03024nas a2200373   4500008004100000022001400041245014900055210006900204260000900273300001100282490000600293520185500299100002302154700002002177700002002197700001302217700002102230700001902251700002102270700002002291700002202311700002202333700002102355700002302376700001902399700002102418700001902439700002102458700002002479700002202499710005502521710003802576856003602614       2012                        eng d  a2213-158200aCommon folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment.0 aCommon folate gene variant MTHFR C677T is associated with brain   c2012  a179-870 v13 a<p>A commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75 ± 7.1 years) scanned with brain MRI and genotyped as part of Alzheimer's Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76 ± 5.5 years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR 'T' alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2-8% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5-1.5% per T allele at 1 year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5-12% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI. </p>1 aRajagopalan, Priya1 aJahanshad, Neda1 aStein, Jason, L1 aHua, Xue1 aMadsen, Sarah, K1 aKohannim, Omid1 aHibar, Derrek, P1 aToga, Arthur, W1 aJack, Clifford, R1 aSaykin, Andrew, J1 aGreen, Robert, C1 aWeiner, Michael, W1 aBis, Joshua, C1 aKuller, Lewis, H1 aRiverol, Mario1 aBecker, James, T1 aLopez, Oscar, L1 aThompson, Paul, M1 aAlzheimer's Disease Neuroimaging Initiative (ADNI)1 aCardiovascular Health Study (CHS)  uhttps://chs-nhlbi.org/node/6135