Compromised white matter integrity in obesity

Obesity is associated with both structural and functional changes of the central nervous system. While gray matter alterations in obesity point to a consistent reduction with increasing body mass index (BMI), volumetric changes in white matter are more complex and less conclusive. Hence, more recently, diffusion tensor imaging (DTI) has been employed as a highly sensitive tool to investigate microstructural changes in white matter structure. Parameters of diffusivity and anisotropy are used to evaluate white matter and fibre integrity as well as axonal and myelin degeneration. Fractional anisotropy (FA) is the most commonly used parameter as it is the best estimate of fibre integrity. The focus of this review was on the relationship between obesity and brain alterations assessed by DTI. Altogether, these studies have shown a loss of white matter integrity with obesity‐related factors, especially in tracts within the limbic system and those connecting the temporal and frontal lobe. More specifically, multiple studies found an inverse association between BMI and FA in the corpus callosum, fornix, cingulum and corona radiata in elderly and young adults as well as children. Furthermore, significant interactions were observed between BMI and age, pointing to accelerated ageing of white matter structure in obese.     

Alterations in white matter volume and integrity in obesity and type 2 diabetes

Type 2 diabetes mellitus (T2DM) is characterized by obesity, hyperglycemia and insulin resistance. Both T2DM and obesity are associated with cerebral complications, including an increased risk of cognitive impairment and dementia, however the underlying mechanisms are largely unknown. In the current study, we aimed to determine the relative contributions of obesity and the presence of T2DM to altered white matter structure. We used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to measure white matter integrity and volume in obese T2DM patients without micro- or macrovascular complications, age- gender- and BMI-matched normoglycemic obese subjects and age- and gender-matched normoglycemic lean subjects. We found that obese T2DM patients compared with lean subjects had lower axial diffusivity (in the right corticospinal tract, right inferior fronto-occipital tract, right superior longitudinal fasciculus and right forceps major) and reduced white matter volume (in the right inferior parietal lobe and the left external capsule region). In normoglycemic obese compared with lean subjects axial diffusivity as well as white matter volume tended to be reduced, whereas there were no significant differences between normoglycemic obese subjects and T2DM patients. Decreased white matter integrity and volume were univariately related to higher age, being male, higher BMI, HbA1C and fasting glucose and insulin levels. However, multivariate analyses demonstrated that only BMI was independently related to white matter integrity, and age, gender and BMI to white matter volume loss. Our data indicate that obese T2DM patients have reduced white matter integrity and volume, but that this is largely explained by BMI, rather than T2DM per se.     

Brain white matter structure and COMT gene are linked to second-language learning in adults

Adult human brains retain the capacity to undergo tissue reorganization during second-language learning. Brain-imaging studies show a relationship between neuroanatomical properties and learning for adults exposed to a second language. However, the role of genetic factors in this relationship has not been investigated. The goal of the current study was twofold: (i) to characterize the relationship between brain white matter fiber-tract properties and second-language immersion using diffusion tensor imaging, and (ii) to determine whether polymorphisms in the catechol-O-methyltransferase (COMT) gene affect the relationship. We recruited incoming Chinese students enrolled in the University of Washington and scanned their brains one time. We measured the diffusion properties of the white matter fiber tracts and correlated them with the number of days each student had been in the immersion program at the time of the brain scan. We found that higher numbers of days in the English immersion program correlated with higher fractional anisotropy and lower radial diffusivity in the right superior longitudinal fasciculus. We show that fractional anisotropy declined once the subjects finished the immersion program. The relationship between brain white matter fiber-tract properties and immersion varied in subjects with different COMT genotypes. Subjects with the Methionine (Met)/Valine (Val) and Val/Val genotypes showed higher fractional anisotropy and lower radial diffusivity during immersion, which reversed immediately after immersion ended, whereas those with the Met/Met genotype did not show these relationships. Statistical modeling revealed that subjects’ grades in the language immersion program were best predicted by fractional anisotropy and COMT genotype.Second-language learning in adulthood is becoming increasingly prevalent as globalization advances. Previous studies show that gray matter volume and density are related to foreign language speech learning (1, 2), and that the degree of volumetric change in an individual predicts the level of foreign language proficiency achieved by that person (3, 4). Recent studies using diffusion tensor imaging (DTI) techniques further show that diffusion properties of brain white matter structure are correlated with foreign language learning (5–7). One of these studies demonstrated that the changes in diffusion properties predicted students’ second-language proficiency at the end of a language immersion program (7). These findings suggest that the properties of brain structure change with the acquisition of a new language, and that the adult human brain is capable of tissue reorganization in response to intense use of a new language after the putative “critical period.”What remains unknown is whether and how genetic factors are related to brain white matter fiber-tract properties as learning ensues. Cumulative evidence using DTI analysis has suggested that brain white matter fiber-tract properties are related to skill learning (for a review, see ref. 8). A DTI index, fractional anisotropy (FA), which reflects the degree of water diffusion’s directional dependency, shows increased FA values as various skills are learned (5–7, 9–12). Another DTI index, radial diffusivity (RD), reflects water diffusion in a direction perpendicular to the fiber tracts. Increased FA and decreased RD values were associated with improved reading skills in children (11, 13). A recent study showed that a polymorphism in the catechol-O-methyltransferase (COMT) gene is related to FA values in children and adolescents (14). Taken together, these observations led us to explore the relationship between FA values and college students’ participation in an English immersion class. We further explored whether COMT polymorphisms can change the observed relationships.COMT encodes an enzyme that degrades catecholamines (for a review, see ref. 15) and the protein of COMT is present in neuron and glial cells, including oligodendrocyte cells that produce myelin (16). COMT activity is also found in the cerebromicrovascular endothelial and smooth muscle walls, as well as in the capillary walls in brains (17, 18). A common polymorphism of COMT affects enzyme activity (19–21): the Methionine (Met) variant at position 158 in COMT leads to lower thermostability than the Valine (Val) variant. COMT-deficient mice showed increased dopamine or dopamine metabolite (3,4-Dihydroxyphenylacetic acid, DOPAC), but not norepinephrine, in the cortex compared with the heterozygotes and wild-type littermates (22, 23). Using family data, COMT activity was first shown to be recessive (24) and later confirmed to be the two codominant alleles at the same locus (25), suggesting three potential phenotypes corresponding to three genotypes. Consistent with this idea, COMT activity measured in whole-blood samples were shown to be highest in individuals with the Val/Val genotype, the intermediate level for Val/Met genotype, and the lowest for the Met/Met genotype (26). Studies using functional imaging techniques have suggested that the COMT genotype may have effects on brain activation responses (for a review, see ref. 27). For example, subjects with the Met/Met genotype showed lower prefrontal activation responses than the subjects with the Met/Val and Val/Val genotypes (28) or Val/Val genotype alone (29). One additional study also showed a different relationship between the midbrain dopamine synthesis and prefrontal activity compared with subjects with the Met/Val and Val/Val genotypes (30).In this study, we: (i) characterize whether diffusion properties of white matter fiber tracts are related to subjects’ participation in a short-term English immersion program; (ii) examine whether diffusion properties of white matter fiber tracts vary between subjects with different COMT genotypes; and finally, (iii) predict subjects’ class grades in the immersion program based on individuals’ brain diffusion properties of white matter and their COMT genotype.We recruited Chinese freshmen students who enrolled in an intensive English immersion program at the University of Washington to prepare for college-level instruction (n = 44). These were the experimental subjects. The program consisted of 16 training lessons, each of 3.5-h duration. Thus, students experienced a total of 56 h of immersion by the time they completed the program. The program focused on advanced skills in English comprehension and writing. In addition, we recruited Chinese students at the University of Washington who arrived in the United States at the same time but did not enroll in the immersion program (n = 35). These were the control subjects. The experimental (E) and control (C) student participants were matched for their prior exposure to English, including their age of first exposure to English, their parental/sibling English proficiency levels, and the amount of time they lived outside of China (see Materials and Methods for details).We performed brain scans during a 14-d period, beginning 7 d after students entered the United States (11 d after the short-term immersion program began for students enrolled in the immersion program). All subjects had one brain scan. All brain scans were completed 8 d after the immersion program ended.Our preliminary DTI analyses on E subjects revealed that FA/RD measures varied depending on whether the brain scan occurred while the immersion experience was still ongoing, versus after the immersion experience ended. Taking this into account, we separated subjects’ FA and RD data based on when the brain scans occurred. For E subjects who had been in the immersion program at the time of the scan, we examined FA and RD values as a function of the number of days (ND1) they had been in class. For subjects who had already finished the immersion class at the time of the scan, we examined the FA and RD values as a function of the number of days after the immersion program ended (ND2). We expected different trends to be observed in ND1 and ND2 data.     

Brain iron deposition in white matter hyperintensities: a 3-T MRI study

Iron accumulation has been implicated in the pathogenesis of demyelinating diseases. Therefore, we hypothesized that abnormal high cerebral iron deposition may be involved in the development of white matter hyperintensities (WMHs). We used R2* relaxometry to assess whether iron levels in different brain regions correlate with the severity of WMHs. This technique has been recently validated in a postmortem study to demonstrate in vivo brain iron accumulation in a quantitative manner. Fifty-two consecutive WMH patients and 30 healthy controls with 3-T magnetic resonance imaging (MRI) were reviewed in this study. We measured WMH volume (as a marker of the severity of WMHs) on MRI, and the transverse relaxation rate R2*, as an estimate of iron content in seven brain regions. We found that R2* in globus pallidus was associated with WMH volume after adjusting for sociodemographic variables (partial correlation coefficient = 0.521, P < 0.001) and in a multivariate analysis adjusted for common vascular risk factors (partial correlation coefficient = 0.572, P = 0.033). Regional R2* in globus pallidus was also significantly higher in WMHs than in controls (P = 0.042). Iron content in globus pallidus, as assessed by R2* relaxometry, is independently linked to the severity of WMHs in our cohort of patients, suggesting that iron deposition in the brain may play a role in the pathogenesis of WMHs. This may provide prognostic information on patients with WMHs and may have implications for therapeutic interventions in WMHs.     

Development of human white matter pathways in utero over the second and third trimester

During the second and third trimesters of human gestation, rapid neurodevelopment is underpinned by fundamental processes including neuronal migration, cellular organization, cortical layering, and myelination. In this time, white matter growth and maturation lay the foundation for an efficient network of structural connections. Detailed knowledge about this developmental trajectory in the healthy human fetal brain is limited, in part, due to the inherent challenges of acquiring high-quality MRI data from this population. Here, we use state-of-the-art high-resolution multishell motion-corrected diffusion-weighted MRI (dMRI), collected as part of the developing Human Connectome Project (dHCP), to characterize the in utero maturation of white matter microstructure in 113 fetuses aged 22 to 37 wk gestation. We define five major white matter bundles and characterize their microstructural features using both traditional diffusion tensor and multishell multitissue models. We found unique maturational trends in thalamocortical fibers compared with association tracts and identified different maturational trends within specific sections of the corpus callosum. While linear maturational increases in fractional anisotropy were seen in the splenium of the corpus callosum, complex nonlinear trends were seen in the majority of other white matter tracts, with an initial decrease in fractional anisotropy in early gestation followed by a later increase. The latter is of particular interest as it differs markedly from the trends previously described in ex utero preterm infants, suggesting that this normative fetal data can provide significant insights into the abnormalities in connectivity which underlie the neurodevelopmental impairments associated with preterm birth.

In the human fetus, the brain’s major white matter pathways develop over the second to third trimester of gestation in an extremely rapid yet distinctly hierarchical order (1, 2). The structure and the integrity of these white matter connections have an integral role in supporting the efficiency and coordination of functional networks. Current understanding about these processes has been largely reliant on postmortem data (2–6). Fetal MRI can capture whole-brain development in its living, functioning state, thereby providing crucial additional insight into normal growth. In the case of white matter in particular, this can include detailed investigation of developing long-range connections and region-specific trajectories.The importance of better understanding this key period is emphasized by the high prevalence of cognitive and motor problems in children born preterm. In these infants, early exposure to the ex utero environment likely influences later trajectories of neurodevelopment (7–9). Multiple lines of evidence suggest that white matter abnormalities are the dominant pathology, further suggesting that this specific tissue type is both at a critical stage in its development and vulnerable to external influences (10–15). In this context, characterization of in utero maturation of white matter has a critical role as a normative reference.Precise characterization of in vivo fetal development of white matter tracts using noninvasive methods such as MRI is challenging due to difficulties inherent to acquiring imaging data from this population, such as addressing image artifacts related to maternal tissue and constant fetal motion, as well as recruiting enough subjects to account for population heterogeneity and age effects (11, 16–27). Previous studies are also difficult to generalize as representing typical development as they have included clinical populations with brain abnormalities or ex utero preterm infants (8, 28, 29). All existing studies have used diffusion-tensor imaging (DTI) to describe changes in microstructure (30); however, the results have been inconsistent. While some studies have reported linear relationships between DTI metrics and gestational age (GA) (16, 22, 23, 31), others have fit nonlinear models (18, 32) and others still have found no clear age-dependence (19, 21).In this study, we address the limitations of DTI and challenges of fetal imaging using a state-of-the-art high angular resolution multishell diffusion-weighted MRI (dMRI) acquisition, as well as a reconstruction and processing pipeline developed specifically for studying challenging fetal data as part of the developing Human Connectome Project (dHCP) (http://www.developingconnectome.org) (33, 34). We applied newly developed and optimized methods for in utero tractography and microstructure estimation in a large cohort of 113 healthy fetuses from 22 to 37 wk GA. With these methods, we were able to delineate specific white matter bundles including the left and right corticospinal tracts (CST) (an example of a projection tract), the optic radiations (ORs) and inferior longitudinal fasciculus (ILF) (examples of association tracts), and the corpus callosum (CC) (example of a commissural tract). These specific tracts were selected due to known differences in their developmental trajectories and because their injury or abnormal development has been implicated in the pathophysiology of neurodevelopmental disorders or intellectual disability (10, 12, 35). This study represents the largest and most detailed in utero characterization of maturational changes in white matter microstructure across the second to third trimester of human gestation and represents a valuable resource for improving our understanding of the neuropathophysiology underlying neurodevelopmental disorders.     

Efficacy of octreotide-LAR in dieting women with abdominal obesity and polycystic ovary syndrome

CONTEXT: Somatostatin reduces LH, GH, and insulin, and somatostatin receptors are present at the ovarian level; somatostatin analogs are thus potential candidates for treatment of the polycystic ovary syndrome (PCOS). OBJECTIVE: The purpose of this study was to evaluate the effect of octreotide-LAR, a long-acting somatostatin analog, in anovulatory abdominal obese women with PCOS. DESIGN: A single-blind, placebo-controlled study was performed, lasting for 7 months. SETTING: The patients were ambulatory throughout the study. PATIENTS: Twenty PCOS subjects were enrolled. Eighteen completed the study. INTERVENTIONS: A low-calorie diet was given during the first month, a low-calorie diet plus octreotide-LAR (10 mg; n = 10 subjects) or placebo (n = 10 subjects) was then given, with one im injection every 28 d (for 6 months). MAIN OUTCOME MEASURES: The main outcome measures were clinical features, computerized tomography measurement of fat distribution, androgens, GH, IGF-I, IGF-binding proteins (IGFBPs), fasting and glucose-stimulated insulin, and ovulation. RESULTS: Octreotide had no additional effect in reducing body fat or improving fat distribution than placebo. Conversely, octreotide produced an additional decrease in fasting (P = 0.018) and glucose-stimulated (P = 0.038) insulin levels, an increase in IGFBP-2 (P = 0.042) and IGFBP-3 (P = 0.047), and an improvement in hirsutism (P = 0.004). Moreover, a trend toward greater reductions in testosterone (P = 0.061) and androstenedione (P = 0.069) was observed in women treated with octreotide-LAR compared with those given placebo. All women treated with octreotide ovulated at the end of the study compared with only one of those receiving placebo (P < 0.001). CONCLUSIONS: Octreotide-LAR may be usefully applied to hypocalorically dieting, abdominal obese PCOS women to improve hyperandrogenism and the insulin-IGF-I system. Restoration of ovulatory menstrual cycles appears to be another advantage of this treatment.     

Brain white matter abnormalities in paediatric Gaucher Type I and Type III using diffusion tensor imaging

Objective  

Biomarkers to monitor neurological dysfunction in Neuronopathic Gaucher disease (NGD) are lacking. Diffusion tensor imaging (DTI) is a technique which allows us to probe the microstructure of the white-matter of the brain, in-vivo. The aim of this study was to investigate the value of DTI to visualise and quantify white matter integrity in children with NGD and Type I Gaucher.     

Biochemical studies on frontal lobe white matter of young and old human brains

Frontal lobe white matter obtained at autopsy from 5 young (45–60 yr) and 5 non-demented old (77–78 yr) individuals was studied. Water, total protein, myelin basic protein (BP) content and 2′,3′-cyclic nucleotide 3′phosphohydrolase (CNP) activity in the frontal white matter of the two groups were compared. Myelin BP was measured by two different methods, RIA and batch extraction. Results indicated no significant changes in water and in total protein content. Myelin BP, as measured by both methods, however, was found to be significantly decreased in brains of the older group. CNP activity was also decreased but only slightly. This data suggests that with advancing age, myelin may undergo some qualitative changes.     

Rho激酶抑制剂对缺血性脑白质损伤的实验性干预研究

目的探讨Rho激酶对缺血性脑白质损害的影响及Rho激酶抑制剂对缺血性脑白质损害的干预效果。方法雄性Wistar大鼠60只,随机分为对照组、缺血组和治疗组,每组20只。缺血组和治疗组给予双侧颈总动脉结扎,对照组给予假手术处理;术后治疗组给予法舒地尔腹腔注射,对照组和缺血组给予生理盐水腹腔注射。手术1个月后评价测定各组大鼠脑深部白质纤维密度、星形胶质细胞数目以及Rho激酶mRNA表达水平。结果缺血组大鼠脑深部白质纤维密度较对照组明显降低,星形胶质细胞数目明显增多,Rho激酶mRNA表达水平明显增高,差异有统计学意义(P<0.05);治疗组大鼠脑深部白质纤维密度较缺血组明显增高,星形胶质细胞数目明显减少,差异有统计学意义(P<0.05)。结论 Rho激酶异常活化与缺血性白质损害相关,Rho激酶抑制剂可改善慢性低灌注状态下大鼠脑白质损害。     

Selective effect of mannitol-induced hyperosmolality on brain interstitial fluid and water content in white matter

We studied the effect of mannitol-induced hyperosmolality on brain interstitial fluid (ISF) by autoradiography. Adult cats underwent intracerebral infusion of the extracellular marker,¹⁴C-sucrose. Nine animals were given 2 g/kg of mannitol intravenously, and another nine animals without mannitol were controls. Plasma and cerebrospinal fluid (CSF) osmolalities were measured. After 2 hr the brains were removed for determination of water and electrolyte content and for preparation of the autoradiograms. Diffusion coefficients were calculated for intracerebral transport with equations for radial diffusion. We found that mannitol increased the plasma osmolality but did not affect that of the CSF. Water and potassium contents were significantly lower in the white matter of mannitol-treated animals than in controls. Diffusion was reduced in the direction of gray matter into the white matter. We conclude that lower doses of mannitol control CSF pressure by selectively removing water from white matter, reducing the CSF volume, and affecting molecular transport at the gray/white interface.     

Development of white matter and reading skills

White matter tissue properties are highly correlated with reading proficiency; we would like to have a model that relates the dynamics of an individual’s white matter development to their acquisition of skilled reading. The development of cerebral white matter involves multiple biological processes, and the balance between these processes differs between individuals. Cross-sectional measures of white matter mask the interplay between these processes and their connection to an individual’s cognitive development. Hence, we performed a longitudinal study to measure white-matter development (diffusion-weighted imaging) and reading development (behavioral testing) in individual children (age 7–15 y). The pattern of white-matter development differed significantly among children. In the left arcuate and left inferior longitudinal fasciculus, children with above-average reading skills initially had low fractional anisotropy (FA) that increased over the 3-y period, whereas children with below-average reading skills had higher initial FA that declined over time. We describe a dual-process model of white matter development comprising biological processes with opposing effects on FA, such as axonal myelination and pruning, to explain the pattern of results.