0.09) and HC (1.65 ± 0.07, P = 0.54), between T1D-NAH (1.50 ± 0.09) and HC (P = 0.19), and between T1D-IAH and T1D-NAH (P = 0.53). Subjects with T1D with sufficient exposure to recurrent hypoglycemia to create IAH did not have alteration of Tmax/CMRglc or neurochemical profile compared with participants with T1D-NAH or HC.

Propofol Anesthesia Alters Spatial and Topologic Organization of Rat Brain Metabolism.

Loss of consciousness during anesthesia reduces local and global rate of cerebral glucose metabolism. Despite this, the influence of gradual anesthetic-induced changes on consciousness across the entire brain metabolic network has barely been studied. The purpose of the present study was to identify specific cerebral metabolic patterns characteristic of different consciousness/anesthesia states induced by intravenous anesthetic propofol. At various times, 20 Sprague-Dawley adult rats were intravenously administered three different dosages of propofol to induce different anesthetic states: mild sedation (20 mg · kg · h), deep sedation (40 mg · kg · h), and deep anesthesia (80 mg · kg · h). Using [F]fluorodeoxyglucose positron emission tomography brain imaging, alterations in the spatial pattern of metabolic distribution and metabolic topography were investigated by applying voxel-based spatial covariance analysis and graph-theory analysis. Evident reductions were found in baseline metabolism along with altered metabolic spatial distribution during propofol-induced anesthesia. Moreover, graph-theory analysis revealed a disruption in global and local efficiency of the metabolic brain network characterized by decreases in metabolic connectivity and energy efficiency during propofol-induced deep anesthesia (mild sedation global efficiency/local efficiency = 0.6985/0.7190, deep sedation global efficiency/local efficiency = 0.7444/0.7875, deep anesthesia global efficiency/local efficiency = 0.4498/0.6481; mild sedation vs. deep sedation, global efficiency: P = 0.356, local efficiency: P = 0.079; mild sedation vs. deep anesthesia, global efficiency: P < 0.0001, local efficiency: P < 0.0001; deep sedation vs. deep anesthesia, global efficiency: P < 0.0001, local efficiency: P < 0.0001). A strong spatial correlation was also found between cerebral metabolism and metabolic connectivity strength, which decreased significantly with deepening anesthesia level (correlation coefficients: mild sedation, r = 0.55, deep sedation, r = 0.47; deep anesthesia, r = 0.23; P < 0.0001 between the sedation and deep anesthesia groups). The data revealed anesthesia-related alterations in spatial and topologic organization of metabolic brain network, as well as a close relationship between metabolic connectivity and cerebral metabolism during propofol anesthesia. These findings may provide novel insights into the metabolic mechanism of anesthetic-induced loss of consciousness.

Alzheimer's deterioration in intellectual and neurobiological staging supports the retrogenesis model: a double dissociation between verbal/non-verbal judgments and the left/right parieto-temporal glucose metabolism. A retrospective data analysis from the Tajiri Project.

Alzheimer disease (AD) patients demonstrate various clinical features reminiscent of children (the retrogenesis model). The Binet test is available for assessing mental development and deterioration. However, neuroimaging correlations remain to be clarified. Although AD patients also manifest social judgment disability, there are few cognitive tests, contrary to so many memory tests. Among the database, we noticed that the Binet test includes the subscale of social judgement using illogical sentences and pictures. The aim of this study is to clarify the neuroimaging correlations for the Binet test, especially for the illogical questions. Forty participants were selected from the database of the Tajiri Project. The Tanaka-Binet test was used to evaluate the mental age and the basic age. The latter is the age level at which the patient can completely accomplish all questions at the immediately lower age level and is used for calculating the mental age. Using the subtests of illogical sentences/pictures, logical judgment abilities were assessed. Using magnetic resonance imaging, we performed four-grade visual evaluation for cortical atrophy. The cerebral metabolic rate for glucose (CMRglc) was measured using an autoradiographic method of 18 F-fluoreodeoxyglucose - positron emission tomography (FDG-PET). There was a significant Spearman's correlation between the clinical stage and the basic age. Degree of frontal, temporal and hippocampal atrophy were correlated with the basic age. The entire grey matter and frontal and temporal CMRglc were associated with the basic age. The illogical sentences scores were correlated with the bilateral temporal, hippocampal and the left parieto-temporal CMRglc, whereas the illogical picture scores were correlated with the right parieto-temporal CMRglc. We found that frontal and temporal atrophy as well as hypometabolism were associated with the basic age. Regarding the illogical judgment, the current PET data analysis disclosed that there may be a double dissociation between verbal/non-verbal judgments and the left/right parieto-temporal areas.

Neural correlates of different behavioral response to transcranial direct current stimulation between patients in the unresponsive wakefulness syndrome and minimally conscious state.

In this study, we used event-related potential (ERP) and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) to study the neural correlates of different behavioral response to transcranial direct current stimulation (tDCS) between patients in unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). Thirteen patients (eight in UWS and five in MCS) underwent 20 anodal tDCS sessions of the left dorsolateral prefrontal cortex (DLPFC). Before tDCS, all the patients and six age-matched healthy subjects underwent a cerebral FDG-PET scan and ERP test. The coma recovery scale-revised (CRS-R) results revealed that after tDCS, a significant improvement was observed only in the MCS group. The ERP results supported that MCS patients preserved more high-order cortical information processing capacities. The residual brain metabolism in the left DLPFC in MCS patients supported that a residual brain activity in the stimulated area was necessary for a behavioral response to tDCS. Our study also demonstrated that the cerebral metabolic rates of glucose (CMRgl) ratios in intrinsic network were correlated significantly with CRS-R in MCS patients. In addition, the right prefrontal region might be another potential therapeutic target for MCS patients.

Promise of Fully Integrated PET/MRI: Noninvasive Clinical Quantification of Cerebral Glucose Metabolism.

We describe a fully automated processing pipeline to support the noninvasive absolute quantification of the cerebral metabolic rate for glucose (CMRGlc) in a clinical setting. This pipeline takes advantage of “anatometabolic” information associated with fully integrated PET/MRI. Methods: Ten healthy volunteers (5 men and /5 women; 27 ± 7 y old; 70 ± 10 kg) underwent a test-retest 18F-FDG PET/MRI examination of the brain. The imaging protocol consisted of a 60-min PET list-mode acquisition with parallel MRI acquisitions, including 3-dimensional time-of-flight MR angiography, MRI navigators, and a T1-weighted MRI scan. State-of-the-art MRI-based attenuation correction was derived from T1-weighted MRI (pseudo-CT [pCT]). For validation purposes, a low-dose CT scan was also performed. Arterial blood samples were collected as the reference standard (arterial input function [AIF]). The developed pipeline allows the derivation of an image-derived input function (IDIF), which is subsequently used to create CMRGlc maps by means of a Patlak analysis. The pipeline also includes motion correction using the MRI navigator sequence as well as a novel partial-volume correction that accounts for background heterogeneity. Finally, CMRGlc maps are used to generate a normative database to facilitate the detection of metabolic abnormalities in future patient scans. To assess the performance of the developed pipeline, IDIFs extracted by both CT-based attenuation correction (CT-IDIF) and MRI-based attenuation correction (pCT-IDIF) were compared with the reference standard (AIF) using the absolute percentage difference between the areas under the curves as well as the absolute percentage difference in regional CMRGlc values. Results: The absolute percentage differences between the areas under the curves for CT-IDIF and pCT-IDIF were determined to be 1.4% ± 1.0% and 3.4% ± 2.6%, respectively. The absolute percentage difference in regional CMRGlc values based on CT-IDIF and pCT-IDIF differed by less than 6% from the reference values obtained from the AIF. Conclusion: By taking advantage of the capabilities of fully integrated PET/MRI, we developed a fully automated computational pipeline that allows the noninvasive determination of regional CMRGlc values in a clinical setting. This methodology might facilitate the proliferation of fully quantitative imaging into the clinical arena and, as a result, might contribute to improved diagnostic efficacy.

Association Between Reduced Brain Glucose Metabolism and Cortical Thickness in Alcoholics: Evidence of Neurotoxicity.

Excessive alcohol consumption is associated with reduced cortical thickness (CT) and lower cerebral metabolic rate of glucose (CMRGlu), but the correlation between these 2 measures has not been investigated. We tested the association between CT and cerebral CMRGlu in 19 participants with alcohol use disorder (AUD) and 20 healthy controls. Participants underwent 2-Deoxy-2-[18F]fluoroglucose positron emission tomography to map CMRGlu and magnetic resonance imaging to assess CT. Although performance accuracy on a broad range of cognitive domains did not differ significantly between AUD and HC, AUD had widespread decreases in CT and CMRGlu. CMRGlu, normalized to cerebellum (rCMRGlu), showed significant correlation with CT across participants. Although there were large group differences in CMRGlu (>17%) and CT (>6%) in medial orbitofrontal and BA 47, the superior parietal cortex showed large reductions in CMRGlu (~17%) and minimal CT differences (~2.2%). Though total lifetime alcohol (TLA) was associated with CT and rCMRGlu, the causal mediation analysis revealed significant direct effects of TLA on rCMRGlu but not on CT, and there were no significant mediation effects of TLA, CT, and rCMRGlu. The significant correlation between decrements in CT and CMRGlu across AUD participants is suggestive of alcohol-induced neurotoxicity, whereas the findings that the most metabolically affected regions in AUD had minimal atrophy and vice versa indicates that changes in CT and CMRGlu reflect distinct responses to alcohol across brain regions.

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures. ClinicalTrials.gov identifier: NCT02167256.

Plasma Neurofilament Light Chain Levels Are Associated With Cortical Hypometabolism in Alzheimer Disease Signature Regions.

Neurofilament light chain (NFL) has been recently introduced as a biomarker of early dementia. 18-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is a proxy for regional hypometabolism in Alzheimer disease (AD). Globally normalized 18F-FDG-PET values and levels of NFL and tau were obtained from 149 patients with mild cognitive impairment (MCI) from the baseline cohort of the Alzheimer's Disease Neuroimaging Initiative database. We adopted a stepwise partial correlation model using plasma NFL, plasma tau, CSF NFL, and regional cerebral metabolic rate of glucose (CMRGlc) as main variables, and age, sex, and Alzheimer's Disease Rating Scale (ADAS) as covariates. Significant regions were entered into a stepwise multiple regression analysis to investigate the independent correlation of each biomarker to baseline regional CMRGlc and its progression in patients with MCI. Higher baseline CSF NFL levels correlated with hypometabolism in bilateral precuneal and posterior cingulate cortex. After correction for age, sex, and ADAS score, plasma NFL levels correlated with hypometabolism in bilateral parahippocampal and middle temporal gyri. Cortical hypometabolism in bilateral parahippocampal gyri and right fusiform and middle temporal gyri was independently predicted by higher baseline plasma NFL levels in a multiple regression model. Plasma NFL promises to be an early biomarker of cortical hypometabolism in MCI and for MCI progression to AD.

Effects of 6-month at-home transcranial direct current stimulation on cognition and cerebral glucose metabolism in Alzheimer's disease

BackgroundAlthough single or multiple sessions of transcranial direct current stimulation (tDCS) on the prefrontal cortex over a few weeks improved cognition in patients with Alzheimer's disease (AD), effects of repeated tDCS over longer period and underlying neural correlates remain to be elucidated. ObjectiveThis study investigated changes in cognitive performances and regional cerebral metabolic rate for glucose (rCMRglc) after administration of prefrontal tDCS over 6 months in early AD patients. MethodsPatients with early AD were randomized to receive either active (n = 11) or sham tDCS (n = 7) over the dorsolateral prefrontal cortex (DLPFC) at home every day for 6 months (anode F3/cathode F4, 2 mA for 30 min). All patients underwent neuropsychological tests and brain 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) scans at baseline and 6-month follow-up. Changes in cognitive performances and rCMRglc were compared between the two groups. ResultsCompared to sham tDCS, active tDCS improved global cognition measured with Mini-Mental State Examination (p for interaction = 0.02) and language function assessed by Boston Naming Test (p for interaction = 0.04), but not delayed recall performance. In addition, active tDCS prevented decreases in executive function at a marginal level (p for interaction < 0.10). rCMRglc in the left middle/inferior temporal gyrus was preserved in the active group, but decreased in the sham group (p for interaction < 0.001). ConclusionsDaily tDCS over the DLPFC for 6 months may improve or stabilize cognition and rCMRglc in AD patients, suggesting the therapeutic potential of repeated at-home tDCS.

228-OR: Cerebral Glucose Transport and Metabolism in Obesity

Metabolic derangement triggered by a high fat diet has been associated with decreased brain glucose uptake in mice through downregulation of GLUT-1 expression at the blood-brain barrier. Likewise, a prior study by our group using 1H magnetic resonance spectroscopy (MRS) showed diminished change in brain glucose level during acute hyperglycemia in patients with obesity and diabetes. However, whether this reflected differences in absolute brain concentrations remains unknown. We utilized 13C MRS scanning at 4 Tesla to compare the rate of glucose transport (Tmax) and cerebral metabolic rate of glucose (CMRgl) in the occipital lobe during a 2-hour hyperglycemic clamp. Plasma glucose concentration of ∼180mg/dl was achieved using a variable 1-13C-glucose infusion. The study included 8 healthy lean (1M/7F, age 29 ± 5 years, BMI 21 ± 2 kg/m2, HgbA1c 5.4 ± 0.2%) and 6 obese participants (4M/2F, age 30 ± 3 years, BMI 33 ± 3 kg/m2, HgbA1c 5.5 ± 0.2%). Insulin and free fatty acids (FFA) levels were measured during the clamp. Despite nearly identical plasma glucose concentrations at steady state (lean 182.5 ± 9.0 mg/dL, obese 186.5 ± 13.5 mg/dL, P=0.55, averaged over time 60-120 minutes), the absolute brain glucose concentrations were 30% less in obese compared to lean participants (P=0.02). Moreover, using previously reported Michaelis-Menten Kt of 1.1 mM, the calculated Tmax/CMRgl at steady state were 37% less in obese participants (P=0.01), suggesting reduced glucose transport. A trend of higher insulin and FFA levels in obese participants during hyperglycemia was observed. In addition, FFA levels at steady state were negatively correlated with absolute brain glucose concentrations (r= -0.575, P=0.05). We conclude that obesity is associated with diminished absolute concentration of brain glucose during acute hyperglycemia, likely explained by reduced cerebral glucose transport capacity. These findings may have implications for understanding the impact of obesity on central regulation of feeding behavior as well as neurocognitive function. Disclosure F. Gunawan: None. L. Jiang: None. J. Leventhal: None. J.J. Pach: None. E. Sanchez Rangel: None. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitchens, Inc. A. Coppoli: None. D.L. Rothman: None. R. Sherwin: Other Relationship; Self; ICON plc., IQVIA, MannKind Corporation. G.F. Mason: None. J.J. Hwang: None. Funding American Diabetes Association (1-17-ICTS-013 to J.J.H.)

1817-P: Metabolic Surgery Affects Brain Glucose Metabolism, Cognitive Function, and Neuroplasticity in Humans

Risk of neurodegenerative disorders, cognitive dysfunction and impaired neuroplasticity (NP) is increased in obesity. We evaluated the effect of metabolic surgery (RYGB) on insulin sensitivity, brain glucose utilization, cognitive function and NP. Thirteen obese subjects (BMI 46±4.9 kg/m2; HbA1c 40.1±5.9 mmol/mol; age 42.4±9.8 years) with no history of psychiatric illness and psychoactive drug use and major brain disorders were recruited. Subjects underwent a 75 gr OGTT during a 60 min FDG dynamic brain PET study, standardized neurocognitive tests and NP by psychophysical technique at baseline and 6-months after RYGB. Plasma glucose, insulin, GLP-1, GIP, VIP, BDNF and leptin were measured during OGTT. After RYGB, BMI declined (45.7±1.6 to 34.3±1.6 kg/m2; p&amp;lt;0.001) and insulin sensitivity improved (HOMA-IR 4.7±0.9 to 1.6±0.4; P=0.006). Cerebral glucose metabolic rate (CMRg; by voxel-wise paired analysis) declined in several brain regions (p=0.005, kE&amp;gt;50). Token and Trail Making Test score change correlated with CMRg change in orbitofrontal (r=0.6, r=-0.81), parietal (r=0.64, r=-0.77), temporal (r=0.6, r=-0.78) and visual cortex (r=0.64, r=-0.75), hippocampus (r=0.6, r=-0.71) and caudate/putamen (r=0.64, r=-0.80; all p=0.03 or less), respectively. After RYGB, NP increased (0.01± 0.03 to 0.11±0.04; p=0.008) and correlated with CMRg change in orbitofrontal cortex (r=0.59; p=0.03) and hippocampus (r=0.58; p=0.03). CMRg of several cortical and subcortical areas correlated with HOMA-IR (p&amp;lt;0.001) but not with BMI. GLP-1/GIP levels increased (P&amp;lt;0.002) with no correlation with CMRg, VIP or BDNF levels. Fasting leptin decreased (73.8±45.5 to 14.3±5.9 pmol/l; p&amp;lt;0.008) and correlated with CMRg change in hippocampus (r=0.6; r=0.03). These results show that metabolic surgery modulates CMRg in brain areas involved in cognitive function and neuroplasticity, suggesting reduction of brain glucose utilization decrease may contribute to brain neuroprotection. Disclosure G. Daniele: None. A. Dardano: None. D. Volterrani: None. A. Ciccarone: None. L. Giusti: None. G. Aghakhanyan: None. G. Ceccarini: None. F. Santini: None. C. Moretto: None. P. Binda: None. C. Lunghi: None. M. Morrone: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited.