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Background <p>Vascular cognitive impairment (VCI) is a devastating clinical endpoint of microvascular senescence. However, the mechanisms by which age-related focal vascular insults cause systemic brain network failure and molecular vulnerability remain unknown.&#xa0;To decode the multi-scale neurobiology of VCI, we conducted a systematic review and meta-analysis of whole-brain voxel-based morphometry studies comparing patients with VCI and healthy controls.</p> Methods <p>We used coordinate-based network mapping on a normative functional connectome to identify convergent structural atrophy networks. To decode multi-scale biological substrates, we checked the resulting macroscopic topography against the Allen Human Brain Atlas and 28 positron emission tomography-derived neurotransmitter maps.</p> Results <p>18 studies contributed to the analysis, including 682 VCI patients and 643 healthy controls. VCI-related atrophy, despite appearing disparate, functionally converges onto a robust macroscopic architecture that is anchored predominantly in the somatomotor and salience networks. Transcriptomic profiling further showed that this network colocalizes significantly with Layer 6 corticothalamic and subcortical projection neurons. These neuron populations feature exceptionally long axonal projections, a property that heightens their metabolic susceptibility to chronic hypoperfusion.&#xa0;At the neurochemical level, this structural degradation exhibited profound spatial coherence with the macroscopic distribution of dopamine transporter (DAT) and 5-hydroxytryptamine transporter (5‑HTT).</p> Conclusion <p>These findings suggest that VCI may represent a quintessential “disconnection syndrome” associated with the vulnerability of long-range projection pathways to vascular aging, providing a novel multi-scale neurobiological template to identify network-level targets for intervention.</p>

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Mapping the multi-scale landscape of vascular cognitive impairment: from structural atrophy networks to cellular and neurochemical substrates

  • 期刊论文

  • 发表日期：

    2026年6月20日

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  • Qing Du,
  • Yifan Fang,
  • Wenwen Liang,
  • Tianyi Li,
  • Feiyan Zhang,
  • Yingjie Liu,
  • Siyi Chen,
  • Chensheng Pan,
  • Guo Li,
  • Zhou Zhu

摘要

Background

Vascular cognitive impairment (VCI) is a devastating clinical endpoint of microvascular senescence. However, the mechanisms by which age-related focal vascular insults cause systemic brain network failure and molecular vulnerability remain unknown. To decode the multi-scale neurobiology of VCI, we conducted a systematic review and meta-analysis of whole-brain voxel-based morphometry studies comparing patients with VCI and healthy controls.

Methods

We used coordinate-based network mapping on a normative functional connectome to identify convergent structural atrophy networks. To decode multi-scale biological substrates, we checked the resulting macroscopic topography against the Allen Human Brain Atlas and 28 positron emission tomography-derived neurotransmitter maps.

Results

18 studies contributed to the analysis, including 682 VCI patients and 643 healthy controls. VCI-related atrophy, despite appearing disparate, functionally converges onto a robust macroscopic architecture that is anchored predominantly in the somatomotor and salience networks. Transcriptomic profiling further showed that this network colocalizes significantly with Layer 6 corticothalamic and subcortical projection neurons. These neuron populations feature exceptionally long axonal projections, a property that heightens their metabolic susceptibility to chronic hypoperfusion. At the neurochemical level, this structural degradation exhibited profound spatial coherence with the macroscopic distribution of dopamine transporter (DAT) and 5-hydroxytryptamine transporter (5‑HTT).

Conclusion

These findings suggest that VCI may represent a quintessential “disconnection syndrome” associated with the vulnerability of long-range projection pathways to vascular aging, providing a novel multi-scale neurobiological template to identify network-level targets for intervention.