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Early functional disconnection of the basal forebrain-hippocampal system predicts memory impairment in amnestic mild cognitive impairment.

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Title: Early functional disconnection of the basal forebrain-hippocampal system predicts memory impairment in amnestic mild cognitive impairment.
Authors: Lu JJ; Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China., Xu ZJ; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China., Ma J; Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China. Electronic address: drmajie@126.com., Wu JJ; Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China., Xue X; Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China., Hua XY; Department of Traumatology and Orthopedics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China. Electronic address: huaxuyun@shutcm.edu.cn., Xu JG; Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China. Electronic address: xjg@shutcm.edu.cn.
Source: Neuroscience [Neuroscience] 2026 Oct 15; Vol. 614, pp. 125-134. Date of Electronic Publication: 2026 Aug 06.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier Science Country of Publication: United States NLM ID: 7605074 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7544 (Electronic) Linking ISSN: 03064522 NLM ISO Abbreviation: Neuroscience Subsets: MEDLINE
Imprint Name(s): Publication: [New York?] : Elsevier Science
Original Publication: Oxford, Elmsford, N. Y., Pergamon Press
MeSH Terms: Cognitive Dysfunction*/physiopathology , Cognitive Dysfunction*/diagnostic imaging , Cognitive Dysfunction*/complications , Cognitive Dysfunction*/pathology , Hippocampus*/physiopathology , Hippocampus*/diagnostic imaging , Hippocampus*/pathology , Basal Forebrain*/physiopathology , Basal Forebrain*/diagnostic imaging , Basal Forebrain*/pathology , Amnesia*/physiopathology , Amnesia*/diagnostic imaging , Memory Disorders*/physiopathology , Memory Disorders*/diagnostic imaging , Memory Disorders*/etiology, Neural Pathways/physiopathology ; Neural Pathways/diagnostic imaging ; Neural Pathways/pathology ; Humans ; Magnetic Resonance Imaging ; Female ; Male ; Aged ; Neuropsychological Tests ; Middle Aged
Abstract: While central remodeling in amnestic mild cognitive impairment (aMCI) is well documented, prevailing studies emphasize whole-brain networks or undirected functional connectivity, largely neglecting specific neuromodulatory systems. We therefore investigated structural integrity and directional effective connectivity within the basal forebrain (BF)-hippocampal-cortical axis to elucidate early pathophysiology. Fifty-one aMCI patients and 67 cognitively healthy controls underwent multimodal MRI and comprehensive neuropsychological assessment. Spectral dynamic causal modeling (spDCM) characterized directional BF-hippocampal connectivity, generalized linear modeling (GLM) identified memory-related BF-cortical circuits, and system dynamics modeling (SDM) quantified pathways linking neural architecture, functional coupling, and cognitive performance. Macroscopic BF and hippocampal volumes did not differ significantly between groups. However, spDCM revealed altered effective connectivity patterns in aMCI patients, characterized by reduced negative effective connectivity. GLM demonstrated that BF-cortical modulation, specifically within medial septum/diagonal band (MS/DB) -parietal circuits, significantly interacted with diagnostic status to predict memory scores. Furthermore, SDM indicated that effective connectivity between the nucleus basalis of Meynert (NBM) and frontoparietal regions significantly predicted NBM structural integrity, which in turn was positively associated with hippocampal volume and long-term memory performance. Collectively, directional connectivity alterations within the BF-hippocampal-cortical axis were observed in patients with aMCI in the absence of detectable macroscopic atrophy, highlighting the potential contribution of BF-related network dysfunction to early disease processes.
(Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Amnestic mild cognitive impairment; Basal forebrain; Cholinergic system; Effective connectivity; Hippocampus; System dynamics modeling
Entry Date(s): Date Created: 20260806 Date Completed: 20260907 Latest Revision: 20260907
Update Code: 20260908
DOI: 10.1016/j.neuroscience.2026.08.008
PMID: 42562306
Database: MEDLINE
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  Data: Early functional disconnection of the basal forebrain-hippocampal system predicts memory impairment in amnestic mild cognitive impairment.
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  Data: While central remodeling in amnestic mild cognitive impairment (aMCI) is well documented, prevailing studies emphasize whole-brain networks or undirected functional connectivity, largely neglecting specific neuromodulatory systems. We therefore investigated structural integrity and directional effective connectivity within the basal forebrain (BF)-hippocampal-cortical axis to elucidate early pathophysiology. Fifty-one aMCI patients and 67 cognitively healthy controls underwent multimodal MRI and comprehensive neuropsychological assessment. Spectral dynamic causal modeling (spDCM) characterized directional BF-hippocampal connectivity, generalized linear modeling (GLM) identified memory-related BF-cortical circuits, and system dynamics modeling (SDM) quantified pathways linking neural architecture, functional coupling, and cognitive performance. Macroscopic BF and hippocampal volumes did not differ significantly between groups. However, spDCM revealed altered effective connectivity patterns in aMCI patients, characterized by reduced negative effective connectivity. GLM demonstrated that BF-cortical modulation, specifically within medial septum/diagonal band (MS/DB) -parietal circuits, significantly interacted with diagnostic status to predict memory scores. Furthermore, SDM indicated that effective connectivity between the nucleus basalis of Meynert (NBM) and frontoparietal regions significantly predicted NBM structural integrity, which in turn was positively associated with hippocampal volume and long-term memory performance. Collectively, directional connectivity alterations within the BF-hippocampal-cortical axis were observed in patients with aMCI in the absence of detectable macroscopic atrophy, highlighting the potential contribution of BF-related network dysfunction to early disease processes.<br /> (Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.)
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  Data: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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  Data: <i>Keywords: </i>Amnestic mild cognitive impairment; Basal forebrain; Cholinergic system; Effective connectivity; Hippocampus; System dynamics modeling
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