Background
Methods
Clinical and neurobehavioral assessments
Homocysteine and Apolipoprotein E genotype analysis
Cerebrovascular risk confounders
Image acquisition
TBSS for topographies of Homocysteine levels
WM tract parcellation for 11 associated bundles
Statistical analysis
Results
Clinical data and biomarkers levels
Mean | ± | SD | Hcy correlation※ |
P value | |
---|---|---|---|---|---|
Age | 73.5 | ± | 7.5 | 0.12 | 0.19 |
Education (year) | 7.2 | ± | 4.8 | 0.07 | 0.44 |
Apolipoprotein E4 carrier (positive case, %) | 58 (43.9%) | – | |||
Sex (male/female) | 63/69 | – | |||
Mini-Mental State Examination | 20.1 | ± | 6.5 | 0.00294 | 0.97 |
CASI total scores | 67.4 | ± | 21.1 | 0.01 | 0.89 |
CASI executive function test scores | 25.1 | ± | 8.3 | −0.01 | 0.87 |
CASI Subdomains | ± | ||||
Short Term Memory | 5.4 | ± | 3.7 | 0.00087 | 0.99 |
Orientation | 12.7 | ± | 5.3 | −0.02 | 0.86 |
Long Term Memory | 8.3 | ± | 2.5 | 0.08 | 0.36 |
Language | 8.1 | ± | 2.3 | 0.01 | 0.93 |
Drawing | 7.9 | ± | 2.8 | 0.10 | 0.26 |
Attention | 6.3 | ± | 1.4 | −0.04 | 0.65 |
Verbal fluency | 5.2 | ± | 2.8 | −0.06 | 0.51 |
Abstract thinking | 8.1 | ± | 2.9 | 0.02 | 0.85 |
Mental manipulation | 5.5 | ± | 3.3 | 0.01 | 0.88 |
Cerebrovascular Risk Biomarkers | |||||
High sensitive C reactive protein (mg/L) | 2.7 | ± | 4.9 | −0.13 | 0.14 |
Homocysteine [Hcy] (umol/L) | 12.7 | ± | 4.4 |
–
|
–
|
Hemoglobin-A1C (%)
| 6.2 | ± | 1.1 | 0.00069 | 0.99 |
Creatinine (mg%) | 0.9 | ± | 0.4 | 0.54 | 3.7 × 10−11
|
Glomerular filtration rate (mL/min) | 74.7 | ± | 20.5 | −0.47 | 1.4 × 10−8
|
high-density lipoprotein (mg/dl) | 58.0 | ± | 17.0 | −0.22 | 0.01 |
low-density lipoprotein (mg/dl) | 104.8 | ± | 36.6 | 0.01 | 0.95 |
Hemoglobin (mg/dl) | 13.4 | ± | 1.6 | 0.01 | 0.93 |
Total Cholesterol (mg/dl) | 187.5 | ± | 39.9 | −0.07 | 0.43 |
Triglyceride (mg/dl) | 119.3 | ± | 60.6 | 0.09 | 0.31 |
Vitamin B12 (pg/dl) | 608.4 | ± | 341.1 | −0.36 | 2.7 × 10−5
|
Folate (ng/dl) | 12.2 | ± | 5.6 | −0.40 | 1.6 × 10−6
|
Topography and fiber integrities using diffusion parameters to assess the impact of homocysteine
Fiber name | Mean ± SD | Hcy | Hcy Adjusteda
| ||
---|---|---|---|---|---|
Forceps.major | |||||
Fractional Anisotropy | 0.475 | ± | 0.041 | −0.415* | −0.358* |
Axial Diffusivity(×10−3) | 1.487 | ± | 0.136 | 0.227* | 0.060 |
Radial Diffusivity(×10−3) | 0.696 | ± | 0.129 | 0.339* | 0.214 |
Mean Diffusivity(×10−3) | 0.960 | ± | 0.128 | 0.307* | 0.164 |
Forceps.minor | |||||
Fractional Anisotropy | 0.351 | ± | 0.026 | −0.351* | −0.258* |
Axial Diffusivity(×10−3) | 1.415 | ± | 0.066 | 0.216 | 0.053 |
Radial Diffusivity(×10−3) | 0.820 | ± | 0.070 | 0.328* | 0.173 |
Mean Diffusivity(×10−3) | 1.018 | ± | 0.067 | 0.301* | 0.139 |
Anterior.thalamic.radiation | |||||
Fractional Anisotropy | 0.605 | ± | 0.056 | −0.339* | −0.248* |
Axial Diffusivity(×10−3) | 3.052 | ± | 0.440 | 0.346* | 0.179 |
Radial Diffusivity(×10−3) | 2.049 | ± | 0.414 | 0.356* | 0.198 |
Mean Diffusivity(×10−3) | 2.383 | ± | 0.422 | 0.353* | 0.192 |
Corticospinal.tract | |||||
Fractional Anisotropy | 0.992 | ± | 0.055 | −0.282* | −0.302* |
Axial Diffusivity(×10−3) | 2.619 | ± | 0.111 | 0.456* | 0.349* |
Radial Diffusivity(×10−3) | 1.191 | ± | 0.118 | 0.442* | 0.388* |
Mean Diffusivity(×10−3) | 1.667 | ± | 0.110 | 0.467* | 0.393* |
Cingulum._cingulate.gyrus | |||||
Fractional Anisotropy | 0.677 | ± | 0.062 | −0.329* | −0.231* |
Axial Diffusivity(×10−3) | 2.272 | ± | 0.091 | −0.053 | −0.022 |
Radial Diffusivity(×10−3) | 1.379 | ± | 0.105 | 0.214* | 0.154 |
Mean Diffusivity(×10−3) | 1.677 | ± | 0.093 | 0.143* | 0.108 |
Cingulum._hippocampus | |||||
Fractional Anisotropy | 0.578 | ± | 0.068 | −0.177 | −0.102 |
Axial Diffusivity(×10−3) | 2.347 | ± | 0.245 | 0.162 | 0.039* |
Radial Diffusivity(×10−3) | 1.540 | ± | 0.231 | 0.177 | 0.066 |
Mean Diffusivity(×10−3) | 1.809 | ± | 0.233 | 0.173 | 0.057 |
Inferior.frontooccipital.fasciculus | |||||
Fractional Anisotropy | 0.736 | ± | 0.053 | −0.364* | −0.343* |
Axial Diffusivity(×10−3) | 2.554 | ± | 0.133 | 0.392* | 0.285* |
Radial Diffusivity(×10−3) | 1.432 | ± | 0.148 | 0.432* | 0.357* |
Mean Diffusivity(×10−3) | 1.806 | ± | 0.141 | 0.427* | 0.340* |
Inferior.longitudinal.fasciculus | |||||
Fractional Anisotropy | 0.744 | ± | 0.050 | −0.343* | −0.292* |
Axial Diffusivity(×10−3) | 2.413 | ± | 0.125 | 0.243* | 0.186 |
Radial Diffusivity(×10−3) | 1.350 | ± | 0.126 | 0.343* | 0.272* |
Mean Diffusivity(×10−3) | 1.704 | ± | 0.123 | 0.317* | 0.249* |
Superior.longitudinal.fasciculus | |||||
Fractional Anisotropy | 0.631 | ± | 0.049 | −0.266* | −0.281* |
Axial Diffusivity(×10−3) | 2.274 | ± | 0.136 | 0.343* | 0.218 |
Radial Diffusivity(×10−3) | 1.456 | ± | 0.140 | 0.356* | 0.275* |
Mean Diffusivity(×10−3) | 1.729 | ± | 0.137 | 0.357* | 0.261* |
Uncinate.fasciculus | |||||
Fractional Anisotropy | 0.680 | ± | 0.050 | −0.282* | −0.246* |
Axial Diffusivity(×10−3) | 2.664 | ± | 0.265 | 0.218 | 0.092 |
Radial Diffusivity(×10−3) | 1.625 | ± | 0.250 | 0.254* | 0.152 |
Mean Diffusivity(×10−3) | 1.971 | ± | 0.253 | 0.243* | 0.132 |
Superior.longitudinal.fasciculus temporal.part | |||||
Fractional Anisotropy | 0.898 | ± | 0.084 | −0.321* | −0.398* |
Axial Diffusivity(×10−3) | 2.473 | ± | 0.147 | 0.344* | 0.293* |
Radial Diffusivity(×10−3) | 1.179 | ± | 0.146 | 0.445* | 0.466* |
Mean Diffusivity(×10−3) | 1.610 | ± | 0.136 | 0.441* | 0.438* |
WM integrities affected by homocysteine and related confounders for cognitive outcomes
Tract name | Simple correlation | Adjusted for confounders#
| ||||||
---|---|---|---|---|---|---|---|---|
MMSE | CASI total | CASI EFT | STM | MMSE | CASI total | CASI EFT | STM | |
Forceps.major | .284(*) | .294(*) | .358(*) | .246(*) | .329(*) | .342(*) | .396(*) | .278(*) |
Forceps.minor | .291(*) | .300(*) | .364(*) | .252(*) | .333(*) | .342(*) | .395(*) | .285(*) |
Anterior.thalamic.radiation | .271(*) | .276(*) | .333(*) | .241(*) | .298(*) | .302(*) | .350(*) | .266(*) |
Corticospinal.tract | .304(*) | .308(*) | .361(*) | .249(*) | .316(*) | .331(*) | .379(*) | .252(*) |
Cingulum._cingulate.gyrus | .308(*) | .322(*) | .342(*) | .280(*) | .327(*) | .344(*) | .355(*) | .289(*) |
Cingulum._hippocampus | .351(*) | .384(*) | .344(*) | .451(*) | .342(*) | .375(*) | .334(*) | .447(*) |
Inferior.frontooccipital.fasciculus | .222 | .241(*) | .314(*) | .213 | .251(*) | .280(*) | .343(*) | .230(*) |
Inferior.longitudinal.fasciculus | .266(*) | .290(*) | .350(*) | .214 | .216 | .240(*) | .280(*) | .193 |
Superior.longitudinal.fasciculus | .199 | .219 | .269(*) | .182 | .252(*) | .260(*) | .263(*) | .252(*) |
Uncinate.fasciculus | .241(*) | .243(*) | .256(*) | .251(*) | .295(*) | .323(*) | .372(*) | .230(*) |
Superior.longitudinal.fasciculus.temporal.part | .161 | .194 | .248(*) | .103 | .198 | .241(*) | .279(*) | .128 |
Tract name | Simple correlation | Adjusted for confounders#
| ||||||
---|---|---|---|---|---|---|---|---|
MMSE | CASI total | CASI EFT | STM | MMSE | CASI total | CASI EFT | STM | |
Forceps.major | −.220 | −.213 | −.207 | −.138 | −.228(*) | −.210 | −.201 | −.139 |
Forceps.minor | −.324(*) | −.325(*) | −.341(*) | −.250(*) | −.322(*) | −.320(*) | −.339(*) | −.242(*) |
Anterior.thalamic.radiation | −.297(*) | −.306(*) | −.337(*) | −.273(*) | −.331(*) | −.335(*) | −.359(*) | −.308(*) |
Corticospinal.tract | −.154 | −.132 | −.189 | −.034 | −.183 | −.159 | −.207 | −.055 |
Cingulum._cingulate.gyrus | −.374(*) | −.387(*) | −.365(*) | −.314(*) | −.353(*) | −.368(*) | −.355(*) | −.294(*) |
Cingulum._hippocampus | −.463(*) | −.468(*) | −.385(*) | −.486(*) | −.467(*) | −.468(*) | −.380(*) | −.484(*) |
Inferior.frontooccipital.fasciculus | −.372(*) | −.350(*) | −.379(*) | −.241(*) | −.398(*) | −.379(*) | −.400(*) | −.250(*) |
Inferior.longitudinal.fasciculus | −.430(*) | −.409(*) | −.371(*) | −.323(*) | −.443(*) | −.425(*) | −.377(*) | −.318(*) |
Superior.longitudinal.fasciculus | −.392(*) | −.375(*) | −.363(*) | −.286(*) | −.416(*) | −.397(*) | −.376(*) | −.293(*) |
Uncinate.fasciculus | −.319(*) | −.335(*) | −.294(*) | −.352(*) | −.331(*) | −.345(*) | −.296(*) | −.357(*) |
Superior.longitudinal.fasciculus.temporal.part | −.234(*) | −.216 | −.210 | −.129 | −.246(*) | −.234(*) | −.217 | −.134 |
Tract name | Simple correlation | Adjusted for confounders#
| ||||||
---|---|---|---|---|---|---|---|---|
MMSE | CASI total | CASI EFT | STM | MMSE | CASI total | CASI EFT | STM | |
Forceps.major | −.269(*) | −.271(*) | −.296(*) | −.205 | −.295(*) | −.290(*) | −.308(*) | −.220 |
Forceps.minor | −.357(*) | −.365(*) | −.405(*) | −.300(*) | −.383(*) | −.389(*) | −.423(*) | −.318(*) |
Anterior.thalamic.radiation | −.302(*) | −.313(*) | −.349(*) | −.276(*) | −.340(*) | −.345(*) | −.373(*) | −.315(*) |
Corticospinal.tract | −.273(*) | −.268(*) | −.325(*) | −.178 | −.309(*) | −.310(*) | −.358(*) | −.203 |
Cingulum._cingulate.gyrus | −.430(*) | −.450(*) | −.459(*) | −.362(*) | −.430(*) | −.452(*) | −.458(*) | −.356(*) |
Cingulum._hippocampus | −.471(*) | −.488(*) | −.419(*) | −.519(*) | −.474(*) | −.488(*) | −.415(*) | −.519(*) |
Inferior.frontooccipital.fasciculus | −.321(*) | −.322(*) | −.377(*) | −.244(*) | −.361(*) | −.367(*) | −.413(*) | −.266(*) |
Inferior.longitudinal.fasciculus | −.406(*) | −.407(*) | −.414(*) | −.314(*) | −.440(*) | −.444(*) | −.438(*) | −.327(*) |
Superior.longitudinal.fasciculus | −.354(*) | −.356(*) | −.367(*) | −.276(*) | −.384(*) | −.386(*) | −.386(*) | −.292(*) |
Uncinate.fasciculus | −.321(*) | −.340(*) | −.307(*) | −.360(*) | −.336(*) | −.355(*) | −.313(*) | −.369(*) |
Superior.longitudinal.fasciculus.temporal.part | −.232(*) | −.246(*) | −.283(*) | −.139 | −.277(*) | −.303(*) | −.324(*) | −.166 |
Tract name | Simple correlation | Adjusted for confounders#
| ||||||
---|---|---|---|---|---|---|---|---|
MMSE | CASI total | CASI EFT | STM | MMSE | CASI total | CASI EFT | STM | |
Forceps.major | −.258(*) | −.257(*) | −.272(*) | −.186 | −.278(*) | −.268(*) | −.277(*) | −.195 |
Forceps.minor | −.356(*) | −.362(*) | −.395(*) | −.292(*) | −.373(*) | −.377(*) | −.406(*) | −.301(*) |
Anterior.thalamic.radiation | −.301(*) | −.311(*) | −.346(*) | −.275(*) | −.338(*) | −.342(*) | −.369(*) | −.313(*) |
Corticospinal.tract | −.246(*) | −.235(*) | −.294(*) | −.139 | −.284(*) | −.276(*) | −.326(*) | −.164 |
Cingulum._cingulate.gyrus | −.442(*) | −.461(*) | −.461(*) | −.372(*) | −.433(*) | −.454(*) | −.454(*) | −.359(*) |
Cingulum._hippocampus | −.474(*) | −.487(*) | −.412(*) | −.514(*) | −.478(*) | −.488(*) | −.409(*) | −.514(*) |
Inferior.frontooccipital.fasciculus | −.342(*) | −.336(*) | −.383(*) | −.247(*) | −.379(*) | −.378(*) | −.416(*) | −.265(*) |
Inferior.longitudinal.fasciculus | −.424(*) | −.417(*) | −.409(*) | −.324(*) | −.452(*) | −.448(*) | −.428(*) | −.332(*) |
Superior.longitudinal.fasciculus | −.372(*) | −.368(*) | −.372(*) | −.284(*) | −.401(*) | −.396(*) | −.389(*) | −.297(*) |
Uncinate.fasciculus | −.249(*) | −.253(*) | −.277(*) | −.145 | −.337(*) | −.354(*) | −.309(*) | −.367(*) |
Superior.longitudinal.fasciculus.temporal.part | −.258(*) | −.257(*) | −.272(*) | −.186 | −.288(*) | −.302(*) | −.310(*) | −.167 |