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Association of Asymmetrical White Matter Hyperintensities and Apolipoprotein E4 on Cognitive Impairment
Audrey Low1, Kok Pin Ng1, Russell Jude Chander1,2
1Department of Neurology, National Neuroscience Institute, Singapore, Singapore.
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.
Insights
Leftward white matter hyperintensities (WMH) asymmetry is linked to cognitive decline in Alzheimer's disease (AD) and mild cognitive impairment (MCI). This asymmetry is more pronounced in APOE4 carriers but impacts cognition more in non-carriers.
Area of Science:
- Neuroscience
- Neurology
- Neuroimaging
Background:
- Asymmetrical cerebral damage is a hallmark of neurodegenerative diseases like Alzheimer's disease (AD).
- White matter hyperintensities (WMH) are common in aging and neurodegeneration, but their asymmetrical patterns are less understood.
Purpose of the Study:
- To investigate the clinical associations of asymmetrical white matter hyperintensities (WMH) in individuals with mild cognitive impairment (MCI) and AD.
- To determine the relationship between WMH asymmetry, cognitive function, and APOE4 genotype.
Main Methods:
- Quantitative analysis of regional WMH asymmetry in 340 participants (90 controls, 132 MCI, 118 AD).
- WMH asymmetry calculated as hemispheric volume difference, adjusted for structural brain asymmetry.
- Statistical analyses included ANCOVA and regression, controlling for demographic factors and correcting for multiple comparisons.
Main Results:
- Greater left-dominant occipital WMH asymmetry was found in AD patients compared to controls and MCI.
- Left-dominant WMH asymmetry correlated with poorer global cognition, memory, language, and executive functions in MCI and AD.
- APOE4 carriers with cognitive impairment showed greater left-dominant WMH asymmetry, particularly in the frontal lobe.
Conclusions:
- Leftward WMH asymmetry may indicate a more pathological process than symmetrical WMH.
- The negative impact of WMH asymmetry on cognition appears more significant in APOE4-negative cognitive impairment, potentially due to AD pathology.
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