Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/25/2008
Publication Date: 8/26/2008
Citation: Troen, A.M., Shea-Budgell, M., Shukitt Hale, B., Smith, D., Selhub, J., Rosenberg, I. 2008. B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice. Proceedings of the National Academy of Sciences. 105(34):12474-12479.
Interpretive Summary: In older adults, individuals with mildly elevated blood concentrations of the sulfur containing amino acid, homocysteine, may be at higher risk of developing cognitive impairment, cerebrovascular disease and Alzheimer’s disease. The reason for this is unclear, but one possibility is that homocysteine damages small blood vessels in the brain. We found that feeding male mice a B-vitamin deficient diet for 10-weeks to cause blood homocysteine concentrations to rise, also impaired the performance of the vitamin deficient mice learning and remembering how to escape from a maze, and caused a significant loss of small brain blood vessels (capillaries) without causing apparent loss of nerve cells or inflammation. The extent of brain capillary loss correlated with longer escape times from the maze. Our findings suggest that brain capillary loss may be enough to cause cognitive impairment even before brain cells begin to degenerate. Similar brain changes in humans may explain the association of high homocysteine concentrations with human age-related cognitive decline. These findings advance our understanding of the role of nutrition in brain aging and will help to define dietary recommendations for maintaining brain health into old age.
Technical Abstract: In older adults, mildly elevated plasma total homocysteine (Hyperhomocysteinemia) is associated with increased risk of cognitive impairment, cerebrovascular disease and Alzheimer’s disease, but it is uncertain whether this is due to underlying metabolic, neurotoxic or vascular processes. We report here that feeding male C57BL6/J mice a B-vitamin deficient diet for 10-weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies (r=-0.757, p<0.001), and with plasma total homocysteine (r = -0.631, p=0.007). Feeding mice a methionine-rich diet produced similar but less pronounced effects. Our findings suggest that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline.