Brain Age Is Associated with Cognitive Outcomes of Cholinesterase Inhibitor Treatment in Patients with Mild Cognitive Impairment

Article type: Research Article

Authors: Tseng, Wen-Yih Isaac^{a; 1} | Hsu, Yung-Chin^{a; 1} | Huang, Li-Kai^{b; c; 1} | Hong, Chien-Tai^{b; c; d} | Lu, Yueh-Hsun^{c; e; f} | Chen, Jia-Hung^{b; c} | Fu, Chin-Kun^a | Chan, Lung^{b; c; d; *}

Affiliations: [a] AcroViz, Inc. Taipei, Taiwan (R.O.C.) | [b] Department of Neurology, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, Taipei Medical University, New Taipei City, Taiwan (R.O.C.) | [c] Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan (R.O.C.) | [d] Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (R.O.C.) | [e] Department of Radiology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan (R.O.C.) | [f] Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (R.O.C.)

Correspondence: [*] .Correspondence to: Lung Chan, MD, PhD, Department of Neurology, Shuang Ho Hospital, Taipei Medical University, No. 291, Zhongzheng Road, Zhonghe, New Taipei City 23561 Taiwan (R.O.C.). Tel.: +02 22490088 ext 8112; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background: The effect of cholinesterase inhibitor (ChEI) on mild cognitive impairment (MCI) is controversial. Brain age has been shown to predict Alzheimer’s disease conversion from MCI. Objective: The study aimed to show that brain age is related to cognitive outcomes of ChEI treatment in MCI. Methods: Brain MRI, the Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) scores were retrospectively retrieved from a ChEI treatment database. Patients who presented baseline CDR of 0.5 and received ChEI treatment for at least 2 years were selected. Patients with stationary or improved cognition as verified by the CDR and MMSE were categorized to the ChEI-responsive group, and those with worsened cognition were assigned to the ChEI-unresponsive group. A gray matter brain age model was built with a machine learning algorithm by training T1-weighted MRI data of 362 healthy participants. The model was applied to each patient to compute predicted age difference (PAD), i.e. the difference between brain age and chronological age. The PADs were compared between the two groups. Results: 58 patients were found to fit the ChEI-responsive criteria in the patient data, and 58 matched patients that fit the ChEI-unresponsive criteria were compared. ChEI-unresponsive patients showed significantly larger PAD than ChEI-responsive patients (8.44±8.78 years versus 3.87±9.02 years, p = 0.0067). Conclusions: Gray matter brain age is associated with cognitive outcomes after 2 years of ChEI treatment in patients with the CDR of 0.5. It might facilitate the clinical trials of novel therapeutics for MCI.

Keywords: Alzheimer’s disease, brain age, cholinesterase inhibitor, clinical dementia rating, cognitive outcome, magnetic resonance imaging, mild cognitive impairment, mini-mental state examination

DOI: 10.3233/JAD-231109

Journal: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1095-1106, 2024