Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study

Arch Neurol. 2008 May;65(5):642-9. doi: 10.1001/archneur.65.5.642.


Background: Elevated plasma total homocysteine (tHcy) levels have been associated with increased risk of dementia and stroke, but it is uncertain whether the mediating mechanisms are predominantly cellular, vascular, or both.

Objective: To evaluate the relationship between tHcy levels and findings at brain magnetic resonance imaging (MRI) in a community-based sample.

Design: Our sample comprised 1965 participants in the Framingham Offspring Study (1050 women; mean [SD] age, 62 [9] years) who were free of clinical stroke, dementia, or other neurologic disease affecting brain MRI and for whom at least 1 measurement of plasma tHcy level (1991-2001) and a brain MRI (1999-2002) were available. We used multivariate regression analysis to relate initial (1991-1995) and concurrent (1998-2001) plasma tHcy levels to total cerebral brain volume and lobar volumes as measures of neuronal loss and atrophy and to the presence or absence of silent brain infarcts and extensive white matter hyperintensity (log-white matter intensity > or =1 SD above the age-adjusted mean) as separate measures of vascular injury.

Results: Mean total cerebral brain volume was 78%. At MRI, 218 participants had silent brain infarcts and 250 demonstrated extensive white matter hyperintensity. Participants with a plasma tHcy level in the highest age- (-0.37%, P = .01) or sex-specific (-0.48%, P < .001) quartile had smaller total cerebral brain volumes compared with participants with lower tHcy levels. Initial tHcy levels were associated with a higher prevalence of silent brain infarct (relative risk, 1.5; 95% confidence interval, 1.1-2.1; P = .02) and concurrent tHcy levels, with smaller frontal (-0.14%, P = .001) and temporal lobar (-0.10%, P = .04) volumes. Prevalence of extensive white matter hyperintensity did not differ according to initial or concurrent plasma tHcy levels (relative risk, both 1.0; 95% confidence interval, 0.7-1.4 and 0.8-1.4, respectively).

Conclusions: Higher plasma tHcy levels are associated with smaller brain volume and the presence of silent brain infarcts at MRI, even in healthy, middle-aged adults. Thus, both cellular and vascular mechanisms may underlie the association of plasma tHcy level with brain aging, as reflected by the effects on both subclinical and overt disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Atrophy / metabolism
  • Atrophy / pathology
  • Biomarkers / analysis
  • Biomarkers / blood
  • Brain Infarction / blood*
  • Brain Infarction / epidemiology
  • Brain Infarction / pathology*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology*
  • Cohort Studies
  • Comorbidity
  • Female
  • Homocysteine / analysis
  • Homocysteine / blood
  • Humans
  • Hyperhomocysteinemia / blood*
  • Hyperhomocysteinemia / epidemiology
  • Hyperhomocysteinemia / pathology*
  • Magnetic Resonance Imaging
  • Male
  • Massachusetts / epidemiology
  • Middle Aged
  • Nerve Degeneration / blood
  • Nerve Degeneration / pathology
  • Nerve Fibers, Myelinated / metabolism
  • Nerve Fibers, Myelinated / pathology
  • Predictive Value of Tests
  • Prognosis


  • Biomarkers
  • Homocysteine