Jiang Weiqian, Vogelgsang Jonathan, Dan Shu, Durning Peter, McCoy Thomas H, Berretta Sabina, Klengel Torsten
Department of Psychiatry Harvard Medical School McLean Hospital Belmont Massachusetts USA.
Center for Quantitative Health Massachusetts General Hospital, Harvard Medical School Boston Massachusetts USA.
Alzheimers Dement (Amst). 2025 May 9;17(2):e70103. doi: 10.1002/dad2.70103. eCollection 2025 Apr-Jun.
Neuropsychiatric symptoms are common in people with Alzheimer's disease (AD) across all severity stages. Their heterogeneous presentation and variable temporal association with cognitive decline suggest shared and distinct biological mechanisms. We hypothesized that specific patterns of gene expression associate with distinct National Institute of Mental Health Research Domain Criteria (RDoC) domains in AD.
Post-mortem bulk RNA sequencing of the insula and anterior cingulate cortex from 60 brain donors, representing the spectrum of canonical Alzheimer's disease neuropathology, was combined with natural language processing approaches based on the RDoC Clinical Domains to uncover transcriptomic patterns linked to disease progression.
Distinct sets of >100 genes ( < 0.05) were specifically associated with at least one clinical domain (cognitive, social, negative, positive, arousal). In addition, dysregulation of immune response pathways was shared across domains and brain regions.
Our findings provide evidence for distinct transcriptional profiles associated with RDoC domains suggesting that each dimension is characterized by sets of genes providing insight into the underlying mechanisms.
brain tissue investigations are critically important for Alzheimer's disease (AD) research.Neuropsychiatric symptoms in AD are common and an important aspect of AD.Categorical phenotypes are commonly used, but insufficiently describe the heterogenous presentation of AD.Using natural language processing (NLP) of brain donor health records provides insight into dimensional phenotypes of AD.We provide evidence for distinct RNA expression profiles associated with NLP-derived Research Domain Criteria clinical domain scores.
神经精神症状在各个严重程度阶段的阿尔茨海默病（AD）患者中都很常见。它们的异质性表现以及与认知衰退的可变时间关联表明存在共同和独特的生物学机制。我们假设基因表达的特定模式与AD中不同的美国国立精神卫生研究所研究领域标准（RDoC）领域相关。
对60名脑捐赠者的脑岛和前扣带回皮质进行死后批量RNA测序，这些捐赠者代表了典型阿尔茨海默病神经病理学的范围，并将其与基于RDoC临床领域的自然语言处理方法相结合，以揭示与疾病进展相关的转录组模式。
超过100个基因的不同集合（<0.05）与至少一个临床领域（认知、社交、消极、积极、唤醒）特异性相关。此外，免疫反应途径的失调在各领域和脑区中是共同存在的。
我们的研究结果为与RDoC领域相关的不同转录谱提供了证据，表明每个维度都有一组基因作为特征，有助于深入了解潜在机制。
脑组织研究对阿尔茨海默病（AD）研究至关重要。AD中的神经精神症状很常见，是AD的一个重要方面。分类表型常用，但不足以描述AD的异质性表现。对脑捐赠者健康记录使用自然语言处理（NLP）可深入了解AD的维度表型。我们为与NLP衍生的研究领域标准临床领域评分相关的不同RNA表达谱提供了证据。
