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
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, influe...
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Frontiers Media S.A.
2021-08-01
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Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2021.716594/full |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jakob Norgren Makrina Daniilidou Makrina Daniilidou Ingemar Kåreholt Ingemar Kåreholt Shireen Sindi Shireen Sindi Ulrika Akenine Ulrika Akenine Karin Nordin Staffan Rosenborg Tiia Ngandu Tiia Ngandu Miia Kivipelto Miia Kivipelto Miia Kivipelto Miia Kivipelto Miia Kivipelto Anna Sandebring-Matton Anna Sandebring-Matton Anna Sandebring-Matton |
spellingShingle |
Jakob Norgren Makrina Daniilidou Makrina Daniilidou Ingemar Kåreholt Ingemar Kåreholt Shireen Sindi Shireen Sindi Ulrika Akenine Ulrika Akenine Karin Nordin Staffan Rosenborg Tiia Ngandu Tiia Ngandu Miia Kivipelto Miia Kivipelto Miia Kivipelto Miia Kivipelto Miia Kivipelto Anna Sandebring-Matton Anna Sandebring-Matton Anna Sandebring-Matton 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 Frontiers in Aging Neuroscience ketosis brain-derived neurotrophic factor proBDNF signaling metabolites repeatability aged humans |
author_facet |
Jakob Norgren Makrina Daniilidou Makrina Daniilidou Ingemar Kåreholt Ingemar Kåreholt Shireen Sindi Shireen Sindi Ulrika Akenine Ulrika Akenine Karin Nordin Staffan Rosenborg Tiia Ngandu Tiia Ngandu Miia Kivipelto Miia Kivipelto Miia Kivipelto Miia Kivipelto Miia Kivipelto Anna Sandebring-Matton Anna Sandebring-Matton Anna Sandebring-Matton |
author_sort |
Jakob Norgren |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Aging Neuroscience |
issn |
1663-4365 |
publishDate |
2021-08-01 |
description |
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. |
topic |
ketosis brain-derived neurotrophic factor proBDNF signaling metabolites repeatability aged humans |
url |
https://www.frontiersin.org/articles/10.3389/fnagi.2021.716594/full |
work_keys_str_mv |
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doaj-03760df5966c4c26a29808cdfd8abc342021-08-20T10:07:44ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652021-08-011310.3389/fnagi.2021.716594716594Serum 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 AdultsJakob Norgren0Makrina Daniilidou1Makrina Daniilidou2Ingemar Kåreholt3Ingemar Kåreholt4Shireen Sindi5Shireen Sindi6Ulrika Akenine7Ulrika Akenine8Karin Nordin9Staffan Rosenborg10Tiia Ngandu11Tiia Ngandu12Miia Kivipelto13Miia Kivipelto14Miia Kivipelto15Miia Kivipelto16Miia Kivipelto17Anna Sandebring-Matton18Anna Sandebring-Matton19Anna Sandebring-Matton20Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenDivision of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenDivision of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenAging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, SwedenInstitute of Gerontology, School of Health and Welfare, Aging Research Network - Jönköping (ARN-J), Jönköping University, Jönköping, SwedenDivision of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenAgeing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, United KingdomDivision of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenTheme Inflammation and Aging, Medical Unit Aging, Karolinska University Hospital, Stockholm, SwedenClinical Pharmacology, Karolinska University Hospital, Stockholm, SwedenClinical Pharmacology, Karolinska University Hospital, Stockholm, SwedenDivision of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenPopulation Health Unit, Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, FinlandDivision of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenAgeing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, United KingdomTheme Inflammation and Aging, Medical Unit Aging, Karolinska University Hospital, Stockholm, SwedenDepartment of Neurology, Institute of Clinical Medicine and Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland0Research & Development Unit, Stockholms Sjukhem, Stockholm, SwedenDivision of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenDivision of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SwedenAgeing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, United KingdomBackground: 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.https://www.frontiersin.org/articles/10.3389/fnagi.2021.716594/fullketosisbrain-derived neurotrophic factorproBDNFsignaling metabolitesrepeatabilityaged humans |