早期盲人大脑灰质不对称的基于体素脑形态学初步研究

目的初步探讨视觉剥夺对人脑灰质结构不对称的影响。方法早期失明的成年盲人组（14例，右利手）与正常对照组（16例，右利手，年龄、性别匹配）在1．5T磁共振成像系统下获取全脑高分辨率的脑结构像（T1W）。通过基于体素的脑形态学（VBM）方法比较两组间脑灰质不对称的异同。结果与正常对照相比，早期盲人的一些脑区呈灰质左侧化增高，包括额叶（BA 10／8）、体感区（BA 3）及颞极（BA 43），以及枕叶视皮层（中枕回，BA 18／19）灰质右侧化增高。结论早期盲人大脑多个系统发生了结构重组，可以表现为灰质不对称的变化。     

Age- and sex-related effects on the neuroanatomy of healthy elderly

Effects of age and sex, and their interaction on the structural brain anatomy of healthy elderly were assessed thanks to a cross-sectional study of a cohort of 662 subjects aged from 63 to 75 years. T1- and T2-weighted MRI scans were acquired in each subject and further processed using a voxel-based approach that was optimized for the identification of the cerebrospinal fluid (CSF) compartment. Analysis of covariance revealed a classical neuroanatomy sexual dimorphism, men exhibiting larger gray matter (GM), white matter (WM), and CSF compartment volumes, together with larger WM and CSF fractions, whereas women showed larger GM fraction. GM and WM were found to significantly decrease with age, while CSF volume significantly increased. Tissue probability map analysis showed that the highest rates of GM atrophy in this age range were localized in primary cortices, the angular and superior parietal gyri, the orbital part of the prefrontal cortex, and in the hippocampal region. There was no significant interaction between "Sex" and "Age" for any of the tissue volumes, as well as for any of the tissue probability maps. These findings indicate that brain atrophy during the seventh and eighth decades of life is ubiquitous and proceeds at a rate that is not modulated by "Sex".     

Investigating association of brain volumes with intracranial capacity in schizophrenia

Intracranial volume (ICV) is usually treated as a global or nuisance covariate in almost all volumetric studies of schizophrenia. However, validation for this analytic method has seldom been accomplished. In this study, we aimed to determine the effects of ICV on gray matter (GM) and white matter (WM) volumes. Sixty-three patients with schizophrenia and sixty normal controls were recruited; and high resolution T1 weighted images were obtained by 3T-MRI. After segmentation and normalization of the images into GM, WM, and cerebrospinal fluid (CSF), multiple regression analyses of global GM and WM volumes were performed using explanatory variables such as diagnosis, ICV, and diagnosis-ICV interaction. In addition, associations between regional GM and WM volumes with ICV were also investigated using voxel-based morphometry (VBM). No significant interaction between diagnosis and ICV was found for global GM volume, whereas interactions were detected in restricted GM areas using VBM. On the other hand, an interaction between ICV and diagnosis was found in WM not only for regional volumes, but also for global WM volume. The regression slope of global WM volumes against ICV was steeper in patients with schizophrenia than in healthy controls. These results imply that ICV should be carefully evaluated in the analyses of volumetric studies of schizophrenia, especially when analyzing WM volumes.     

Modifications of brain tissue volumes in facioscapulohumeral dystrophy

Facioscapulohumeral muscular dystrophy (FSHD), a pathology primarily characterized by involvement of the muscles in the face, shoulder and upper arm, can be associated to several CNS disorders, including sensorineural hearing deficits, schizophrenia, epilepsy and mental retardation. Aim of our study was to verify if brain tissue volumes, as measured by segmentation of MRI studies, are altered in FSHD. Volumes of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were compared, taking into account head size age and sex, both globally (by multiple regression analysis) and regionally (by optimized voxel-based morphometry-VBM) in thirty patients with FSHD and 39 normal subjects (NS). FSHD patients had significantly lower GM volumes and higher CSF volumes (P < 10(-4)). GM loss showed a borderline correlation with clinical severity (P < 0.05). Brain tissue volumes did not correlate with disease duration, size of the genetic deletion, age at onset and the presence at MRI of WM hyperintensities (detected in 4/22 patients). At VBM three clusters of GM loss were detected, in the left precentral cortex (Brodmann areas 6, 2 and 44, P < 10(-14) corrected for multiple comparisons at cluster level), in the anterior cingulate (Brodmann areas 33, 24 and 11, P < 10(-4)) and in the right fronto-polar region (Brodmann area 10, P < 5.10(-3)). To the best of our knowledge, this is the first study to demonstrate a reduction in GM volume in FSHD. We hypothesize that localized GM loss in FSHD is the consequence of a selective involvement of specific CNS structures.     

Mapping brain structure and personality in late adulthood

Cerebral gray matter (GM) volume decreases in normal aging with a parallel increase in intracranial cerebrospinal fluid (CSF) volume. There is considerable interindividual variation in these changes, and the consequences of age-related GM shrinkage and CSF expansion are unclear. The present study examined whether late adulthood brain structural differences are related to differences in temperament and character. Personality structures of 42 healthy aged adults (mean age 60 years) were examined together with global and regional GM, CSF, and white matter (WM) volumes calculated from structural magnetic resonance images using voxel-based morphometry (VBM). A positive relationship was seen between GM volume at the border of the temporal, parietal, and frontal cortices, and self-transcendence, a character personality trait that reflects mature creativity and spiritualism. The relationship remained significant after a conservative correction for multiple comparisons and it was seen both using uncorrected raw values and after a correction for the effects of age and sex. The results suggest that high self-transcendence, which has adaptive advantages in the later part of life, is associated with relatively greater temporal cortical GM volumes.     

Sex differences in regional gray matter in healthy individuals aged 44-48 years: a voxel-based morphometric study

The study examined sex-related differences in regional gray matter (GM) in 44-48 year old healthy individuals. T1-weighted MRI scans were acquired in 411 subjects aged 44-48 from a random community sample and optimized voxel-based morphometry was applied to detect regional GM difference between men and women, correcting for effects of age, years of education, handedness, and total intracranial volume (TIV). Men had larger brain volumes and higher white matter (WM) to TIV ratios compared with women. Women had higher GM to TIV ratios than men. After controlling for age, years of education, handedness, and TIV, there were no significant differences between men and women in the total GM volumes. Regional sex dimorphism was present, with men having more GM volume in midbrain, left inferior temporal gyrus, right occipital lingual gyrus, right middle temporal gyrus, and both cerebellar hemispheres. Women showed more GM in dorsal anterior, posterior and ventral cingulate cortices, and right inferior parietal lobule. Our results suggest sex dimorphism in GM in middle aged healthy individuals, which is not likely to be explained by brain pathology. These differences may provide the structural brain basis for sex differences in certain cognitive functions.     

Semi-automatic brain region extraction (SABRE) reveals superior cortical and deep gray matter atrophy in MS

In multiple sclerosis (MS), atrophy occurs in various cortical and subcortical regions. However, it is unclear whether this is mostly due to gray (GM) or white matter (WM) loss. Recently, a new semi-automatic brain region extraction (SABRE) technique was developed to quantify parenchyma volume in 13 hemispheric regions. This study utilized SABRE and tissue segmentation to examine whether regional brain atrophy in MS is mostly due to GM or WM loss, correlated with disease duration, and moderated by disease course. We studied 68 MS patients and 39 normal controls with 1.5 T brain MRI. As expected, MS diagnosis was associated with significantly lower (P < 0.001) regional brain parenchymal fractions (RBPFs). While significant findings emerged in 11 GM comparisons, only four WM comparisons were significant. The largest mean RBPF percent differences between groups (MS < NC) were in the posterior basal ganglia/thalamus region (-19.3%), superior frontal (-15.7%), and superior parietal (-14.3%) regions. Logistic regression analyses showed GM regions were more predictive of MS diagnosis than WM regions. Eight GM RBPFs were significantly correlated (P < 0.001) with disease duration compared to only one WM region. Significant trends emerged for differences in GM, but not WM between secondary progressive (SP) and relapsing-remitting MS patients. Percent differences in GM between the two groups were largest in superior frontal (-9.9%), medial superior frontal (-6.5%), and superior parietal (-6.1%) regions, with SP patients having lower volumes. Overall, atrophy in MS is diffuse and mostly related to GM loss particularly in deep GM and superior frontal-parietal regions.     

Validating cortical surface analysis of medial prefrontal cortex.

This paper describes cortical analysis of 19 high resolution MRI subvolumes of medial prefrontal cortex (MPFC), a region that has been implicated in major depressive disorder. An automated Bayesian segmentation is used to delineate the MRI subvolumes into cerebrospinal fluid (CSF), gray matter (GM), white matter (WM), and partial volumes of either CSF/GM or GM/WM. The intensity value at which there is equal probability of GM and GM/WM partial volume is used to reconstruct MPFC cortical surfaces based on a 3-D isocontouring algorithm. The segmented data and the generated surfaces are validated by comparison with hand segmented data and semiautomated contours, respectively. The L(1) distances between Bayesian and hand segmented data are 0.05-0.10 (n = 5). Fifty percent of the voxels of the reconstructed surface lie within 0.12-0.28 mm (n = 14) from the semiautomated contours. Cortical thickness metrics are generated in the form of frequency of occurrence histograms for GM and WM labelled voxels as a function of their position from the cortical surface. An algorithm to compute the surface area of the GM/WM interface of the MPFC subvolume is described. These methods represent a novel approach to morphometric chacterization of regional cortex features which may be important in the study of psychiatric disorders such as major depression.     

Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis

BACKGROUND: There is little information available on grey and white matter (GM and WM) atrophy in primary progressive multiple sclerosis (PPMS) and on their relationships with clinical and other magnetic resonance imaging (MRI) measures. AIM: To evaluate disease progression in the early phase of PPMS, focusing on axonal loss as assessed by volumetric MRI measures of WM and GM, and to determine their relationships with clinical outcomes and lesion load measures. METHODS: Forty-three patients with PPMS within 5 years of symptom onset and 45 control subjects were studied. Three-dimensional brain scans were acquired and segmented into WM, GM, and cerebrospinal fluid (CSF) using SPM99. Brain parenchymal (BPF), WM (WMF), and GM fractions (GMF) normalized against total intracranial volumes were estimated. T2-weighted (T2) and enhancing lesion loads were also determined. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were recorded in all patients. RESULTS: There were significant differences between patients and controls in BPF, WMF, and GMF values (P < 0.001). BPF (r = -0.469; P = 0.002) and WMF (r = -0.532; P < 0.001) but not GMF (r = -0.195; P = 0.2) correlated with EDSS scores. BPF (r = 0.518; P = 0.001), WMF (r = 0.483; P = 0.001), and GMF (r = 0.337; P = 0.031) correlated with MSFC scores. Correlations with enhancing lesion and T2 loads were only significant for BPF and WMF. CONCLUSIONS: Brain atrophy is seen in the early stages of PPMS and affects both GM and WM. WM atrophy appears more closely related to clinical outcome and WM focal damage than GM atrophy in this patient group.     

Feasibility of grey matter and white matter segmentation of the upper cervical cord in vivo: A pilot study with application to magnetisation transfer measurements

Spinal cord pathology can be functionally very important in neurological disease. Pathological studies have demonstrated the involvement of spinal cord grey matter (GM) and white matter (WM) in several diseases, although the clinical relevance of abnormalities detected histopathologically is difficult to assess without a reliable way to assess cord GM and WM in vivo. In this study, the feasibility of GM and WM segmentation was investigated in the upper cervical spinal cord of 10 healthy subjects, using high-resolution images acquired with a commercially available 3D gradient-echo pulse sequence at 3T. For each healthy subject, tissue-specific (i.e. WM and GM) cross-sectional areas were segmented and total volumes calculated from a 15mm section acquired at the level of C2-3 intervertebral disc and magnetisation transfer ratio (MTR) values within the extracted volumes were also determined, as an example of GM and WM quantitative measurements in the cervical cord. Mean (±SD) total cord cross-sectional area (TCA) and total cord volume (TCV) of the section studied across 10 healthy subjects were 86.9 (±7.7) mm(2) and 1302.8 (±115) mm(3), respectively; mean (±SD) total GM cross-sectional area (TGMA) and total GM volume (TGMV) were 14.6 (±1.1) mm(2) and 218.3 (±16.8) mm(3), respectively; mean (±SD) GM volume fraction (GMVF) was 0.17 (±0.01); mean (±SD) MTR of the total WM volume (WM-MTR) was 51.4 (±1.5) and mean (±SD) MTR of the total GM volume (GM-MTR) was 49.7 (±1.6). The mean scan-rescan, intra- and inter-observer % coefficient of variation for measuring the TCA were 0.7%, 0.5% and 0.5% and for measuring the TGMA were 6.5%, 5.4% and 12.7%. The difference between WM-MTR and GM-MTR was found to be statistically significant (p=0.00006). This study has shown that GM and WM segmentation in the cervical cord is possible and the MR imaging protocol and analysis method presented here in healthy controls can be potentially extended to study the cervical cord in disease states, with the option to explore further quantitative measurements alongside MTR.     

Aging: compensation or maturation?

Neuroimaging studies of healthy aging often reveal differences in neural activation patterns between young and elderly groups for episodic memory tasks, even though there are no differences in behavioral performance. One explanation typically offered is that the elderly compensate for their memory deficiencies through the recruitment of additional prefrontal regions. The present study of healthy aging compared magnetoencephalographic (MEG) time-courses localized to specific cortical regions in two groups of subjects (20-29 years and >or=65 years) during a visual delayed-match-to-sample (DMS) task. MR morphometrics and neuropsychological test results were also examined with the hope of providing insight into the nature of the age-related differences. The behavioral results indicated no differences in performance between young and elderly groups. Although there was a main effect of age on the latency of the initial peak in primary/secondary visual cortex, these longer latencies were not correlated with the performance of elderly on the DMS task. The lateral occipital gyrus (LOG) revealed qualitatively different patterns of activity for the two age groups corroborated by neuropsychological test results. Morphometric results for the young versus elderly groups revealed less white (WM) and gray matter (GM) volumes in the frontal lobes of the elderly. When a group of middle-aged subjects (33-43 years) was included in the morphometric analyses, the middle-aged subjects revealed statistically greater WM volumes in frontal and parietal cortex suggesting immature WM tracts in the young. Perhaps our elderly utilized a different strategy compared to the young due to the different brain maturation levels of these groups.     

Migraine-Related Gray Matter and White Matter Changes at a 1-Year Follow-Up Evaluation

To assess the longitudinal gray matter (GM) and white matter (WM) changes between repeated observations 1 year apart in a group of the early clinical stage of migraine patients without aura, and to explore the relationship of such structural changes with headache activity, we studied patients newly diagnosed with episodic migraine lasting 8 to 14 weeks. Optimized voxel-based morphometry and tract-based spatial statistical analyses were used to evaluate changes in GM and WM by using 3-dimensional T1-weighted and diffusion-tensor imaging, respectively. At the 1-year follow-up examination, GM reduction was observed in the dorsolateral and medial part of the superior frontal gyrus, orbitofrontal cortex, hippocampus, precuneus, and primary and secondary somatosensory cortices. No significant differences were found in the fractional anisotropy and longitudinal, radial, and mean diffusivity of WM in migraine patients without aura within a year. Negative results were found for the association between changes in headache activity parameters and GM. Our results indicated that the GM and WM changed in different pathophysiological conditions of migraine patients without aura. The WM probably evolves slowly in the course of migraine chronicity.     

Reproducibility of brain tissue volumes in longitudinal studies: effects of changes in signal-to-noise ratio and scanner software

It is imperative that users of voxel-based morphometry (VBM) be aware of its reproducibility and the factors which influence results. We assessed the reproducibility of a VBM software package (SPM5) in measuring gray matter (GM) and white matter (WM) volumes from at least two consecutive 3D T1-weighted studies in 64 subjects. Factors investigated were the inter-study interval (ISI: 2.2 h to 124 days), signal-to-noise ratio (SNR: number of image averages (NA)=1 or 2), scanner software version and idle time. SNR was measured by direct estimation of tissue noise (SNR(TN)) and mean intensity in noise-only voxels (SNR(NO)). After the scanner software upgrade, voxel intensity increased 5-fold and WM mean SNR(TN) by 24% (p<0.001). Mean WM and GM volume changes in consecutive studies were near 0% (absolute SD of 7 ml and 10 ml respectively). Studies acquired with original scanner software showed a small (1.6%) mean GM volume increase attributed to SNR(TN) increases in five subjects due to scanner maintenance. GM volumes increased with SNR(TN) across the software upgrade (up to 4.3%; p<0.01) and NA=2 acquisitions (up to 4.1%; p<0.001). GM and WM volumes were independent of ISI when ISI did not encompass the software change. Scanner idle times of >6 h decreased SNR by 7% (p<0.001). SPM5 failed to include visible peripheral GM in only 2 subjects. SNR(TN) increases were greater than SNR(NO) increases across the software upgrade. It was concluded that SNR changes significantly influence SPM5-derived GM volumes. SNR may be influenced by scanner software upgrades and hardware condition and should be routinely assessed in studies of brain volume.     

Grey matter volume alterations in CADASIL: a voxel-based morphometry study

CADASIL is a hereditary disease characterized by cerebral subcortical microangiopathy leading to early onset cerebral strokes and progressive severe cognitive impairment. Until now, only few studies have investigated the extent and localization of grey matter (GM) involvement. The purpose of our study was to evaluate GM volume alterations in CADASIL patients compared to healthy subjects. We also looked for correlations between global and regional white matter (WM) lesion load and GM volume alterations. 14 genetically proved CADASIL patients and 12 healthy subjects were enrolled in our study. Brain MRI (1.5 T) was acquired in all subjects. Optimized-voxel based morphometry method was applied for the comparison of brain volumes between CADASIL patients and controls. Global and lobar WM lesion loads were calculated for each patient and used as covariate-of-interest for regression analyses with SPM-8. Compared to controls, patients showed GM volume reductions in bilateral temporal lobes (p < 0.05; FDR-corrected). Regression analysis in the patient group revealed a correlation between total WM lesion load and temporal GM atrophy (p < 0.05; uncorrected), not between temporal lesion load and GM atrophy. Temporal GM volume reduction was demonstrated in CADASIL patients compared to controls; it was related to WM lesion load involving the whole brain but not to lobar and, specifically, temporal WM lesion load. Complex interactions between sub-cortical and cortical damage should be hypothesized.     

Linking white matter tracts to associated cortical grey matter: a tract extension methodology

Quantitative diffusion analysis of white matter (WM) tracts has been utilised in many diseases for determining damage to, and changes in, WM tracts throughout the brain. However, there are limited studies investigating associations between quantitative measures in WM tracts and anatomically linked grey matter (GM), due to the difficulty in determining GM regions connected with a given WM tract.This work describes a straightforward method for extending a WM tract through GM based on geometry. The tract is extended by following a straight line from each point on the tract boundary to the outer boundary of the cortex. A comparison between a multiplanar 2D approach and a 3D method was made. This study also tested an analysis pipeline from tracking WM tracts to quantifying magnetisation transfer ratios (MTR) in the associated cortical GM, and assessed the applicability of the method to healthy control subjects. Tract and associated cortical volumes and MTR values for the cortico-spinal tracts, genu and body of the corpus callosum were extracted; the between-subjects standard deviation was calculated.It was found that a multiplanar 2D approach produced a more anatomically plausible volume of GM than a 3D approach, at the expense of possible overestimation of the GM volume. The between-subjects standard deviation of the tract specific quantitative measurements (from both the WM and GM masks) ranged between 1.2 and 7.3% for the MTR measures, and between 10 and 45% for the absolute volume measures.The results show that the method can be used to produce anatomically plausible extensions of the WM tracts through the GM, and regions defined in this way yield reliable estimates of the MTR from the regions.     

Brain tissue volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load

The aim of this study was to simultaneously measure in vivo volumes of gray matter (GM), normal white matter (WM), abnormal white matter (aWM), and cerebro-spinal fluid (CSF), and to assess their relationship in 50 patients with relapsing-remitting multiple sclerosis (RR-MS) (age range, 21-59; mean EDSS, 2.5; mean disease duration, 9.9 years), using an unsupervised multiparametric segmentation procedure applied to brain MR studies. Tissue volumes were normalized to total intracranial volume providing corresponding fractional volumes (fGM, faWM, fWM, and fCSF), subsequently corrected for aWM-related segmentation inaccuracies and adjusted to mean patients' age according to age-related changes measured in 54 normal volunteers (NV) (age range 16-70). In MS patients aWM was 23.8 +/- 29.8 ml (range 0.4-138.8). A significant decrease in fGM was present in MS patients as compared to NV (49.5 +/- 3.2% vs 53.3 +/- 2.1%; P < 0.0001), with a corresponding increase in fCSF (13.0 +/- 3.8% vs 9.1 +/- 2.4%; P < 0.0001). No difference could be detected between the two groups for fWM (37.5 +/- 2.6% vs 37.6 +/- 2.2%). faWM correlated inversely with fGM (R = -0.434, P < 0.001 at regression analysis), and directly with fCSF (R = 0.473, P < 0.001), but not with fWM. There was a significant correlation between disease duration and EDSS, while no relationship was found between EDSS or disease duration and fractional volumes. Brain atrophy in RR-MS is mainly related to GM loss, which correlates with faWM. Both measures do not appear to significantly affect EDSS, which correlates to disease duration.     

Regional white matter volume differences in nondemented aging and Alzheimer's disease

Accumulating evidence suggests that altered cerebral white matter (WM) influences normal aging, and further that WM degeneration may modulate the clinical expression of Alzheimer's disease (AD). Here we conducted a study of differences in WM volume across the adult age span and in AD employing a newly developed, automated method for regional parcellation of the subcortical WM that uses curvature landmarks and gray matter (GM)/WM surface boundary information. This procedure measures the volume of gyral WM, utilizing a distance constraint to limit the measurements from extending into the centrum semiovale. Regional estimates were first established to be reliable across two scan sessions in 20 young healthy individuals. Next, the method was applied to a large clinically-characterized sample of 299 individuals including 73 normal older adults and 91 age-matched participants with very mild to mild AD. The majority of measured regions showed a decline in volume with increasing age, with strong effects found in bilateral fusiform, lateral orbitofrontal, superior frontal, medial orbital frontal, inferior temporal, and middle temporal WM. The association between WM volume and age was quadratic in many regions suggesting that WM volume loss accelerates in advanced aging. A number of WM regions were further reduced in AD with parahippocampal, entorhinal, inferior parietal and rostral middle frontal WM showing the strongest AD-associated reductions. There were minimal sex effects after correction for intracranial volume, and there were associations between ventricular volume and regional WM volumes in the older adults and AD that were not apparent in the younger adults. Certain results, such as the loss of WM in the fusiform region with aging, were unexpected and provide novel insight into patterns of age associated neural and cognitive decline. Overall, these results demonstrate the utility of automated regional WM measures in revealing the distinct patterns of age and AD associated volume loss that may contribute to cognitive decline.     

Fractional anisotropy of cerebral white matter and thickness of cortical gray matter across the lifespan

We examined age trajectories of fractional anisotropy (FA) of cerebral white matter (WM) and thickness of cortical gray matter (GM) in 1031 healthy human subjects (aged 11-90 years). Whole-brain FA and GM thickness values followed quadratic trajectories with age but the relationship between them was linear, indicating that a putative biological mechanism may explain the non-linearity of their age trajectories. Inclusion of the FA values into the quadratic model of the whole-brain and regional GM thickness changes with age made the effect of the age(2) term no longer significant for the whole-brain GM thickness and greatly reduced its significance for regional GM thickness measurements. The phylogenetic order of cerebral myelination helped to further explain the intersubject variability in GM thickness. FA values for the early maturing WM were significantly better (p=10(-6)) at explaining variability in GM thickness in maturing (aged 11-20) subjects than FA values for the late maturing WM. The opposite trend was observed for aging subjects (aged 40-90) where FA values for the late maturing WM were better (p=10(-16)) at explaining the variability in GM thickness. We concluded that the non-linearity of the age trajectory for GM thickness, measured from T1-weighted MRI, was partially explained by the heterogeneity and the heterochronicity of the age-related changes in the microintegrity of cerebral WM. We consider these findings as the evidence that the measurements of age-related changes in GM thickness and FA are driven, in part, by a common biological mechanism, presumed to be related to changes in cerebral myelination.     

Convergent evidence of the contribution of TP53 genetic variation (Pro72Arg) to metabolic activity and white matter volume in the frontal lobe in schizophrenia patients

Abnormalities in white matter (WM) volumes and integrity in schizophrenia, together with post-mortem studies showing reduced expression of oligodendrocyte/myelination genes and apoptotic processes taking place in oligodendrocytes, suggest the interest of major regulators of apoptosis as candidate genes for some features related to myelin integrity in schizophrenia. Protein p53, encoded by TP53 gene, has a central role in the control of apoptosis and is involved in oligodendrocyte development. TP53 gene polymorphisms may account for variability in WM features, metabolic activity and biochemical markers of neuronal integrity and membrane turnover. Pro72Arg and Ins16bp polymorphisms at TP53 gene were analyzed in 20 DSM-IV schizophrenia patients. T1/T2-weighted sequences of these patients were acquired using a 1.5T Philips Gyroscan system. Scans were transformed into Talairach space and segmented into gray matter (GM), WM and cerebrospinal fluid (CSF) using Statistical Parametric Mapping under a ROI approach. Likewise dorsolateral prefrontal cortex (DLPFC) metabolic activity was measured using a procedure based on MRI/PET image fusion. In 13 of these patients proton magnetic resonance spectroscopy was used to examine N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) levels in dorsolateral-medial prefrontal cortex (DLMPFC). MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n=45). Patients Pro/Arg heterozygous (Pro72Arg polymorphism) showed a generalized deficit in whole-brain WM that was especially prominent in frontal lobe and a lower metabolic activity in the DLPFC as compared to Pro/Pro homozygous. Pro/Arg subjects also showed decreased NAA/Cho and increased Cho/Cr ratios in right DLMPFC. TP53 genetic variability influences WM volumes in frontal lobes and it seems to modulate the metabolic activity in this region. Our results suggest that TP53 might influence aspects of myelin and white matter integrity which may account for some of the frontal dysfunction features commonly described in these patients.     

Genetic and environmental influences of white and gray matter signal contrast: a new phenotype for imaging genetics?

The estimation of cortical thickness is in part dependent on the degree of contrast in T1 signal intensity between white matter and gray matter along the cortical mantle. The ratio of white matter to gray matter signal (WM/GM contrast) has been found to vary as a function of age and Alzheimer's disease status, suggesting a biological component to what might otherwise be labeled as a nuisance variable. The aim of the present study was to determine if measures of WM/GM contrast are genetically influenced, as well as the degree to which this phenotype may be related to the genetic and environment determinants of cortical thickness. Participants were 514 male twins (130 monozygotic, 97 dizygotic pairs, and 60 unpaired individuals) from the Vietnam Era Twin Study of Aging. Ages ranged from 51 to 59 years. Measures of WM/GM contrast and cortical thickness were derived for 66 cortical regions of interest (ROI) using FreeSurfer-based methods. Univariate and bivariate twin analyses were used in order to estimate the heritability of WM/GM contrast, as well as the degree of shared genetic and environmental variance between WM/GM contrast and cortical thickness. WM/GM contrast was found to be significantly heritable in the majority of ROIs. The average heritability across individual ROIs was highest in the occipital lobe (.50), and lowest in the cingulate cortex (.24). Significant phenotypic correlations between WM/GM contrast and cortical thickness were observed for most of the ROIs. The majority of the phenotypic correlations were negative, ranging from ?.11 to ?.54. Of the 66 associations, only 17 significant genetic correlations were found, ranging from ?.16 to ?.34, indicating small amounts of shared genetic variance. The majority of the phenotypic correlations were accounted for by small unique environmental effects common between WM/GM contrast and cortical thickness. These findings demonstrate that like cortical thickness, WM/GM contrast is a genetically influenced brain structure phenotype. The lack of significant genetic correlations with cortical thickness suggests that this measure potentially represents a unique source of genetic variance, one that has yet to be explored by the field of imaging genetics.