Norgren Jakob, Daniilidou Makrina, Kåreholt Ingemar, Sindi Shireen, Akenine Ulrika, Nordin Karin, Rosenborg Staffan, Ngandu Tiia, Kivipelto Miia, Sandebring-Matton Anna
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Front Aging Neurosci. 2021 Aug 20;13:716594. doi: 10.3389/fnagi.2021.716594. eCollection 2021.
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). 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. proBDNF increased more in vs. between 0 and 4 h (z-score: β = 0.25, 95% CI 0.07-0.44; = 0.007). Individual change in BHB 0-2 h, predicted change in proBDNF 0-4 h, (β = 0.40, CI 0.12-0.67; = 0.006). Change in mBDNF was lower in vs. at 0-2 h (β = -0.88, CI -1.37 to -0.40; < 0.001) and cumulatively 0-4 h (β = -1.01, CI -1.75 to -0.27; = 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. 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. ClinicalTrials.gov, NCT03904433.
β-羟基丁酸酯（BHB）可上调小鼠脑源性神经营养因子（BDNF），但BHB与人类BDNF之间的关联鲜为人知。本研究的主要目的是调查生酮补充剂诱导的酮症（即升高的BHB水平）是否会影响健康老年人血清中成熟BDNF（mBDNF）及其前体proBDNF的水平。次要目的是确定这些生物标志物的个体内稳定性（重复性），以组内相关系数（ICC）衡量。在一项6臂随机交叉试验中，其中3个组用于当前的子研究。15名健康志愿者，年龄65 - 75岁，53%为女性，每周测试一次。在禁食12小时后，将测试油混入咖啡和奶油中服用。根据酮症水平标记，这些组分别为：葵花籽油（低酮）；椰子油（中酮）；辛酸 + 椰子油（高酮）。摄入后4小时内重复采集血样。分析血清BDNF水平从基线到1小时、2小时和4小时的变化，以比较不同组。横断面分析BHB与BDNF之间的个体关联以及延迟反应（0 - 2小时BHB的变化与0 - 4小时BDNF的变化）。ICC估计值根据三个研究日的基线水平计算。在0至4小时之间，proBDNF在[具体组]中的升高幅度大于[另一组]（z分数：β = 0.25，95%置信区间0.07 - 0.44；P = 0.007）。0 - 2小时BHB的个体变化可预测0 - 4小时proBDNF的变化（β = 0.40，置信区间0.12 - 0.67；P = 0.006）。在0 - 2小时，[具体组]中mBDNF的变化低于[另一组]（β = -0.88，置信区间 -1.37至 -0.40；P < 0.001），在0 - 4小时累计变化中也是如此（β = -1.01，置信区间 -1.75至 -0.27；P = 0.01），但这无法通过BHB水平预测。proBDNF的ICC为0.96（95%置信区间0.92 - 0.99），mBDNF的ICC为0.72（置信区间0.47 - 0.89）。这些发现支持健康老年人外周BHB变化与proBDNF之间存在联系。对于mBDNF，不同组之间变化不同，但与BHB水平无关。由于样本量小，有必要进行重复研究。出色的重复性鼓励未来将proBDNF作为脑健康预测指标进行研究。ClinicalTrials.gov，NCT03904433。
