Serum proBDNF Is Associated With Changes in the Ketone Body β-Hydroxybutyrate and Shows Superior Repeatability Over Mature BDNF: Secondary Outcomes From a Cross-Over Trial in Healthy Older Adults

Jakob Norgren, Makrina Daniilidou, Ingemar Kåreholt, Shireen Sindi, Ulrika Akenine, Karin Nordin, Staffan Rosenborg, Tiia Ngandu, Miia Kivipelto, Anna Sandebring-Matton, Jakob Norgren, Makrina Daniilidou, Ingemar Kåreholt, Shireen Sindi, Ulrika Akenine, Karin Nordin, Staffan Rosenborg, Tiia Ngandu, Miia Kivipelto, Anna Sandebring-Matton

Abstract

Background: β-hydroxybutyrate (BHB) can upregulate brain-derived neurotrophic factor (BDNF) in mice, but little is known about the associations between BHB and BDNF in humans. The primary aim here was to investigate whether ketosis (i.e., raised BHB levels), induced by a ketogenic supplement, influences serum levels of mature BDNF (mBDNF) and its precursor proBDNF in healthy older adults. A secondary aim was to determine the intra-individual stability (repeatability) of those biomarkers, measured as intra-class correlation coefficients (ICC). Method: Three of the arms in a 6-arm randomized cross-over trial were used for the current sub-study. Fifteen healthy volunteers, 65-75 y, 53% women, were tested once a week. Test oils, mixed in coffee and cream, were ingested after a 12-h fast. Labeled by their level of ketosis, the arms provided: sunflower oil (lowK); coconut oil (midK); caprylic acid + coconut oil (highK). Repeated blood samples were collected for 4 h after ingestion. Serum BDNF levels were analyzed for changes from baseline to 1, 2 and 4 h to compare the arms. Individual associations between BHB and BDNF were analyzed cross-sectionally and for a delayed response (changes in BHB 0-2 h to changes in BDNF at 0-4 h). ICC estimates were calculated from baseline levels from the three study days. Results: proBDNF increased more in highK vs. lowK between 0 and 4 h (z-score: β = 0.25, 95% CI 0.07-0.44; p = 0.007). Individual change in BHB 0-2 h, predicted change in proBDNF 0-4 h, (β = 0.40, CI 0.12-0.67; p = 0.006). Change in mBDNF was lower in highK vs. lowK at 0-2 h (β = -0.88, CI -1.37 to -0.40; p < 0.001) and cumulatively 0-4 h (β = -1.01, CI -1.75 to -0.27; p = 0.01), but this could not be predicted by BHB levels. ICC was 0.96 (95% CI 0.92-0.99) for proBDNF, and 0.72 (CI 0.47-0.89) for mBDNF. Conclusions: The findings support a link between changes in peripheral BHB and proBDNF in healthy older adults. For mBDNF, changes differed between arms but independent to BHB levels. Replication is warranted due to the small sample. Excellent repeatability encourages future investigations on proBDNF as a predictor of brain health. Clinical Trial Registration:ClinicalTrials.gov, NCT03904433.

Keywords: aged humans; brain-derived neurotrophic factor; cognitive health; ketosis; proBDNF; repeatability; signaling metabolites; β-hydroxybutyrate.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Norgren, Daniilidou, Kåreholt, Sindi, Akenine, Nordin, Rosenborg, Ngandu, Kivipelto and Sandebring-Matton.

Figures

Figure 1
Figure 1
Comparisons of biomarker differences between arms (A–E), and individual associations between BHB and BDNF (F–H). (A,B) Profile plots describing the dynamic changes in mean proBDNF-log and mBDNF, respectively. (C) The cumulative ketogenic response in arms, measured as nAUC (area under the curve normalized to T0 [min]) for β-hydroxybutyrate (BHB). (D,E) Box plots describing the response per arm for proBDNF and mBDNF, respectively. (F,G) Partial residual plots showing individual associations between BHB and BDNF outcomes. (H) Point estimates of cross-sectional associations between BHB and BDNF on an individual level at different timepoints. BDNF: brain-derived neurotropic factor. Box plots indicate median, interquartile range and maximum/minimum values.
Figure 2
Figure 2
Post-hoc analyses. (A) The early ketogenic response as a predictor of change in mBDNF, T0-120 (B) Changes in the log-ratio mBDNF/proBDNF by arm.
Figure 3
Figure 3
Distribution of proBDNF-log and mBDNF per individual, and the significance of pair-wise comparisons of differences in baseline means (A) Values from baseline (T0) at three study days within a month. The boxes indicate minimum, maximum and median values. ID: 1–15 represent individuals. (B) The proportion of pair-wise comparisons of individual baseline means, by categories p < 0.001, p < 0.05 and p ≥ 0.05.

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