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Background <p>Cerebral small vessel disease (CSVD) is a major contributor to vascular dementia. Given the absence of effective treatments, the development of blood-based biomarkers for early diagnosis and prediction is paramount to facilitate targeted clinical interventions. We aimed to identified blood-based extracellular vesicle (EV) biomarkers for screening CSVD with normal cognition (CSVD-NC) or cognitive impairment (CSVD-CI), and predicting disease progression.</p> Methods <p>We conducted a multi-center cross-sectional and longitudinal study involving patients with CSVD-NC and CSVD-CI, healthy controls (HCs), and patients with CI due to Alzheimer’s disease (AD-CI). Plasma EV proteomics were profiled using LC-MS/MS in a discovery set. Candidate EV biomarkers identified in this phase were subsequently validated in a larger independent set using parallel reaction monitoring. Machine learning was applied to develop and optimize diagnostic combinations for identifying CSVD and predicting disease progression.</p> Results <p>Plasma EV proteins exhibiting progressive changes during CSVD progression were predominantly enriched in immune-inflammatory and ribosomal dysfunction. Three plasma EV proteins (ATP6V1F, HNRNPU, and RPL38) demonstrated robust, cross-dataset consistency from HC to CSVD-NC to CSVD-CI continuum, and displayed distinct expression patterns between CSVD-CI and AD-CI (<i>P</i> &lt; 0.001). These EV biomarkers demonstrated high diagnostic accuracy for CSVD with or without CI (AUC = 0.849–0.897), and effectively stratified high-risk versus low-risk populations for CSVD cognitive progression (<i>P</i> = 0.005). Moreover, they were associated with CSVD-related structural injury and specific cognitive functions: EV ATP6V1F with hippocampal atrophy, language, and memory; EV RPL38 with WMH burden and white matter integrity; and EV HNRNPU with visuospatial function and executive function.</p> Conclusion <p>The identified plasma EV biomarkers reliably reflect CSVD-related vascular injury and cognitive decline, and hold promise as minimally invasive tools for early screening and risk stratification of CSVD-related CI, especially in community settings.</p>

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Plasma extracellular vesicle proteins biomarker for cerebral small vessel disease related cognitive impairment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Dan Yang,
  • Pinyi Liu,
  • Mengxi Han,
  • Zhihong Ke,
  • Yi Tan,
  • Linjie Yu,
  • Zheqi Hu,
  • Chenglu Mao,
  • Yue Cheng,
  • Hao Zhang,
  • Yun Zhang,
  • Xiaolei Zhu,
  • Yun Xu

摘要

Background

Cerebral small vessel disease (CSVD) is a major contributor to vascular dementia. Given the absence of effective treatments, the development of blood-based biomarkers for early diagnosis and prediction is paramount to facilitate targeted clinical interventions. We aimed to identified blood-based extracellular vesicle (EV) biomarkers for screening CSVD with normal cognition (CSVD-NC) or cognitive impairment (CSVD-CI), and predicting disease progression.

Methods

We conducted a multi-center cross-sectional and longitudinal study involving patients with CSVD-NC and CSVD-CI, healthy controls (HCs), and patients with CI due to Alzheimer’s disease (AD-CI). Plasma EV proteomics were profiled using LC-MS/MS in a discovery set. Candidate EV biomarkers identified in this phase were subsequently validated in a larger independent set using parallel reaction monitoring. Machine learning was applied to develop and optimize diagnostic combinations for identifying CSVD and predicting disease progression.

Results

Plasma EV proteins exhibiting progressive changes during CSVD progression were predominantly enriched in immune-inflammatory and ribosomal dysfunction. Three plasma EV proteins (ATP6V1F, HNRNPU, and RPL38) demonstrated robust, cross-dataset consistency from HC to CSVD-NC to CSVD-CI continuum, and displayed distinct expression patterns between CSVD-CI and AD-CI (P < 0.001). These EV biomarkers demonstrated high diagnostic accuracy for CSVD with or without CI (AUC = 0.849–0.897), and effectively stratified high-risk versus low-risk populations for CSVD cognitive progression (P = 0.005). Moreover, they were associated with CSVD-related structural injury and specific cognitive functions: EV ATP6V1F with hippocampal atrophy, language, and memory; EV RPL38 with WMH burden and white matter integrity; and EV HNRNPU with visuospatial function and executive function.

Conclusion

The identified plasma EV biomarkers reliably reflect CSVD-related vascular injury and cognitive decline, and hold promise as minimally invasive tools for early screening and risk stratification of CSVD-related CI, especially in community settings.