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

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.

Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice

“…Here, it is further elucidated the role of BHB in the protection from DR, by evidencing its association with retinal BDNF levels and activity. This was in line with previous evidence reporting the induction of specific BDNF promoters by BHB in hippocampus neuron cell lines [ 12 , 13 , 14 , 26 , 27 ] and a link between serum BHB and proBDNF in healthy older adults [ 28 ]. However, our results suggested a BDNF promotion by BHB in diabetic mice retinas, which has not been previously highlighted by other studies.…”

Pro-Brain-Derived Neurotrophic Factor (BDNF), but Not Mature BDNF, Is Expressed in Human Skeletal Muscle: Implications for Exercise-Induced Neuroplasticity

“… 48 Our data showed that a 3-day fast, resulting in a 10-fold increase in plasma β-HB, had no impact on plasma mBDNF but induced a small but significant increase in plasma pro-BDNF. The concomitant pro-BDNF and β-HB increase is in line with recent data by Norgren et al 49 who showed that fatty acid-induced β-HB levels correlated with circulating pro-BDNF in humans. The reason for the lack of change in mBDNF in the present study is not clear.…”

Influence of Nutritional Ketosis Achieved through Various Methods on Plasma Concentrations of Brain Derived Neurotropic Factor

“…Thus, there does not appear to be a strong effect of chronic elevations in ketones on plasma BDNF. None of the participants in the three studies were in a cognitive deficit, which may inhibit the potential cognitive effects that may be seen in people with schizophrenia, autism and depression [ 34 , 35 , 36 ]. This lack of change across all methods of induced ketosis, requires further research on the level of ketosis needed to achieve an increase in BDNF levels for populations with and without cognitive decline.…”