Use of R-beta-[1-11C]hydroxybutyrate in PET studies of regional cerebral uptake of ketone bodies in humans

1995 ◽  
Vol 269 (5) ◽  
pp. E948-E959 ◽  
Author(s):  
G. Blomqvist ◽  
J. O. Thorell ◽  
M. Ingvar ◽  
V. Grill ◽  
L. Widen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Animal Studies ◽  
Time Course ◽  
Ketone Bodies ◽  
Tracer Uptake ◽  
Utilization Rate ◽  
Rate Limiting Step ◽  
Positron Emission ◽  
Beta Hydroxybutyrate ◽  
The Brain

A method for determining regional cerebral utilization of ketone bodies in humans is described. After a bolus injection of R-beta-[1-11C]hydroxybutyrate, the time course of the tracer in the brain was measured with positron emission tomography in five healthy volunteers. The regional cerebral blood flow was measured separately. The tracer uptake in the brain could be well described by a single rate constant, indicating that the concentration of unmetabolized ketone bodies in the brain is very low and that transport across the blood-brain barrier is the rate-limiting step. At an average plasma concentration of beta-hydroxybutyrate of 0.043 mumol/ml, the utilization rate was estimated to be 0.48 nmol.ml-1.min-1. In accordance with previous animal studies, the utilization rate was found to increase almost linearly with increasing plasma concentration of beta-hydroxybutyrate. Furthermore, the utilization was higher in gray than in white matter. Finally, the ratio between the utilization in the basal ganglia and the brain as a whole was lower for ketone bodies than for glucose.

Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients

2002 ◽  
Vol 283 (1) ◽  
pp. E20-E28 ◽  
Author(s):  
G. Blomqvist ◽  
M. Alvarsson ◽  
V. Grill ◽  
G. Von Heijne ◽  
M. Ingvar ◽  
...  
Keyword(s):  
Time Course ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Tissue Concentration ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Utilization Rate ◽  
Resonance Spectroscopy ◽  
Significant Difference ◽  
The Brain

Using R-β-[1-11C]hydroxybutyrate and positron emission tomography, we studied the effect of acute hyperketonemia (range 0.7–1.7 μmol/ml) on cerebral ketone body utilization in six nondiabetic subjects and six insulin-dependent diabetes mellitus (IDDM) patients with average metabolic control (HbA1c = 8.1 ± 1.7%). An infusion of unlabeled R-β-hydroxybutyrate was started 1 h before the bolus injection of R-β-[1-11C]hydroxybutyrate. The time course of the radioactivity in the brain was measured during 10 min. For both groups, the utilization rate of ketone bodies was found to increase nearly proportionally with the plasma concentration of ketone bodies (1.0 ± 0.3 μmol/ml for nondiabetic subjects and 1.3 ± 0.3 μmol/ml for IDDM patients). No transport of ketone bodies from the brain could be detected. This result, together with a recent study of the tissue concentration of R-β-hydroxybutyrate in the brain by magnetic resonance spectroscopy, indicate that, also at acute hyperketonemia, the rate-limiting step for ketone body utilization is the transport into the brain. No significant difference in transport and utilization of ketone bodies could be detected between the nondiabetic subjects and the IDDM patients.

Validation and optimisation of an automatic blood sampler for preclinical positron emission tomography research in domestic pigs

2021 ◽  
pp. 002367722110490
Author(s):  
Sofia Vestergaard Nielsen ◽  
Mie Ringgaard Dollerup ◽  
Simone Larsen Bærentzen ◽  
Anne M Landau ◽  
Ole Lajord Munk ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Animal Studies ◽  
Time Course ◽  
Activity Concentration ◽  
Blood Sampling ◽  
Emission Tomography ◽  
Domestic Pigs ◽  
Arterial Blood ◽  
Positron Emission

In preclinical positron emission tomography animal studies, continuous blood sampling is used to measure the time course of the activity concentration in arterial blood. However, pigs have hypercoagulable blood that tends to clot inside plastic tubes. We tested several tube materials and lengths and the use of three-way connectors. We validated set-ups for automated blood sampling with and without blood recirculation that could run for 90 minutes without problematic clots and without any evidence of emboli formation during necropsy.

scholarly journals Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential

2021 ◽  
Vol 23 (6) ◽  
Author(s):  
Firda Juhairiyah ◽  
Elizabeth C. M. de Lange
Keyword(s):  
Drug Delivery ◽  
Drug Transport ◽  
Animal Studies ◽  
Time Course ◽  
Liposomal Formulation ◽  
Liposomal Drug ◽  
Brain Drug Delivery ◽  
Liposomal Formulations ◽  
The Impact ◽  
The Brain

AbstractBrain drug delivery may be restricted by the blood-brain barrier (BBB), and enhancement by liposome-based drug delivery strategies has been investigated. As access to the human brain is limited, many studies have been performed in experimental animals. Whereas providing interesting data, such studies have room for improvement to provide mechanistic insight into the rate and extent of specifically BBB transport and intrabrain distribution processes that all together govern CNS target delivery of the free drug. This review shortly summarizes BBB transport and current liposome-based strategies to overcome BBB transport restrictions, with the emphasis on how to determine the individual mechanisms that all together determine the time course of free drug brain concentrations, following their administration as such, and in liposomes. Animal studies using microdialysis providing time course information on unbound drug in plasma and brain are highlighted, as these provide the mechanistic information needed to understand BBB drug transport of the drug, and the impact of a liposomal formulations of that drug on BBB transport. Overall, these studies show that brain distribution of a drug administered as liposomal formulation depends on both drug properties and liposomal formulation characteristics. In general, evidence suggests that active transporters at the BBB, either being influx or efflux transporters, are circumvented by liposomes. It is concluded that liposomal formulations may provide interesting changes in BBB transport. More mechanistic studies are needed to understand relevant mechanisms in liposomal drug delivery to the brain, providing an improved basis for its prediction in human using animal data.

Glucose and Ketone Metabolism in the Aging Brain

2016 ◽  
Author(s):  
Stephen C. Cunnane ◽  
Alexandre Courchesne-Loyer ◽  
Valerie St-Pierre ◽  
Camille Vandenberghe ◽  
Etienne Croteau ◽  
...  
Keyword(s):  
Alternative Fuels ◽  
Ketone Bodies ◽  
Therapeutic Strategies ◽  
Cognitive Outcomes ◽  
Aging Brain ◽  
High Fat ◽  
Medium Chain Triglycerides ◽  
Acute Dependence ◽  
Beta Hydroxybutyrate ◽  
The Brain

Brain glucose uptake is impaired in Alzheimer’s disease (AD). A key question is whether cognitive decline could be delayed if this defect were at least partly corrected or bypassed. Ketones (or ketone bodies) such as beta-hydroxybutyrate and acetoacetate are the brain’s main alternative fuels. Several studies have shown that in mild-to-moderate AD, brain ketone uptake is similar to that of healthy age-matched controls. Published clinical trials show that increasing ketone availability to the brain via nutritional ketosis has modest benefits on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet or supplements providing medium chain triglycerides. Given the acute dependence of the brain on its energy supply and the ineffectiveness of current therapeutic strategies for AD consideration be given to correcting the underlying problem of deteriorating brain fuel supply during aging.

scholarly journals Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by 11C-PBR28 MR-PET

2019 ◽  
Vol 26 (6) ◽  
pp. 668-678 ◽  
Author(s):  
Valeria T Barletta ◽  
Elena Herranz ◽  
Costantina A Treaba ◽  
Russell Ouellette ◽  
Ambica Mehndiratta ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Tracer Uptake ◽  
Emission Tomography ◽  
7 Tesla ◽  
Healthy Controls ◽  
Multilinear Regression ◽  
Neurological Disability ◽  
Standardized Uptake Values ◽  
Positron Emission ◽  
The Brain

Background: Activated microglia, which can be detected in vivo by 11C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. Objectives: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. Methods: Twenty-eight MS patients and 16 healthy controls underwent 11C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11C-PBR28 binding was assessed in regions of interest using 60–90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. Results: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. Conclusion: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment.

Regional ketone body utilization by rat brain in starvation and diabetes

1986 ◽  
Vol 250 (2) ◽  
pp. E169-E178 ◽  
Author(s):  
R. A. Hawkins ◽  
A. M. Mans ◽  
D. W. Davis
Keyword(s):  
Energy Metabolism ◽  
Plasma Clearance ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Energy Requirement ◽  
Diabetic Rats ◽  
Beta Hydroxybutyrate ◽  
The Brain ◽  
Brain Energy ◽  
Cerebral Structures

The rate of ketone body (beta-hydroxybutyrate and acetoacetate) metabolism was measured in individual cerebral structures of fed, starved, and diabetic rats. This was done by infusing beta-[3-14C]hydroxybutyrate intravenously and measuring the incorporation of 14C into brain by quantitative autoradiography. The capacity of the brain to use ketone bodies, expressed as plasma clearance, increased in starvation and diabetes by approximately 50-60%. Plasma clearance was near maximal after 2 days starvation and was not significantly increased after 4 days starvation, 6 days of diabetes or 28 days of diabetes. In all situations the ketone bodies provided only a modest amount of fuel for brain energy metabolism; 3.2% after 2 days starvation and 6.5 and 9.9% after 6 and 28 days of diabetes. The fraction of their energy requirement which the various structures could derive from the ketone bodies differed widely. In general the telencephalon made greatest use of ketone bodies, whereas the hindbrain used least. There was no correlation between the energy requirement of structures (estimated from glucose use in fed rats) and the fraction of energy they could derive from ketone bodies.

scholarly journals Human Cerebral Glucose Metabolism Determined by Positron Emission Tomography: A Revisit

1987 ◽  
Vol 7 (4) ◽  
pp. 427-432 ◽  
Author(s):  
Rodney A. Brooks ◽  
Jun Hatazawa ◽  
Giovanni Di Chiro ◽  
Stephen M. Larson ◽  
Donn S. Fishbein
Keyword(s):  
Positron Emission Tomography ◽  
White Matter ◽  
Glucose Utilization ◽  
Direct Determination ◽  
Macaque Monkey ◽  
Jugular Bulb ◽  
Emission Tomography ◽  
Utilization Rate ◽  
Positron Emission ◽  
The Brain

The cerebral glucose utilization rate was studied for 27 normal volunteers with 18F-deoxyglucose positron emission tomography (PET). The scanner has a spatial resolution of 6–7 mm and contains corrections for scatter, attenuation, and random coincidences. The lumped constant (tracer-to-glucose dynamic uptake ratio) was determined by comparing the average global uptake of tracer in representative slices with average glucose utilization rates measured by the Kety-Schmidt method as reported in the literature. The resulting value of 0.50 is in excellent agreement with a recent direct determination done by arterial and jugular bulb blood sampling. Gray and white matter values of glucose utilization in various areas of the brain were determined by placing small regions of interest over various cortical, basal, and white matter structures. These values are within 20% of published autoradiographic data on the macaque monkey. The average ratio of gray to white glucose utilization was 2.9, compared with a range of 3–5 for the monkey study and 1.6–2.2 reported in previous PET studies. The effect of instrumental errors on the results is analyzed and discussed.

Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia

1996 ◽  
Vol 270 (5) ◽  
pp. E746-E751 ◽  
Author(s):  
S. G. Hasselbalch ◽  
P. L. Madsen ◽  
L. P. Hageman ◽  
K. S. Olsen ◽  
N. Justesen ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glucose Metabolism ◽  
Carbohydrate Metabolism ◽  
Ketone Bodies ◽  
Regional Analysis ◽  
Oxygen Metabolism ◽  
Blood Concentrations ◽  
Positron Emission ◽  
The Brain

During starvation, brain energy metabolism in humans changes toward oxidation of ketone bodies. To investigate if this shift is directly coupled to circulating blood concentrations of ketone bodies, we measured global cerebral blood flow (CBF) and global cerebral carbohydrate metabolism with the Kety-Schmidt technique before and during intravenous infusion with ketone bodies. During acute hyperketonemia (mean beta-hydroxybutyrate blood concentration 2.16 mM), cerebral uptake of ketones increased from 1.11 to 5.60 mumol.100 g-1.min-1, counterbalanced by an equivalent reduction of the cerebral glucose metabolism from 25.8 to 17.2 mumol.100 g-1.min-1, with the net result being an unchanged cerebral uptake of carbohydrates. In accordance with this, global cerebral oxygen metabolism was not significantly altered (144 vs. 135 mumol.100 g-1.min-1). The unchanged global cerebral metabolic activity was accompanied by a 39% increase in CBF from 51.0 to 70.9 ml.100 g-1.min-1. Regional analysis of the glucose metabolism by positron emission tomography-[18F]fluoro-2-deoxy-D-glucose indicated that mesencephalon does not oxidize ketone bodies to the same extent as the rest of the brain. It was concluded that the immediate oxidation of ketone bodies induced a decrease in cerebral glucose uptake in spite of an adequate glucose supply to the brain. Furthermore, acute hyperketonemia caused a resetting of the coupling between CBF and metabolism that could not be explained by alterations in arterial CO2 tension or pH.

scholarly journals Effects of Timing and Duration of Cognitive Activation in [15O]Water PET Studies

1994 ◽  
Vol 14 (3) ◽  
pp. 423-430 ◽  
Author(s):  
Richard R. Hurtig ◽  
Richard D. Hichwa ◽  
Daniel S. O'Leary ◽  
Laura L. Boles Ponto ◽  
Shalini Narayana ◽  
...  
Keyword(s):  
Cognitive Processing ◽  
Time Course ◽  
Checkerboard Pattern ◽  
Cognitive Activation ◽  
Homogeneity Assumption ◽  
Positron Emission ◽  
Baseline Task ◽  
Temporal Placement ◽  
Short Time ◽  
The Brain

The multiple injection [15O]water method offers unique opportunities for studying cognitive processing by the human brain. The influence of the duration and temporal placement of an activation task, in relation to the arrival of the radiotracer in the brain, is a fundamental methodologic question for cognitive activation studies. A quantitative positron emission tomography (PET) study of five normal volunteers was performed in which the stimulation consisted of a visual activation task (alternating checkerboard pattern) superimposed on an auditory baseline task (syllable monitoring). Ten injection conditions, with varying duration and timing of the visual activation, were used. Regional CBF (rCBF) in visual cortex was measured quantitatively using the autoradiographic method. A 20-s stimulation, centered on the bolus arrival in the brain, produced significant changes in rCBF. Because varying the duration and timing of the activation task technically violates the temporal homogeneity assumption of the autoradiographic model, a mathematical simulation was formulated to evaluate the potential influence of these variations. Results of the simulation are consistent with the PET data and suggest that activation can be limited to a narrow temporal window centered on the radiotracer uptake. The ability to observe significant changes in rCBF with short stimulation intervals is of particular interest in the use of [15O]water PET for studies of cognitive processes with a short time course.

Morphological Changes in the Brain of Acutely Ill and Weight-Recovered Patients with Anorexia Nervosa

2014 ◽  
Vol 42 (1) ◽  
pp. 7-18 ◽  
Author(s):  
Jochen Seitz ◽  
Katharina Bühren ◽  
Georg G. von Polier ◽  
Nicole Heussen ◽  
Beate Herpertz-Dahlmann ◽  
...  
Keyword(s):  
Anorexia Nervosa ◽  
Cognitive Deficits ◽  
Time Course ◽  
Morphological Changes ◽  
Meta Analysis ◽  
Short Term ◽  
Clinical Prognosis ◽  
Qualitative Review ◽  
Brain Changes ◽  
The Brain

Objective: Acute anorexia nervosa (AN) leads to reduced gray (GM) and white matter (WM) volume in the brain, which however improves again upon restoration of weight. Yet little is known about the extent and clinical correlates of these brain changes, nor do we know much about the time-course and completeness of their recovery. Methods: We conducted a meta-analysis and a qualitative review of all magnetic resonance imaging studies involving volume analyses of the brain in both acute and recovered AN. Results: We identified structural neuroimaging studies with a total of 214 acute AN patients and 177 weight-recovered AN patients. In acute AN, GM was reduced by 5.6% and WM by 3.8% compared to healthy controls (HC). Short-term weight recovery 2–5 months after admission resulted in restitution of about half of the GM aberrations and almost full WM recovery. After 2–8 years of remission GM and WM were nearly normalized, and differences to HC (GM: –1.0%, WM: –0.7%) were no longer significant, although small residual changes could not be ruled out. In the qualitative review some studies found GM volume loss to be associated with cognitive deficits and clinical prognosis. Conclusions: GM and WM were strongly reduced in acute AN. The completeness of brain volume rehabilitation remained equivocal.

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