血浆proBDNF、mBDNF与t-PA水平对脑小血管病认知障碍的预测价值及机制探讨

doi:10.3969/j.issn.1673-5765.2026.03.005

摘要/Abstract

摘要： 目的探讨血浆脑源性神经营养因子前体（precursor of brain-derived neurotrophic factor，proBDNF）、成熟型脑源性神经营养因子（mature brain-derived neurotrophic factor，mBDNF）及组织型纤溶酶原激活物（tissue-type plasminogen activator，t-PA）水平对脑小血管病（cerebral small vessel disease，CSVD）认知障碍的预测价值及相关机制。
方法采用横断面病例对照设计，纳入2021年11月—2022年11月于昆明医科大学第二附属医院神经内科就诊的CSVD患者，并根据患者受教育程度和MoCA总分分为CSVD认知正常组、CSVD认知障碍组。同时选取同期健康体检者或CSVD患者家属、陪护人员中的合格志愿者作为对照组。采用酶联免疫吸附测定法检测血浆proBDNF、mBDNF、t-PA浓度；使用CSVD总负担评分（0～4分）评估CSVD总负担；采用MoCA进行认知功能评定。通过协方差分析校正混杂因素，比较三组间血浆生物标志物水平差异；基于偏相关分析，探讨血浆生物标志物水平与MoCA总分的相关性；采用ROC曲线评估血浆生物标志物水平及联合模型对CSVD认知障碍与CSVD认知正常的区分效能。
结果共纳入受试者131例，其中对照组32例，CSVD认知正常组38例，CSVD认知障碍组61例。校正混杂因素后，CSVD认知障碍组血浆proBDNF水平低于CSVD认知正常组和对照组，血浆mBDNF水平低于对照组，血浆t-PA水平高于对照组（均P<0.05）。偏相关分析显示，血浆proBDNF、mBDNF水平均与MoCA总分呈正相关（r=0.439，P<0.001；r=0.269，P=0.007），血浆t-PA水平与MoCA总分呈负相关（r=-0.270，P=0.007）。ROC曲线分析显示，血浆proBDNF、t-PA水平在区分CSVD认知障碍与CSVD认知正常时，具有中等预测价值（AUC 0.709，P<0.001；AUC 0.684，P<0.001）。基于血浆proBDNF、mBDNF、t-PA水平及CSVD总负担评分构建的联合模型预测效能最优（AUC 0.844，95%CI 0.779～0.908）。
结论 CSVD认知障碍患者的血浆proBDNF、mBDNF水平降低，t-PA水平升高，且其变化与认知功能损害程度相关。血浆proBDNF、t-PA水平对CSVD认知障碍具有中等预测价值，联合CSVD总负担评分构建的联合模型，可有效提升预测效能。

文章导读： 本研究结果证实CSVD认知障碍患者存在血浆proBDNF、mBDNF水平降低与t-PA水平升高的特征性改变。基于血浆proBDNF、mBDNF、t-PA水平，并联合CSVD总负担评分构建的联合模型，有助于临床识别CSVD认知障碍患者。本研究为深入理解CSVD认知障碍的分子机制提供了新线索，为探索潜在的血浆生物标志物组合、早期识别CSVD认知障碍高危患者提供了依据。

关键词: 脑小血管病; 认知障碍; 脑源性神经营养因子前体; 组织型纤溶酶原激活物

Abstract: Objective To explore the predictive value and underlying mechanisms of plasma precursor of brain-derived neurotrophic factor (proBDNF), mature brain-derived neurotrophic factor (mBDNF), and tissue-type plasminogen activator (t-PA) levels for cognitive impairment in cerebral small vessel disease (CSVD).
Methods A cross-sectional case-control study was conducted to enroll CSVD patients admitted to the Department of Neurology, the Second Affiliated Hospital of Kunming Medical University from November 2021 to November 2022. The patients were classified into a CSVD with normal cognition group and a CSVD with cognitive impairment group based on their educational level and MoCA score. Meanwhile, eligible healthy volunteers receiving physical examination, as well as family members and caregivers of CSVD patients during the same period, were selected as the control group. Enzyme linked immunosorbent assay was used to detect plasma concentrations of proBDNF, mBDNF, and t-PA. The total CSVD burden was assessed by the total CSVD burden score (0-4 points), and cognitive function was evaluated by the MoCA. Analysis of covariance was performed to adjust for confounding factors and compare the differences in plasma biomarker levels among the three groups. Partial correlation analysis was applied to explore the correlations between plasma biomarker levels and MoCA scores. ROC curves were used to evaluate the discriminatory efficacy of plasma biomarker levels and the combined model in distinguishing CSVD with cognitive impairment from CSVD with normal cognition.
Results A total of 131 subjects were enrolled, including 32 in the control group, 38 in the CSVD with normal cognition group, and 61 in the CSVD with cognitive impairment group. After adjusting for confounding factors, plasma proBDNF level in the CSVD with cognitive impairment group was lower than that in the CSVD with normal cognition group and the control group, and plasma mBDNF level was lower than that in the control group, whereas plasma t-PA level was higher than that in the control group (all P<0.05). Partial correlation analysis showed that plasma proBDNF and mBDNF levels were positively correlated with total MoCA scores (r=0.439, P<0.001; r=0.269, P=0.007), while plasma t-PA level was negatively correlated with total MoCA scores (r=-0.270, P=0.007). ROC curve analysis indicated that plasma proBDNF and t-PA levels had moderate predictive value in distinguishing CSVD with cognitive impairment from CSVD with normal cognition (AUC 0.709, P<0.001; AUC 0.684, P<0.001). The combined model constructed based on plasma levels of proBDNF, mBDNF, and t-PA, and the total CSVD burden score had the optimal predictive efficacy (AUC 0.844, 95%CI 0.779-0.908).
Conclusions Reduced plasma proBDNF and mBDNF levels and elevated t-PA level were observed in CSVD patients with cognitive impairment, and the changes were associated with the severity of cognitive impairment. Plasma proBDNF and t-PA levels have moderate predictive value for cognitive impairment in CSVD, and the combined model incorporating the total CSVD burden score can effectively improve the predictive efficacy.

Key words: Cerebral small vessel disease; Cognitive impairment; Precursor of brain-derived neurotrophic factor; Tissue-type plasminogen activator

中图分类号:

熊静, 刘凤, 李馨蕊, 刘利民, 刘宏明, 李云媛. 血浆proBDNF、mBDNF与t-PA水平对脑小血管病认知障碍的预测价值及机制探讨[J]. 中国卒中杂志, 2026, 21(3): 293-302.

XIONG Jing, LIU Feng, LI Xinrui, LIU Limin, LIU Hongming, LI Yunyuan. Predictive Value and Mechanism of Plasma proBDNF, mBDNF, and t-PA Levels for Cognitive Impairment in Cerebral Small Vessel Disease [J]. Chinese Journal of Stroke, 2026, 21(3): 293-302.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://www.chinastroke.org.cn/CN/10.3969/j.issn.1673-5765.2026.03.005

https://www.chinastroke.org.cn/CN/Y2026/V21/I3/293

参考文献

[1] 中国研究型医院学会脑小血管病专业委员会《中国脑小血管病诊治专家共识》编写组. 中国脑小血管病诊治专家共识2021[J]. 中国卒中杂志，2021，16（7）：716-726.
Writing Group for the Chinese Expert Consensus on the Diagnosis and Treatment of Cerebral Small Vessel Disease，Specialty Committee on Cerebral Small Vessel Disease，Chinese Research Hospital Association. Chinese expert consensus on the diagnosis and treatment of cerebral small vessel disease（2021）[J]. Chin J Stroke，2021，16（7）：716-726.
[2] ZHAO W N，SUN W Q，LI S O，et al. Exosomal miRNA-223-3p as potential biomarkers in patients with cerebral small vessel disease cognitive impairment[J/OL]. Ann Transl Med，2021，9（24）：1781[2025-10-30]. https://doi.org/10.21037/atm-21-6086.
[3] QUICK S，PROCTER T V，MOSS J，et al. Loss of the heterogeneous expression of flippase ATP11B leads to cerebral small vessel disease in a normotensive rat model[J]. Acta Neuropathol，2022，144（2）：283-303.
[4] QUICK S，MOSS J，RAJANI R M，et al. A vessel for change：endothelial dysfunction in cerebral small vessel disease[J]. Trends Neurosci，2021，44（4）：289-305.
[5] GAO L N，ZHANG Y，STERLING K，et al. Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential[J/OL]. Transl Neurodegener，2022，11（1）：4[2025-10-30]. https://doi.org/10.1186/s40035-022-00279-0.
[6] MIZUI T，OHIRA K，KOJIMA M. BDNF pro-peptide：a novel synaptic modulator generated as an N-terminal fragment from the BDNF precursor by proteolytic processing[J]. Neural Regen Res，2017，12（7）：1024-1027.
[7] MORI Y，TSUJI M，OGUCHI T，et al. Serum BDNF as a potential biomarker of Alzheimer’s Disease：verification through assessment of serum，cerebrospinal fluid，and medial temporal lobe atrophy[J/OL]. Front Neurol，2021，12：653267[2025-10-30]. https://doi.org/10.3389/fneur.2021.653267.
[8] YI X，YANG Y J，ZHAO Z F，et al. Serum mBDNF and proBDNF expression levels as diagnosis clue for early stage Parkinson’s disease[J/OL]. Front Neurol，2021，12：680765[2025-10-30]. https://doi.org/10.3389/fneur.2021.680765.
[9] GUNSTAD J，BENITEZ A，SMITH J，et al. Serum brain-derived neurotrophic factor is associated with cognitive function in healthy older adults[J]. J Geriatr Psychiatry Neurol，2008，21（3）：166-170.
[10] KOMULAINEN P，PEDERSEN M，HÄNNINEN T，et al. BDNF is a novel marker of cognitive function in ageing women：the DR’s EXTRA study[J]. Neurobiol Learn Mem，2008，90（4）：596-603.
[11] HUMPHREYS S J，MUTCH N J，WHYTE C S. Endothelial cell source dictates the expression and release of fibrinolytic markers in a proinflammatory environment[J/OL]. Res Pract Thromb Haemost，2025，9（5）：102929[2025-10-30]. https://doi.org/10.1016/j.rpth.2025.102929.
[12] ABDULLAH Z，BAYRAKTUTAN U. Suppression of PKC-α attenuates TNF-α-evoked cerebral barrier breakdown via regulations of MMP-2 and plasminogen-plasmin system[J]. Biochim Biophys Acta，2016，1862（7）：1354-1366.
[13] 王婷，杨可，张圆. 早期血脑屏障损伤在急性缺血性卒中tPA溶栓后出血性转化中的作用及其机制[J]. 国际脑血管病杂志，2016，24（11）：1033-1038.
WANG T，YANG K，ZHANG Y. Roles and mechanisms of early blood-brain barrier damage in hemorrhagic transformation in acute ischemic stroke after tPA thrombolysis[J]. Int J Cerebrovasc Dis，2016，24（11）：1033-1038.
[14] ZHANG B X，LEUNG L，SU E J，et al. PA system in the pathogenesis of ischemic stroke[J]. Arterioscler Thromb Vasc Biol，2025，45（5）：600-608.
[15] SPANÒ R，PORTIOLI C，GEROSKI T，et al. Enhancing thrombolysis safety in post-acute ischemic stroke with tissue plasminogen activator-associated microparticles[J]. ACS Nano，2025，19（25）：22882-22899.
[16] SALEEM S，WANG D，ZHAO T Q，et al. Matrix metalloproteinase-9 expression is enhanced by ischemia and tissue plasminogen activator and induces hemorrhage，disability and mortality in experimental stroke[J/OL]. Neuroscience，2021，460：120-129[2025-10-30]. https://doi.org/10.1016/j.neuroscience.2021.01.003.
[17] KNOTTNERUS I L H，GOVERS-RIEMSLAG J W P，HAMULYAK K，et al. Endothelial activation in lacunar stroke subtypes[J]. Stroke，2010，41（8）：1617-1622.
[18] SAMSON A L，MEDCALF R L. Tissue-type plasminogen activator：a multifaceted modulator of neurotransmission and synaptic plasticity[J]. Neuron，2006，50（5）：673-678.
[19] RODIER M，PRIGENT-TESSIER A，BÉJOT Y，et al. Exogenous t-PA administration increases hippocampal mature BDNF levels. Plasmin-or NMDA-dependent mechanism？[J/OL]. PLoS One，2014，9（3）：e92416[2025-10-30]. https://doi.org/10.1371/journal.pone.0092416.
[20] PANG P T，TENG H K，ZAITSEV E，et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity[J]. Science，2004，306（5695）：487-491.
[21] DOBRYNINA L A，SHABALINA A A，ZABITOVA M R，et al. Tissue plasminogen activator and MRI signs of cerebral small vessel disease[J/OL]. Brain Sci，2019，9（10）：266[2025-10-30]. https://doi.org/10.3390/brainsci9100266.
[22] KLARENBEEK P，VAN OOSTENBRUGGE R J，LODDER J，et al. Higher ambulatory blood pressure relates to enlarged Virchow-Robin spaces in first-ever lacunar stroke patients[J]. J Neurol，2013，260（1）：115-121.
[23] STAALS J，MAKIN S D J，DOUBAL F N，et al. Stroke subtype，vascular risk factors，and total MRI brain small-vessel disease burden[J]. Neurology，2014，83（14）：1228-1234.
[24] CHOI S H，BYLYKBASHI E，CHATILA Z K，et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model[J/OL]. Science，2018，361（6406）：eaan8821[2025-10-30]. https://doi.org/10.1126/science.aan8821.
[25] GUO S Z，KIM W J，LOK J，et al. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons[J]. Proc Natl Acad Sci U S A，2008，105（21）：7582-7587.
[26] PIKULA A，BEISER A S，CHEN T C，et al. Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury：Framingham study[J]. Stroke，2013，44（10）：2768-2775.
[27] GOLDEN E，EMILIANO A，MAUDSLEY S，et al. Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health：data from the Baltimore longitudinal study of aging[J/OL]. PLoS One，2010，5（4）：e10099[2025-10-30]. https://doi.org/10.1371/journal.pone.0010099.
[28] CHEN J，ZHANG T，JIAO S S，et al. proBDNF accelerates brain amyloid-β deposition and learning and memory impairment in APPswePS1dE9 transgenic mice[J]. J Alzheimers Dis，2017，59（3）：941-949.
[29] DINIZ C R A F，CASAROTTO P C，RESSTEL L，et al. Beyond good and evil：a putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment[J/OL]. Neurosci Biobehav Rev，2018，90：70-83[2025-10-30]. https://doi.org/10.1016/j.neubiorev.2018.04.001.
[30] POLYAKOVA M，SCHROETER M L，ELZINGA B M，et al. Brain-derived neurotrophic factor and antidepressive effect of electroconvulsive therapy：systematic review and meta-analyses of the preclinical and clinical literature[J/OL]. PLoS One，2015，10（11）：e0141564[2025-10-30]. https://doi.org/10.1371/journal.pone.0141564.
[31] LOMMATZSCH M，ZINGLER D，SCHUHBAECK K，et al. The impact of age，weight and gender on BDNF levels in human platelets and plasma[J]. Neurobiol Aging，2005，26（1）：115-123.
[32] TSAI S J. Role of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in psychological stress and depression[J]. Oncotarget，2017，8（68）：113258-113268.
[33] ANGELUCCI F，ČECHOVÁ K，PRŮŠA R，et al. Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease：consequences on extracellular maturation of brain-derived neurotrophic factor and therapeutic implications[J]. CNS Neurosci Ther，2019，25（3）：303-313.
[34] YANG E Y，CAI Y，YAO X H，et al. Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia[J]. Aging（Albany NY），2019，11（22）：10167-10182.
[35] YANG Y，ROSENBERG G A. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease[J]. Stroke，2011，42（11）：3323-3328.
[36] STEVENSON T K，MOORE S J，MURPHY G G，et al. Tissue plasminogen activator in central nervous system physiology and pathology：from synaptic plasticity to Alzheimer’s disease[J]. Semin Thromb Hemost，2022，48（3）：288-300.