Core-Centered Connection Abnormalities Associated with Pathological Features Mediate the Progress of Cognitive Impairments in Alzheimer’s Disease Spectrum Patients

Article type: Research Article

Authors: Yao, Weina^a | Chen, Haifeng^{b; c; d; e} | Sheng, Xiaoning^{b; c} | Zhao, Hui^{b; c; d; e} | Xu, Yun^{b; c; d; e} | Bai, Feng^{b; c; d; e; *} | Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China | [b] Department of Neurology, Nanjing Drum Tower Hospital of The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China | [c] The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China | [d] Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, China | [e] Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China

Correspondence: [*] Correspondence to: Feng Bai, Department of Neurology, Nanjing Drum Tower Hospital of The Affiliated Hospital of Nanjing University Medical School, and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing 210008, China. E-mail: baifeng515@126.com.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Abstract: Background:Abnormal default mode network (DMN) was associated with the progress of Alzheimer’s disease (AD). Rather than treat the DMN as a unitary network, it can be further divided into three subsystems with different functions. Objective:It remains unclear the interactions of DMN subsystems associated with the progress of cognitive impairments and AD pathological features. Methods:This study has recruited 187 participants, including test data and verification data. Firstly, an imaging analysis approach was utilized to investigate disease-related differences in the interactions of DMN subsystems in test data (n = 149), including 42 cognitively normal subjects, 43 early mild cognitive impairment (EMCI), 32 late mild cognitive impairment (LMCI), and 32 AD patients. Brain-behavior-pathological relationships regarding to the interactions among DMN subsystems were then further examined. Secondly, DMN subsystems abnormalities for classifying AD spectrum population in the independent verification data (n = 38). Results:This study found that the impaired cognition relates to disturbances in the interactions between DMN subsystems but preferentially in core subsystem, and the abnormal regulatory processes of core subsystem were significantly associated with the levels of cerebrospinal fluid Aβ and tau in AD-spectrum patients. Meantime, the nonlinear relationship between dysfunctional core subsystem and impaired cognition was observed as one progresses through the stages of MCI to AD. Importantly, this classification presented a higher sensitivity and specificity dependent on the core-centered connection abnormalities. Conclusion:The abnormal interaction patterns of DMN subsystems at an early stage of AD appeared and presented as core-centered connection abnormalities, which were the potential neuroimaging features for monitoring the development of AD.

Keywords: Alzheimer’s disease, classification, cognitive impairment, default mode network, regulation, subsystems

DOI: 10.3233/JAD-210481

Journal: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1499-1511, 2021