Mapping hippocampal subfield heterogeneity across neurological disorders by normative modeling

The hippocampus serves as a hub of cognition, and its subfields differ in their susceptibility to aging and neurological disorders. Here, we established normative references for hippocampal and subfield volumes using 3D T1-weighted magnetic resonance imaging (MRI) scans from 34,789 healthy individuals (range from 4 to 85 years), revealing varied peak ages (27.4-40.1 years) across subfields. We then mapped the hippocampus and its subfields across various neurological disorders (mild cognitive impairment, Alzheimer’s disease, Parkinson’s disease, cerebral small vessel disease, and multiple sclerosis) by deriving personalized deviation (centile) scores from these references in 3,521 patients. These centile scores captured disease-specific hippocampal abnormalities, supported disease classification, and were associated with cognitive performance, longitudinal cognitive outcomes, and disease progression across disorders. Finally, a personalized hippocampal health report was developed to facilitate clinical translation. These findings demonstrate the value of hippocampal and subfield normative references for personalized diagnosis, cognitive assessment, and prognostic evaluation across neurological diseases. This study establishes age-specific reference ranges for hippocampal subfields and shows that personalized deviations from these norms can distinguish neurological disorders and help assess cognition and disease progression.

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Nature Communications
Published
2026-11-03
DOI
https://doi.org/10.1038/s41467-026-79269-z
Primary Topic
Dementia and Cognitive Impairment Research
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article
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article

Mapping hippocampal subfield heterogeneity across neurological disorders by normative modeling

吴飞云, Guoguang Fan, Xiaona Xia, Su Lui et al.
Nature Communications
Dementia and Cognitive Impairment Research
article

Mapping hippocampal subfield heterogeneity across neurological disorders by normative modeling

吴飞云, Guoguang Fan, Xiaona Xia, Su Lui, Yang Hou, Feiyan Chen, Zhiqiang Zhang, Yuerong Lizhu, Junkai Wang, Lanxi Meng, Ruimeng Yang, Haiyan Wu, Linghui Meng, Haiyan Liao, Yuqi Luo, Kun Chen, Yaojing Chen, Jun Liang Xu, Zaixu Cui, Yiheng Tu, Yuhui Du, Ning Mao, Yulong Yin, Jie Luo, Lubin Gou, Min Guo, Wanyu Liu, Chu‐Chung Huang, Zhen Yuan, Jinyuan Weng, Hongjian He, Ching‐Po Lin, De‐Cai Tian, Yuankui Wu, Peipeng Liang, Ping Wang, Yinshan Wang, Feng Chen, Jinhui Wang, Wen Wang, Zheng Wang, Yilong Wang, Yunfei Li, Ya Guo, Huijie Li, Qing Cai, Yao Li, Zhenyu Shu, Li Chai, Peng Gao, Jianping Hu, Xiaolu Xu, Feng Ao, Junqiang Lei, Haihua Bao, Li Yang, Jiaheng Xu, Kexuan Li, Hui Dai, Liping Ai, Chunjie Guo, Zheqi Gao, Yalin Bai, Juwei Shao, Yongmei Li, Ying Fu, Shanshan Lu, Tianyu Gao, Junlin Li, Xinyu Li, Songtao Yin, Jiancang Cao, Yulu Shi, Rui Xu, Yutong Bai, Peiyu Huang, Qin Shen, Hailian Zhang, Yuankui Wu, Ying Liu, Jungang Liu, Xiaochun Wang, Cheng Xu, Xinxiang Zhao, Wenling Li, Yong Wang, Xiaozhou Du, Dan Cheng, Jun Qiu, Feifei Zhang, Fei Wang, Xi Yin, Yinfeng Qian, Hailin Ma, Siyao Xu, Xuemei Han, Jianrui Li, Basheng Hu, Shaowu Li, Jun Liu
article en

Abstract

The hippocampus serves as a hub of cognition, and its subfields differ in their susceptibility to aging and neurological disorders. Here, we established normative references for hippocampal and subfield volumes using 3D T1-weighted magnetic resonance imaging (MRI) scans from 34,789 healthy individuals (range from 4 to 85 years), revealing varied peak ages (27.4-40.1 years) across subfields. We then mapped the hippocampus and its subfields across various neurological disorders (mild cognitive impairment, Alzheimer’s disease, Parkinson’s disease, cerebral small vessel disease, and multiple sclerosis) by deriving personalized deviation (centile) scores from these references in 3,521 patients. These centile scores captured disease-specific hippocampal abnormalities, supported disease classification, and were associated with cognitive performance, longitudinal cognitive outcomes, and disease progression across disorders. Finally, a personalized hippocampal health report was developed to facilitate clinical translation. These findings demonstrate the value of hippocampal and subfield normative references for personalized diagnosis, cognitive assessment, and prognostic evaluation across neurological diseases. This study establishes age-specific reference ranges for hippocampal subfields and shows that personalized deviations from these norms can distinguish neurological disorders and help assess cognition and disease progression.

Nature Communications
Shihezi University (CN), Qingdao University (CN), Hebei Medical University (CN), University of Science and Technology of China (CN), Hubei University of Medicine (CN), Fujian Medical University (CN), Central South University (CN), National Yang Ming Chiao Tung University (TW), Shandong University (CN), Chongqing University (CN), Shanxi Medical University (CN), Shanxi University (CN), Zunyi Medical University (CN), Shanghai Jiao Tong University (CN), Capital Medical University (CN), South China Normal University (CN), Yunnan University (CN), Jilin University (CN), Chinese Academy of Sciences (CN), University of Washington (US), Peking University (CN), University of Macau (MO), Hainan University (CN), Fudan University (CN), Beijing Normal University (CN), Kunming Medical University (CN), Nanjing General Hospital of Nanjing Military Command (CN), Sheng Jing Hospital (CN), First Affiliated Hospital of Xinjiang Medical University (CN), Yuhuangding Hospital (CN), Taipei Municipal YangMing Hospital (TW), Philips (China) (CN), Qinghai University Affiliated Hospital (CN), Beijing Tian Tan Hospital (CN), Third Hospital of Hebei Medical University (CN), West China Hospital of Sichuan University (CN), Xuan Wu Hospital of the Capital Medical University (CN), Nanfang Hospital (CN), Aerospace Center Hospital (CN), Gansu Provincial Hospital (CN), Chinese Institute for Brain Research (CN), Guangzhou First People's Hospital (CN), Taipei City Hospital (TW), Zhejiang Hospital (CN), First Affiliated Hospital of Fujian Medical University (CN), Fourth Affiliated Hospital of Harbin Medical University (CN), First Hospital of Shijiazhuang (CN), Inner Mongolia People's Hospital (CN), First Hospital of Jilin University (CN), First Hospital of Shanxi Medical University (CN), Hainan General Hospital (CN), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Zhejiang Provincial People's Hospital (CN), Institute of Psychology, Chinese Academy of Sciences (CN), Chongqing Emergency Medical Center (CN), First Affiliated Hospital of Shihezi University Medical College (CN), First Affiliated Hospital of Anhui Medical University (CN), Ningxia Medical University General Hospital (CN), First Hospital of China Medical University (CN), Obstetrics and Gynecology Hospital of Fudan University (CN), Jiangsu Province Hospital (CN), Second Xiangya Hospital of Central South University (CN), First Affiliated Hospital of Hebei Medical University (CN), Second Affiliated Hospital of Zhejiang University (CN), Xiangya Hospital Central South University (CN), Shanxi Provincial People’s Hospital (CN), Children’s Hospital of Fudan University Xiamen Branch (CN), First Hospital of Lanzhou University (CN), University of Chinese Academy of Sciences (CN), State Key Laboratory of Cognitive Neuroscience and Learning (CN), Southern Medical University (CN), East China Normal University (CN), Northwest Normal University (CN), Zhejiang University (CN), Lanzhou University (CN), Nanjing Medical University (CN), Nanjing University (CN), South China University of Technology (CN), Capital Normal University (CN), Tsinghua University (CN), Air Force Medical University (CN)
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