Background: Plasma homocysteine levels are increasingly studied as a potential risk factor for dementia. Elevated homocysteine levels have been linked with gray and white matter volume reduction among individuals with mild cognitive impairment and Alzheimer's disease. However, the effects of homocysteine on brain changes in preclinical stages of dementia remain unexplored.
Objective: To examine the association of elevated homocysteine levels with markers of neurodegeneration, i.e., white and gray matter volume in an elderly population.
Methods: The study included 768 participants (mean age: 69.6±6.5 years, 51.3% women) from the Epidemiology of Dementia In Singapore study. Participants underwent a brain MRI scan and blood tests. Serum homocysteine was measured using competitive immunoassay. Cortical thickness and subcortical structural volume were quantified using FreeSurfer whereas white matter volume was quantified using a previous validated method.
Results: Higher homocysteine levels were significantly associated with decreased global white matter volume [mean difference (β) in volume (ml) per micromole per liter (μmol/l) increase in homocysteine levels: - 0.555, 95% Confidence Interval (CI): - 0.873; - 0.237], decreased parietal cortical thickness [β in thickness (μm) per μmol/l increase in homocysteine levels:- 1.429, 95% CI: - 2.781; - 0.077], and smaller volumes of the thalamus [β: - 0.017, 95% CI: - 0.026; - 0.008], brainstem [β: - 0.037, 95% CI: - 0.058; - 0.016], and accumbens [β: - 0.004, 95% CI: - 0.006; - 0.002].
Conclusion: Higher homocysteine levels were associated with cerebral atrophy. Further studies are required to assess whether lowering plasma homocysteine levels may prevent neurodegenerative changes or delay progression of clinical symptoms before the development of dementia.

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Keywords Cortical thinning, dementia, homocysteine, subcortical atrophy, white matter atrophy
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Journal Journal of Alzheimer's Disease
Tan, B. (Bryce), Venketasubramanian, N, Vrooman, H.A, Cheng, C-Y, Wong, T.Y, Ikram, M.K, … Hilal, S. (2018). Homocysteine and Cerebral Atrophy. Journal of Alzheimer's Disease, 62(2), 877–885. doi:10.3233/JAD-170796