Age-related decline in white matter tract integrity and cognitive performance: A DTI tractography and structural equation modeling study

Age-related decline in microstructural integrity of certain white matter tracts may explain cognitive decline associated with normal aging. Whole brain tractography and a clustering segmentation in 48 healthy individuals across the adult lifespan were used to examine: interhemispheric (corpus callosum), intrahemispheric association (cingulum, uncinate, arcuate, inferior longitudinal, inferior occipitofrontal), and projection (corticospinal) fibers. Principal components analysis reduced cognitive tests into 6 meaningful factors: (1) memory and executive function; (2) visuomotor dexterity; (3) motor speed; (4) attention and working memory; (5) set-shifting/flexibility; and (6) visuospatial construction. Using theory-based structural equation modeling, relationships among age, white matter tract integrity, and cognitive performance were investigated. Parsimonious model fit demonstrated relationships where decline in white matter integrity may explain age-related decline in cognitive performance: inferior longitudinal fasciculus (ILF) with visuomotor dexterity; the inferior occipitofrontal fasciculus with visuospatial construction; and posterior fibers (i.e., splenium) of the corpus callosum with memory and executive function. Our findings suggest that decline in the microstructural integrity of white matter fibers can account for cognitive decline in normal aging.     

Myelination-related genes are associated with decreased white matter integrity in schizophrenia

Disruptions in white matter (WM) tract structures have been implicated consistently in the pathophysiology of schizophrenia. Global WM integrity – as measured by fractional anisotropy (FA) – is highly heritable and may provide a good endophenotype for genetic studies of schizophrenia. WM abnormalities in schizophrenia are not localized to one specific brain region but instead reflect global low-level decreases in FA coupled with focal abnormalities. In this study, we sought to investigate whether functional gene sets associated with schizophrenia are also associated with WM integrity. We analyzed FA and genetic data from the Mind Research Network Clinical Imaging Consortium to study the effect of multiple oligodendrocyte gene sets on schizophrenia and WM integrity using a functional gene set analysis in 77 subjects with schizophrenia and 104 healthy controls. We found that a gene set involved in myelination was significantly associated with schizophrenia and FA. This gene set includes 17 genes that are expressed in oligodendrocytes and one neuronal gene (NRG1) that is known to regulate myelination. None of the genes within the gene set were associated with schizophrenia or FA individually, suggesting that no single gene was driving the association of the gene set. Our findings support the hypothesis that multiple genetic variants in myelination-related genes contribute to the observed correlation between schizophrenia and decreased WM integrity as measured by FA.     

Frontal white matter integrity in adults with Down syndrome with and without dementia

Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease after the age of 40 years. To detect white matter (WM) changes in the brain linked to dementia, fractional anisotropy (FA) from diffusion tensor imaging was used. We hypothesized that adults with DS without dementia (DS n = 10), DS with dementia (DSAD n = 10) and age matched non-DS subjects (CTL n = 10) would show differential levels of FA and an association with scores from the Brief Praxis Test and the Severe Impairment Battery. WM integrity differences in DS compared with CTL were found predominantly in the frontal lobes. Across all DS adults, poorer Brief Praxis Test performance correlated with reduced FA in the corpus callosum as well as several association tracts, primarily within frontoparietal regions. Our results demonstrate significantly lower WM integrity in DS compared with controls, particularly in the frontal tracts. DS-related WM integrity reductions in a number of tracts were associated with poorer cognition. These preliminary results suggest that late myelinating frontal pathways may be vulnerable to aging in DS.     

A genome-wide search for genetic influences and biological pathways related to the brain's white matter integrity

A genome-wide search for genetic variants influencing the brain's white matter integrity in old age was conducted in the Lothian Birth Cohort 1936 (LBC1936). At ～73 years of age, members of the LBC1936 underwent diffusion MRI, from which 12 white matter tracts were segmented using quantitative tractography, and tract-averaged water diffusion parameters were determined (n = 668). A global measure of white matter tract integrity, g(FA), derived from principal components analysis of tract-averaged fractional anisotropy measurements, accounted for 38.6% of the individual differences across the 12 white matter tracts. A genome-wide search was performed with g(FA) on 535 individuals with 542,050 single nucleotide polymorphisms (SNPs). No single SNP association was genome-wide significant (all p > 5 × 10(-8)). There was genome-wide suggestive evidence for two SNPs, one in ADAMTS18 (p = 1.65 × 10(-6)), which is related to tumor suppression and hemostasis, and another in LOC388630 (p = 5.08 × 10(-6)), which is of unknown function. Although no gene passed correction for multiple comparisons in single gene-based testing, biological pathways analysis suggested evidence for an over-representation of neuronal transmission and cell adhesion pathways relating to g(FA).     

Gray matter density and white matter integrity in pianists' brain: a combined structural and diffusion tensor MRI study

The current study combined structural magnetic resonance imaging (sMRI) and diffusion tensor MRI (DT-MRI) to investigate both gray matter density (GMD) and white matter integrity (WMI) in 18 pianists and 21 age-matched non-musicians. The pianists began their piano training at a mean age of 12. Voxel-based morphometry of the sMRI data showed that the pianists had higher GMD in the left primary sensorimotor cortex and right cerebellum. Voxel-based analysis of the DT-MRI data showed that pianists had higher fractional anisotropy (FA) (indicating higher WMI) in the right posterior limb of the internal capsule. The sMRI and DT-MRI results indicate that both the GMD and WMI of pianists may exhibit movement-related increases during adolescence or even early adulthood compared with non-musicians.     

首发精神分裂症患者的运动协调功能与前额叶白质及皮质脊髓束完整性

目的:应用弥散张量成像(DTI)探讨首发精神分裂症患者神经系统软体征中的运动协调功能与前额叶白质及皮质脊髓束各向异性比值(FA)的关系。方法:纳入42例符合美国精神障碍诊断与统计手册第4版(DSM-IV)诊断标准的首发精神分裂症患者和46例年龄、性别及受教育年限相匹配的健康对照。两组研究对象均用剑桥神经科检查(CNI)评定神经系统软体征,并接受头颅磁共振成像检查。用阳性与阴性症状量表(PANSS)评估患者组基线和半年后的临床症状。用感兴趣区测定的方法,分析患者组和对照组神经系统软体征中的运动协调领域分与前额叶白质及皮质脊髓束各层面(内囊、大脑脚、小脑中脚水平)FA值间的关系。结果:神经系统软体征中的运动协调领域分在患者组中与前额叶白质FA值呈正相关(r=0.35,P0.05),在健康对照中则与小脑中脚水平皮质脊髓束FA值呈正相关(r=0.34,P0.05)。将患者按半年后阴性症状分为高分组和低分组,高分组运动协调领域分与前额叶白质(r=0.68,P0.05)呈正相关,与小脑中脚水平皮质脊髓束(r=-0.67,P0.05)FA值呈负相关;低分组则与内囊FA值呈正相关(r=0.60,P0.05)。结论:本研究提示首发精神分裂症患者半年后阴性症状高分组、低分组及正常人群中,运动协调功能相关的脑区分别为前额叶、内囊和小脑中脚层面的皮质脊髓束,提示有必要进一步研究运动协调功能相关的脑区不同对患者预后的预测意义。     

Age-related slowing of memory retrieval: contributions of perceptual speed and cerebral white matter integrity

Previous research suggests that, in reaction time (RT) measures of episodic memory retrieval, the unique effects of adult age are relatively small compared to the effects aging shares with more elementary abilities such as perceptual speed. Little is known, however, regarding the mechanisms of perceptual speed. We used diffusion tensor imaging (DTI) to test the hypothesis that white matter integrity, as indexed by fractional anisotropy (FA), serves as one mechanism of perceptual slowing in episodic memory retrieval. Results indicated that declines in FA in the pericallosal frontal region and in the genu of the corpus callosum, but not in other regions, mediated the relationship between perceptual speed and episodic retrieval RT. This relation held, though to a different degree, for both hits and correct rejections. These findings suggest that white matter integrity in prefrontal regions is one mechanism underlying the relation between individual differences in perceptual speed and episodic retrieval.     

Age-dependent visuomotor performance and white matter structure: a DTI study

The Trail Making Test (TMT), which assesses motor performance, selective attention, working memory and cognitive flexibility is highly sensitive to age-related performance differences. However, the structural basis of this age-performance association is largely unknown. This DTI study examined the influence of white matter characteristics on the association between TMT performance (i.e., speed of processing) and age in a sample of 86 healthy, middle-aged subjects (mean age 27.9 years, range 18–55). Voxel-wise correlation yielded a significant negative association between FA in the body of the corpus callosum (CC) and TMT-A performance (i.e., time taken to complete the test). There was also a significant association between age and TMT-A performance. However, this association between age and TMT-A performance was neither mediated nor moderated by FA in the CC. Results suggest that fast motor performance is strongly dependent on individual white matter characteristics of the CC. This indicates that interindividual variations in white matter of the CC known to be relevant for interhemispheric motor signal transduction critically influence speed of motor processing. However, these interindividual variations do not explain the observed association between age and TMT performance.     

White matter tract integrity predicts visual search performance in young and older adults

Functional imaging research has identified frontoparietal attention networks involved in visual search, with mixed evidence regarding whether different networks are engaged when the search target differs from distracters by a single (elementary) versus multiple (conjunction) features. Neural correlates of visual search, and their potential dissociation, were examined here using integrity of white matter connecting the frontoparietal networks. The effect of aging on these brain-behavior relationships was also of interest. Younger and older adults performed a visual search task and underwent diffusion tensor imaging (DTI) to reconstruct 2 frontoparietal (superior and inferior longitudinal fasciculus; SLF and ILF) and 2 midline (genu, splenium) white matter tracts. As expected, results revealed age-related declines in conjunction, but not elementary, search performance; and in ILF and genu tract integrity. Importantly, integrity of the superior longitudinal fasciculus, ILF, and genu tracts predicted search performance (conjunction and elementary), with no significant age group differences in these relationships. Thus, integrity of white matter tracts connecting frontoparietal attention networks contributes to search performance in younger and older adults.     

Age-related slowing of task switching is associated with decreased integrity of frontoparietal white matter

A body of research has demonstrated age-related slowing on tasks that emphasize cognitive control, such as task switching. However, little is known about the neural mechanisms that contribute to this age-related slowing. To address this issue, the present study used both fMRI and DTI in combination with a standard task switching paradigm. Results from the fMRI experiment demonstrated task switching cost (switching vs. nonswitching) activations in a network of frontoparietal and striatal regions in the young group. The older group recruited a similar network of regions, but showed decreased spatial extent of activation and recruited several regions not activated in the young group. White matter (WM) ROIs bordering the cortical network showing task switching activation were then selected to explore potential relationships between task switching reaction time (RT) cost and fractional anisotropy (FA) in the same groups of participants. Results demonstrated a negative correlation between switch cost RT and FA in left frontoparietal WM in both young and older groups. In addition, age-related FA decline in the same frontoparietal WM region was found to mediate age-related increases in RT switch costs. These findings identify decreased integrity of frontoparietal WM as one mechanism contributing to age-related increases in RT switch costs.     

Effects of language usage on the emotional experience of Spanish-English and English-Spanish bilinguals

This study assessed the effects of the mother tongue and the second tongue on the affective experience of 80 English-Spanish and Spanish-English coordinate bilinguals. Ss were randomly assigned to a mother tongue condition or a 2nd language condition. It was predicted that Ss would express more affect in their mother tongue. Results of a MANCOVA revealed a statistically significant interaction in which English-Spanish bilinguals expressed more affect in their 2nd language (Spanish) and Spanish-English bilinguals expressed more affect in their mother tongue (Spanish). That is, all Ss answered with significantly greater affect in the Spanish language condition, and they differed in levels of anxiety and depression depending on which language they were using. Implications are discussed for the psychological assessment of bilinguals as well as for psychotherapy.     

ADRB2, brain white matter integrity and cognitive ageing in the Lothian Birth Cohort 1936

The non-synonymous mutations arg16gly (rs1042713) and gln27glu (rs1042714) in the adrenergic β-2 receptor gene (ADRB2) have been associated with cognitive function and brain white matter integrity. The current study aimed to replicate these findings and expand them to a broader range of cognitive and brain phenotypes. The sample used is a community-dwelling group of older people, the Lothian Birth Cohort 1936. They had been assessed cognitively at age 11 years, and undertook further cognitive assessments and brain diffusion MRI tractography in older age. The sample size range for cognitive function variables was N = 686–765, and for neuroimaging variables was N = 488–587. Previously-reported findings with these genetic variants did not replicate in this cohort. Novel, nominally significant associations were observed; notably, the integrity of the left arcuate fasciculus mediated the association between rs1042714 and the Digit Symbol Coding test of information processing speed. No significant associations of cognitive and brain phenotypes with ADRB2 variants survived correction for false discovery rate. Previous findings may therefore have been subject to type 1 error. Further study into links between ADRB2, cognitive function and brain white matter integrity is required.     

Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical "disconnection" in aging and Alzheimer's disease

Human and non-human primate data suggest that the structural integrity of myelin sheaths deteriorates during normal aging, especially in the late-myelinating association regions and may result in "disconnection" of widely distributed neural networks. Magnetic resonance imaging (MRI) was used to assess the heterogeneity of this process and its impact on brain aging and Alzheimer's disease (AD) by evaluating early- and later-myelinating regions of the corpus callosum, the splenium (Scc) and genu (Gcc), respectively. Calculated transverse relaxation rates (R2), an indirect measure of white matter structural integrity for the Gcc and Scc, were examined. The relationship between age and R2 differed in the two regions. A quadratic (inverted U) function with an accelerating rate of decline beginning at age 31 best represented the Gcc pattern while the Scc decline was three-fold smaller, gradual, and linear. These data suggest that the severity of age-related myelin breakdown is regionally heterogeneous, consistent with the hypothesis that differences in myelin properties make later-myelinating regions more susceptible to this process. In AD this process is globally exacerbated, consistent with an extracellular deleterious process such as amyloid beta-peptide toxicity. Non-invasive measures such as R2 may be useful in primary prevention studies of AD.     

Increased body mass index is associated with a global and distributed decrease in white matter microstructural integrity

Objective Obesity and decreased physical health are linked to deficits in several cognitive domains. The broad range of cognitive problems linked to obesity suggests a global mechanism that may interfere with multiple neural systems. We examined how variation in body mass index (BMI) is associated with the microstructural integrity of fiber connections in the human brain. Methods White matter structure was measured using diffusion tensor imaging in 28 participants (mean age = 30 years) with BMI scores ranging from normal weight to obese (19.5-45.7 kg/m(2)) based on standard BMI criteria. Results Using a whole-brain voxelwise analysis, we found that, across participants, the fractional anisotropy of white matter voxels parametrically decreased with increasing BMI (63% of white matter voxels). Midbrain and brainstem tracts were among the pathways most strongly associated with obesity (r = -0.18 to -0.33, df = 27, all p values < .05). We also observed a weaker overall diffusion signal in individuals with higher BMI than controls with normal weight (r = -0.14 to -0.71, df = 27, for 67% of fiber pathways tested, all p values < .05). After controlling for this decrease in general diffusivity, we found that decreases in fractional anisotropy stemmed from both a decrease in axial diffusivity (p < .05) and an increase in radial diffusivity (p < .05). Conclusions Our results show that increased BMI is globally associated with a reduction in white matter integrity throughout the brain, elucidating a potential mechanism by which changes in physical health may influence cognitive health.     

An 8‐month exercise intervention alters frontotemporal white matter integrity in overweight children

In childhood, excess adiposity and low fitness are linked to poor academic performance, lower cognitive function, and differences in brain structure. Identifying ways to mitigate obesity‐related alterations is of current clinical importance. This study examined the effects of an 8‐month exercise intervention on the uncinate fasciculus, a white matter fiber tract connecting frontal and temporal lobes. Participants consisted of 18 unfit, overweight 8‐ to 11‐year‐old children (94% Black) who were randomly assigned to either an aerobic exercise (n = 10) or a sedentary control group (n = 8). Before and after the intervention, all subjects participated in a diffusion tensor MRI scan. Tractography was conducted to isolate the uncinate fasciculus. The exercise group showed improved white matter integrity as compared to the control group. These findings are consistent with an emerging literature suggesting beneficial effects of exercise on white matter integrity.     

Effects of language context on executive control in unbalanced bilinguals: An ERPs study

The influence of the language context on language control has been widely discussed in the bilingualism literature, and there is an increase in studies examining the effect of language context on domain-general executive control. However, it remains unclear how language contexts affect executive control performance. In the present study, we created single- and mixed-language comprehension contexts. Unbalanced Chinese-English bilinguals completed a modified flanker task that was interleaved with a single-language or mixed-language picture-word matching task. The effects of language comprehension context on language control were reflected by the N2 and LPC effects. Executive control processes also differed depending on the language comprehension context, with faster behavioral responses and larger N2 but smaller P3 electrophysiological components in the mixed-language context. Moreover, the LPC amplitude in the mixed-language context predicted the behavioral performance in the executive control task. These findings suggested that flexible language control during language comprehension altered executive control processes in unbalanced bilinguals.