Improved Characterization of Diffusion in Normal and Cancerous Prostate Tissue Through Optimization of Multicompartmental Signal Models.

BACKGROUND: Multicompartmental modeling outperforms conventional diffusion-weighted imaging (DWI) in the assessment of prostate cancer. Optimized multicompartmental models could further improve the detection and characterization of prostate cancer. PURPOSE: To optimize multicompartmental signal models and apply them to study diffusion in normal and cancerous prostate tissue in vivo. STUDY TYPE: Retrospective. SUBJECTS: Forty-six patients who underwent MRI examination for suspected prostate cancer; 23 had prostate cancer and 23 had no detectable cancer. FIELD STRENGTH/SEQUENCE: 3T multishell diffusion-weighted sequence. ASSESSMENT: Multicompartmental models with 2-5 tissue compartments were fit to DWI data from the prostate to determine optimal compartmental apparent diffusion coefficients (ADCs). These ADCs were used to compute signal contributions from the different compartments. The Bayesian Information Criterion (BIC) and model-fitting residuals were calculated to quantify model complexity and goodness-of-fit. Tumor contrast-to-noise ratio (CNR) and tumor-to-background signal intensity ratio (SIR) were computed for conventional DWI and multicompartmental signal-contribution maps. STATISTICAL TESTS: Analysis of variance (ANOVA) and two-sample t-tests (α = 0.05) were used to compare fitting residuals between prostate regions and between multicompartmental models. T-tests (α = 0.05) were also used to assess differences in compartmental signal-fraction between tissue types and CNR/SIR between conventional DWI and multicompartmental models. RESULTS: The lowest BIC was observed from the 4-compartment model, with optimal ADCs of 5.2e-4, 1.9e-3, 3.0e-3, and >3.0e-2 mm2 /sec. Fitting residuals from multicompartmental models were significantly lower than from conventional ADC mapping (P < 0.05). Residuals were lowest in the peripheral zone and highest in tumors. Tumor tissue showed the largest reduction in fitting residual by increasing model order. Tumors had a greater proportion of signal from compartment 1 than normal tissue (P < 0.05). Tumor CNR and SIR were greater on compartment-1 signal maps than conventional DWI (P < 0.05) and increased with model order. DATA CONCLUSION: The 4-compartment signal model best described diffusion in the prostate. Compartmental signal contributions revealed by this model may improve assessment of prostate cancer. Level of Evidence 3 Technical Efficacy Stage 3 J. MAGN. RESON. IMAGING 2021;53:628-639.

High temporal resolution motion estimation using a self-navigated simultaneous multi-slice echo planar imaging acquisition.

BACKGROUND: Subject motion is known to produce spurious covariance among time-series in functional connectivity that has been reported to induce distance-dependent spurious correlations. PURPOSE: To present a feasibility study for applying the extended Kalman filter (EKF) framework for high temporal resolution motion correction of resting state functional MRI (rs-fMRI) series using each simultaneous multi-slice (SMS) echo planar imaging (EPI) shot as its own navigator. STUDY TYPE: Prospective feasibility study. POPULATION/SUBJECTS: Three human volunteers. FIELD STRENGTH/SEQUENCE: 3T GE DISCOVERY MR750 scanner using a 32-channel head coil. Simultaneous multi-slice rs-fMRI sequence with repetition time (TR)/echo time (TE) = 800/30 ms, and SMS factor 6. ASSESSMENT: Motion estimates were computed using two techniques: a conventional rigid-body volume-wise registration; and a high-temporal resolution motion estimation rigid-body approach. The reference image was resampled using the estimates obtained from both approaches and the difference between these predicted volumes and the original moving series was summarized using the normalized mean squared error (NMSE). STATISTICAL TESTS: Direct comparison of NMSE values. RESULTS: High-temporal motion estimation was always superior to volume-wise motion estimation for the sample presented. For staged continuous rotations, the NMSE using high-temporal resolution motion estimates ranged between [0.130, 0.150] for the first volunteer (in-plane rotations), between [0.060, 0.068] for the second volunteer (in-plane rotations), and between [0.063, 0.080] for the third volunteer (through-plane rotations). These values went up to [0.384, 0.464]; [0.136, 0.179]; and [0.080, 0.096], respectively, when using volume-wise motion estimates. DATA CONCLUSION: Accurate high-temporal rigid-body motion estimates can be obtained for rs-fMRI taking advantage of simultaneous multi-slice EPI sub-TR shots. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.

Global Visual Motion Sensitivity: Associations with Parietal Area and Children's Mathematical Cognition.

Sensitivity to global visual motion has been proposed as a signature of brain development, related to the dorsal rather than ventral cortical stream. Thresholds for global motion have been found to be elevated more than for global static form in many developmental disorders, leading to the idea of "dorsal stream vulnerability." Here we explore the association of global motion thresholds with individual differences in children's brain development, in a group of typically developing 5- to 12-year-olds. Good performance was associated with a relative increase in parietal lobe surface area, most strongly around the intraparietal sulcus and decrease in occipital area. In line with the involvement of intraparietal sulcus, areas in visuospatial and numerical cognition, we also found that global motion performance was correlated with tests of visuomotor integration and numerical skills. Individual differences in global form detection showed none of these anatomical or cognitive correlations. This suggests that the correlations with motion sensitivity are unlikely to reflect general perceptual or attentional abilities required for both form and motion. We conclude that individual developmental variations in global motion processing are not linked to greater area in the extrastriate visual areas, which initially process such motion, but in the parietal systems that make decisions based on this information. The overlap with visuospatial and numerical abilities may indicate the anatomical substrate of the "dorsal stream vulnerability" proposed as characterizing neurodevelopmental disorders.

The Pediatric Imaging, Neurocognition, and Genetics (PING) Data Repository.

The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING portal and filing a data use agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal.

Long-term influence of normal variation in neonatal characteristics on human brain development.

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences.

Multimodal imaging of the self-regulating developing brain.

Self-regulation refers to the ability to control behavior, cognition, and emotions, and self-regulation failure is related to a range of neuropsychiatric problems. It is poorly understood how structural maturation of the brain brings about the gradual improvement in self-regulation during childhood. In a large-scale multicenter effort, 735 children (4-21 y) underwent structural MRI for quantification of cortical thickness and surface area and diffusion tensor imaging for quantification of the quality of major fiber connections. Brain development was related to a standardized measure of cognitive control (the flanker task from the National Institutes of Health Toolbox), a critical component of self-regulation. Ability to inhibit responses and impose cognitive control increased rapidly during preteen years. Surface area of the anterior cingulate cortex accounted for a significant proportion of the variance in cognitive performance. This finding is intriguing, because characteristics of the anterior cingulum are shown to be related to impulse, attention, and executive problems in neurodevelopmental disorders, indicating a neural foundation for self-regulation abilities along a continuum from normality to pathology. The relationship was strongest in the younger children. Properties of large-fiber connections added to the picture by explaining additional variance in cognitive control. Although cognitive control was related to surface area of the anterior cingulate independently of basic processes of mental speed, the relationship between white matter quality and cognitive control could be fully accounted for by speed. The results underscore the need for integration of different aspects of brain maturation to understand the foundations of cognitive development.

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Combining diffusion and perfusion differentiates tumor from bevacizumab-related imaging abnormality (bria).

A subset of patients with high-grade glioma and brain metastases who are treated with bevacizumab develop regions of marked and persistent restricted diffusion that do not reflect recurrent tumor. Here, we quantify the degree of restricted diffusion and the relative cerebral blood volume (rCBV) within these regions of bevacizumab-related imaging abnormality (BRIA) in order to facilitate differentiation of these lesions from recurrent tumor. Six patients with high-grade glioma and two patients with brain metastases who developed regions of restricted diffusion after initiation of bevacizumab were included. Six pre-treatment GBM controls were also included. Restriction spectrum imaging (RSI) was used to create diffusion maps which were co-registered with rCBV maps. Within regions of restricted diffusion, mean RSI values and mean rCBV values were calculated for patients with BRIA and for the GBM controls. These values were also calculated for normal-appearing white matter (NAWM). RSI values in regions of restricted diffusion were higher for both BRIA and tumor when compared to NAWM; furthermore RSI values in BRIA were slightly higher than in tumor. Conversely, rCBV values were very low in BRIA-lower than both tumor and NAWM. However, there was only a trend for rCBV values to be higher in tumor than in NAWM. When evaluating areas of restricted diffusion in patients with high-grade glioma or brain metastases treated with bevacizumab, RSI is better able to detect the presence of pathology whereas rCBV is better able to differentiate BRIA from tumor. Thus, combining these tools may help to differentiate necrotic tissue related to bevacizumab treatment from recurrent tumor.

A Multicompartmental Diffusion Model for Improved Assessment of Whole-Body Diffusion-weighted Imaging Data and Evaluation of Prostate Cancer Bone Metastases.

Purpose To develop a multicompartmental signal model for whole-body diffusion-weighted imaging (DWI) and apply it to study the diffusion properties of normal tissue and metastatic prostate cancer bone lesions in vivo. Materials and Methods This prospective study (ClinicalTrials.gov: NCT03440554) included 139 men with prostate cancer (mean age, 70 years ± 9 [SD]). Multicompartmental models with two to four tissue compartments were fit to DWI data from whole-body scans to determine optimal compartmental diffusion coefficients. Bayesian information criterion (BIC) and model-fitting residuals were calculated to quantify model complexity and goodness of fit. Diffusion coefficients for the optimal model (having lowest BIC) were used to compute compartmental signal-contribution maps. The signal intensity ratio (SIR) of bone lesions to normal-appearing bone was measured on these signal-contribution maps and on conventional DWI scans and compared using paired t tests (α = .05). Two-sample t tests (α = .05) were used to compare compartmental signal fractions between lesions and normal-appearing bone. Results Lowest BIC was observed from the four-compartment model, with optimal compartmental diffusion coefficients of 0, 1.1 × 10-3, 2.8 × 10-3, and >3.0 ×10-2 mm2/sec. Fitting residuals from this model were significantly lower than from conventional apparent diffusion coefficient mapping (P < .001). Bone lesion SIR was significantly higher on signal-contribution maps of model compartments 1 and 2 than on conventional DWI scans (P < .008). The fraction of signal from compartments 2, 3, and 4 was also significantly different between metastatic bone lesions and normal-appearing bone tissue (P ≤ .02). Conclusion The four-compartment model best described whole-body diffusion properties. Compartmental signal contributions from this model can be used to examine prostate cancer bone involvement. Keywords: Whole-Body MRI, Diffusion-weighted Imaging, Restriction Spectrum Imaging, Diffusion Signal Model, Bone Metastases, Prostate Cancer Clinical trial registration no. NCT03440554 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Margolis in this issue.

Association of Potentially Damaging De Novo Gene Variants With Neurologic Outcomes in Congenital Heart Disease.

Importance: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD), but medical and sociodemographic factors explain only one-third of the variance in outcomes. Objective: To examine whether potentially damaging de novo variants (dDNVs) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD and, post hoc, whether some dDNVs or rare putative loss-of-function variants (pLOFs) in specific gene categories are associated with outcomes. Design, Setting, and Participants: This cross-sectional study was conducted from September 2017 to June 2020 in 8 US centers. Inclusion criteria were CHD, age 8 years or older, and available exome sequencing data. Individuals with pathogenic gene variants in known CHD- or neurodevelopment-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. Exposures: Heterozygous for (cases) or lacking (controls) dDNVs in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNVs and/or pLOFs in 4 gene categories: chromatin modifying, constrained, high level of brain expression, and neurodevelopmental risk. Main Outcomes and Measures: Main outcomes were neurodevelopmental assessments of academic achievement, intelligence, fine motor skills, executive function, attention, memory, social cognition, language, adaptive functioning, and anxiety and depression, as well as 7 structural, diffusion, and functional brain magnetic resonance imaging metrics. Results: The study cohort included 221 participants in the post hoc analysis and 219 in the case-control analysis (109 cases [49.8%] and 110 controls [50.2%]). Of those 219 participants (median age, 15.0 years [IQR, 10.0-21.2 years]), 120 (54.8%) were male. Cases and controls had similar primary outcomes (reading composite, spelling, and math computation on the Wide Range Achievement Test, Fourth Edition) and secondary outcomes. dDNVs and/or pLOFs in chromatin-modifying genes were associated with lower mean (SD) verbal comprehension index scores (91.4 [20.4] vs 103.4 [17.8]; P = .01), Social Responsiveness Scale, Second Edition, scores (57.3 [17.2] vs 49.4 [11.2]; P = .03), and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores (73.8 [16.4] vs 97.2 [15.7]; P = .03), as well as higher likelihood of autism spectrum disorder (28.6% vs 5.2%; P = .01). dDNVs and/or pLOFs in constrained genes were associated with lower mean (SD) scores on the Wide Range Assessment of Memory and Learning, Second Edition (immediate story memory: 9.7 [3.7] vs 10.7 [3.0]; P = .03; immediate picture memory: 7.8 [3.1] vs 9.0 [2.9]; P = .008). Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores (mean [SD], 55.5 [15.4] vs 46.6 [12.3]; P = .007). Conclusions and Relevance: The study findings suggest neurodevelopmental outcomes are not associated with dDNVs as a group but may be worse in individuals with dDNVs and/or pLOFs in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific gene variants to brain function and structure.

Tri-Compartmental Restriction Spectrum Imaging Breast Model Distinguishes Malignant Lesions from Benign Lesions and Healthy Tissue on Diffusion-Weighted Imaging.

Diffusion-weighted MRI (DW-MRI) offers a potential adjunct to dynamic contrast-enhanced MRI to discriminate benign from malignant breast lesions by yielding quantitative information about tissue microstructure. Multi-component modeling of the DW-MRI signal over an extended b-value range (up to 3000 s/mm2) theoretically isolates the slowly diffusing (restricted) water component in tissues. Previously, a three-component restriction spectrum imaging (RSI) model demonstrated the ability to distinguish malignant lesions from healthy breast tissue. We further evaluated the utility of this three-component model to differentiate malignant from benign lesions and healthy tissue in 12 patients with known malignancy and synchronous pathology-proven benign lesions. The signal contributions from three distinct diffusion compartments were measured to generate parametric maps corresponding to diffusivity on a voxel-wise basis. The three-component model discriminated malignant from benign and healthy tissue, particularly using the restricted diffusion C1 compartment and product of the restricted and intermediate diffusion compartments (C1 and C2). However, benign lesions and healthy tissue did not significantly differ in diffusion characteristics. Quantitative discrimination of these three tissue types (malignant, benign, and healthy) in non-pre-defined lesions may enhance the clinical utility of DW-MRI in reducing excessive biopsies and aiding in surveillance and surgical evaluation without repeated exposure to gadolinium contrast.

Prospective motion correction improves diagnostic utility of pediatric MRI scans.

A new technique for prospectively correcting head motion (called PROMO) during acquisition of high-resolution MRI scans has been developed to reduce motion artifacts. To evaluate the efficacy of PROMO, four T1-weighted image volumes (two with PROMO enabled, two uncorrected) were acquired for each of nine children. A radiologist, blind to whether PROMO was used, rated image quality and artifacts on all sagittal slices of every volume. These ratings were significantly better in scans collected with PROMO relative to those collected without PROMO (Mann-Whitney U test, P < 0.0001). The use of PROMO, especially in motion-prone patients, should improve the accuracy of measurements made for clinical care and research, and potentially reduce the need for sedation in children.

Efficient correction of inhomogeneous static magnetic field-induced distortion in Echo Planar Imaging.

Single-shot Echo Planar Imaging (EPI) is one of the most efficient magnetic resonance imaging (MRI) acquisition schemes, producing relatively high-definition images in 100 ms or less. These qualities make it desirable for Diffusion Tensor Imaging (DTI), functional MRI (fMRI), and Dynamic Susceptibility Contrast MRI (DSC-MRI). However, EPI suffers from severe spatial and intensity distortion due to B(0) field inhomogeneity induced by magnetic susceptibility variations. Anatomically accurate, undistorted images are essential for relating DTI and fMRI images with anatomical MRI scans, and for spatial registration with other modalities. We present here a fast, robust, and accurate procedure for correcting EPI images from such spatial and intensity distortions. The method involves acquisition of scans with opposite phase encoding polarities, resulting in opposite spatial distortion patterns, and alignment of the resulting images using a fast nonlinear registration procedure. We show that this method, requiring minimal additional scan time, provides superior accuracy relative to the more commonly used, and more time consuming, field mapping approach. This method is also highly computationally efficient, allowing for direct "real-time" implementation on the MRI scanner. We further demonstrate that the proposed method can be used to recover dropouts in gradient echo (BOLD and DSC-MRI) EPI images.

Prospective motion correction of high-resolution magnetic resonance imaging data in children.

Motion artifacts pose significant problems for the acquisition and analysis of high-resolution magnetic resonance imaging data. These artifacts can be particularly severe when studying pediatric populations, where greater patient movement reduces the ability to clearly view and reliably measure anatomy. In this study, we tested the effectiveness of a new prospective motion correction technique, called PROMO, as applied to making neuroanatomical measures in typically developing school-age children. This method attempts to address the problem of motion at its source by keeping the measurement coordinate system fixed with respect to the subject throughout image acquisition. The technique also performs automatic rescanning of images that were acquired during intervals of particularly severe motion. Unlike many previous techniques, this approach adjusts for both in-plane and through-plane movement, greatly reducing image artifacts without the need for additional equipment. Results show that the use of PROMO notably enhances subjective image quality, reduces errors in Freesurfer cortical surface reconstructions, and significantly improves the subcortical volumetric segmentation of brain structures. Further applications of PROMO for clinical and cognitive neuroscience are discussed.

Associations Between Microstructure, Amyloid, and Cognition in Amnestic Mild Cognitive Impairment and Dementia.

BACKGROUND: Although amyloid-ß (Aß) and microstructural brain changes are both effective biomarkers of Alzheimer's disease, their independent or synergistic effects on cognitive decline are unclear. OBJECTIVE: To examine associations of Aß and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. METHODS: Restriction spectrum imaging, cerebrospinal fluid Aß, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer's disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aß with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aß on cognitive decline. RESULTS: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aß or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aß correlated with whole-brain, rather than regional, ND and IF. CONCLUSION: Aß correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid.

Microstructural brain changes track cognitive decline in mild cognitive impairment.

Improved characterization of the microstructural brain changes occurring in the early stages of Alzheimer's disease may permit more timely disease detection. This study examined how longitudinal change in brain microstructure relates to cognitive decline in aging and prodromal Alzheimer's disease. At baseline and two-year follow-up, 29 healthy controls and 21 individuals with mild cognitive impairment or mild Alzheimer's disease underwent neuropsychological evaluation and restriction spectrum imaging (RSI). Microstructural change in the hippocampus, entorhinal cortex, and white matter tracts previously shown to be vulnerable to Alzheimer's disease, was compared between healthy controls and impaired participants. Partial correlations and stepwise linear regressions examined whether baseline RSI metrics predicted subsequent cognitive decline, or change in RSI metrics correlated with cognitive change. In medial temporal gray and white matter, restricted isotropic diffusion and crossing fibers were lower, and free water diffusion was higher, in impaired participants. Restricted isotropic diffusion in the hippocampus declined more rapidly for cognitively impaired participants. Baseline hippocampal restricted isotropic diffusion predicted cognitive decline, and change in hippocampal and entorhinal restricted isotropic diffusion correlated with cognitive decline. Within controls, changes in white matter restricted oriented diffusion and crossing fibers correlated with memory decline. In contrast, there were no correlations between rates of cortical atrophy and cognitive decline in the full sample or within controls. Changes in medial temporal lobe microarchitecture were associated with cognitive decline in prodromal Alzheimer's disease, and these changes were distinct from microstructural changes in normal cognitive aging. RSI metrics of brain microstructure may hold value for predicting cognitive decline in aging and for monitoring the course of Alzheimer's disease.

Williams Syndrome neuroanatomical score associates with GTF2IRD1 in large-scale magnetic resonance imaging cohorts: a proof of concept for multivariate endophenotypes.

Despite great interest in using magnetic resonance imaging (MRI) for studying the effects of genes on brain structure in humans, current approaches have focused almost entirely on predefined regions of interest and had limited success. Here, we used multivariate methods to define a single neuroanatomical score of how William's Syndrome (WS) brains deviate structurally from controls. The score is trained and validated on measures of T1 structural brain imaging in two WS cohorts (training, n = 38; validating, n = 60). We then associated this score with single nucleotide polymorphisms (SNPs) in the WS hemi-deleted region in five cohorts of neurologically and psychiatrically typical individuals (healthy European descendants, n = 1863). Among 110 SNPs within the 7q11.23 WS chromosomal region, we found one associated locus (p = 5e-5) located at GTF2IRD1, which has been implicated in animal models of WS. Furthermore, the genetic signals of neuroanatomical scores are highly enriched locally in the 7q11.23 compared with summary statistics based on regions of interest, such as hippocampal volumes (n = 12,596), and also globally (SNP-heritability = 0.82, se = 0.25, p = 5e-4). The role of genetic variability in GTF2IRD1 during neurodevelopment extends to healthy subjects. Our approach of learning MRI-derived phenotypes from clinical populations with well-established brain abnormalities characterized by known genetic lesions may be a powerful alternative to traditional region of interest-based studies for identifying genetic variants regulating typical brain development.

The Adolescent Brain Cognitive Development (ABCD) study: Imaging acquisition across 21 sites.

The ABCD study is recruiting and following the brain development and health of over 10,000 9-10 year olds through adolescence. The imaging component of the study was developed by the ABCD Data Analysis and Informatics Center (DAIC) and the ABCD Imaging Acquisition Workgroup. Imaging methods and assessments were selected, optimized and harmonized across all 21 sites to measure brain structure and function relevant to adolescent development and addiction. This article provides an overview of the imaging procedures of the ABCD study, the basis for their selection and preliminary quality assurance and results that provide evidence for the feasibility and age-appropriateness of procedures and generalizability of findings to the existent literature.

Williams syndrome-specific neuroanatomical profile and its associations with behavioral features.

Williams Syndrome (WS) is a rare genetic disorder with unique behavioral features. Yet the rareness of WS has limited the number and type of studies that can be conducted in which inferences are made about how neuroanatomical abnormalities mediate behaviors. In this study, we extracted a WS-specific neuroanatomical profile from structural magnetic resonance imaging (MRI) measurements and tested its association with behavioral features of WS. Using a WS adult cohort (22 WS, 16 healthy controls), we modeled a sparse representation of a WS-specific neuroanatomical profile. The predictive performances are robust within the training cohort (10-fold cross-validation, AUC = 1.0) and accurately identify all WS individuals in an independent child WS cohort (seven WS, 59 children with diverse developmental status, AUC = 1.0). The WS-specific neuroanatomical profile includes measurements in the orbitofrontal cortex, superior parietal cortex, Sylvian fissures, and basal ganglia, and variability within these areas related to the underlying size of hemizygous deletion in patients with partial deletions. The profile intensity mediated the overall cognitive impairment as well as personality features related to hypersociability. Our results imply that the unique behaviors in WS were mediated through the constellation of abnormalities in cortical-subcortical circuitry consistent in child WS and adult WS. The robustness of the derived WS-specific neuroanatomical profile also demonstrates the potential utility of our approach in both clinical and research applications.

Sensitivity of restriction spectrum imaging to memory and neuropathology in Alzheimer's disease.

BACKGROUND: Diffusion imaging has demonstrated sensitivity to structural brain changes in Alzheimer's disease (AD). However, there remains a need for a more complete characterization of microstructural alterations occurring at the earliest disease stages, and how these changes relate to underlying neuropathology. This study evaluated the sensitivity of restriction spectrum imaging (RSI), an advanced diffusion magnetic resonance imaging (MRI) technique, to microstructural brain changes in mild cognitive impairment (MCI) and AD. METHODS: MRI and neuropsychological test data were acquired from 31 healthy controls, 12 individuals with MCI, and 13 individuals with mild AD, aged 63-93 years. Cerebrospinal fluid amyloid-ß levels were measured in a subset (n = 38) of participants. RSI measures of neurite density (ND) and isotropic free water (IF) were computed in fiber tracts and in hippocampal and entorhinal cortex gray matter, respectively. Analyses evaluated whether these measures predicted memory performance, correlated with amyloid-ß levels, and distinguished impaired individuals from controls. For comparison, analyses were repeated with standard diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity. RESULTS: Both RSI and DTI measures correlated with episodic memory and disease severity. RSI, but not DTI, measures correlated with amyloid-ß42 levels. ND and FA in the arcuate fasciculus and entorhinal cortex IF most strongly predicted recall performance. RSI measures of arcuate fasciculus ND and entorhinal cortex IF best discriminated memory impaired participants from healthy participants. CONCLUSIONS: RSI is highly sensitive to microstructural changes in the early stages of AD, and is associated with biochemical markers of AD pathology. Reduced ND in cortical association fibers and increased medial temporal lobe free-water diffusion predicted episodic memory, distinguished cognitively impaired from healthy individuals, and correlated with amyloid-ß. Although further research is needed to assess the sensitivity of RSI to preclinical AD and disease progression, these results suggest that RSI may be a promising tool to better understand neuroanatomical changes in AD and their association with neuropathology.