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Original Contribution
September 2004

Homocysteine and the Brain in Midadult Life: Evidence for an Increased Risk of Leukoaraiosis in Men

Author Affiliations

Author Affiliations: School of Psychiatry, University of New South Wales, Sydney, Australia (Drs Sachdev and Wen); Neuropsychiatric Institute, The Prince of Wales Hospital, Randwick, Australia (Drs Sachdev and Wen); the Centre for Mental Health Research, Australian National University, Canberra (Drs Parslow, Kumar, Christensen, and Jorm); and Clinical Chemistry, South Eastern Area Laboratory Services, Randwick (Mr Salonikas and Drs Lux and Naidoo).

Arch Neurol. 2004;61(9):1369-1376. doi:10.1001/archneur.61.9.1369

Background  High serum homocysteine (HCY) levels have been associated with thromboembolic cerebrovascular disease, but their relationship to microvascular disease is uncertain. Homocysteine also has a direct neurotoxic effect and has been linked to brain atrophy and an increased risk of Alzheimer disease.

Objective  To examine the relationship of HCY levels to brain and cognitive measures in a healthy community sample.

Design  Cross-sectional study.

Setting  Individuals residing in Canberra and Queanbeyan, Australia, who were participating in the longitudinal PATH Through Life Project.

Participants  Individuals aged 60 to 64 years selected randomly from the community, 196 men and 189 women.

Main Outcome Measures  Regression coefficients with HCY level as the putative determinant and various magnetic resonance imaging measures (brain atrophy index, ventricle-brain ratios, volume of periventricular and deep white matter hyperintensities) and cognitive measures (information processing speed, verbal memory, fine motor speed) as dependent measures.

Results  Homocysteine levels did not have a significant relationship with brain atrophy index or ventricle-brain ratios. High HCY levels were related to increased deep white matter hyperintensities but not periventricular white matter hyperintensities, after correcting for levels of folate, vitamin B12, creatinine, and thyrotropin; hypertension; smoking; and diabetes, the relationship being significant only in men. Homocysteine levels were related to impairment in verbal memory and fine motor speed but not after the previously mentioned correction.

Conclusions  Total HCY level is independently related to leukoaraiosis in middle-aged men, and this may be functionally relevant in the form of mild cognitive impairment. The remediation of hyperhomocysteinemia should begin early in life if its deleterious effects on the brain are to be prevented.