title: Relative impact of amyloid-β, lacunes, and downstream imaging markers on cognitive trajectories.
abstract: SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-β and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-β and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-β and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized β = -0.79, P < 0.001; visual memory test, unstandardized β = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized β = -0.05, P = 0.002; Stroop colour test, unstandardized β = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized β = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness (standardized β = 0.21, P = 0.010) and time-varying nodal efficiency (standardized β = 0.17, P = 0.024). Time-varying lacune number (standardized β = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized β = 0.17, P = 0.021). Finally, time-varying lacune number (β = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized β = 0.19, P = 0.026). Our multimodal imaging analyses suggest that cognitive trajectories related to amyloid-β and lacunes have distinct paths, and that amyloid-β or lacunes have greatest impact on cognitive decline. Our results provide rationale for the targeting of amyloid-β and lacunes in therapeutic strategies aimed at ameliorating cognitive decline.
authors.affiliation: 1 Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Neuroscience Center, Samsung Medical Center, Seoul, Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: 3 Department of Biomedical Engineering, Hanyang University, Seoul, Korea.
authors.forename: Jin Ju
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: 3 Department of Biomedical Engineering, Hanyang University, Seoul, Korea.
authors.forename: Hunki
authors.initials: H
authors.lastname: Kwon
authors.affiliation: 4 Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Changsoo
authors.initials: C
authors.lastname: Kim
authors.affiliation: 3 Department of Biomedical Engineering, Hanyang University, Seoul, Korea.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: 5 Department of Emergency Medicine Behavioral Emergencies Research Lab, San Diego, CA, USA 6 Department of Biology, University of California San Diego, CA, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Chun
authors.affiliation: 1 Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Neuroscience Center, Samsung Medical Center, Seoul, Korea 7 Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea.
authors.forename: Yeo Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: 1 Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Neuroscience Center, Samsung Medical Center, Seoul, Korea 8 Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea.
authors.forename: Na-Yeon
authors.initials: NY
authors.lastname: Jung
authors.affiliation: 1 Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Neuroscience Center, Samsung Medical Center, Seoul, Korea.
authors.forename: Juhee
authors.initials: J
authors.lastname: Chin
authors.affiliation: 9 Biostatistics team, Samsung Biomedical Research Institute.
authors.forename: Seonwoo
authors.initials: S
authors.lastname: Kim
authors.affiliation: 9 Biostatistics team, Samsung Biomedical Research Institute.
authors.forename: Sook-Young
authors.initials: SY
authors.lastname: Woo
authors.affiliation: 10 Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Yearn Seong
authors.initials: YS
authors.lastname: Choe
authors.affiliation: 10 Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Kyung-Han
authors.initials: KH
authors.lastname: Lee
authors.affiliation: 11 Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sung Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: 12 Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: 13 Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Lee
authors.affiliation: 14 Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: 1 Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Neuroscience Center, Samsung Medical Center, Seoul, Korea 15 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
authors.forename: Duk L
authors.initials: DL
authors.lastname: Na
authors.affiliation: 1 Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Neuroscience Center, Samsung Medical Center, Seoul, Korea 16 Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Korea sangwonseo@empal.com.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Seo
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D059345:Cerebral Small Vessel Diseases / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D056344:Executive Function / Q000502:physiology*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008569:Memory Disorders / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D049268:Positron-Emission Tomography / Q000379:methods*; D059409:Stroke, Lacunar / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D013844:Thiazoles
keywords: amyloid-β; cerebral small vessel disease; cognitive trajectory; downstream imaging markers; mild cognitive impairment