Decline In Glucose Metabolism Research Articles

Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.

Several studies demonstrated that mitochondrial dynamics and metabolic pathways control T cell fate in the periphery. However, little is known about their implication in thymocyte development. Our results showed that thymic progenitors (CD3-CD4-CD8- triple negative, TN), in active division, have essentially a fused mitochondrial morphology and rely on high glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). As TN cells differentiate to double positive (DP, CD4+CD8+) and single positive (SP, CD4+ and CD8+) stages, they became more quiescent, their mitochondria fragment and they downregulate glycolysis and OXPHOS. Accordingly, in vitro inhibition of the mitochondrial fission during progenitor differentiation on OP9-DL4 stroma, affected the TN to DP thymocyte transition by enhancing the percentage of TN and reducing that of DP, leading to a decrease in the total number of thymic cells including SP T cells. We demonstrated that the stage 3 triple negative pre-T (TN3) and the stage 4 triple negative pre-T (TN4) have different metabolic and functional behaviors. While their mitochondrial morphologies are both essentially fused, the LC-MS based analysis of their metabolome showed that they are distinct: TN3 rely more on OXPHOS whereas TN4 are more glycolytic. In line with this, TN4 display an increased Hexokinase II expression in comparison to TN3, associated with high proliferation and glycolysis. The in vivo inhibition of glycolysis using 2-deoxyglucose (2-DG) and the absence of IL-7 signaling, led to a decline in glucose metabolism and mitochondrial membrane potential. In addition, the glucose/IL-7R connection affects the TN3 to TN4 transition (also called β-selection transition), by enhancing the percentage of TN3, leading to a decrease in the total number of thymocytes. Thus, we identified additional components, essential during β-selection transition and playing a major role in thymic development.

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

Age- and Sex-Associated Glucose Metabolism Decline in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by a high etiological and clinical heterogeneity, which has obscured the diagnostic and treatment efficacy, as well as limited the development of potential drugs. Sex differences are among the risk factors that contribute to the variability of disease manifestation. Unlike men, women are at greater risk of developing AD and suffer from higher cognitive deterioration, together with important changes in pathological features. Alterations in glucose metabolism are emerging as a key player in the pathogenesis of AD, which appear even decades before the presence of clinical symptoms. We aimed to study whether AD-related sex differences influence glucose metabolism. We used male and female APPswe/PS1dE9 (APP/PS1) transgenic mice of different ages to examine glucose metabolism effects on AD development. Our analysis suggests an age-dependent decline of metabolic responses, cognitive functions, and brain energy homeostasis, together with an increase of Aβ levels in both males and females APP/PS1 mice. The administration of Andrographolide (Andro), an anti-inflammatory and anti-diabetic compound, was able to restore several metabolic disturbances, including the glycolytic and the pentose phosphate pathway fluxes, ATP levels, AMPKα activity, and Glut3 expression in 8-month-old mice, independent of the sex, while rescuing these abnormalities only in older females. Similarly, Andro also prevented Aβ accumulation and cognitive decline in all but old males. Our study provides insight into the heterogeneity of the disease and supports the use of Andro as a potential drug to promote personalized medicine in AD.

Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice.

Alzheimer's disease (AD) is an insidious neurodegenerative disorder representing a serious continuously escalating medico-social problem. The AD-associated progressive dementia is followed by gradual formation of amyloid plaques and neurofibrillary tangles in the brain. Though, converging evidence indicates apparent metabolic dysfunctions as key AD characteristic. In particular, late-onset AD possesses a clear metabolic signature. Considerable brain insulin signaling impairment and a decline in glucose metabolism are common AD attributes. Thus, positron emission tomography (PET) with glucose tracers is a reliable non-invasive tool for early AD diagnosis and treatment efficacy monitoring. Various approaches and agents have been trialed to modulate insulin signaling. Accumulating data point to arginase inhibition as a promising direction to treat AD via diverse molecular mechanisms involving, inter alia, the insulin pathway. Here, we use a transgenic AD mouse model, demonstrating age-dependent brain insulin signaling abnormalities, reduced brain insulin receptor levels, and substantial energy metabolism alterations, to evaluate the effects of arginase inhibition with Norvaline on glucose metabolism. We utilize fluorodeoxyglucose whole-body micro-PET to reveal a significant treatment-associated increase in glucose uptake by the brain tissue in-vivo. Additionally, we apply advanced molecular biology and bioinformatics methods to explore the mechanisms underlying the effects of Norvaline on glucose metabolism. We demonstrate that treatment-associated improvement in glucose utilization is followed by significantly elevated levels of insulin receptor and glucose transporter-3 expression in the mice hippocampi. Additionally, Norvaline diminishes the rate of Tau protein phosphorylation. Our results suggest that Norvaline interferes with AD pathogenesis. These findings open new avenues for clinical evaluation and innovative drug development.

Clinical significance of visually equivocal amyloid PET findings from the Alzheimer's Disease Neuroimaging Initiative cohort.

To evaluate the clinical and imaging characteristics of patients with visually equivocal amyloid PET images, patients from the Alzheimer's Disease Neuroimaging Initiative cohort who had fluorine-18-florbetapir PET scans both at baseline and 24 months were selected. Five nuclear medicine physicians visually assessed the PET images and classified them as either positive or negative. Images not reaching a majority agreement were classified as equivocal. Among a total of 379 patients, the number of patients in each fluorine-18-florbetapir PET negative/equivocal/positive categories was 218 (57.5%), 32 (8.4%), and 129 (34.0%). Eight to 9% of patients with normal cognition (N=12/141), mild cognitive impairment (N=20/214), and no Alzheimer's disease (N=0/24) showed equivocal PET finding for each. In negative/equivocal/positive groups, positive cerebrospinal fluid Aβ1-42 was observed in 25.7, 81.5, and 98.3%, respectively. Baseline standardized uptake value ratios of fluorine-18-florbetapir PET were 0.75±0.05, 0.86±0.09, and 1.01±0.09, respectively [F(2, 376)=603.547; P<0.001]. After 24 months of follow-up, the standardized uptake value ratios increased by 0.81±2.62, 2.81±2.90, and 2.17±3.66%, respectively [F(2, 376)=7.905, P<0.05 vs. the negative group]. Among mild cognitive impairment patients, the equivocal group showed a more rapid decline in glucose metabolism than the negative group [5.52±5.36 vs. 0.67±4.45; F(2, 122)=9.028, P<0.01]. 8.4% of the patients in this study showed a visually equivocal result of amyloid PET. These patients showed a moderate amount of amyloid accumulation and a rapid rate of accumulation.

FUELING THE GLUCOSE-STARVED ALZHEIMER’S BRAIN: CATABOLISM OF WHITE MATTER IN THE BRAIN TO GENERATE KETONE BODIES

The brain is the most energetically demanding organ of the body, and is thus vulnerable to even a modest decline in glucose availability and metabolism required to generate ATP. Glucose hypometabolism is an early endophenotype of risk for Alzheimer's disease (AD) which progressively worsens with disease. Analyses were conducted in the aging female mouse followed by analyses in brain of gene expression, biochemical analyses and electron microscopy of myelin with AD relevant brain regions. Early during female brain aging the decline in estrogenic control of the bioenergetic system is associated with decline in glucose metabolism and activation of a systems biology adaptive response which involves activation of a starvation response pathway and reliance on ketone bodies as an alternative fuel to generate ATP. Activation of the myelin catabolism pathway was initiated by decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and induction of the cytosolic-phospholipase-A2 sphingomyelinase pathway. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its sequentially phased activation, links glucose hypometabolism and mitochondrial dysfunction associated with endocrine aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. The mechanistic pathway leading to white matter catabolism in the aging female brain provides multiple therapeutic targets to prevent and treat white matter degeneration in AD. Further, the pathways leading to catabolism of white matter in the female brain is likely to be relevant to the aging male brain at risk for AD. Therapeutically targeting stages of disease and associated mechanisms will be critical. Research was supported by NIH National Institute on Aging P01AG026572 and R01AG032236 to RDB.

IMPACT OF APOE GENOTYPE ON THE SEX-DIFFERENTIATED BIOENERGETIC TRAJECTORIES AND AD RISKS IN AGING MOUSE BRAINS

Age, APOE4 genotype, and female sex are top risk factors for AD. Our previous studies demonstrated that the bioenergetic shifts occurring in the perimenopausal female brain could contribute to an increased AD risk in women. We also observed substantial sex disparities in brain bioenergetic trajectories in normal aging mice. The goal of this study is to determine the sex differences in the impact of APOE genotype on AD at-risk phenotypes during brain aging. Female and male, APOE3- and APOE4 targeted replacement (TR) mice were assessed for: (a) bioenergetic-, inflammatory-, and AD pathology-related gene expression in hippocampus followed by bioinformatic analysis, and (b) key metabolic parameters in the periphery. Functional assessments are undergoing, including: (a) FDG-microPET for cerebral glucose metabolism, (b) brain mitochondrial function, and (c) glucose tolerance test for peripheral metabolism. Gene expression analyses revealed that female APOE4 mice at pre-menopause age (6-month old) exhibited a significantly different bioenergetic profile relative to APOE3 controls: APOE4 mice showed a higher expression of genes involved in mitochondrial oxidative phosphorylation, mitochondrial membrane transport, and mitochondrial fusion. These changes in female APOE4 brains could represent an adaptive response to deficits in brain glucose availability and a shift in energy fuels from glucose to ketone bodies and glucose. This hypothesis is further supported by: (a) APOE4 mice had lower levels of plasma glucose in both sexes while the higher levels of ketone bodies and triglycerides were only seen in the females; (b) both APOE3 and APOE4 females had lower peripheral glucose levels and higher ketone body levels than their genotype-matched male counterparts, indicating a potential earlier shift in bioenergetic fuel usage in females. These findings suggest that APOE4 genotype interacts with the age-related decline in glucose metabolism and the bioenergetic shift to alternative fuels, particularly in females. Outcomes of this study will provide mechanistic details of the APOE4 genetic burden on the sex-differentiated bioenergetic fluctuation during aging and its contribution to higher AD risks in women. This work was supported by NIA 5P01AG026572 to RDB and Alzheimer's Association SAGA-17–419459 to RDB.

RELATIONSHIPS BETWEEN TAU BURDEN MEASURED USING AV1451 PET, REGIONAL CEREBRAL GLUCOSE METABOLISM, AND COGNITIVE STATUS

In amyloid positive (Am+) subjects at all stages of the AD pathway, the expression of an AD-like pattern of hypometabolism detected using a multivariate FDG classifier correlates with the rate of subsequent cognitive decline (Figure 1), supporting clinical trial enrichment. However, the pathology underlying Am+ subjects negative for an AD-like pattern is unknown. Using AV1451 PET scans, we studied the temporal and spatial relationship between FDG AD-like pattern expression and tau burden with the goal of understanding these differences. The AV1451 scans of 36 ADNI2 subjects (Table 1) were downloaded with their closest MRI, AV45, FDG, CSF Abeta, tau, and ptau, demographic, and cognitive data. Regions of interest were measured in structures aligned with Braak stages I–VI (Scholl, 2016). SUVRs were calculated using cerebellar cortex (AV1451) and pons (FDG), and Z-scores generated using Normal Am- references. FDG scans were scored for expression of an AD-like pattern using a multivariate AD Progression classifier (FDG CV1). AV1451 and FDG PET scores and patterns were compared across diagnostic and amyloid classes, and between subjects who expressed an AD like FDG pattern vs. those who did not. Using a threshold of z-score ≥2, only NL and SMC subjects with Am+ PET were Tau PET+ with Braak stage-like progression. Most Tau- subjects were negative for a FDG CV1 pattern. Compared to Am-Tau- subjects, Tau+ subjects expressed a tau pattern highly similar to AD hypometabolism (FDG CV1 pattern), differing in sensorimotor cortex (Figure 2). In Tau+ subjects, greater FDG CV1+ pattern expression was associated with greater deposition in FDG CV1 regions (Figure 3). Two of three Am+Tau+ subjects who were FDG CV1- had atypical, asymmetric tau patterns or relatively minimal tau burden and showed corresponding atypical hypometabolism (Figure 4). Regional glucose metabolism decline is associated with tau deposition in this preliminary data set, consistent with other findings (Ossenkoppele, 2016). Typical vs. atypical tau patterns and their extent may help to explain the correlation between FDG CV1 and subsequent rate of clinical decline, and to understand whether cognitive decline arises from tau or the extent of neurodegenerative response to burden. a) FDG CV1 pattern: Blue = hypometabolism, Red = hypermetabolism (preservation), relative to whole brain. Higher CV1 score corresponds to greater pattern expression. b) 36 month MMSE scores for Late MCI subjects stratified by baseline CV1. Subjects negative for AD-like pattern at baseline typically remain stable in contrast to higher scoring subjects who decline at greater rates. SPM-t comparison of Am+ Tau+ subjects with AD-like FDG CV1 vs. Am- Tau- subjects (p<0.005 uncorrected, N=5 Tau+,9 Tau-). Comparison of Am+ Tau+ subjects who exhibit AD-like hypometabolism vs. those who do not. AV1451 scan of Am+ Tau+ EMCI subject with atypical deposition pattern superimposed on MRI reference (with two different axial slices). Subject was negative for a typical AD-like pattern, but had hypometabolism in regions overlapping those with tau, including amygdala, lingual gyrus, fusiform gyrus, parahippocampus, and additionally in cerebellum and subcortical white matter relative to pons. Brightest color intensity corresponds with greater tau z-score (z = 4 to 5).

Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer's

Previously, we demonstrated that reproductive senescence in female triple transgenic Alzheimer's (3×TgAD) mice was paralleled by a shift towards a ketogenic profile with a concomitant decline in mitochondrial activity in brain, suggesting a potential association between ovarian hormone loss and alteration in the bioenergetic profile of the brain. In the present study, we investigated the impact of ovariectomy and 17β-estradiol replacement on brain energy substrate availability and metabolism in a mouse model of familial Alzheimer's (3×TgAD). Results of these analyses indicated that ovarian hormones deprivation by ovariectomy (OVX) induced a significant decrease in brain glucose uptake indicated by decline in 2-[18F]fluoro-2-deoxy-D-glucose uptake measured by microPET-imaging. Mechanistically, OVX induced a significant decline in blood-brain-barrier specific glucose transporter expression, hexokinase expression and activity. The decline in glucose availability was accompanied by a significant rise in glial LDH5 expression and LDH5/LDH1 ratio indicative of lactate generation and utilization. In parallel, a significant rise in ketone body concentration in serum occurred which was coupled to an increase in neuronal MCT2 expression and 3-oxoacid-CoA transferase (SCOT) required for conversion of ketone bodies to acetyl-CoA. In addition, OVX-induced decline in glucose metabolism was paralleled by a significant increase in Aβ oligomer levels. 17β-estradiol preserved brain glucose-driven metabolic capacity and partially prevented the OVX-induced shift in bioenergetic substrate as evidenced by glucose uptake, glucose transporter expression and gene expression associated with aerobic glycolysis. 17β-estradiol also partially prevented the OVX-induced increase in Aβ oligomer levels. Collectively, these data indicate that ovarian hormone loss in a preclinical model of Alzheimer's was paralleled by a shift towards the metabolic pathway required for metabolism of alternative fuels in brain with a concomitant decline in brain glucose transport and metabolism. These findings also indicate that estrogen plays a critical role in sustaining brain bioenergetic capacity through preservation of glucose metabolism.

Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity

Normal aging is characterized by brain glucose metabolism decline predominantly in the prefrontal cortex. The goal of the present study was to assess whether this change was associated with age-related alteration of white matter (WM) structural integrity and/or functional connectivity. FDG-PET data from 40 young and 57 elderly healthy participants from two research centers (n=49/48 in Center 1/2) were analyzed. WM volume from T1-weighted MRI (Center 1), fractional anisotropy from diffusion-tensor imaging (Center 2), and resting-state fMRI data (Center 1) were also obtained. Group comparisons were performed within each imaging modality. Then, positive correlations were assessed, within the elderly, between metabolism in the most affected region and the other neuroimaging modalities. Metabolism decline in the elderly predominated in the left inferior frontal junction (LIFJ). LIFJ hypometabolism was significantly associated with macrostructural and microstructural WM disturbances in long association fronto-temporo-occipital fibers, while no relationship was found with functional connectivity. The findings offer new perspectives to understand normal aging processes and open avenues for future studies to explore causality between age-related metabolism and connectivity changes.

Oxidative stress in the etiology of age-associated decline in glucose metabolism.

One of the most common pathologies in aging humans is the development of glucose metabolism dysfunction. The high incidence of metabolic dysfunction, in particular type 2 diabetes mellitus, is a significant health and economic burden on the aging population. However, the mechanisms that regulate this age-related physiological decline, and thus potential preventative treatments, remain elusive. Even after accounting for age-related changes in adiposity, lean mass, blood lipids, etc., aging is an independent factor for reduced glucose tolerance and increased insulin resistance. Oxidative stress has been shown to have significant detrimental impacts on the regulation of glucose homeostasis in vitro and in vivo. Furthermore, oxidative stress has been shown to be modulated by age and diet in several model systems. This review provides an overview of these data and addresses whether increases in oxidative stress with aging may be a primary determinant of age-related metabolic dysfunction.

P1‐135: Ovarian hormone loss induced decline in glucose availability and shift to alternative substrates in brain

Background: Reproductive senescence is associated with decline in brain mitochondrial function. Further, enzymes for ketogenic/fatty acid metabolism were significantly increased, indicating shift towards a ketogenic phenotype. Herein, we investigated impact of reproductive senescence and ovarian hormone loss on brain substrate system. Methods: Aging female mice underwent FDG-MicroPET/Micro-CT imagin g, followed by analyses of brain bioenergetic substrates and their transporter profile. 6-month Female mice were also ovariectomized and underwent FDG-MicroPET/Micro-CT imagin g. Initial analysis was conducted to assess whole brain glucose uptake. ROI analyses were conducted in collaboration with Drs. Chen and Reiman and colleagues.Results:Age-related decline in brain glucose uptake was statistically significant at 9-month-of-age in the female mouse brain. Pathway analyses identified a concomitant decline in hexokinase activity, neuronal glucose transporter (GLUT3) expression and increased neuronal monocarboxylate transporter expression (MCT2), indicating a decline in glucose metabolism and increased transport of alternative fuels, ketone bodies or/and lactate in brains. However, MCT1 in BBB and astrocytes significantly decreased at 12-month-of-age, indicative of decreased transport of alternative substrates. Because these changes occurred during the period of reproductive senescence, we investigated regulation of substrate transport system by ovarian hormones. Contrary to expectation, the GLUTs increased in the absence of ovarian hormones. However, the increase in glucose transporters did not result in an increase in brain glucose uptake as brain glucose uptake was significantly decreased in OVX-female brain. These data indicate that despite the increase in GLUTs, the function of these transporters was compromised. Regional analyses indicated that glucose metabolism was significantly decreased in thalamus, consistent with hypometabolism in ApoE4-carriers. Estrogen treatment at the time of OVX prevented decline in transporters and brain glucose uptake to sustain brain metabolism.Conclusions:Reproductive senescence is associated with a decline in transporters for both glucose and ketone bodies, adaptive responses to increase substrate transporters is thwarted by post-translational modifications. Within 5 weeks of ovarian hormone loss, which translates into 2-3 years of human life span, thalamic hypometabolism developed, which is evident in ApoE4 Latino carriers, at-risk for AD. Estrogen treatment at the time of ovariectomy prevented declines in transporter expression and function, evidenced by brain glucose uptake.

Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington’s disease mice

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Positron emission tomography studies have revealed a decline in glucose metabolism in the brain of patients with HD by a mechanism that has not been established. We examined glucose utilization in embryonic primary cortical neurons of wild-type (WT) and HD knock-in mice, which have 140 CAG repeats inserted in the endogenous mouse huntingtin gene (HD140Q/140Q). Primary HD140Q/140Q cortical neurons took up significantly less glucose than did WT neurons. Expression of permanently inactive and permanently active forms of Rab11 correspondingly altered glucose uptake in WT neurons, suggesting that normal activity of Rab11 is needed for neuronal uptake of glucose. It is known that Rab11 activity is diminished in HD140Q/140Q neurons. Expression of dominant active Rab11 to enhance the activity of Rab11 normalized glucose uptake in HD140Q/140Q neurons. These results suggest that deficient activity of Rab11 is a novel mechanism for glucose hypometabolism in HD.

Effects of a 6-Month Cognitive Intervention Program on Brain Metabolism in Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease

The effect of cognitive intervention on brain metabolism in Alzheimer's disease (AD) is largely unexplored. Therefore, we aimed to investigate clinical cognitive parameters and 18FDG PET to test for effects of a cognitive intervention in patients with amnestic mild cognitive impairment (aMCI) or mild AD. Patients with aMCI (n = 24) or mild AD (n = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET images were analyzed using voxel-based SPM5 approaches to determine longitudinal changes, group-by-time interactions, and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left superior temporal- and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD.

Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI

The Functional Activities Questionnaire (FAQ) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) are frequently used indices of cognitive decline in Alzheimer's disease (AD). The goal of this study was to compare FDG-PET and clinical measurements in a large sample of elderly subjects with memory disturbance. We examined relationships between glucose metabolism in FDG-PET regions of interest (FDG-ROIs), and ADAS-cog and FAQ scores in AD and mild cognitive impairment (MCI) patients enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Low glucose metabolism at baseline predicted subsequent ADAS-cog and FAQ decline. In addition, longitudinal glucose metabolism decline was associated with concurrent ADAS-cog and FAQ decline. Finally, a power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients. Glucose metabolism is a sensitive measure of change in cognition and functional ability in AD and MCI, and has value in predicting future cognitive decline.

Longitudinal multimodal imaging in mild to moderate Alzheimer disease: a pilot study with memantine

Objective: To study the feasibility of multimodal neuroimaging in mild to moderate Alzheimer disease (AD) and to estimate the size of possible treatment effects of memantine on potential functional, structural...

Human brain glucose metabolism may evolve during activation: Findings from a modified FDG PET paradigm

In human brain, short-term physiological stimulation results in dramatic and proportional increase in blood flow and metabolic rate of glucose but minimal change in oxygen utilization, however, with continuing stimulation, we have observed that blood flow response diminishes and oxygen utilization increases. Given the temporal limitation of conventional methods to measure glucose metabolism in the human brain, we modified [18F]fluorodeoxyglucose (FDG) PET paradigm to evaluate the short-term and long-term effects of visual stimulation on human brain glucose metabolism. In the present study, seven healthy volunteers each underwent three dynamic FDG PET studies: at rest and after 1 min and 15 min of visual stimulation (using reversing black–white checkerboard) which continued for only 5 min after FDG injection. We found that increase in FDG uptake in the visual cortex was attenuated by 28% when preceded by 15 min of continuous visual stimulation (p<0.001). This decline in metabolism occurred in the absence of any behavior changes in task performance. The similarity in behavior of blood flow and glucose metabolism over time supports the hypothesis that, in activated brain, blood flow is modulated by changes in cytosolic free NADH/NAD+ ratio related to increased glycolysis. Furthermore, the observed decline in glucose metabolism may reflect a shift from glycolytic to oxidative glucose metabolism with continued activation.

Monitoring Targeted Therapy: Is Fluorodeoxylucose Uptake a Marker of Early Response?

In this issue, Su et al. ([1][1]) present the results of studies of early cellular changes in response to gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in cell lines and a preliminary xenograft model. The EGFR pathway family has been implicated in the pathogenesis

Glucose metabolism in early onset versus late onset Alzheimer's disease: an SPM analysis of 120 patients

The aims of this cross-sectional study were (i) to compare the overall glucose metabolism between early onset and late onset Alzheimer's disease in a large sample of patients; and (ii) to investigate the pattern of glucose metabolism as a function of dementia severity in early onset versus late onset Alzheimer's disease, using a statistical parametric mapping (SPM) analysis. Subjects consisted of four groups: 74 patients with early onset Alzheimer's disease, 46 patients with late onset of the disease, and two control groups age matched to each patient group. All the subjects underwent 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET under the same scanning conditions. Severity of dementia was rated with the Clincial Dementia Rating (CDR). Voxel-based SPM99 was used for statistical analyses. Overall glucose hypometabolism of early onset Alzheimer's disease patients was much greater in magnitude and extent than that of late onset patients, though both groups were similar in dementia severity: the early onset group showed more severe hypometabolism in parietal, frontal and subcortical (basal ganglia and thalamus) areas. When the decline of glucose metabolism was compared as a function of CDR stage, the slope was steeper in early onset than in late onset Alzheimer's disease. The rapid decline occurred at CDR 0.5-1 in the early onset group, whereas similar changes occurred at CDR 2-3 in the late onset group. The greater hypometabolism in early onset than in late onset patients is required to reach the same severity of dementia, probably reflecting greater functional reserve in younger than in older subjects. Alternatively, the metabolic decline curve suggests that the early onset patients may take a more rapid course in the reduction of glucose metabolism than the late onset patients.

Functional Neuroimaging of Cortical Dysfunction in Alcoholic Korsakoff's Syndrome

Many neuropsychological investigations of human memory have focused on the amnesic deficits of alcoholic Korsakoff's syndrome. Structural neuroimaging suggests that the syndrome results from midline diencephalic damage, but functional neuroimaging has the potential to reveal additional neuropathology that may be responsible for cognitive dysfunction. Accordingly, high-resolution positron emission tomography (PET) was used to measure regional cerebral metabolic rates for glucose utilization in five alcoholic Korsakoff patients and nine alcoholic control subjects. Results from a continuous recognition test administered during the radiotracer uptake period indicated that all subjects performed normally with respect to immediate memory, whereas Korsakoff patients demonstrated a marked memory impairment in delayed recognition. PET results from the Korsakoff group showed a widespread decline in glucose metabolism in frontal, parietal, and cingulate regions, suggesting that these functional abnormalities in the cerebral cortex contribute to the memory impairment. Hippocampal glucose metabolism did not differ between the groups. Thus, the evidence did not support the hypothesis that parallel brain dysfunctions are responsible for the similar amnesic symptomatology after hippocampal and diencephalic damage. We hypothesize that the amnesic dysfunction of Korsakoff's syndrome depends on a disruption of thalamocortical interactions that mediate a function critical for normal memory storage.