Hourly analysis of cerebrospinal fluid glucose shows large diurnal                     fluctuations

Verbeek, Marcel M.; Leen, Wilhelmina G.; Willemsen, M.A.A.P.; Slats, Diane; Claassen, Jurgen A.H.R.

doi:10.1177/0271678x16637612

Cited by 21 publications

(17 citation statements)

References 8 publications

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“…Currently, the routine diagnostic tools in clinical use for GLUT1-DS are low glucose in CSF and a reduced CSF glucose to blood glucose ratio. Glucose values can vary depending on age [ 16 – 18 ], and screening for glucose levels versus a pediatric-matched population can identify perturbations in metabolites, such as carbohydrate metabolism, to identify signatures of disease ( Table 2 ). The metabolomics approach in three CSF samples of GLUT1-DS not on ketogenic diet patients was applied to achieve a more comprehensive mirror of glucose-dependent pathways in the brain.…”

Section: Discussionmentioning

confidence: 99%

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

et al. 2017

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Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.

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Section: Discussionmentioning

confidence: 99%

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

et al. 2017

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“…Animals were kept under a regular light/dark cycle, and brain samples were collected every 4 hours, to obtain 6 time points. Since the distribution of transcripts is heterogeneous along the septo-temporal axis of the hippocampus (22), we focused on its ventral part (23), which is most epileptogenic in human TLE and experimental models (24). Using Affymetrix microarrays and the Jonckheere-Terpstra-Kendall (JTK) algorithm (30), we identified 1256 transcripts oscillating in the ventral hippocampus of control mice ( Fig.…”

Section: Circadian Regulation Of Genes and Proteins In The Mouse Hippmentioning

confidence: 99%

“…Patients with epilepsy display altered metabolic activity in specific brain regions; a clinical information that can be used for diagnosis purposes (21). Although debated, several studies report regional and circadian changes in energy metabolism in healthy humans, as measured by PET, functional MRI, MR spectroscopy, and glucose sensing in the cerebrospinal fluid (10,(22)(23)(24)(25)(26). Circadian changes in metabolism may be altered in epilepsy, as already demonstrated in patients with depression as compared to healthy controls (27).…”

Section: Introductionmentioning

confidence: 99%

The circadian hippocampus and its reprogramming in epilepsy: impact for chronotherapeutics

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et al. 2017

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Gene and protein expression displays circadian oscillations in numerous body organs. These oscillations can be disrupted in diseases, thus contributing to the disease pathology. Whether the molecular architecture of cortical brain regions oscillates daily and whether these oscillations are modified in brain disorders is less understood. We identified 1200 daily oscillating transcripts in the hippocampus of control mice. More transcripts (1600) were oscillating in experimental epilepsy, with only one fourth oscillating in both conditions. Proteomics confirmed these results. Metabolic activity and targets of antiepileptic drugs displayed different circadian regulation in control and epilepsy. Hence, the hippocampus, and perhaps other cortical regions, shows a daily remapping of its molecular landscape, which would enable different functioning modes during the night/day cycle. The impact of this remapping in brain pathologies needs to be taken into account not only to study their mechanisms, but also to design drug treatments and time their delivery.

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“…Since metabolism is an integral part of the circadian machinery (20,21), energy metabolism should oscillate accordingly. Although debated, several studies report regional and circadian changes in energy metabolism in healthy humans, as measured by positron emission tomography, functional magnetic resonance imaging, magnetic resonance spectroscopy, and glucose sensing in the cerebrospinal fluid (22)(23)(24)(25)(26)(27). Patients with epilepsy display altered metabolic activity in specific brain regions, important information for diagnosis purposes (28).…”

Section: Introductionmentioning

confidence: 99%

The circadian dynamics of the hippocampal transcriptome and proteome is altered in experimental temporal lobe epilepsy

et al. 2020

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Gene and protein expressions display circadian oscillations, which can be disrupted in diseases in most body organs. Whether these oscillations occur in the healthy hippocampus and whether they are altered in epilepsy are not known. We identified more than 1200 daily oscillating transcripts in the hippocampus of control mice and 1600 in experimental epilepsy, with only one-fourth oscillating in both conditions. Comparison of gene oscillations in control and epilepsy predicted time-dependent alterations in energy metabolism, which were verified experimentally. Although aerobic glycolysis remained constant from morning to afternoon in controls, it increased in epilepsy. In contrast, oxidative phosphorylation increased in control and decreased in epilepsy. Thus, the control hippocampus shows circadian molecular remapping, which is altered in epilepsy. We suggest that the hippocampus operates in a different functioning mode in epilepsy. These alterations need to be considered when studying epilepsy mechanisms, designing drug treatments, and timing their delivery.

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Hourly analysis of cerebrospinal fluid glucose shows large diurnal fluctuations

Cited by 21 publications

References 8 publications

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

The circadian hippocampus and its reprogramming in epilepsy: impact for chronotherapeutics

The circadian dynamics of the hippocampal transcriptome and proteome is altered in experimental temporal lobe epilepsy

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