journal articles
MULTIMODAL NEUROIMAGING UNVEILS BASAL FOREBRAIN-LIMBIC SYSTEM CIRCUIT DYSREGULATION IN COGNITIVE IMPAIRMENT WITH DEPRESSION: A PATHWAY TO EARLY DIAGNOSIS AND INTERVENTION
Xiaowen Xu, Xiereniguli Anayiti, Peiying Chen, Zhongfeng Xie, Mengling Tao, Yongsheng Xiang, Mingyu Tan, Yingying Liu, Ling Yue, Shifu Xiao, Peijun Wang
BACKGROUND: Alzheimer’s disease (AD) frequently co-occurs with depressive symptoms, exacerbating both cognitive decline and clinical complexity, yet the neural substrates linking this co-occurrence remain poorly understood. We aimed to investigate the role of basal forebrain-limbic system circuit dysregulation in the interaction between cognitive impairment and depressive symptoms, identifying potential biomarkers for early diagnosis and intervention.
METHODS: This cross-sectional study included participants stratified into normal controls (NC), cognitive impairment without depression (CI-nD), and cognitive impairment with depression (CI-D). Multimodal MRI (structural, diffusion, functional, perfusion, iron-sensitive imaging) and plasma biomarkers were analyzed. Machine learning models classified subgroups using neuroimaging features.
RESULTS: CI-D exhibited distinct basal forebrain-limbic circuit alterations versus CI-nD and NC: (1) Elevated free-water fraction (FW) in basal forebrain subregions (Ch123/Ch4, p < 0.04), indicating early neuroinflammation; (2) Increased iron deposition in the anterior cingulate cortex and entorhinal cortex (p < 0.05); (3) Hyperperfusion and functional hyperactivity in Ch123 and amygdala; (4) Plasma neurofilamentlightchain exhibited correlated with hippocampal inflammation in CI-nD (p = 0.03) but linked to basal forebrain dysfunction in CI-D (p < 0.05). Multimodal support vector machine achieved 85 % accuracy (AUC=0.96) in distinguishing CI-D from CI-nD, with Ch123 and Ch4 as key discriminators. Pathway analysis in the CI-D group further revealed that FW-related neuroinflammation in the basal forebrain (Ch123/Ch4) indirectly contributed to cognitive impairment via structural atrophy.
CONCLUSION: We identified a neuroinflammatory-cholinergic pathway in the basal forebrain as an early mechanism driving depression-associated cognitive decline. Multimodal imaging revealed distinct spatiotemporal patterns of circuit dysregulation, suggesting neuroinflammation and iron deposition precede structural degeneration. These findings position the basal forebrain-limbic system circuit as a therapeutic target and provide actionable biomarkers for early intervention in AD with depressive symptoms.
CITATION:
Xiaowen Xu ; Xiereniguli Anayiti ; Peiying Chen ; Zhongfeng Xie ; Mengling Tao ; Yongsheng Xiang ; Mingyu Tan ; Yingying Liu ; Ling Yue ; Shifu Xiao ; Peijun Wang (2025): Multimodal neuroimaging unveils basal forebrain-limbic system circuit dysregulation in cognitive impairment with depression: a pathway to early diagnosis and intervention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100298