TL;DR
Exercise is associated with significant BDNF increases in neurological populations with MS and PD, particularly with longer sessions and combined training, and findings should be considered hypothesis-generating.
Background and Objectives: Brain-derived neurotrophic factor (BDNF) supports neuronal function and plasticity, but exercise meta-analyses may reuse primary studies and combine distinct outcomes. We evaluated review-level evidence while preventing direct reuse of the same primary-study evidence within pooled syntheses in this umbrella review and meta-analysis. Methods: Thirty-nine systematic reviews with quantitative syntheses of peripheral BDNF were assessed. Review–primary-study links were normalized, methodological quality was appraised with AMSTAR 2, and estimates were classified by exercise timing and comparison design. Only reviews meeting the zero-overlap criterion were pooled using restricted maximum likelihood random-effects models with Hartung–Knapp inference. Prediction intervals were calculated; network and dose–response findings were summarized separately. Results: The corpus included 507 review–primary-study occurrences representing 289 unique normalized primary-study identities (corrected covered area [CCA], 1.99%). AMSTAR 2 overall confidence was low in eight reviews and critically low in 31. Seven reviews meeting the zero-overlap criterion contributed to the chronic-controlled synthesis, yielding a pooled SMD of 0.85 (95% CI 0.07–1.64; I2 = 93.9%; 95% prediction interval −1.20 to 2.91). Acute-controlled effects were inconclusive (four reviews; SMD 0.49, 95% CI −0.07 to 1.05; I2 = 53.8%), as were chronic pre–post effects (three reviews; SMD 0.32, 95% CI −0.04 to 0.69; I2≈0%). Quality-restricted meta-analysis was not estimable, and small-study-effect tests were not performed because no synthesis set contained at least 10 independent reviews. Conclusions: Exercise may increase peripheral BDNF in some chronic-controlled settings, but effects vary substantially. Circulating BDNF does not directly establish central BDNF engagement or enhanced neuroplasticity, and current review-level evidence does not establish a universal response, clinical benefit, superior modality, or optimal dose.
Background Global aging leads to increased age-related cognitive decline and neurodegenerative diseases like dementia. Brain-derived neurotrophic factor (BDNF) is crucial for neuronal survival, synaptic plasticity, and cognitive function, but its levels often decline with age. Physical exercise can potentially elevate BDNF levels in older adults. Previous meta-analyses had limitations in comparing diverse exercise types simultaneously and exploring dose-response relationships. Objective To comprehensively compare the relative effects of exercise types on BDNF levels in older adults and explore dose-response relationships using a multilevel Bayesian network meta-analysis. Methods A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for randomized controlled trials (RCTs) involving exercise interventions in older adults was conducted until April 2025. Data on BDNF levels, exercise type, duration, frequency, and intensity were collected. A multilevel Bayesian network meta-analysis was performed to compare exercise interventions and explore dose-response relationships. Results Forty-seven RCTs with 1815 participants were included. Aquatic exercise showed the largest point estimate (SMD = 1.00), followed by mind-body exercise (SMD = 0.61) and mixed exercise (SMD = 0.30). However, the AQE estimate was based on sparse evidence and should be interpreted cautiously. Several exercise modalities exceeded a 0.5-SD distribution-based interpretability threshold. Aerobic, combined aerobic and resistance, and resistance exercises also improved BDNF levels, whereas HIIT remained uncertain in the primary analysis, although the active-comparator-exclusion sensitivity analysis yielded a positive estimate that requires confirmation. Dose-response analyses showed non-linear relationships, with effects observed across dosages and after intervention cessation. Advanced age was linked to diminished effects. Conclusion Several exercise modalities may increase BDNF levels in older adults, but AQE and HIIT should be interpreted as preliminary or hypothesis-generating. Complex dose-response relationships exist, and age and sex may moderate effectiveness. Treatment rankings should be interpreted cautiously in light of evidence certainty.
Objective To systematically evaluate the effects of exercise interventions on brain-derived neurotrophic factor (BDNF) in patients with stroke, and to examine the dose–response relationships associated with acute and long-term exercise. Methods PubMed, Embase, Web of Science, the Cochrane Library, and APA PsycINFO were searched for studies of exercise interventions in patients with stroke that reported BDNF outcomes. Risk of bias was assessed using RoB 2.0 and ROBINS-I. A network dose–response meta-regression was conducted within a Bayesian random-effects framework. Results Twenty-three studies involving 903 participants were included, comprising 14 randomized controlled trials, 8 non-randomized studies, and 1 randomized crossover trial. Acute overall exercise showed a modest positive trend at lower dose levels; however, at a dose of 250 METs⋅min/week, the 95% credible interval included zero, indicating substantial uncertainty regarding whether a single bout of low-dose exercise produces a reliable increase in BDNF. For long-term overall exercise, posterior estimates generally favored a positive BDNF response as dose increased. The 95% credible interval first no longer included zero at 1300 METs⋅min/week, and estimates at 1700, 2000, 2300, and 2700 METs⋅min/week remained compatible with positive effects. However, these findings should be interpreted cautiously because the evidence base was limited and precision varied across dose levels. Clear differences were also observed across long-term exercise modalities. Multicomponent exercise showed the most favorable directional pattern across the 1700–2700 METs⋅min/week range, although several estimates were imprecise and the apparent advantage of this modality should be regarded as exploratory. By contrast, walking, cycling, and exercise combined with cognitive training all showed positive directional trends, but the 95% credible intervals included zero across dose levels, indicating substantial uncertainty regarding these modality-specific effects. Conclusion The effects of exercise on BDNF in patients with stroke are jointly shaped by intervention duration, dose level, and exercise modality. Compared with acute exercise, long-term exercise at moderate-to-high doses, particularly multicomponent exercise, may be associated with a more favorable BDNF response. However, because the certainty of evidence was mostly moderate to low or very low and publication bias was detected, these findings should be considered preliminary and hypothesis-generating rather than definitive exercise prescription recommendations. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261350793, identifier CRD420261350793.
Background: Exercise is a central regulator of metabolic and neurotrophic processes, in which irisin and brain-derived neurotrophic factor (BDNF) play key roles in mediating muscle–brain communication. Objective: This systematic review aimed to summarize the effects of different exercise modalities and immobilization on irisin and BDNF expression, focusing on the PGC-1alpha–FNDC5–irisin signaling pathway. Methods: The review followed the PRISMA 2020 guidelines. Studies published between January 1995 and September 2025 were identified through PubMed, Scopus, Web of Science, and Google Scholar using Boolean search combinations (‘irisin’ AND ‘BDNF’ AND ‘exercise’). Inclusion criteria covered human and animal studies exploring the irisin–BDNF axis. Data were extracted independently and synthesized qualitatively. Risk of bias was assessed using Cochrane domains. Results: Evidence indicates endurance, resistance, and high-intensity interval training increase circulating irisin and hippocampal BDNF levels. Acute exercise induces transient increases, whereas chronic training produces sustained adaptations. Immobilization reduces both irisin and BDNF expression. Conclusions: Current evidence suggests the PGC-1alpha–FNDC5–irisin–BDNF axis may constitute a molecular link between skeletal muscle activity and brain health; causal conclusions are limited by the associative and largely preclinical nature of the evidence. This review was not prospectively registered. Methodological heterogeneity precluded meta-analysis. Data extraction sheets and full search strings are available as supplementary material.
Postoperative cognitive dysfunction (POCD) is a frequent complication after surgery, particularly among older adults, and its underlying mechanisms remain incompletely understood. Brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal survival and synaptic plasticity, and has been implicated in POCD but published findings are inconsistent. We therefore performed a systematic review and meta-analysis to evaluate the association between perioperative BDNF levels and POCD across surgical time points. Following PRISMA guidelines, we searched PubMed, EMBASE, Web of Science, and Scopus were searched for observational studies that reported perioperative BDNF levels in patients with and without POCD. Two reviewers independently extraction data and assessed study quality using the Newcastle-Ottawa Scale. Statistical analyses were conducted in RevMan 5.3, with mean differences (MD) with 95% confidence intervals (CI) were calculated for absolute BDNF levels and perioperative changes (ΔBDNF) at preoperative, intraoperative, and postoperative stages. Six studies including 135 patients with POCD and 247 without POCD met the inclusion criteria. The fixed-effects meta-analysis showed lower intraoperative BDNF levels in the POCD group (MD = −5.62, 95% CI[−8.95, −2.29], P = 0.0009; I2 = 0%). Similarly, intraoperative ΔBDNF was reduced in the POCD group under a fixed-effects meta-model (MD = −9.73, 95% CI[−16.08, −3.38], P = 0.003; I2 = 0%). The subgroup analysis indicated that the type of surgery may contribute to the high heterogeneity observed in 24-h postoperative BDNF and in 24-h postoperative ΔBDNF. These findings suggest that intraoperative BDNF levels and their dynamic changes may serve as preliminary exploratory biomarker for POCD. The intraoperative phase appears to be a critical window for BDNF monitoring, yet prospective cohort studies are urgently needed to externally validate its uesfulness for screening patients at high risk of POCD before clinical implementation. Current evidence remains preliminary, since only six small observational studies were included and substantial statistical heterogeneity was present in multiple postoperative subgroup analyses. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251265921.
The aim of this review was to examine if Brain-Derived Neurotrophic Factor (BDNF) could be a predictor for post-stroke depression (PSD). We searched Web of Science, Embase, PubMed, and Scopus databases for all relevant studies, with no language restrictions from inception of databases to 1st September 2025. We analyzed average BDNF levels in PSD versus non-PSD groups to estimate the Mean Difference (MD) with 95% confidence intervals (CI). Additionally, pooled odds ratios (OR) with 95% CI were determined to assess the link between reduced BDNF levels and PSD risk. Ten studies were included. In the meta-analysis of nine studies, patients with PSD had significantly lower circulating BDNF levels compared with non-PSD patients (MD: -4.21, 95% CI -6.65 to -1.77; I2 = 97%). Six studies reporting OR showed that low BDNF was associated with an increased risk of PSD (OR 0.84: 95% CI 0.76-0.92; I2 = 77%). Publication bias was noted in the later analysis. Sensitivity analyses confirmed the stability of results, and subgroup analyses demonstrated consistent associations across study location, stroke type, follow-up duration, and diagnostic method. BDNF may be a potential biomarker for PSD. Lower levels of BDNF are noted in PSD as compared to non-PSD patients. Lower levels of BDNF seem to be significantly associated with higher risk of PSD. Evidence must be interpreted with caution given the presence of publication bias. Further studies are needed to increase the validity of these conclusions.
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