Haemoglobin, magnetic resonance imaging markers and cognition: A subsample of population-based study 11 Medical and Health Sciences 1109 Neurosciences 11 Medical and Health Sciences 1103 Clinical Sciences

Background: Low haemoglobin is highly prevalent among the elderly and has been associated with dementia. However, the mechanisms underlying this association with cognitive dysfunction, either through cerebrovascular disease or neurodegeneration, remain poorly understood. We aimed to examine the association of decreased haemoglobin levels with markers of cerebral small vessel disease (CSVD), neurodegeneration and cognitive impairment in an elderly Asian population. Methods: A total of 796 Chinese, Malay and Indian participants aged 60 years and older from the Epidemiology of Dementia in Singapore study were included in this study. After providing information on demographics, anthropometry and cardiovascular risk factors, participants underwent 3-T brain magnetic resonance imaging (MRI) to measure markers of CSVD, including cerebral microbleeds, cortical cerebral microinfarcts, lacunes, enlarged perivascular spaces and white matter hyperintensities, as well as neurodegenerative markers, including cortical thickness and subcortical structure volumes quantified using FreeSurfer. Cognition was assessed using a detailed neuropsychological assessment. Logistic and linear regression models were constructed, adjusting for age, gender, education, race, body mass index, smoking, hypertension, hyperlipidaemia, diabetes, glomerular filtration rate and other MRI markers, to test the association between haemoglobin levels and the MRI markers and cognition. Results: Decreased haemoglobin levels were associated with cerebral microbleeds, specifically lobar microbleeds (OR, 1.21; 95% CI, 1.04-1.40; p = 0.015). Decreased haemoglobin levels were also associated with occipital cortical thinning (mean difference, - 0.011; 95% CI, - 0.019, - 0.004; p = 0.003) and smaller accumbens volume (mean difference, - 0.01; 95% CI, - 0.02, 0.00; p = 0.005). A significant association was also observed between decreased haemoglobin levels and poorer global cognitive performance (mean difference, - 0.04; 95% CI, - 0.09, 0.00; p = 0.048). In cognitive domain analysis, associations were again observed between decreased haemoglobin levels and worse performance on attention (mean difference, - 0.05; 95% CI, - 0.10, - 0.01; p = 0.028) and language (mean difference, - 0.06; 95% CI, - 0.12, 0.00; p = 0.048) domains; however, these associations did not survive multiple comparison. Conclusions: Decreased haemoglobin levels were associated with lobar microbleeds, neurodegenerative markers and cognitive dysfunction. Future studies should ascertain whether iron, folate or vitamin B12 supplementation is able to ameliorate the onset and progression of cognitive impairment and dementia associated with low haemoglobin.

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