Jiang Jiwei, Zhao Kun, Li Wenyi, Zheng Peiyang, Jiang Shirui, Ren Qiwei, Duan Yunyun, Yu Huiying, Kang Xiaopeng, Li Junjie, Hu Ke, Jiang Tianlin, Zhao Min, Wang Linlin, Yang Shiyi, Zhang Huiying, Liu Yaou, Wang Anxin, Liu Yong, Xu Jun
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China.
School of Artificial Intelligence, Beijing University of Posts and Telecommunications, Beijing, China; Queen Mary School Hainan, Beijing University of Posts and Telecommunications, Hainan, China.
Biol Psychiatry. 2025 Jun 1;97(11):1067-1078. doi: 10.1016/j.biopsych.2024.08.027. Epub 2024 Oct 16.
The high heterogeneity of neuropsychiatric symptoms (NPSs) hinders further exploration of their role in neurobiological mechanisms and Alzheimer's disease (AD). We aimed to delineate NPS patterns based on brain macroscale connectomics to understand the biological mechanisms of NPSs on the AD continuum.
We constructed regional radiomics similarity networks for 550 participants (AD with NPSs [n = 376], AD without NPSs [n = 111], and normal control participants [n = 63]) from the CIBL (Chinese Imaging, Biomarkers, and Lifestyle) study. We identified regional radiomics similarity network connections associated with NPSs and then clustered distinct subtypes of AD with NPSs. An independent dataset (n = 189) and internal validation were performed to assess the robustness of the NPS subtypes. Subsequent multiomics analysis was performed to assess the distinct clinical phenotype and biological mechanisms in each NPS subtype.
AD patients with NPSs were clustered into severe (n = 187), moderate (n = 87), and mild (n = 102) NPS subtypes, each exhibiting distinct brain network dysfunction patterns. A high level of consistency in clustering NPSs was internally and externally validated. Severe and moderate NPS subtypes were associated with significant cognitive impairment, increased plasma p-tau181 (tau phosphorylated at threonine 181) levels, extensive decreased brain volume and cortical thickness, and accelerated cognitive decline. Gene set enrichment analysis revealed enrichment of differentially expressed genes in ion transport and synaptic transmission with variations for each NPS subtype. Genome-wide association study analysis defined the specific gene loci for each subtype of AD with NPSs (e.g., logical memory), consistent with clinical manifestations and progression patterns.
This study identified and validated 3 distinct NPS subtypes, underscoring the role of NPSs in neurobiological mechanisms and progression of the AD continuum.
神经精神症状（NPSs）的高度异质性阻碍了对其在神经生物学机制和阿尔茨海默病（AD）中作用的进一步探索。我们旨在基于脑宏观连接组学描绘NPS模式，以了解NPSs在AD连续体上的生物学机制。
我们为来自CIBL（中国影像、生物标志物和生活方式）研究的550名参与者（伴有NPSs的AD患者[n = 376]、不伴有NPSs的AD患者[n = 111]和正常对照参与者[n = 63]）构建了区域放射组学相似性网络。我们确定了与NPSs相关的区域放射组学相似性网络连接，然后对伴有NPSs的AD不同亚型进行聚类。进行了独立数据集（n = 189）和内部验证，以评估NPS亚型的稳健性。随后进行多组学分析，以评估每个NPS亚型中不同的临床表型和生物学机制。
伴有NPSs的AD患者被聚类为重度（n = 187）、中度（n = 87）和轻度（n = 102）NPS亚型，每种亚型都表现出独特的脑网络功能障碍模式。在内部和外部验证中，NPSs聚类具有高度一致性。重度和中度NPS亚型与显著的认知障碍、血浆p-tau181（苏氨酸181磷酸化的tau）水平升高、广泛的脑容量和皮质厚度降低以及认知衰退加速相关。基因集富集分析显示，离子转运和突触传递中差异表达基因的富集因每个NPS亚型而异。全基因组关联研究分析确定了伴有NPSs的AD各亚型的特定基因位点（如逻辑记忆），与临床表现和进展模式一致。
本研究识别并验证了3种不同的NPS亚型，强调了NPSs在AD连续体的神经生物学机制和进展中的作用。
