S. Muñoz Maniega

The effects of a neuregulin 1 variant on white matter density and integrity.

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T1-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

Brain white matter tract integrity as a neural foundation for general intelligence

General intelligence is a robust predictor of important life outcomes, including educational and occupational attainment, successfully managing everyday life situations, good health and longevity. Some neuronal correlates of intelligence have been discovered, mainly indicating that larger cortices in widespread parieto-frontal brain networks and efficient neuronal information processing support higher intelligence. However, there is a lack of established associations between general intelligence and any basic structural brain parameters that have a clear functional meaning. Here, we provide evidence that lower brain-wide white matter tract integrity exerts a substantial negative effect on general intelligence through reduced information-processing speed. Structural brain magnetic resonance imaging scans were acquired from 420 older adults in their early 70s. Using quantitative tractography, we measured fractional anisotropy and two white matter integrity biomarkers that are novel to the study of intelligence: longitudinal relaxation time (T1) and magnetisation transfer ratio. Substantial correlations among 12 major white matter tracts studied allowed the extraction of three general factors of biomarker-specific brain-wide white matter tract integrity. Each was independently associated with general intelligence, together explaining 10% of the variance, and their effect was completely mediated by information-processing speed. Unlike most previously established neurostructural correlates of intelligence, these findings suggest a functionally plausible model of intelligence, where structurally intact axonal fibres across the brain provide the neuroanatomical infrastructure for fast information processing within widespread brain networks, supporting general intelligence.

A diffusion tensor MRI study of white matter integrity in subjects at high genetic risk of schizophrenia

Diffusion tensor imaging (DTI) has previously shown compromised white matter integrity in frontotemporal white matter fibers in patients with schizophrenia, as indicated by reduced fractional anisotropy (FA). In the present study we investigated whether reduced white matter FA is also present in relatives of individuals with schizophrenia who are at high risk (HR) for genetic reasons. Twenty-two HR subjects, 31 patients with schizophrenia and 51 control subjects underwent DTI. We compared FA between the three groups in the cingulum cingulate gyri, the uncinate and the arcuate fasciculi and the anterior limb of the internal capsules (ALIC). A voxel-based analysis showed lower FA in patients with schizophrenia compared to controls in left and right uncinate (p<0.03), the left arcuate (p<0.03) and left and right ALIC (p<0.01). Using an automatic region-of-interest analysis, less sensitive to potential misregistration errors, produced essentially the same results, as well as reduced FA of the ALIC in the HR group compared to controls (p<0.05). This study replicates previous findings showing lower FA in frontotemporal white matter fibers of schizophrenia patients. We also found reduced FA in the ALIC of both patients and subjects at high risk of schizophrenia when compared to controls. This may be a possible indicator of the higher vulnerability of relatives to develop the disorder.

Temporal evolution of water diffusion parameters is different in grey and white matter in human ischaemic stroke

Objectives: Our purpose was to investigate whether differences exist in the values and temporal evolution of mean diffusivity () and fractional anisotropy (FA) of grey and white matter after human ischaemic stroke. Methods: Thirty two patients with lesions affecting both grey and white matter underwent serial diffusion tensor magnetic resonance imaging (DT-MRI) within 24 hours, and at 4–7 days, 10–14 days, 1 month, and 3 months after stroke. Multiple small circular regions of interest (ROI) were placed in the grey and white matter within the lesion and in the contralateral hemisphere. Values of {grey}, {white}, FA{grey} and FA{white} were measured in these ROI at each time point and the ratios of ischaemic to normal contralateral values (R and FAR) calculated. Results: and FA showed different patterns of evolution after stroke. After an initial decline, the rate of increase of {grey} was faster than {white} from 4–7 to 10–14 days. FA{white} decreased more rapidly than FA{grey} during the first week, thereafter for both tissue types the FA decreased gradually. However, FA{white} was still higher than FA{grey} at three months indicating that some organised axonal structure remained. This effect was more marked in some patients than in others. R{grey} was significantly higher than R{white} within 24 hours and at 10–14 days (p<0.05), and FAR{white} was significantly more reduced than FAR{grey} at all time points (p<0.001). Conclusions: The values and temporal evolution of and FA are different for grey and white matter after human ischaemic stroke. The observation that there is patient-to-patient variability in the degree of white matter structure remaining within the infarct at three months may have implications for predicting patient outcome.

Changes in NAA and lactate following ischemic stroke A serial MR spectroscopic imaging study

Objective: Although much tissue damage may occur within the first few hours of ischemic stroke, the duration of tissue injury is not well defined. We assessed the temporal pattern of neuronal loss and ischemia after ischemic stroke using magnetic resonance spectroscopic imaging (MRSI) and diffusion-weighted imaging (DWI). Methods: We measured N-acetylaspartate (NAA) and lactate in 51 patients with acute ischemic stroke at five time points, from admission to 3 months, in voxels classified as normal, possibly or definitely abnormal (ischemic) according to the appearance of the stroke lesion on the admission DWI. We compared changes in NAA and lactate in different voxel classes using linear mixed models. Results: NAA was significantly reduced from admission in definitely and possibly abnormal (p < 0.01) compared to contralateral normal voxels, reaching a nadir by 2 weeks and remaining reduced at 3 months. Lactate was significantly increased in definitely and possibly abnormal voxels (p < 0.01) during the first 5 days, falling to normal at 2 weeks, rising again later in these voxels. Conclusion: The progressive fall in N-acetylaspartate suggests that some additional neuronal death may continue beyond the first few hours for up to 2 weeks or longer. The mechanism is unclear but, if correct, then it is possible that interventions to limit this ongoing subacute tissue damage might add to the benefit of hyperacute treatment, making further improvements in outcome possible. DT-MRI = diffusion tensor MRI; DWI = diffusion-weighted imaging; [DWI] = directionally averaged DWI; FOV = field of view; MRSI = magnetic resonance spectroscopic imaging; MS = multiple sclerosis; NAA = N-acetylaspartate; NIHSS = NIH Stroke Scale; PRESS = point resolved spectroscopy; TE = echo time; VOI = volume of interest.

The Relationship of Anterior Thalamic Radiation Integrity to Psychosis Risk Associated Neuregulin-1 Variants

The relationship of anterior thalamic radiation integrity to psychosis risk associated neuregulin-1 variants

Childhood cognitive ability accounts for associations between cognitive ability and brain cortical thickness in old age

Associations between brain cortical tissue volume and cognitive function in old age are frequently interpreted as suggesting that preservation of cortical tissue is the foundation of successful cognitive aging. However, this association could also, in part, reflect a lifelong association between cognitive ability and cortical tissue. We analyzed data on 588 subjects from the Lothian Birth Cohort 1936 who had intelligence quotient (IQ) scores from the same cognitive test available at both 11 and 70 years of age as well as high-resolution brain magnetic resonance imaging data obtained at approximately 73 years of age. Cortical thickness was estimated at 81 924 sampling points across the cortex for each subject using an automated pipeline. Multiple regression was used to assess associations between cortical thickness and the IQ measures at 11 and 70 years. Childhood IQ accounted for more than two-third of the association between IQ at 70 years and cortical thickness measured at age 73 years. This warns against ascribing a causal interpretation to the association between cognitive ability and cortical tissue in old age based on assumptions about, and exclusive reference to, the aging process and any associated disease. Without early-life measures of cognitive ability, it would have been tempting to conclude that preservation of cortical thickness in old age is a foundation for successful cognitive aging when, instead, it is a lifelong association. This being said, results should not be construed as meaning that all studies on aging require direct measures of childhood IQ, but as suggesting that proxy measures of prior cognitive function can be useful to take into consideration.

Brain age predicts mortality

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, ‘brain-predicted age’, derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N=2001), then tested in the Lothian Birth Cohort 1936 (N=669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death.

Neuroticism, depressive symptoms and white-matter integrity in the Lothian Birth Cohort 1936

BACKGROUND Clinical depression is associated with reductions in white-matter integrity in several long tracts of the brain. The extent to which these findings are localized or related to depressive symptoms or personality traits linked to disease risk remains unclear. Method Members of the Lothian Birth Cohort 1936 (LBC936) were assessed in two waves at mean ages of 70 and 73 years. At wave 1, they underwent assessments of depressive symptoms and the personality traits of neuroticism and extraversion. Brain diffusion magnetic resonance imaging (MRI) data were obtained at the second wave and mood assessments were repeated. We tested whether depressive symptoms were related to reduced white-matter tract fractional anisotropy (FA), a measure of integrity, and then examined whether high neuroticism or low extraversion mediated this relationship. RESULTS Six hundred and sixty-eight participants provided useable data. Bilateral uncinate fasciculus FA was significantly negatively associated with depressive symptoms at both waves (standardized β=0.12-0.16). Higher neuroticism and lower extraversion were also significantly associated with lower uncinate FA bilaterally (standardized β=0.09-0.15) and significantly mediated the relationship between FA and depressive symptoms. CONCLUSIONS Trait liability to depression and depressive symptoms are associated with reduced structural connectivity in tracts connecting the prefrontal cortex with the amygdala and anterior temporal cortex. These effects suggest that frontotemporal disconnection is linked to the etiology of depression, in part through personality trait differences.

Morphologic, Distributional, Volumetric, and Intensity Characterization of Periventricular Hyperintensities

These authors sought to characterize white matter lesions of elderly adults and determine if some were artifacts. Using FLAIR they imaged 665 subjects without dementia, carefully measured and evaluated periventricular white matter lesions, and correlated these with several aspects of cardiovascular disease. They concluded that periventricular white matter hyperintensity levels, distribution, and association with risk factors and disease suggest that in old age, these are true tissue abnormalities and therefore should not be dismissed as artifacts. BACKGROUND AND PURPOSE: White matter hyperintensities are characteristic of old age and identifiable on FLAIR and T2-weighted MR imaging. They are typically separated into periventricular or deep categories. It is unclear whether the innermost segment of periventricular white matter hyperintensities is truly abnormal or is imaging artifacts. MATERIALS AND METHODS: We used FLAIR MR imaging from 665 community-dwelling subjects 72–73 years of age without dementia. Periventricular white matter hyperintensities were visually allocated into 4 categories: 1) thin white line; 2) thick rim; 3) penetrating toward or confluent with deep white matter hyperintensities; and 4) diffuse ill-defined, labeled as “subtle extended periventricular white matter hyperintensities.” We measured the maximum intensity and width of the periventricular white matter hyperintensities, mapped all white matter hyperintensities in 3D, and investigated associations between each category and hypertension, stroke, diabetes, hypercholesterolemia, cardiovascular disease, and total white matter hyperintensity volume. RESULTS: The intensity patterns and morphologic features were different for each periventricular white matter hyperintensity category. Both the widths (r = 0.61, P < .001) and intensities (r = 0.51, P < .001) correlated with total white matter hyperintensity volume and with each other (r = 0.55, P < .001) for all categories with the exception of subtle extended periventricular white matter hyperintensities, largely characterized by evidence of erratic, ill-defined, and fragmented pale white matter hyperintensities (width: r = 0.02, P = .11; intensity: r = 0.02, P = .84). The prevalence of hypertension, hypercholesterolemia, and neuroradiologic evidence of stroke increased from periventricular white matter hyperintensity categories 1 to 3. The mean periventricular white matter hyperintensity width was significantly larger in subjects with hypertension (mean difference = 0.5 mm, P = .029) or evidence of stroke (mean difference = 1 mm, P < .001). 3D mapping revealed that periventricular white matter hyperintensities were discontinuous with deep white matter hyperintensities in all categories, except only in particular regions in brains with category 3. CONCLUSIONS: Periventricular white matter hyperintensity intensity levels, distribution, and association with risk factors and disease suggest that in old age, these are true tissue abnormalities and therefore should not be dismissed as artifacts. Dichotomizing periventricular and deep white matter hyperintensities by continuity from the ventricle edge toward the deep white matter is possible.