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Peculiar cases of a \"sleeping\" brain in alert cancer patients

TL;DR: It is speculated that the low CMRglc reflects a switch to an alternative energy source that is mediated by cancers remotely, which may help to understand how cancers can change body metabolism.
Abstract: Cognitive and constitutional symptomatology is common in cancer patients but the causes are not well understood. To investigate whether cancers cause these symptoms by changing cerebral metabolism, we measured the cerebral rate of glucose consumption (CMRglc) in patients diagnosed with a lung lesion. Methods: The CMRglc was quantified in 20 patients undergoing 18F-FDG PET for lesion staging. The cognitive status was assessed by neuropsychological testing. Results: Paradoxically, despite being alert three of the patients had CMRglc typical of people who are in deep sleep or anesthetized. All three had cancers, two died within 2 months of scanning. Remaining patients including four with early stage cancer had CMRglc within normal range. Conclusions: We speculate that the low CMRglc reflects a switch to an alternative energy source that is mediated by cancers remotely. Identifying the underlying mechanism and the alternative energy sources may help to understand how cancers can change body metabolism.

Summary (1 min read)

Jump to: [Introduction][Materials and methods][Results:][Discussion:] and [Legends]

Introduction

  • Lung cancer is often diagnosed at an advanced stage when the majority of patients already have constitutional and central nervous system (CNS) symptomatology, including fatigue and sleep perturbations, but how cancers cause these debilitating symptoms is poorly understood.
  • One possibility is that cancers can affect CNS remotely.
  • In a retrospective study, patients with lung cancers had altered glucose uptake (standard uptake values, SUV) in various regions of the brain (1) but whether these changes could cause CNS dysfunction is unknown.
  • Moreover, assessing brain function requires measuring the absolute cerebral metabolic rate of glucose consumption , which SUV does not provide.
  • CMRglc was calculated by combining this procedure with measurement of 18F timeactivity in blood (2).

Materials and methods

  • The research protocol was approved by the Institutional Review Board at Stony Brook University and written informed consent was obtained from each patient.
  • The data from twenty healthy subjects reported previously (3) were used as controls.
  • The time-course of the arterialized-venous plasma 18F activity was determined and corrected for radioactive decay to the scan start time (2).
  • PET scans were conducted with a Biograph Truepoint 40 PET-CT scanner (Siemens Medical Solutions USA Inc., Malvern, Pennsylvania, USA) with a 40-detector-row helical CT scanner.
  • Global CMRglc values were calculated by a volume-weighted average of all VOI’s defined including the cerebellum and brainstem.

Results:

  • Moreover, when compared to 20 normal subjects who were analyzed previously (3), the CMRglc decrease of the three patients (Fig. 1) approached the 42% reduction reported for coma patients (11).
  • Thus, according to common knowledge, the brain function of the three patients had to be near the threshold beyond which conscious activity cannot be maintained (11).
  • The authors found no errors that could account for their observation.
  • The authors therefore concluded that the calculated CMRglc in all patients faithfully represented the actual glucose consumption.

Discussion:

  • The authors documented that in some cancer patients the cerebral rate of glucose consumption can be as low as in individuals who are asleep, under anesthesia or comatose.
  • None of the conditions known to us that can switch energy consumption to lactate or ketones were applicable in their case, as the patients were resting, not intoxicated, were not heavy drinkers by history, and maintained a regular diet (Supplemental Table 2S).
  • Likewise, measuring SUV of glucose uptake is sufficient to compare the activities of different brain area.
  • In summary, the authors provide evidence consistent with the hypothesis that malignancy can affect brain energy metabolism remotely, the phenomenon they named ‘Cancer Associated Energy Switch’, or CAES.

Legends

  • The authors declare no conflicts of interest.
  • Certified by peer review) is the author/funder.
  • The copyright holder for this preprint (which was notthis version posted August 13, 2019.

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Journal ArticleDOI
TL;DR: The data indicate that cerebral FDG‐6‐PO4 in humans increases for about 90 minutes, plateaus, and then slowly decreases, and that cerebral blood FDG activity levels were found to be a minor fraction of tissue activity.
Abstract: Tracer techniques and quantitative autoradiographic and tissue counting models for measurement of metabolic rates were combined with positron computed tomography (PCT) and (F-18)2-fluoro-2-deoxy-D-glucose (FDG) for the measurement of local cerebral metabolic rate for glucose (LCMRGlc) in humans. A three-compartment model, which incorporates hydrolysis of FDG-6-PO4 to FDG, was developed for the measure of kinetic constants and calculation of LCMRGlc. Our model is an extension of that developed by Sokoloff et al. Although small, hydrolysis of FDG-6-PO4 was found to be significant. A PCT system, the ECAT, was used to determine the rate constants, lumped constant, and stability of the model in human beings. The data indicate that cerebral FDG-6-PO4 in humans increases for about 90 minutes, plateaus, and then slowly decreases. After 10 minutes, cerebral blood FDG activity levels were found to be a minor fraction of tissue activity. Precursor pool turnover rate, distribution volumes, and red blood cell-plasma concentration ratios were determined. Reproducibility (precision) of LCMRGlc measurements (approximate 2 cm2 regions) was +/- 5.5% over a 5-hour period. The replacement of arterial blood sampling with venous sampling was validated.

2,252 citations

Journal ArticleDOI
TL;DR: The rate constants of FDG in man were found to be comparable to those of deoxyglucose in rat and in rhesus monkey and the subject-to-subject variation of LCMRGlc as measured by the present method was comparable to that of other methods that measure whole-brain CMRglc.
Abstract: A method for the determination of local cerebral metabolic rates of glucose (LCMRGlc) in normal man is described. The method employs [18F]2-fluoro-2-deoxy-D-glucose (FDG) and emission-computed tomography (ECT). FDG was injected intravenously as a bolus. Radioactivities in separate brain regions were measured with ECT. Plasma FDG concentration following injection was measured from blood samples. A mathematical model that describes the kinetics of FDG transports was employed to determine the transport rate constants of FDG and to convert the radioactivity measurements to metabolic rates. The model has taken into account the possible dephosphorylation reaction from FDG-6-PO4 (FDG-6-P) to free FDG in brain tissues. Experiments were performed in 13 normal volunteers. The rate constants of FDG in man were found to be comparable to those of deoxyglucose in rat and in rhesus monkey. The average LCMRGlc in gray and in white matter were found to be 7.30 +/- 1.18 (SD) and 3.41 +/- 0.64 mg/min per 100 g brain tissue, respectively. The subject-to-subject variation of LCMRGlc as measured by the present method was comparable to those of other methods that measure whole-brain CMRGlc.

999 citations


"Peculiar cases of a \"sleeping\" br..." refers methods in this paper

  • ...6 LLC, Zurich Switzerland) based on an autoradiographic solution model (5)....

    [...]

Journal ArticleDOI
TL;DR: The data indicate that cerebral FDG-6-PO4 in humans increases for about 90 minutes, plateaus, and then slowly decreases, and that cerebral blood FDG activity levels were found to be a minor fraction of tissue activity.
Abstract: Tracer techniques and quantitative autoradiographic and tissue counting models for measurement of metabolic rates were combined with positron computed tomography (PCT) and (F-18)2-fluoro-2-deoxy-D-glucose (FDG) for the measurement of local cerebral metabolic rate for glucose (LCMRGlc) in humans. A three-compartment model, which incorporates hydrolysis of FDG-6-PO4 to FDG, was developed for the measure of kinetic constants and calculation of LCMRGlc. Our model is an extension of that developed by Sokoloff et al. Although small, hydrolysis of FDG-6-PO4 was found to be significant. A PCT system, the ECAT, was used to determine the rate constants, lumped constant, and stability of the model in human beings. The data indicate that cerebral FDG-6-PO4 in humans increases for about 90 minutes, plateaus, and then slowly decreases. After 10 minutes, cerebral blood FDG activity levels were found to be a minor fraction of tissue activity. Precursor pool turnover rate, distribution volumes, and red blood cell-plasma concentration ratios were determined. Reproducibility (precision) of LCMRGlc measurements (approximate 2 cm2 regions) was +/- 5.5% over a 5-hour period. The replacement of arterial blood sampling with venous sampling was validated.

992 citations


"Peculiar cases of a \"sleeping\" br..." refers background in this paper

  • ...One venous catheter was inserted in a dorsal hand vein which was kept warm to arterialize the venous blood for sampling (4)....

    [...]

Journal ArticleDOI
TL;DR: Using the rate constants and lumped constants determined in humans for the glucose metabolic rate kinetic model used to measure local cerebral glucose consumption, the average whole-brain metabolic rates for glucose in normal subjects measured with [18F]FDG and [11C]DG are 5.66 ± 0.37 (n = 6) and 4.99 mg/100 g/min, respectively.
Abstract: The rate constants and lumped constants (LCs) for [18F]fluorodeoxyglucose ([18F]FDG) and [11C]deoxyglucose ([11C]DG) were determined in humans for the glucose metabolic rate kinetic model used to measure local cerebral glucose consumption. The mean values (±SE) of the LCs for [18F]FDG and [11C]DG are 0.52 ± 0.028 (n = 9) and 0.56 ± 0.043 (n = 6), respectively. The mean values (±SE) of the rate constants k*1, k*2, k*3, and k*4 for [18F]FDG for gray matter are 0.095 ± 0.005, 0.125 ± 0.002, 0.069 ± 0.002, and 0.0055 ± 0.0003, respectively. The corresponding values for white matter are 0.065 ± 0.005, 0.126 ± 0.003, 0.066 ± 0.002, and 0.0054 ± 0.0006, respectively. Using these values and previously published values for the rate constants for [11C]DG, the average whole-brain metabolic rates for glucose in normal subjects measured with [18F]FDG and [11C]DG are 5.66 ± 0.37 (n = 6) and 4.99 ± 0.23 (n = 6) mg/100 g/min, respectively. These values are not significantly different (t = 1.56, p > 0.10) and agree well w...

434 citations


"Peculiar cases of a \"sleeping\" br..." refers methods in this paper

  • ...The time-course of the arterialized-venous plasma (18)F activity was determined and corrected for radioactive decay to the scan start time (2)....

    [...]

  • ...CMRglc was calculated by combining this procedure with measurement of (18)F timeactivity in blood (2)....

    [...]

Journal ArticleDOI
TL;DR: Evidence of viable tissue in the border zone of ischemia up to 48 h after stroke is furnished, while this viable peri-infarct tissue exhibits some potential for effective treatment of ischemic stroke.
Abstract: Sixteen patients were studied by multitracer positron emission tomography (PET) within 6-48 (mean of 23) h of onset of a hemispheric ischemic stroke and again 13-25 (mean of 15.6) days later. Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) were measured each time by standard methods, and the sets of brain slices obtained at the two studies were matched using a three-dimensional alignment procedure. On matched brain slices, regions of interest (ROIs) for infarct and peri-infarct tissue, contralateral mirror regions, and major brain structures were outlined. In the core of infarction, blood flow and metabolism were significantly lower than in the corresponding contralateral regions at the first study, and did not change during the observation period. In the peri-infarct tissue, CMRO2 was moderately decreased at the first measurement; over time, the CMRO2 deteriorated progressively while flow did not change. When peri-infarct regions were selected on the basis of increased OEF (25 +/- 29.8% above corresponding contralateral regions) on the early scans, the CBF was significantly decreased (23 +/- 6.6%) while the CMRO2 showed only a slight difference from the mirror region. Within the observation period, the CBF improved but the CMRO2, OEF, and CMRglc deteriorated. Only in a few regions with increased OEF and slightly impaired CMRO2 was metabolism preserved close to normal values. These data from repeat PET studies in reproducibly defined tissue compartments furnish evidence of viable tissue in the border zone of ischemia up to 48 h after stroke. While this viable peri-infarct tissue exhibits some potential for effective treatment of ischemic stroke, therapeutic routines available today cannot prevent subsequent metabolic derangement and progression to necrosis. Multitracer PET studies identifying viable tissue could be of value in the development of effective treatment of ischemic stroke.

429 citations


"Peculiar cases of a \"sleeping\" br..." refers background in this paper

  • ...1) and in the range reported for anesthesia (6), deep wave sleep (7), Alzheimer’s dementia (8), locked-in state (9), or stroke (10)....

    [...]

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Lerna et al. this paper measured the absolute cerebral metabolic rate of glucose consumption ( CMRglc ) in patients diagnosed with lung nodules while they were undergoing whole-body 18F-FDG-PET.