Independent and Reproducible Hippocampal Radiomic Biomarkers for Multisite Alzheimer's Disease: Diagnosis, Longitudinal Progress and Biological Basis

Hippocampal morphological change is one of the main hallmarks of Alzheimer's disease (AD). However, whether hippocampal radiomic features are reproducible and robust as predictors of progression from mild cognitive impairment (MCI) to AD dementia and provide a neurobiological foundation remains unclear. The primary aim of this study was to verify whether hippocampal radiomic features are robust MRI markers for AD. Multivariate classifier-based SVM analysis provided individual-level predictions for distinguishing AD patients (N=261) from normal controls (NCs; N=231) with accuracy=88.21% with inter-site cross-validation. Further analyses of a large, independent ADNI dataset (N=1228) reinforced these findings. In mild cognitive impairment (MCI) groups, a systemic analysis demonstrated that the identified features were significantly associated with clinical features (e.g., apolipoprotein E (APOE) genotype, polygenic risk scores, cerebrospinal fluid (CSF) Aβ, CSF Tau), and longitudinal changes in cognition ability; more importantly, the radiomic features have a consistently altered pattern with changes in the MMSE scores over 5 years of follow-up. These comprehensive results suggest that hippocampal radiomic features can serve as a robust biomarker for clinical applications in AD/MCI, further provide evidence for predicting whether MCI subject would convert to AD or not based on hippocampus, without doubt has significantly meaning for early diagnosis of AD/MCI. Funding Statement: This work was partially supported by the National Key Research and Development Program of China (grant no. 2016YFC1305904), the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (grant no. XDB32020200), the National Natural Science Foundation of China (grant nos. 81871438, 81901101, 61633018, 81571062, 81400890, 61431012), and the Primary Research & Development Plan of Shandong Province (grant no. 2017GGX10112). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH 12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and generous contributions from AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provide funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. The ADNI data are disseminated by the Laboratory for Neuro-Imaging at the University of Southern California. Declaration of Interests: This study includes the databases which were approved by the Medical Ethics Committee of local Hospitals.