Do white matter hyperintensities mediate the association between brain iron deposition and cognitive abilities in older people?
Several studies have reported associations between brain iron deposits (IDs), white matter hyperintensities (WMHs) and cognitive ability in older individuals. Whether the association between brain IDs and cognitive abilities in older people is mediated by or independent of total brain tissue damage represented by WMHs visible on structural magnetic resonance imaging (MRI) was examined.



Data from 676 community-dwelling individuals from the Lothian Birth Cohort 1936, with Mini-Mental State Examination scores >24, who underwent detailed cognitive testing and multimodal brain MRI at mean age 72.7 years were analysed. Brain IDs were assessed automatically following manual editing. WMHs were assessed semi-automatically. Brain microbleeds were visually counted. Structural equation modelling was used to test for mediation.



Overall, 72.8% of the sample had IDs with a median total volume of 0.040 ml (i.e. 0.004% of the total brain volume). The total volume of IDs, significantly and negatively associated with general cognitive function (standardized β = -0.17, P < 0.01), was significantly and positively associated with WMH volume (std β = 0.13, P = 0.03). WMH volume had a significant negative association with general cognitive function, independent of IDs (std β = -0.13, P < 0.01). The association between cognition and IDs in the brain stem (and minimally the total brain iron load) was partially and significantly mediated by WMH volume (P = 0.03).



The negative association between brain IDs and cognitive ability in the elderly is partially mediated by WMHs, with this mediation mainly arising from the iron deposition load in the brain stem. IDs might be an indicator of small vessel disease that predisposes to white matter damage, affecting the neuronal networks underlying higher cognitive functioning.
Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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Valdés Hernández
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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Allerhand
Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
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Glatz
College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
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Clayson
Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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Muñoz Maniega
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, School of Life Sciences, Heriot-Watt University, Edinburgh, UK.
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A
Gow
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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Royle
Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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Bastin
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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Starr
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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Deary
Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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Wardlaw
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology* / Q000523:psychology; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000502:physiology*; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D066127:White Matter / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology
D007501:Iron
MRI; ageing; cognition; iron deposits; white matter hyperintensities