Kim Vang

Brain energy metabolism and blood flow differences in healthy aging

Cerebral metabolic rate of oxygen consumption (CMRO 2 ), cerebral blood flow (CBF), and oxygen extraction fraction (OEF) are important indices of healthy aging of the brain. Although a frequent topic of study, changes of CBF and CMRO 2 during normal aging are still controversial, as some authors find decreases of both CBF and CMRO 2 but increased OEF, while others find no change, and yet other find divergent changes. In this reanalysis of previously published results from positron emission tomography of healthy volunteers, we determined CMRO 2 and CBF in 66 healthy volunteers aged 21 to 81 years. The magnitudes of CMRO 2 and CBF declined in large parts of the cerebral cortex, including association areas, but the primary motor and sensory areas were relatively spared. We found significant increases of OEF in frontal and parietal cortices, excluding primary motor and somatosensory regions, and in the temporal cortex. Because of the inverse relation between OEF and capillary oxygen tension, increased OEF can compromise oxygen delivery to neurons, with possible perturbation of energy turnover. The results establish a possible mechanism of progression from healthy to unhealthy brain aging, as the regions most affected by age are the areas that are most vulnerable to neurodegeneration.

Normalization in PET group comparison studies--the importance of a valid reference region.

INTRODUCTION In positron emission tomography (PET) studies of cerebral blood flow (CBF) and metabolism, the large interindividual variation commonly is minimized by normalization to the global mean prior to statistical analysis. This approach requires that no between-group or between-state differences exist in the normalization region. Given the variability typical of global CBF and the practical limit on sample size, small group differences in global mean easily elude detection, but still bias the comparison, with profound consequences for the physiological interpretation of the results. MATERIALS AND METHODS Quantitative [15O]H2O PET recordings of CBF were obtained in 45 healthy subjects (21-81 years) and 14 patients with hepatic encephalopathy (HE). With volume-of-interest (VOI) and voxel-based statistics, we conducted regression analyses of CBF as function of age in the healthy group, and compared the HE group to a subset of the controls. We compared absolute CBF values, and CBF normalized to the gray matter (GM) and white matter (WM) means. In additional simulation experiments, we manipulated the cortical values of 12 healthy subjects and compared these to unaltered control data. RESULTS In healthy aging, CBF was shown to be unchanged in WM and central regions. In contrast, with normalization to the GM mean, CBF displayed positive correlation with age in the central regions. Very similar artifactual increases were seen in the HE comparison and also in the simulation experiment. CONCLUSION Ratio normalization to the global mean readily elevates CBF in unchanged regions when a systematic between-group difference exists in gCBF, also when this difference is below the detection threshold. We suggest that the routine normalization to the global mean in earlier studies resulted in spurious interpretations of perturbed CBF. Normalization to central WM yields less biased results in aging and HE and could potentially serve as a normalization reference region in other disorders as well.

In Alzheimer's Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

In animal models, the incretin hormone GLP-1 affects Alzheimer’s disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [11C]PIB (PIB), CMRglc with [18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMRglc declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMRglc after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMRglc that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered.

Relief of fecal incontinence by sacral nerve stimulation linked to focal brain activation.

OBJECTIVE: This study aimed to test the hypothesis that sacral nerve stimulation affects afferent vagal projections to the central nervous system associated with frontal cortex activation in patients with fecal incontinence. PATIENTS: Nine women and one man received temporary sacral nerve stimulation with permanent electrodes as a treatment for fecal incontinence. INTERVENTIONS: We used positron emission tomography to record indices of regional cerebral blood flow before and after 30 minutes of continuous stimulation. We repeated this procedure after 2 weeks of continued stimulation, before and 30 minutes after arrest of the stimulation. RESULTS: The initial stimulation activated a region of the contralateral frontal cortex that normally is active during focused attention. After 2 weeks of stimulation, this activation had been replaced by activity in parts of the ipsilateral caudate nucleus, a region of the brain thought to be specifically involved in learning and reward processing. CONCLUSIONS: Sacral nerve stimulation induces changes in cerebral activity consistent with an effect on afferent projections of the vagus. The initial activation of the frontal cortex may reflect focused attention, whereas the subsequent activation of the caudate nucleus may reflect recruitment of mechanisms involved in learning and reward processing. These changes may contribute to the improved continence, which is an acquired result of the stimulation.

Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia

Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimers disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P = 0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P = 0.039) but not to the same extent in all regions (P = 0.022). The unidirectional glucose transfer across the blood-brain barrier remained unchanged (P = 0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P = 0.013 and 0.017), leading to increased net clearance of the glucose tracer (P = 0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.

Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning.

J. Neurochem (2012) 120, 806–817.

Glucose metabolism in small subcortical structures in Parkinson's disease

Objectives –  Evidence from experimental animal models of Parkinson’s disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high‐resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei.

Oxygen consumption and blood flow coupling in human motor cortex during intense finger tapping: implication for a role of lactate.

Rates of cerebral blood flow (CBF) and glucose consumption (CMRglc) rise in cerebral cortex during continuous stimulation, while the oxygen-glucose index (OGI) declines as an index of mismatched coupling of oxygen consumption (cerebral metabolic rate of oxygen—CMRO2) to CBF and CMRglc. To test whether the mismatch reflects a specific role of aerobic glycolysis during functional brain activation, we determined CBF and CMRO2 with positron emission tomography (PET) when 12 healthy volunteers executed finger-to-thumb apposition of the right hand. Movements began 1, 10, or 20 minutes before administration of the radiotracers. In primary and supplementary motor cortices and cerebellum, CBF had increased at 1 minute of exercise and remained elevated for the duration of the 20-minute session. In contrast, the CMRO2 numerically had increased insignificantly in left M1 and supplementary motor area at 1 minute, but had declined significantly at 10 minutes, returning to baseline at 20 minutes. As measures of CMRglc are impossible during short-term activations, we used measurements of CBF as indices of CMRglc. The decline of CMRO2 at 10 minutes paralleled a calculated decrease of OGI at this time. The implied generation of lactate in the tissue suggested an important hypothetical role of the metabolite as regulator of CBF during activation.

Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven healthy men in a randomized, double-blinded placebo-controlled cross-over experimental design. The acute effect of GLP-1 on glucose transfer in the brain was measured by positron emission tomography (PET) during a hypoglycemic clamp (3 mM plasma glucose) with 18F-fluoro-2-deoxy-glucose (FDG) as tracer of glucose. In addition, we jointly analyzed cerebrometabolic effects of GLP-1 from the present hypoglycemia study and our previous hyperglycemia study to estimate the Michaelis-Menten constants of glucose transport and metabolism. The GLP-1 treatment lowered the vascular volume of brain tissue. Loading data from hypo- to hyperglycemia into the Michaelis-Menten equation, we found increased maximum phosphorylation velocity (Vmax) in the gray matter regions of cerebral cortex, thalamus, and cerebellum, as well as increased blood-brain glucose transport capacity (Tmax) in gray matter, white matter, cortex, thalamus, and cerebellum. In hypoglycemia, GLP-1 had no effects on net glucose metabolism, brain glucose concentration, or blood-brain glucose transport. Neither hexokinase nor transporter affinities varied significantly with treatment in any region. We conclude that GLP-1 changes blood-brain glucose transfer and brain glucose metabolic rates in a PG concentration-dependent manner. One consequence is that hypoglycemia eliminates these effects of GLP-1 on brain glucose homeostasis.

Mapping α2 Adrenoceptors of the Human Brain with 11C-Yohimbine

A previous study from this laboratory suggested that 11C-yohimbine, a selective α2-adrenoceptor antagonist, is an appropriate ligand for PET of α2 adrenoceptors that passes readily from blood to brain tissue in pigs but not in rodents. To test usefulness in humans, we determined blood–brain clearances, volumes of distribution, and receptor availability by means of PET with 11C-yohimbine in healthy male adults. Methods: We recorded the distribution of 11C-yohimbine with 90-min dynamic PET and sampled arterial blood to measure intact 11C-yohimbine in plasma. For analysis, we coregistered PET images to individual MR images and automatically identified 27 volumes of interest. We used 1-tissue-compartment graphical analysis with 6 linearized solutions of the fundamental binding equation, with the metabolite-corrected arterial plasma curves as input function, to estimate the kinetic parameters of 11C-yohimbine. With the lowest steady-state distribution volume (VT), determined in the corpus callosum, we calculated the binding potential (receptor availability) of the radioligand in other regions. Results: The linear regressions yielded similar estimates of the kinetic parameters. The cortical values of VT ranged from 0.82 mL cm−3 in the right frontal cortex to 0.46 mL cm−3 in the corpus callosum, with intermediate VT values in subcortical structures. Binding potentials averaged 0.6–0.8 in the cortex and 0.2–0.5 in subcortical regions. Conclusion: The maps of 11C-yohimbine binding to α2 adrenoceptors in human brain had the highest values in cortical areas and hippocampus, with moderate values in subcortical structures, as found also in vitro. The results confirm the usefulness of the tracer 11C-yohimbine for mapping α2 adrenoceptors in human brain in vivo.