Background-Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.

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Language lateralization in the brain is dependent on family history of handedness, personal handedness, pathology, and other factors. The influence of age on language lateralization is not completely understood. Increasing left lateralization of language with age has been observed in children while the reverse has been noted in healthy young adults. It is not known whether the trend of decreasing language lateralization with age continues in the late decades of life and at what age the inflection in language lateralization trend as a function of age occurs. In this study, we examined the effect of age on language lateralization in 170 healthy right-handed children and adults ages 5 -67 using functional MRI (fMRI) and a verb generation task. Our findings indicate that language lateralization to the dominant hemisphere increases between the ages 5 and 20 years, plateaus between 20 and 25 years, and slowly decreases between 25 and 70 years.

PURPOSE-To evaluate differences in white matter diffusion properties as a function of age in healthy children and adolescents.MATERIALS AND METHODS-Echo-planar diffusion-tensor magnetic resonance (MR) imaging was performed in 33 healthy subjects aged 5-18 years who were recruited from a functional imaging study of normal language development. Results of neurologic, psychologic, and structural MR imaging examinations were within the normal range for all subjects. The trace of the apparent diffusion coefficient and fractional anisotropy in white matter were correlated as a function of age by using Spearman rank correlation.RESULTS-Statistically significant negative correlation of the trace of the apparent diffusion coefficient with age was found throughout the white matter. Significant positive correlation of fractional anisotropy with age was found in the internal capsule, corticospinal tract, left arcuate fasciculus, and right inferior longitudinal fasciculus.CONCLUSION-Diffusion-tensor MR imaging results indicate that white matter maturation assessed at different ages involves increases in both white matter density and organization during childhood and adolescence. The trace of the apparent diffusion coefficient and fractional anisotropy may reflect different physiologic processes in healthy children and adolescents. Index termsAnisotropy; Brain, diffusion, 10.12144; Brain, growth and development, 10.92; Brain, MR, 10.121411, 10.12144; Brain, white matter, 10.92; Children, central nervous system; Diffusion tensor; Magnetic resonance (MR), diffusion study, 10.12144, 10.92; Myelin, 10.92 Although most of the myelination in brain white matter is complete by the age of 5 years (1), maturation of brain white matter is an ongoing process into at least the 3rd decade of life (2)(3)(4)(5). This maturation of brain structures and their connecting pathways is essential for the continuing development of both cognitive and motor functions, as the speed of neural transmission depends on the axon diameter and the thickness of the insulating myelin sheath (6). Results of previous postmortem analysis have shown that axon diameter and myelin sheath Address correspondence to V.J.S. (e-mail: vince@athena.chmcc.org grow markedly from birth until about the age of 2 years (7) and that these maturation processes may continue during adolescence and adulthood (8). However, little postmortem analysis information is available for childhood and adolescence. Thus, it is difficult to draw definite conclusions about the development of white matter in this age group.Diffusion-tensor magnetic resonance (MR) imaging can be used to investigate and visualize the microscopic diffusion properties of water in living tissue. White matter fiber orientation can be determined by using diffusion-tensor MR imaging because water diffuses faster parallel to the longitudinal axis of axons than it does perpendicular to it (9,10). Therefore, among the in vivo MR imaging techniques, diffusion-tensor MR imaging in particular is an extremely useful to...

Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and -8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.

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A possible relationship between cognitive abilities and white matter structure as assessed by magnetic resonance diffusion tensor imaging (DTI) was investigated in the pediatric population. DTI was performed on 47 normal children ages 5–18. Using a voxelwise analysis technique, the fractional anisotropy (FA) and mean diffusivity (MD) were tested for significant correlations with Wechsler full‐scale IQ scores, with subject age and gender used as covariates. Regions displaying significant positive correlations of IQ scores with FA were found bilaterally in white matter association areas, including frontal and occipito‐parietal areas. No regions were found exhibiting correlations of IQ with MD except for one frontal area significantly overlapping a region containing a significant correlation with FA. The positive direction of the correlation with FA is the same as that found previously with age, and indicates a positive relationship between fiber organization and/or density with cognitive function. The results are consistent with the hypothesis that regionally specific increased fiber organization is a mechanism responsible for the normal development of white matter tracts. Hum Brain Mapp, 2005. © 2005 Wiley‐Liss, Inc.

Changes in the distribution of language function in the brain have been documented from infancy through adulthood. Even macroscopic measures of language lateralization reflect a dynamic process of language development. In this review, we summarize a series of functional MRI studies of language skills in children ages of five to 18 years, both typically-developing children and children with brain injuries or neurological disorders that occur at different developmental stages with different degrees of severity. These studies used a battery of fMRI-compatible language tasks designed to tap sentential and lexical language skills that develop early and later in childhood. In typically-developing children, lateralization changes with age are associated with language skills that have a protracted period of development, reflecting the developmental process of skill acquisition rather than general maturation of the brain. Normative data, across the developmental period, acts as a reference for disentangling developmental patterns in brain activation from changes due to developmental or acquired abnormalities. This review emphasizes the importance of considering age and child development in neuroimaging studies of language.