Circulating brain‑derived neurotrophic factor as a potential biomarker of cognitive reserve in post-stroke cognitive impairment
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Abstract
Post-stroke cognitive impairment (PSCI) is a prevalent and disabling neurological complication, affecting approximately 40-60% of stroke survivors within the first year and carrying a substantial risk of progression to vascular dementia. The observation that the severity of cognitive dysfunction is frequently disproportionate to the extent of structural brain injury implicates the modulatory role of cognitive reserve (CR). Yet the precise neurobiological mechanism through which CR confers this protection remains incompletely characterised. Brain-derived neurotrophic factor (BDNF), the principal regulator of synaptogenesis, neurogenesis, and long-term potentiation (LTP) via TrkB-mediated PI3K/Akt, MAPK/ERK, and PLC-γ signalling cascades, has emerged as a plausible biological mediator linking CR to post-stroke cognitive outcomes. This structured narrative review examined the biological pathomechanisms through which CR modulates circulating BDNF levels and thereby influences PSCI risk in patients with ischaemic stroke. A systematic search was performed in PubMed/MEDLINE, Scopus, and Google Scholar (January-April 2026), yielding 52 eligible publications (2015-2026) identified through the terms brain-derived neurotrophic factor, cognitive reserve, post-stroke cognitive impairment, neuroplasticity, and ischaemic stroke, with Boolean operators. The review demonstrated that individuals with high CR, quantified using the Cognitive Reserve Index questionnaire (CRIq; score ≥115), exhibit significantly more robust mBDNF responses during the subacute post-stroke phase (days 7-14), the optimal window of neuroplasticity, than those with lower CR. CR determinants, including educational attainment, occupational complexity, and leisure-time cognitive engagement correlate positively with serum BDNF levels through upregulation of activity-dependent BDNF gene expression, enhanced plasmin-mediated proBDNF-to-mBDNF conversion, and promotion of neural efficiency and compensation mechanisms. In addition, high CR was associated with better-preserved frontoparietal control network, salience network, and default mode network integrity, attenuating the neurological impact of diaschisis and global connectivity disruption. Integrating serum BDNF measurement with CRIq assessment at the subacute post-stroke phase offers a clinically applicable strategy for PSCI risk stratification and the personalisation of neuroplasticity-based cognitive rehabilitation programmes.
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