Llum, and increased oxidative stress has been observed in the cerebellum of aged animals [47]. If the increased expression of Bcl-2 represents a response to age-related oxidative challenge Table 1. Demographical characteristics and preclinical assessments between Bcl-2 genotype groups.Demographic variablesA-Carriers (n = 228)G/G (n = 102) 57.0 (21.1) 56/46 12.3 (6.7) 4/98 0.78 (0.07) 27.7 (2.25) 13.8 (2.54) 7.07 (4.33)P valueAge (y) Sex (male/female) Education (y) Handedness (left/right) GMV (L) MMSE Digits Span 
Forward Digits Span Backward55.9 (22.5) 135/93 12.5 (6.1) 6/222 0.78 (0.08) 27.9 (2.37) 13.4 (2.64) 7.68 (3.93).689 .472 .771 .506 .915 .414 .322 .The 12926553 variables are demonstrated as means (6 standard deviation). Abbreviation: GMV, gray matter volume; MMSE, Mini-Mental Status Examination. doi:10.1371/journal.pone.0056663.tand cerebellum is highly susceptible to this challenge [25], the higher level of Bcl-2 expression from the homozygous G allele may protect against the age-related loss of neurons in the cerebellum. Our study also demonstrated that Bcl-2 polymorphism influences the GM volume in the bilateral lingual gyrus, the right middle temporal gyrus, and the right parahippocampal gyrus. These findings are consistent with two previous imaging analyses of the genetic effects of Bcl-2. Salvadore et al. [23] reported that Bcl-2 rs956572 was associated with GM volume in the subcortical structures. Our prior study found that the Bcl-2 genotype could modulate GM volume in the lingual gyrus and middle temporal gyrus in elderly men [24]. The distribution of Bcl-2 JSI-124 varies among these regions, and the level of Bcl-2 expression has been shown to be associated with neurotoxin-triggered apoptosis and cellular injury [25,45,48,49]. During the development of the human central nervous system, Bcl-2 expression declines gradually at more advanced stages, and an inverse correlation between apoptosis and Bcl-2 expression occurs in the areas surrounding the lingual gyrus [50]. Postmortem evidence supports apoptotic involvement in neuropsychiatric disorders, and low levels 
of Bcl-2 protein have been demonstrated in the middle temporal gyrus [51]. Furthermore, the hippocampus is particularly vulnerable to oxidative stress during aging, and altered Bcl-2 expression has been reported in the hippocampal region of aged rat [25]. Because the age-related changes in GM volume in these brain regions mayBcl-2 and Age-Related Gray Matter Volume ChangesTable 2. Interaction of Bcl-2 genotype and age on regional gray matter volume.MNI Coordinates x y zVoxel sizeAnatomical RegionBrodmann Nafarelin chemical information AreaMain EffectsF-valueP valueCorrelation (r) A-Carrier G/GBcl-2 2 278 241 868 Right Cerebellum 2 Age Bcl-26 Age Bcl-2 16 289 7 67 Right Lingual Gyrus Brodmann area 17 15755315 Age Bcl-26 Age Bcl-2 216 281 211 119 Left Lingual Gyrus Brodmann area 18 Age Bcl-26 Age Bcl-2 38 259 13 60 Right Middle Temporal Gyrus Brodmann area 19 Age Bcl-26 Age Bcl-2 28 215 213 71 Right Parahippocampal Gyrus Hippocampus Age Bcl-26 Age10.32 2.83 13.77 14.21 11.37 11.60 12.39 33.68 13.99 18.09 11.09 32.36 9.36 10.29 11..001 .094 ,.0001 ,.0001 .001 ,.0001 ,.0001 ,.0001 ,.0001 .009 ,.0001 ,.0001 .002 .001 ,.0001 20.35* 20.15 20.32* 20.04 20.50* 20.07 20.29* 20.09 20.22* 20.Z-scores are for the peak statistically significant voxel for each regional cluster with uncorrected P#.001 controlling for sex and education level. 2Indicated that there is no Brodmann area region around the center of a 5-mm radius search rang.Llum, and increased oxidative stress has been observed in the cerebellum of aged animals [47]. If the increased expression of Bcl-2 represents a response to age-related oxidative challenge Table 1. Demographical characteristics and preclinical assessments between Bcl-2 genotype groups.Demographic variablesA-Carriers (n = 228)G/G (n = 102) 57.0 (21.1) 56/46 12.3 (6.7) 4/98 0.78 (0.07) 27.7 (2.25) 13.8 (2.54) 7.07 (4.33)P valueAge (y) Sex (male/female) Education (y) Handedness (left/right) GMV (L) MMSE Digits Span Forward Digits Span Backward55.9 (22.5) 135/93 12.5 (6.1) 6/222 0.78 (0.08) 27.9 (2.37) 13.4 (2.64) 7.68 (3.93).689 .472 .771 .506 .915 .414 .322 .The 12926553 variables are demonstrated as means (6 standard deviation). Abbreviation: GMV, gray matter volume; MMSE, Mini-Mental Status Examination. doi:10.1371/journal.pone.0056663.tand cerebellum is highly susceptible to this challenge [25], the higher level of Bcl-2 expression from the homozygous G allele may protect against the age-related loss of neurons in the cerebellum. Our study also demonstrated that Bcl-2 polymorphism influences the GM volume in the bilateral lingual gyrus, the right middle temporal gyrus, and the right parahippocampal gyrus. These findings are consistent with two previous imaging analyses of the genetic effects of Bcl-2. Salvadore et al. [23] reported that Bcl-2 rs956572 was associated with GM volume in the subcortical structures. Our prior study found that the Bcl-2 genotype could modulate GM volume in the lingual gyrus and middle temporal gyrus in elderly men [24]. The distribution of Bcl-2 varies among these regions, and the level of Bcl-2 expression has been shown to be associated with neurotoxin-triggered apoptosis and cellular injury [25,45,48,49]. During the development of the human central nervous system, Bcl-2 expression declines gradually at more advanced stages, and an inverse correlation between apoptosis and Bcl-2 expression occurs in the areas surrounding the lingual gyrus [50]. Postmortem evidence supports apoptotic involvement in neuropsychiatric disorders, and low levels of Bcl-2 protein have been demonstrated in the middle temporal gyrus [51]. Furthermore, the hippocampus is particularly vulnerable to oxidative stress during aging, and altered Bcl-2 expression has been reported in the hippocampal region of aged rat [25]. Because the age-related changes in GM volume in these brain regions mayBcl-2 and Age-Related Gray Matter Volume ChangesTable 2. Interaction of Bcl-2 genotype and age on regional gray matter volume.MNI Coordinates x y zVoxel sizeAnatomical RegionBrodmann AreaMain EffectsF-valueP valueCorrelation (r) A-Carrier G/GBcl-2 2 278 241 868 Right Cerebellum 2 Age Bcl-26 Age Bcl-2 16 289 7 67 Right Lingual Gyrus Brodmann area 17 15755315 Age Bcl-26 Age Bcl-2 216 281 211 119 Left Lingual Gyrus Brodmann area 18 Age Bcl-26 Age Bcl-2 38 259 13 60 Right Middle Temporal Gyrus Brodmann area 19 Age Bcl-26 Age Bcl-2 28 215 213 71 Right Parahippocampal Gyrus Hippocampus Age Bcl-26 Age10.32 2.83 13.77 14.21 11.37 11.60 12.39 33.68 13.99 18.09 11.09 32.36 9.36 10.29 11..001 .094 ,.0001 ,.0001 .001 ,.0001 ,.0001 ,.0001 ,.0001 .009 ,.0001 ,.0001 .002 .001 ,.0001 20.35* 20.15 20.32* 20.04 20.50* 20.07 20.29* 20.09 20.22* 20.Z-scores are for the peak statistically significant voxel for each regional cluster with uncorrected P#.001 controlling for sex and education level. 2Indicated that there is no Brodmann area region around the center of a 5-mm radius search rang.
