Regional Cerebral Metabolism Research Articles

Neurobiological mechanisms and therapeutic impact of electroconvulsive therapy (ECT).

Electroconvulsive therapy (ECT) is an efficient therapeutic resource for psycho-pharmacotherapeutic resistant forms of depression. ECT is a form of electrical brain stimulation involving the induction of a controlled seizure, clinically similar to an epileptic seizure, that is initiated in the prefrontal region of the brain and spreads to the cortex and subcortex, including the diencephalic structures. This is achieved by creating a transcranial electric field and synchronously depolarizing neuronal membranes. The mechanisms of action of ECT are not yet fully understood, but several hypotheses have been proposed to explain how it affects the brain: neurotransmitter changes, neuroplasticity, network connectivity, endocrine system regulation and changes in regional cerebral blood flow and regional metabolism.

Relationship Between Memory and Brain Metabolism is Markedly Disordered in non‐Demented Patients Who Have Worsening Sleep Over Time

AbstractBackgroundDisturbances in circadian rhythm often emerge during disease progression in patients with dementia. We recently reported that subjects with worsening sleep experienced significantly faster cerebral decline compared to subjects with improved sleep over comparable timeframes. Here we describe relationships between brain metabolism and memory as a function of changing sleep status.MethodA consecutive series of 2,005 cognitively normal and mildly impaired subjects from more than 50 North American sites participating in the first three phases of the Alzheimer’s Disease Neuroimaging Initiative was studied. Changes in cognition assessed through formal neuropsychological testing, and in regional cerebral metabolism assessed through brain PET using the radiotracer [F‐18]fluorodeoxyglucose (FDG), were examined. Activities in 47 standardized volumes of interest (sVOI’s), as normalized to each subject’s whole brain activity, were longitudinally measured, and significance of changes in memory were evaluated using a Pearson correlational analysis and two‐sided one‐sample t tests.ResultIn this consecutive series of 2005 subjects, 211 were documented to have had a change in insomnia status during their participation: 83 who were documented to have insomnia at baseline that was subsequently alleviated (“improving sleep”), and 128 who were documented to have no insomnia at baseline but developed it during the study period (“worsening sleep”); among them, 62 (29%) underwent FDG‐PET scans during both baseline insomnia and subsequent insomnia‐free status, or both baseline normal sleep and subsequent insomnia status periods. In subjects with improving sleep, baseline metabolism of posterior cingulate cortex, the brain region with metabolism that declines most significantly in the earliest stages of Alzheimer’s disease, was strongly associated with memory domain performance (r = 0.65, p = 0.00003). In marked contrast, this relationship was severely degraded in subjects who had worsening sleep (r = 0.20, p = 0.18). Similar relative relationships, though somewhat less statistically dramatic, were also observed with respect to global cognition, as assessed by both ADAS‐COG and MMSE scores in both groups of subjects.ConclusionSubjects with worsening sleep over time showed a highly disordered relationship between their baseline regional brain metabolism and cognitive function, and this effect was most dramatic with respect to their memory domain performance.

Regional cerebral metabolism alterations and functional connectivity in individuals with opioid use disorder: An integrated resting-state PET/fMRI study

Individuals with opioid use disorder (OUD) have been reported to show abnormal brain metabolism and impaired coupling among brain networks such as the default mode network (DMN), salience network (SN), and executive control network (ECN). However, the characteristics of brain glucose metabolism and its related functions in the brain networks in individuals with OUD remain unknown. Thirty-six individuals with OUD and thirty matched healthy controls (HCs) were recruited in this integrated positron emission tomography/magnetic resonance imaging (PET/MRI) study. Differences in glucose metabolism were analyzed by using 18F-fluorodeoxyglucose (18F-FDG), and the corresponding coupling characteristics of the individuals with OUD were also analyzed. The individuals with OUD showed widespread bilateral hypometabolism in the middle temporal gyrus (MTG), superior temporal gyrus, angular gyrus, supramarginal gyrus, inferior parietal lobe, Rolandic operculum, and left insula, but obvious hypermetabolism in the brainstem and left cerebellum. Meanwhile, in individuals with OUD, the hypometabolism of right MTG which is included in the DMN was accompanied by decreased coupling with the left superior frontal gyrus and right superior parietal gyrus which are included in the ECN. Furthermore, individuals with OUD showed a positive correlation between the duration of heroin use and glucose metabolism of the left MTG. The individuals with OUD were characterized by widespread bilateral hypometabolism in the temporal and parietal regions but obvious hypermetabolism in the brainstem and left cerebellum. The results suggest that the hypometabolism in the temporal and parietal regions might be related to DMN dysfunction and the hypermetabolism in the brainstem and left cerebellum may be compensate for other brain regions showing hypometabolism. In particular, hypometabolism in the self-referential-related DMN regions in OUD might attenuate their relationships with the inhibitory-control-related ECN regions. These findings highlight the importance of evaluating the metabolic and functional profiles of the right MTG in future studies on the treatment of OUD.

Abstract 150: Arterial Calcification and Neural Metabolic Activity: Assessing Neurovascular Status Through FDG and NaF PET/CT Imaging

Introduction Atherosclerosis, the occlusion of arteries due to the accumulation of fatty substances, cholesterol, calcium, and fibrin in the arterial walls, can result in reduced blood flow and a subsequent decrease in oxygen delivery to the organs supplied by the affected artery, including the brain. Positron emission tomography‐computed tomography (PET‐CT) utilizing 18F‐fluorodeoxyglucose (FDG) and 18F‐Sodium Fluoride (NaF) have demonstrated efficacy in the assessment of cerebral glucose metabolism and atherosclerotic calcification, respectively. However, the reported literature has not clearly correlated arterial disease throughout the body with cerebral hypometabolism. Utilizing a novel integration of FDG and NaF PET/CT imaging, our study explores the link between cardiovascular risk factors and regional cerebral metabolism. Methods We compared 79 healthy controls (mean age 44.5 ± 13.8 years, 53.2% males) and 40 individuals (mean age 55.9 ± 11.9 years, 50% males) at increased risk for cardiovascular disease (CVD) as assessed by the systematic coronary risk evaluation (SCORE) tool. All subjects underwent whole‐body FDG‐PET/CT imaging. [18F]fluoride PET/CT imaging was performed using hybrid PET/CT scanners with image correction and reconstruction processes following standard protocols. The quantitative regional analysis of PET images was performed using MIMneuro version 7.1.5 (MIM Software, Inc., Cleveland, Ohio). 70 whole brain structures were analyzed in each subject. MIMneuro provided region‐based analysis, with z‐scores generated by comparing the patient to the selected age‐matched set of normal controls. Using OsiriX MD software, [18F]fluoride PET/CT scans were analyzed with regions of interest (ROIs) manually drawn to assess carotid calcification and standardized uptake value mean (SUVmean), along with ROI volume values. Correlations between the degree of molecular calcification and cerebral FDG uptake in patients with cardiovascular risk factors were evaluated using Pearson’s R, with the significance threshold set at P < 0.05. Results Unhealthy patients demonstrated significant negative correlations between increased calcification in the carotid arteries, as assessed by NaF‐PET, and metabolic activity in the anterior cingulate (r = ‐0.42, p = 0.008) and cingulate regions (r = ‐0.34, p = 0.036). Conversely, healthy patients exhibited significant positive correlations in the pons (r = 0.25, p = 0.042) and pontine tegmentum (r = 0.34, p = 0.005), suggestive of a compensatory mechanism to maintain autonomic and motor functions. Conclusion The present study provides insight regarding the interplay between arterial calcification and neural metabolic activity, particularly as it pertains to regions supplied by the anterior cerebral artery. Our investigation suggests that calcification in the carotid arteries, which give rise to the ACA, has a deleterious impact on the function of the cingulate gyrus. Additionally, the observed positive correlation in the pons and pontine tegmentum in healthy individuals raises intriguing questions regarding potential compensatory mechanisms that may help maintain autonomic and motor functions despite vascular impediments. Understanding the temporal progression of vascular calcification allows for the optimization of surgical strategy and timing, potentially reducing stroke risk and improving patient outcomes. These findings underscore the necessity of persistent surveillance and targeted management strategies concerning carotid calcification.

A - 59 Regional Cerebral Metabolism Is Associated with Performance on the Visual Object and Space Perception Battery in those with Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) is a relatively rare clinical syndrome characterized by visuoperceptual/spatial dysfunction with relatively preserved memory, language, and insight in the early stages. Thus, PCA provides a unique population through which to evaluate structure-function relationships for commonly used neuropsychological tests. Here, we evaluated relationships between fluorodeoxyglucose (FDG) positron emission tomography (PET) and performance on the Visual Object and Space Perception (VOSP) Battery. Ten participants with an established diagnosis of PCA underwent baseline neuropsychological testing that included the VOSP, FDG-PET, and structural MRI. We used FreeSurfer to identify anatomical structures in the structural MRI scans, aligned the MRI and PET scans, and then extracted FDG signal from these same regions. Several brain regions relevant for PCA were a priori targeted. We evaluated relationships between the regional FDG values and VOSP performances using Spearman's rank correlation. Silhouettes, Dot Counting, and Number Location showed strong relationships with the superior parietal lobule bilaterally. The right superior parietal lobule showed moderate to strong relationships with Incomplete Letters and Progressive Silhouettes, whereas the left superior parietal lobule showed a strong relationship with Object Decision. Incomplete letters showed a strong relationship with the right supramarginal gyrus. Silhouettes showed a strong relationship with the left fusiform gyrus. These findings from a relatively rare and heterogeneous syndrome provide insight into the regional contributions to visuospatial functioning. Future work will evaluate network-level integrity with these tasks in order to further clarify structure-function relationships.

Evaluation of whole-brain oxygen metabolism in Alzheimer's disease using QSM and quantitative BOLD

ObjectiveThe objective of this study was to evaluate the whole-brain pattern of oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2) perturbation in Alzheimer's disease (AD) and investigate the relationship between regional cerebral oxygen metabolism and global cognition. MethodsTwenty-six AD patients and 25 age-matched healthy controls (HC) were prospectively recruited in this study. Mini-Mental State Examination (MMSE) was used to evaluate cognitive status. We applied the QQ-CCTV algorithm which combines quantitative susceptibility mapping and quantitative blood oxygen level-dependent models (QQ) for OEF calculation. CBF map was computed from arterial spin labeling and CMRO2 was generated based on Fick's principle. Whole-brain and regional OEF, CBF, and CMRO2 analyses were performed. The associations between these measures in substructures of deep brain gray matter and MMSE scores were assessed. ResultsWhole brain voxel-wise analysis showed that CBF and CMRO2 values significantly decreased in AD predominantly in the bilateral angular gyrus, precuneus gyrus and parieto-temporal regions. Regional analysis showed that CBF value decreased in the bilateral caudal hippocampus and left rostral hippocampus and CMRO2 value decreased in left caudal and rostral hippocampus in AD patients. Considering all subjects in the AD and HC groups combined, the mean CBF and CMRO2 values in the bilateral hippocampus positively correlated with the MMSE score. ConclusionCMRO2 mapping with the QQ-CCTV method - which is readily available in MR systems for clinical practice - can be a potential biomarker for AD. In addition, CMRO2 in the hippocampus may be a useful tool for monitoring cognitive impairment.

Lipophilic Statins in Subjects with early Mild Cognitive Impairment and Low Serum Cholesterol: Association with Long‐Term Cerebral Metabolic and Cognitive Decline in a Prospective Longitudinal Multi‐Center Study

AbstractBackgroundWe recently reported that lipophilic statins, known to penetrate the blood‐brain barrier, were associated with accelerated decline in regional cerebral metabolism in subjects with early Mild Cognitive Impairment (eMCI) who had relatively low serum cholesterol levels (J Nucl Med. 2021;62:Suppl 1). In this study, we expand upon our past results by studying the relationship between metabolic decline in lipophilic statin users and their decline in neuropsychological test scores.MethodsSubjects with eMCI were drawn from a consecutive series enrolled in the Alzheimer's Disease Neuroimaging Initiative, identifying 70 having serum cholesterol levels below the 206 mg/dl median of non‐statin users and with clear histories of time‐frames of prescriptions and types of statins used – 41 taking lipophilic statins throughout the 2‐year follow‐up period (LS), and 29 demographically similar non‐statin users (nonS). FDG‐PET scans acquired at baseline and 2 years later were compared for each group, and standardized Volume of Interest (sVOI) methods were used to calculate rates of regional metabolic decline. Correlations between changes in regional metabolism and changes in neuropsychological test scores were assessed by linear regression.ResultsThe strongest association occurred between declining metabolism in the left parietotemporal cortex (PTC) and declining function, as indexed by the Functional Activities Questionnaire (FAQ), which was highly significant among LS users (p=0.0004), but not among nonS subjects (p=0.56). Decline of left PTC was also a significant correlate of decline in LS memory performance (p= 0.001), but not nonS (p = 0.11). Both the left posterior cingulate and right PTC declines correlated with LS MMSE decline (p = 0.01 for both), while that metabolic decline was again uncorrelated for nonS subjects.ConclusionSubjects with eMCI with low serum cholesterol levels , who nevertheless were persistently prescribed lipophilic statins over two years, underwent accelerated metabolic decline in the brain regions most significantly hypometabolic in patients with Alzheimer's disease that was in turn significantly correlated with decline in key measures of both function and cognition, in a manner specific to statin use.

General Anesthesia and Cerebral Function: Changes in Cognition and Regional Brain Metabolism in Patients following Surgery

AbstractBackgroundImproved understanding of relationships between general anesthesia and subsequent cognitive decline is critically needed. In this study, previously healthy and mildly impaired subjects were compared pre‐ and post‐surgery, with respect to longitudinal assessments of their neuropsychologic performance and regional brain metabolism.MethodWe screened records of 1,450 Alzheimer’s Disease Neuroimaging Initiative subjects to identify all those undergoing non‐cancer surgeries involving general anesthesia with a minimum of two pre‐surgical and two post‐surgical ADNI visits, yielding neuropsychological data for this analysis acquired during 256 visits by 64 subjects – 32 surgical patients meeting the above criteria, and 32 controls who were demographically matched but with no reported surgeries during enrollment. Cognitive domain scores were correlated with rates of decline in regional cerebral metabolism based on interval changes in pairs of FDG‐PET scans acquired pre‐ and post‐surgery; analogous calculations were performed in the non‐surgical group by setting “surgery” dates according to median elapsed time from first visit to surgery in the surgical group. Imaging data were quantitatively examined by both standardized volume of interest (sVOI) and statistical parametric mapping (spm) methods of analysis.ResultsVOIs included bilaterally 6 frontal, 5 temporal, 4 parietal, 2 occipital, and sensorimotor cerebral cortical volumes, as well as 7 noncortical volumes. Compared to the non‐surgical group, the surgical group showed greater post‐surgical decline in the two anterior temporal volumes measured (p=0.01), both medially (including the hippocampus and adjacent cortex) and laterally. Within the surgery group, comparing pre‐ versus post‐ timeframes also identified most significant accelerated decline in the two anterior temporal volumes. The spm analyses corroborated significant acceleration of metabolic decline postsurgically in temporal cortex, predominantly in the right hemisphere, with cluster size significant after statistical adjustment for multiple comparisons (P<0.0005, Pcorr = 0.047). Finally, pre‐ and post‐surgical differences in rates of temporal metabolic decline correlated with differences in executive function decline within the surgical group (r=0.785).ConclusionMajor surgeries involving general anesthesia were associated with significantly accelerated decline in temporal metabolism postsurgically. This in turn was correlated with greater acceleration of decline in cognitive function of surgical patients.

Reduction in cerebral oxygen metabolism in subcortical regions may be a biomarker of cognitive decline in people living with human immunodeficiency virus.

Regional cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2 ) in whole brain, white matter, gray matter and lenticular nuclei were studied in people living with human immunodeficiency virus (PLHIV) as well as HIV-associated neurocognitive disorder (HAND). Treatment-naïve PLHIV underwent neurocognitive assessment and magnetic resonance (MR) measurement of rCBF and rCMRO2 with repeat after 12months of antiretroviral therapy (ART). Age- and sex-matched controls underwent single MR measurements. Regional CBF and rCMRO2 were compared amongst symptomatic, asymptomatic, normal HAND and controls using analysis of variance. Longitudinal analysis of HAND worsening (≥1 category) was assessed after 12 months of ART and correlated with rCBF and rCMRO2 measured by MR imaging using the paired-sample t test. Thirty PLHIV completed baseline and 12-month assessments (29 with rCMRO2 measurement). At baseline HAND assessment, 13% had no cognitive impairment, 27% had asymptomatic neurocognitive impairment, 60% had mild neurocognitive disorder and none had HIV-associated dementia. At 12months, 13% had no cognitive impairment, 20% had asymptomatic neurocognitive impairment, 50% had mild neurocognitive disorder and 17% had HIV-associated dementia. In those without HAND worsening (N=21) rCMRO2 remained stable and in those with HAND worsening (N=8) rCMRO2 measurement declined from baseline to 12 months in white matter (2.05±0.40 to 1.73±0.51, p=0.03) and lenticular nuclei (4.32±0.39 to 4.00±0.51, p=0.05). In recently diagnosed PLHIV, no association was found between rCBF or rCMRO2 and cognitive impairment at baseline. There was a reduction in rCMRO2 in those with worsening of cognitive function at 12months on ART. Reduction in rCMRO2 may be a biomarker of cognitive decline in PLHIV.

Risk of falling in mild cognitive impairment: Relationships with diminishing regional cerebral metabolism and clinical parameters in a long‐term prospective longitudinal multi‐center study

AbstractBackgroundWe recently identified visual cortex and cerebellar vermis as the cortical and non‐cortical brain areas, respectively, in which declining metabolism was most predictive of falling (Soc. Nucl. Med. Molec. Imaging, 2021.) We now describe alterations in relationships between rates of change in their metabolism, and cognitive/functional performance.MethodOf 226 FDG‐PET brain scans from 113 Alzheimer’s Disease Neuroimaging Initiative MCI subjects analyzed, 122 were from subjects (MCI‐F ,n=61) suffering a fall subsequent to baseline PET, while 104 were from age‐matched subjects (MCI‐N, n=52) having no documented falls. MCI‐F scans were taken from baseline and last time point preceding date of first fall; MCI‐N scans were taken from baseline and last time point available. Magnitudes of regional metabolism in standardized volumes of interest (sVOI’s) were normalized to metabolism of each subject’s pons. Rates of longitudinal change were calculated as the interval difference in magnitudes between each sVOI pair divided by interval time. Significance of associations between metabolic changes and changes in overall cognition (MMSE), function (FAQ) and four individual domain scores were assessed following Bonferroni‐type statistical correction for multiple comparisons.ResultIn the vermis of MCI‐N subjects, changes in metabolism correlated with changes in overall cognition and function (p=0.00007, p=0.00003, respectively); among individual cognitive domains, metabolic changes most significantly correlated with changes in visuospatial (p=0.005) and language (p=0.001) scores. Interestingly, among MCI‐F subjects, vermis metabolism declined severalfold faster than in their MCI‐N counterparts, while significant associations with changes in MMSE and FAQ (both p>0.30) as well as with visuospatial changes (p>0.99) were entirely lost, yet language changes remained strongly correlated (p=0.00004). Similarly, in bilateral visual cortex of MCI‐N, changes in metabolism correlated with changes in MMSE and memory, and those associations were lost in MCI‐F.ConclusionMetabolism of cerebellar vermis ‐ critical for maintenance of upright posture and locomotion ‐ and of visual cortex ‐ known to diminish in patients with Lewy body involvement (associated with orthostatic hypotension and gait disturbance, both in turn increasing fall risk) ‐ not only underwent accelerated decline, but metabolic decline also became dissociated from cognitive and functional performance in MCI‐F, prior to their first documented fall.

Adrenaline improves regional cerebral blood flow, cerebral oxygenation and cerebral metabolism during CPR in a porcine cardiac arrest model using low-flow extracorporeal support

BackgroundThe effects of adrenaline on cerebral blood vessels during cardiopulmonary resuscitation (CPR) are not well understood. We developed an extracorporeal CPR model that maintains constant low systemic blood flow while allowing adrenaline-associated effects on cerebral vasculature to be assessed at different mean arterial pressure (MAP) levels independently of the effects on systemic blood flow. MethodsAfter eight minutes of cardiac arrest, low-flow extracorporeal life support (ECLS) (30 ml/kg/min) was started in fourteen pigs. After ten minutes, continuous adrenaline administration was started to achieve MAP values of 40 (n = 7) or 60 mmHg (n = 7). Measurements included intracranial pressure (ICP), cerebral perfusion pressure (CePP), laser-Doppler-derived regional cerebral blood flow (CBF), cerebral regional oxygen saturation (rSO2), brain tissue oxygen tension (PbtO2) and extracellular cerebral metabolites assessed by cerebral microdialysis. ResultsDuring ECLS without adrenaline, regional CBF increased by only 5% (25th to 75th percentile: −3 to 14; p = 0.2642) and PbtO2 by 6% (0–15; p = 0.0073) despite a significant increase in MAP to 28 mmHg (25–30; p < 0.0001) and CePP to 10 mmHg (8–13; p < 0.0001). Accordingly, cerebral microdialysis parameters showed a profound hypoxic-ischemic pattern. Adrenaline administration significantly improved regional CBF to 29 ± 14% (p = 0.0098) and 61 ± 25% (p < 0.001) and PbtO2 to 15 ± 11% and 130 ± 82% (both p < 0.001) of baseline in the MAP 40 mmHg and MAP 60 mmHg groups, respectively. Importantly, MAP of 60 mmHg was associated with metabolic improvement. ConclusionThis study shows that adrenaline administration during constant low systemic blood flow increases CePP, regional CBF, cerebral oxygenation and cerebral metabolism.

Identification of metabolic kinetic patterns in different brain regions using metabolomics methods coupled with various discriminant approaches

Metabolomics is widely used as a powerful technique for identifying metabolic patterns and functions of organs and biological systems. Normally, there are multiple groups/targets involved in data processed by discriminant analysis. This is more common in cerebral studies, as there are always several brain regions involved in neuronal studies or brain metabolic dysfunctions. Furthermore, neuronal activity is highly correlated with cerebral energy metabolism, such as oxidation of glucose, especially for glutamatergic (excitatory) and GABAergic (inhibitory) neuronal activities. Thus, regional cerebral energy metabolism recognition is essential for understanding brain functions. In the current study, ten different brain regions were considered for discrimination analysis. The metabolic kinetics were investigated with 13C enrichments in metabolic products of glucose and measured using the nuclear magnetic spectroscopic method. Multiple discriminative methods were used to construct classification models in order to screen out the best method. After comparing all the applied discriminatory analysis methods, the boost-decision tree method was found to be the best method for classification and every cerebral region exhibited its own metabolic pattern. Finally, the differences in metabolic kinetics among these brain regions were analyzed. We, therefore, concluded that the current technology could also be utilized in other multi-class metabolomics studies and special metabolic kinetic patterns could provide useful information for brain function studies.

Glucose-level dependent brain hypometabolism in type 2 diabetes mellitus and obesity

BackgroundMetabolic syndrome and its individual components lead to wide-ranging consequences, many of which affect the central nervous system. In this study, we compared the [18F]FDG regional brain metabolic pattern of participants with type 2 diabetes mellitus (T2DM) and non-DM obese individuals.MethodsIn our prospective study, 51 patients with controlled T2DM (ages 50.6 ± 8.0 years) and 45 non-DM obese participants (ages 52.0 ± 9.6 years) were enrolled. Glucose levels measured before PET/CT examination (pre-PET glucose) as well as laboratory parameters assessing glucose and lipid status were determined. NeuroQ application (NeuroQTM 3.6, Syntermed, Philips) was used to evaluate regional brain metabolic differences. [18F]FDG PET/CT (AnyScan PC, Mediso) scans, estimating brain metabolism, were transformed to MNI152 brain map after T1 registration and used for SPM-based group comparison of brain metabolism corrected for pre-PET glucose, and correlation analysis with laboratory parameters.ResultsNeuroQ analysis did not reveal significant regional metabolic defects in either group. Voxel-based group comparison revealed significantly (PFWE<0.05) decreased metabolism in the region of the precuneus and in the right superior frontal gyrus (rSFG) in the diabetic group as compared to the obese patients. Data analysis corrected for pre-PET glucose level showed a hypometabolic difference only in the rSFG in T2DM. Voxel-based correlation analysis showed significant negative correlation of the metabolism in the following brain regions with pre-PET glucose in diabetes: precuneus, left posterior orbital gyrus, right calcarine cortex and right orbital part of inferior frontal gyrus; whilst in the obese group only the right rolandic (pericentral) operculum proved to be sensitive to pre-PET glucose level.ConclusionsTo our knowledge, this is the first study to perform pre-PET glucose level corrected comparative analysis of brain metabolism in T2DM and obesity. We also examined the pre-PET glucose level dependency of regional cerebral metabolism in the two groups separately. Large-scale future studies are warranted to perform further correlation analysis with the aim of determining the effects of metabolic disturbances on brain metabolism.

FDG-PET Profiles of Extratemporal Metabolism as a Predictor of Surgical Failure in Temporal Lobe Epilepsy.

Objective: Metabolic abnormality in the extratemporal area on fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is not an uncommon finding in drug-resistant temporal lobe epilepsy (TLE), however the correlation between extratemporal metabolic abnormalities and surgical long-term prognosis has not been fully elucidated. We aim to investigate FDG-PET extratemporal metabolic profiles predictive of failure in surgery for TLE patients.Methods: Eighty-two patients with unilateral TLE (48 female, 34 male; 25.6 ± 10.6 years old; 37 left TLE, 45 right TLE) and 30 healthy age-matched controls were enrolled. Patients were classified either as experiencing seizure-recurrence (SZR, Engel class II through IV) or seizure-free (SZF, Engel class I) at least 1 year after surgery. Regional cerebral metabolism was evaluated by FDG-PET with statistical parametric mapping (SPM12). Abnormal metabolic profiles and patterns on FDG-PET in SZR group were evaluated and compared with those of healthy control and SZF subjects on SPM12. Volume and intensity as well as special brain areas of abnormal metabolism in temporal and extratemporal regions were quantified and visualized.Results: With a median follow-up of 1.5 years, 60% of patients achieved Engel class I (SZF). SZR was associated with left TLE and widespread hypometabolism in FDG-PET visual assessment (both p < 0.05). All patients had hypometabolism in the ipsilateral temporal lobe but SZR was not correlated with volume or intensity of temporal hypometabolism (median, 1,456 vs. 1,040 mm3; p > 0.05). SZR was correlated with extratemporal metabolic abnormalities that differed according to lateralization: in right TLE, SZR exhibited larger volume in extratemporal areas compared to SZF (median, 11,060 vs. 2,112 mm3; p < 0.05). Surgical failure was characterized by Cingulum_Ant_R/L, Frontal_Inf_Orb_R abnormal metabolism in extratemporal regions. In left TLE, SZR presented a larger involvement of extratemporal areas similar to right TLE but with no significant (median, 5,873 vs. 3,464 mm3; p > 0.05), Cingulum_Ant_ R/L, Parietal_Inf_L, Postcentral_L, and Precuneus_R involved metabolic abnormalities were correlated with SZR.Conclusions: Extratemporal metabolic profiles detected by FDG-PET may indicate a prominent cause of TLE surgery failure and should be considered in predictive models for epilepsy surgery. Seizure control after surgery might be improved by investigating extratemporal areas as candidates for resection or neuromodulation.

Arterial spin-labelling and magnetic resonance spectroscopy as imaging biomarkers for detection of epileptogenic zone in non-lesional focal impaired awareness epilepsy

BackgroundThe proper identification of an epileptic focus is a pivotal diagnostic issue; particularly in non-lesional focal impaired awareness epilepsy (FIAE). Seizures are usually accompanied by alterations of regional cerebral blood flow (rCBF) and metabolism. Arterial spin labeling-MRI (ASL-MRI) and proton magnetic resonance spectroscopy (1H-MRS) are MRI techniques that can, non-invasively, define the regions of cerebral perfusion and metabolic changes, respectively. The aim of the current study was to recognize the epileptogenic zone in patients with non-lesional FIAE by evaluating the interictal changes in rCBF and cerebral metabolic alterations, using PASL-MRI and 1H-MRS.ResultsFor identification of the epileptogenic zone, increased ASLAI% assessed by PASL-MRI (at a cut-off value ≥ 5.96%) showed 95.78% accuracy, and increased %AF (at a cut-off value ≥ 9.98%) showed 98.14% accuracy, while decreased NAA/(Cho + Cr) ratio estimated by multi-voxels (MV) 1H-MRS (at a cut-off value ≥ 0.59) showed 97.74% accuracy. Moreover, the combined use of PASL-MRI and MV 1H-MRS yielded 100% sensitivity, 98.45% specificity and 98.86% accuracy.ConclusionThe combined use of PASL-MRI and MV 1H-MRS can be considered as in-vivo proficient bio-marker for proper identification of epileptogenic zone in patients with non-lesional FIAE.

Discovery and validation of temporal patterns involved in human brain ketometabolism in cerebral microdialysis fluids of traumatic brain injury patients

BackgroundTraumatic brain injury (TBI) is recognized as a metabolic disease, characterized by acute cerebral glucose hypo-metabolism. Adaptive metabolic responses to TBI involve the utilization of alternative energy substrates, such as ketone bodies. Cerebral microdialysis (CMD) has evolved as an accurate technique allowing continuous sampling of brain extracellular fluid and assessment of regional cerebral metabolism. We present the successful application of a combined hypothesis- and data-driven metabolomics approach using repeated CMD sampling obtained routinely at patient bedside. Investigating two patient cohorts (n = 26 and n = 12), we identified clinically relevant metabolic patterns at the acute post-TBI critical care phase. MethodsClinical and CMD metabolomics data were integrated and analysed using in silico and data modelling approaches. We used both unsupervised and supervised multivariate analysis techniques to investigate structures within the time series and associations with patient outcome. FindingsThe multivariate metabolite time series exhibited two characteristic brain metabolic states that were attributed to changes in key metabolites: valine, 4-methyl-2-oxovaleric acid (4-MOV), isobeta-hydroxybutyrate (iso-bHB), tyrosyine, and 2-ketoisovaleric acid (2-KIV). These identified cerebral metabolic states differed significantly with respect to standard clinical values. We validated our findings in a second cohort using a classification model trained on the cerebral metabolic states. We demonstrated that short-term (therapeutic intensity level (TIL)) and mid-term patient outcome (6-month Glasgow Outcome Score (GOS)) can be predicted from the time series characteristics. InterpretationWe identified two specific cerebral metabolic patterns that are closely linked to ketometabolism and were associated with both TIL and GOS. Our findings support the view that advanced metabolomics approaches combined with CMD may be applied in real-time to predict short-term treatment intensity and long-term patient outcome.

Quantitative measurement of regional cerebral blood flow and oxygen metabolism in a rat model of cerebral hypoperfusion

This study was aimed at evaluating the regional changes in the cerebral metabolic rate of oxygen (CMRO2) in relation to the cerebral blood flow (CBF) in the bilateral common carotid artery occlusion (BCAO) rat model.Ligation of the bilateral common carotid arteries (or a sham operation in control animals) was performed in 10-week-old male Wistar rats. O-15 PET images were acquired in the subacute phase (1 week after the surgery) and chronic phase (6 weeks after the surgery) with the animals under anesthesia, using a small-animal PET system and the O-15 gas steady-state inhalation method with arterial blood sampling developed in our previous study. Histopathological staining by Klüver-Barrera method and immunocytochemistry staining by glial fibrillary acidic protein were performed. Cognitive function was tested by using the apparatus of Y-maze.Significantly lower CBF and higher oxygen extraction fraction were observed in broad areas of the cerebrum in the subacute phase in the BCAO rats, with recovery in the chronic phase. A stable decrease of the CMRO2 in the subacute phase of arterial occlusion and later was observed in the BCAO rat model, mainly in the anterior cerebral artery territory. Atrophy and rarefaction of corpus callosum were found in the BCAO in the chronic phase. Activity of astrocytes in the BCAO was prominent in the both phases. Working memory was impaired in the BCAO in the chronic phase.Regional changes in cerebral perfusion and oxygen metabolism in the subacute and chronic phases of arterial occlusion were clarified in a rat model of BCAO by quantitative O-15 PET based on the steady-state method.

Efficacy of Cilostazol Administration in Alzheimer's Disease Patients with White Matter Lesions: A Positron-Emission Tomography Study.

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer's disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose (18F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer's disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p < 0.005). Mean changes from baseline on the Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and the Clinical Dementia Rating Sum of Boxes did not differ between the two groups. In the cilostazol group, the increase of glucose metabolism correlated with the improvment of the Alzheimer's Disease Assessment Scale-cognitive score. We conclude that cilostazol treatment added to donepezil may delay the decline in regional cerebral metabolism in Alzheimer's disease with white matter lesions compared with donepezil monotherapy. In additon, our results verified the efficacy of cilostazol in improving or protecting cognitive function in Alzheimer's disease through increased glucose metabolism. However, the long-term effect of cilostazol on cognitive function and Alzheimer's disease modification must be tested in further studies with larger sample size and longer study period. Trial registration: http://clinicaltrials.gov : NCT01409564.

Relative cerebral flow from dynamic PIB scans as an alternative for FDG scans in Alzheimer's disease PET studies.

In Alzheimer’s Disease (AD) dual-tracer positron emission tomography (PET) studies with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and 11C-labelled Pittsburgh Compound B (PIB) are used to assess metabolism and cerebral amyloid-β deposition, respectively. Regional cerebral metabolism and blood flow (rCBF) are closely coupled, both providing an index for neuronal function. The present study compared PIB-derived rCBF, estimated by the ratio of tracer influx in target regions relative to reference region (R1) and early-stage PIB uptake (ePIB), to FDG scans. Fifteen PIB positive (+) patients and fifteen PIB negative (-) subjects underwent both FDG and PIB PET scans to assess the use of R1 and ePIB as a surrogate for FDG. First, subjects were classified based on visual inspection of the PIB PET images. Then, discriminative performance (PIB+ versus PIB-) of rCBF methods were compared to normalized regional FDG uptake. Strong positive correlations were found between analyses, suggesting that PIB-derived rCBF provides information that is closely related to what can be seen on FDG scans. Yet group related differences between method’s distributions were seen as well. Also, a better correlation with FDG was found for R1 than for ePIB. Further studies are needed to validate the use of R1 as an alternative for FDG studies in clinical applications.

Cortical thickness, brain metabolic activity, and in vivo amyloid deposition in asymptomatic, middle-aged offspring of patients with late-onset Alzheimer's disease

The natural history of preclinical late-onset Alzheimer's disease (LOAD) remains obscure and has received less attention than that of early-onset AD (EOAD), in spite of accounting for more than 99% of cases of AD. With the purpose of detecting early structural and functional traits associated with the disorder, we sought to characterize cortical thickness and subcortical grey matter volume, cerebral metabolism, and amyloid deposition in persons at risk for LOAD in comparison with a similar group without family history of AD. We obtained 3T T1 images for gray matter volume, FDG-PET to evaluate regional cerebral metabolism, and PET-PiB to detect fibrillar amyloid deposition in 30 middle-aged, asymptomatic, cognitively normal individuals with one parent diagnosed with LOAD (O-LOAD), and 25 comparable controls (CS) without family history of neurodegenerative disorders (CS). We observed isocortical thinning in AD-relevant areas including posterior cingulate, precuneus, and areas of the prefrontal and temporoparietal cortex in O-LOAD. Unexpectedly, this group displayed increased cerebral metabolism, in some cases overlapping with the areas of cortical thinning, and no differences in bilateral hippocampal volume and hippocampal metabolism. Given the importance of age in this sample of individuals potentially developing early AD-related changes, we controlled results for age and observed that most differences in cortical thickness and metabolism became nonsignificant; however, greater deposition of β-amyloid was observed in the right hemisphere including temporoparietal cortex, postcentral gyrus, fusiform inferior and middle temporal and lingual gyri. If replicated, the present observations of morphological, metabolic, and amyloid changes in cognitively normal persons with family history of LOAD may bear important implications for the definition of very early phenotypes of this disorder.