Mark E. Bastin

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.

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging

OBJECTIVES Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders. METHODS DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis. RESULTS Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication. CONCLUSIONS Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.

A theoretical study of the effect of experimental noise on the measurement of anisotropy in diffusion imaging

Diffusion tensor imaging (DTI) is a modality known to be highly sensitive to the detrimental effects of experimental noise. Here, using Monte Carlo simulations, we compare and contrast how noise complicates the measurement of diffusion anisotropy in diffusion tensor and conventional diffusion-weighted imaging (DWI). As the signal-to-noise ratio (SNR) decreases below a value of approximately 20, the eigenvalues (lambda(i)) of the diffusion tensor D are found to diverge rapidly from their true values, with the result that the measured anisotropy can be significantly in error and isotropic structures falsely assigned a high level of anisotropy. The effect of noise on the rotationally variant indices, calculated from a conventional diffusion-weighted imaging experiment, is found to be much less insidious, because the apparent diffusion coefficients (ADCs) diverge only slowly as the signal-to-noise decreases. Thus, although rotationally variant indices almost always underestimate the true diffusion anisotropy, they show only a small susceptibility to experimental noise and hence, are preferred to their rotationally invariant counterparts when the signal-to-noise ratio is small.

White matter integrity and cognition in childhood and old age.

Objective: To test the hypothesis that white matter integrity, as measured by diffusion tensor and magnetization transfer MRI is significantly associated with cognitive ability measured in youth and old age. Methods: Forty, nondemented, surviving participants of the Scottish Mental Survey of 1932 underwent brain MRI and a battery of psychometric tests covering major cognitive domains and tests of information processing efficiency. IQ scores were available from age 11. Mean diffusivity, fractional anisotropy (FA), and magnetization transfer ratio (MTR) were measured in frontal and parieto-occipital white matter and centrum semiovale. Results: Centrum semiovale FA correlated (r = 0.36 to 0.56; p < 0.02) with contemporaneous (age 83) scores on psychometric tests of nonverbal reasoning, working memory, executive function, and information processing efficiency. Centrum semiovale FA also correlated with IQ at age 11 (r = 0.37; p = 0.02). Controlling for IQ at age 11 and information processing at age 83 attenuated the association between centrum semiovale FA and general cognitive ability by approximately 85%. MTR, largely, did not show significant correlations with cognitive test scores. Conclusions: These data support the information processing efficiency hypothesis of cognitive aging and suggest one foundation for individual differences in processing efficiency. They also suggest that studies of imaging and cognition in the elderly should take into account prior mental ability rather than assuming that any associations between imaging parameters and cognitive test scores are the result of age-related changes.

Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the ENIGMA-DTI working group.

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA-DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18-85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/).

Do Acute Diffusion- and Perfusion-Weighted MRI Lesions Identify Final Infarct Volume in Ischemic Stroke?

Background and Purpose— An acute mismatch on diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) may represent the “tissue-at-risk.” It is unclear which “semiquantitative” perfusion parameter most closely identifies final infarct volume. Methods— Acute stroke patients underwent DWI and PWI (dynamic-susceptibility contrast imaging) on admission (baseline), and T2-weighted imaging (T2WI) at 1 or 3 months after stroke. “Semiquantitative” mean transit time (MTTsq=first moment of concentration/time curve), cerebral blood volume (CBVsq=area under concentration/time curve), and cerebral blood flow (CBFsq=CBVsq/MTTsq) were calculated. DWI and PWI lesions were measured at baseline and final infarct volume on T2WI acquired ≥1 month after stroke. Baseline DWI, CBFsq, and MTTsq lesion volumes were compared with final T2WI lesion volume. Results— Among 46 patients, baseline DWI and CBFsq lesions were not significantly different from final T2WI lesion volume, but baseline MTTsq lesions were significantly larger. The correlation with final T2WI lesion volume was strongest for DWI (Spearman rank correlation coefficient &rgr;=0.68), intermediate for CBFsq (&rgr;=0.55), and weakest for MTTsq (&rgr;=0.49) baseline lesion volumes. Neither DWI/CBFsq nor DWI/MTTsq mismatch predicted lesion growth; lesion growth was equally common in those with and without mismatch. Conclusions— Of the 2 PWI parameters, CBFsq lesions most closely identifies, and MTTsq overestimates, final T2WI lesion volume. “DWI/PWI mismatch” does not identify lesion growth. Patients without “DWI/PWI mismatch” are equally likely to have lesion growth as those with mismatch and should not be excluded from acute stroke treatment.

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.

Brain aging, cognition in youth and old age and vascular disease in the Lothian Birth Cohort 1936: rationale, design and methodology of the imaging protocol*

Rationale As the population of the world ages, age-related cognitive decline is becoming an ever-increasing problem. However, the changes in brain structure that accompany normal aging, and the role they play in cognitive decline, remain to be fully elucidated. Aims This study aims to characterize changes in brain structure in old age, and to investigate relationships between brain aging and cognitive decline using the Lothian Birth Cohort 1936. Here, we report the rationale, design and methodology of the brain and neurovascular imaging protocol developed to study this cohort. Design An observational, longitudinal study of the Lothian Birth Cohort 1936, which comprises 1091 relatively healthy individuals now in their 70s and living in the Edinburgh area. They are surviving participants of the Scottish Mental Survey 1947, which involved a test of general intelligence taken at age 11 years. At age 70 years, the Lothian Birth Cohort 1936 undertook detailed cognitive, medical and genetic testing, and provided social, family, nutritional, quality of life and physical activity information. At mean age 73 years they underwent detailed brain MRI and neurovascular ultrasound imaging, repeat cognitive and other testing. The MRI protocol is designed to provide qualitative and quantitative measures of gray and white matter atrophy, severity and location of white matter lesions, enlarged perivascular spaces, brain mineral deposits, microbleeds and integrity of major white matter tracts. The neurovascular ultrasound imaging provides velocity, stenosis and intima–media thickness measurements of the carotid and vertebral arteries. Study This valuable imaging dataset will be used to determine which changes in brain structural parameters have the largest effects on cognitive aging. Analysis will include multimodal image analysis and multivariate techniques, such as factor analysis and structural equation modelling. Especially valuable is the ability within this sample to examine the influence that early life intelligence has on brain structural parameters in old age, and the role of genetic, vascular, educational and lifestyle factors. Outcomes Final outcomes include associations between early and late life cognition and integrity of key white matter tracts, volume of gray and white matter, myelination, brain water content, and visible abnormalities such as white matter lesions and mineral deposits; and influences of vascular risk factors, diet, environment, social metrics, education and genetics on healthy brain aging. It is intended that this information will help to inform and develop strategies for successful cognitive aging.

White Matter Integrity in Individuals at High Genetic Risk of Bipolar Disorder

BACKGROUND Bipolar disorder is a familial psychiatric disorder associated with reduced white matter integrity, but it is not clear whether such abnormalities are present in young unaffected relatives and, if so, whether they have behavioral correlates. We investigated with whole brain diffusion tensor imaging whether increased genetic risk for bipolar disorder is associated with reductions in white matter integrity and whether these reductions are associated with cyclothymic temperament. METHODS Diffusion tensor imaging data of 117 healthy unaffected relatives of patients with bipolar disorder and 79 control subjects were acquired. Cyclothymic temperament was measured with the cyclothymia scale of the Temperament Evaluation of Memphis, Pisa and San Diego auto-questionnaire. Voxel-wise between-group comparisons of fractional anisotropy (FA) and regression of cyclothymic temperament were performed with tract-based spatial statistics. RESULTS Compared to the control group, unaffected relatives had reduced FA in one large widespread cluster. Cyclothymic temperament was inversely related to FA in the internal capsules bilaterally and in left temporal white matter, regions also found to be reduced in high-risk subjects. CONCLUSIONS These results show that widespread white matter integrity reductions are present in unaffected relatives of bipolar patients and that more localized reductions might underpin cyclothymic temperament. These findings suggest that white matter integrity is an endophenotype for bipolar disorder with important behavioral associations previously linked to the etiology of the condition.

Neuroprotective lifestyles and the aging brain Activity, atrophy, and white matter integrity

Objectives: Increased participation in leisure and physical activities may be cognitively protective. Whether activity might protect the integrity of the brains white matter, or reduce atrophy and white matter lesion (WML) load, was examined in the Lothian Birth Cohort 1936 (n = 691), a longitudinal study of aging. Methods: Associations are presented between self-reported leisure and physical activity at age 70 years and structural brain biomarkers at 73 years. For white matter integrity, principal components analysis of 12 major tracts produced general factors for fractional anisotropy (FA) and mean diffusivity. Atrophy, gray and normal-appearing white matter (NAWM) volumes, and WML load were assessed using computational image processing methods; atrophy and WML were also assessed visually. Results: A higher level of physical activity was associated with higher FA, larger gray and NAWM volumes, less atrophy, and lower WML load. The physical activity associations with atrophy, gray matter, and WML remained significant after adjustment for covariates, including age, social class, and health status. For example, physical activity (standardized β = −0.09, nonstandardized β = −0.09, p = 0.029) and stroke (standardized β = 0.18, nonstandardized β = 0.69, p = 0.003) each had an independent effect on rated WML load. Leisure activity was associated with NAWM volume, but was nonsignificant after including covariates. Conclusions: In this large, narrow-age sample of adults in their 70s, physical activity was associated with less atrophy and WML. Its role as a potential neuroprotective factor is supported; however, the direction of causation is unclear from this observational study.