Affiliations: [a] Department of Neurology, National Neuroscience Institute, Singapore, Singapore
| [b] Duke-NUS, Singapore, Singapore
| [c] School of Psychiatry, University of New South Wales, Sydney, Australia
Correspondence:
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Correspondence to: A/Prof Nagaendran Kandiah, Senior Consultant Neurologist, Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. Tel.: +65 6357 7199; Fax: +65 6357 7137; E-mail: [email protected].
Abstract: Background:Asymmetrical patterns of cerebral damage have been widely observed in a range of neurodegenerative diseases, including Alzheimer’s disease (AD). Objective:To elucidate the clinical associations of asymmetrical white matter hyperintensities (WMH) in mild cognitive impairment (MCI) and AD. Methods:Regional WMH asymmetry of 340 participants (90 healthy controls, 132 MCI, 118 AD) was calculated as the difference in normalized hemispheric WMH volume (WMH/ICV) adjusted for structural brain asymmetry of respective lobar regions and total WMH. WMH asymmetry was analyzed in relation to disease classification, cognition, and APOE4 status using ANCOVA and multiple regression analysis, controlling for gender, age, ethnicity, and correcting for multiple comparisons using Bonferroni correction. Moderation analysis examined interaction effects of APOE4 on associations between cognition and WMH asymmetry. Results:Greater left-dominant occipital WMH asymmetry was observed in AD, compared to healthy controls and MCI, and was associated with poorer global cognition, memory, language, and executive functions among cognitively impaired participants (MCI and AD). Cognitively impaired APOE4 carriers displayed greater left-dominant WMH asymmetry in the whole brain and frontal lobe, compared to non-carriers. Importantly, effects were independent of structural brain asymmetry, global cerebral atrophy, and overall WMH burden. Moderation analysis demonstrated associations between left-dominant WMH asymmetry and cognition in cognitively impaired APOE4 non-carriers, but not APOE4 carriers. Conclusion:Leftward asymmetry of WMH may be more pathological in nature, compared to symmetrical WMH. Furthermore, the detrimental effects of WMH asymmetry was more relevant in APOE4-negative cognitive impairment, compared to APOE4-positive which may be driven primarily by AD pathology.
Keywords: Alzheimer’s disease, apolipoprotein E4, cerebral small vessel diseases, cognitive aging, leukoaraiosis, magnetic resonance imaging, mild cognitive impairment
