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<p>Atypical visual processing (AVP) commonly occurs in autism spectrum disorder (ASD) and contributes to social impairments, yet its neurobiological basis remains poorly characterized. To investigate potential lipid and myelin mechanisms, this study integrated multimodal MRI, quantifying lipid (proton density fat fraction) and myelin content (synthetic MRI) of 74 nuclei or brain regions, with serum profiling of iron, lead, and ceruloplasmin in 288 children, including 90 ASD with atypical visual processing (ASD‑AVP), 89 ASD without atypical visual processing (ASD‑AVP), and 109 typically developing (TD). The ASD-AVP subgroup exhibited a distinct co-pathology of elevated lipid and myelin centered on the fusiform gyrus (FG), accompanied by a unique positive lipid-myelin correlation (left: r = 0.47, right: r = 0.41). Serum analyses revealed decreased iron and ceruloplasmin and increased lead in ASD-AVP, and mediation analysis indicated that ceruloplasmin deficiency influences FG myelination via lipid pathways (35%–55%). Crucially, BTBR AVP-like mice recapitulated this phenotype with disorganized hypermyelination, whereas nAVP-like mice showed hypomyelination. A combined FG lipid-myelin signature strongly distinguished ASD-AVP from TD (AUC = 0.93) and ASD-nAVP (AUC = 0.87). Preliminary longitudinal follow-up in a subset of patients revealed that improvement in serum ceruloplasmin was associated with a reduction in FG lipid content and stabilization of myelin, paralleling clinical improvement. These findings identify a ceruloplasmin-driven, FG-centric lipid-myelin co-pathology, representing a maladaptive “inflammatory pseudo-compensation” mechanism specific to a visual ASD subtype, and offer novel biomarkers for biological subtyping and targeted interventions.</p>

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Ceruloplasmin deficiency drives a fusiform-centric lipid–myelin pathology underlying a visual subtype in autism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月17日

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  • Ya‑Yin Deng,
  • Shuang‑Shuang Zhong,
  • Shi-Huan Wang,
  • Bo-Ya Yin,
  • Xiang Zhou,
  • Feng‑Yun Zou,
  • Jia-Yuan Zhao,
  • Yu-Xuan Ni,
  • Xiao‑Wen Luo,
  • Li‑Shan Shen,
  • Jia-Lu Zhang,
  • Zhi-Ping Lin,
  • Wen-Ying Zhou,
  • Hong-Zhu Deng,
  • Ruo‑Mi Guo

摘要

Atypical visual processing (AVP) commonly occurs in autism spectrum disorder (ASD) and contributes to social impairments, yet its neurobiological basis remains poorly characterized. To investigate potential lipid and myelin mechanisms, this study integrated multimodal MRI, quantifying lipid (proton density fat fraction) and myelin content (synthetic MRI) of 74 nuclei or brain regions, with serum profiling of iron, lead, and ceruloplasmin in 288 children, including 90 ASD with atypical visual processing (ASD‑AVP), 89 ASD without atypical visual processing (ASD‑AVP), and 109 typically developing (TD). The ASD-AVP subgroup exhibited a distinct co-pathology of elevated lipid and myelin centered on the fusiform gyrus (FG), accompanied by a unique positive lipid-myelin correlation (left: r = 0.47, right: r = 0.41). Serum analyses revealed decreased iron and ceruloplasmin and increased lead in ASD-AVP, and mediation analysis indicated that ceruloplasmin deficiency influences FG myelination via lipid pathways (35%–55%). Crucially, BTBR AVP-like mice recapitulated this phenotype with disorganized hypermyelination, whereas nAVP-like mice showed hypomyelination. A combined FG lipid-myelin signature strongly distinguished ASD-AVP from TD (AUC = 0.93) and ASD-nAVP (AUC = 0.87). Preliminary longitudinal follow-up in a subset of patients revealed that improvement in serum ceruloplasmin was associated with a reduction in FG lipid content and stabilization of myelin, paralleling clinical improvement. These findings identify a ceruloplasmin-driven, FG-centric lipid-myelin co-pathology, representing a maladaptive “inflammatory pseudo-compensation” mechanism specific to a visual ASD subtype, and offer novel biomarkers for biological subtyping and targeted interventions.