The E4 allele of the ApoE gene has consistently been shown to be related to an increased risk of Alzheimer's disease (AD). The E4 allele is also associated with functional and structural grey matter ...(GM) changes in healthy young, middle-aged and older subjects. Here, we assess volumes of deep grey matter structures of 22 healthy younger ApoE4 carriers and 22 non-carriers (20-38 years). Volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen, thalamus and brain stem were calculated by FMRIB's Integrated Registration and Segmentation Tool (FIRST) algorithm. A significant drop in volume was found in the right hippocampus of ApoE4 carriers (ApoE4+) relative to non-carriers (ApoE4-), while there was a borderline significant decrease in the volume of the left hippocampus of ApoE4 carriers. The volumes of no other structures were found to be significantly affected by genotype. Atrophy has been found to be a sensitive marker of neurodegenerative changes, and our results show that within a healthy young population, the presence of the ApoE4+ carrier gene leads to volume reduction in a structure that is vitally important for memory formation. Our results suggest that the hippocampus may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age. Although volume reductions were noted bilaterally in the hippocampus, atrophy was more pronounced in the right hippocampus. This finding relates to previous work which has noted a compensatory increase in right hemisphere activity in ApoE4 carriers in response to preclinical declines in memory function. Possession of the ApoE4 allele may lead to greater predilection for right hemisphere atrophy even in healthy young subjects in their twenties.
IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, ...owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD. OBJECTIVE: To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years). MAIN OUTCOMES AND MEASURES: Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation. RESULTS: Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (β = −31.92; 95% CI, −52.69 to −11.16; P = .0027) and a 3% smaller total gray matter volume (β = −22.51; 95% CI, −35.07 to −9.96; P = .0005), while total white matter volume was unaltered (β = −10.10; 95% CI, −20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes. CONCLUSIONS AND RELEVANCE: Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD.
The study of multiple indices of diffusion, including axial (DA), radial (DR) and mean diffusion (MD), as well as fractional anisotropy (FA), enables WM damage in Alzheimer's disease (AD) to be ...assessed in detail. Here, tract-based spatial statistics (TBSS) were performed on scans of 40 healthy elders, 19 non-amnestic MCI (MCIna) subjects, 14 amnestic MCI (MCIa) subjects and 9 AD patients. Significantly higher DA was found in MCIna subjects compared to healthy elders in the right posterior cingulum/precuneus. Significantly higher DA was also found in MCIa subjects compared to healthy elders in the left prefrontal cortex, particularly in the forceps minor and uncinate fasciculus. In the MCIa versus MCIna comparison, significantly higher DA was found in large areas of the left prefrontal cortex. For AD patients, the overlap of FA and DR changes and the overlap of FA and MD changes were seen in temporal, parietal and frontal lobes, as well as the corpus callosum and fornix. Analysis of differences between the AD versus MCIna, and AD versus MCIa contrasts, highlighted regions that are increasingly compromised in more severe disease stages. Microstructural damage independent of gross tissue loss was widespread in later disease stages. Our findings suggest a scheme where WM damage begins in the core memory network of the temporal lobe, cingulum and prefrontal regions, and spreads beyond these regions in later stages. DA and MD indices were most sensitive at detecting early changes in MCIa.
Few studies have looked at the potential of using diffusion tensor imaging (DTI) in conjunction with machine learning algorithms in order to automate the classification of healthy older subjects and ...subjects with mild cognitive impairment (MCI). Here we apply DTI to 40 healthy older subjects and 33 MCI subjects in order to derive values for multiple indices of diffusion within the white matter voxels of each subject. DTI measures were then used together with support vector machines (SVMs) to classify control and MCI subjects. Greater than 90% sensitivity and specificity was achieved using this method, demonstrating the potential of a joint DTI and SVM pipeline for fast, objective classification of healthy older and MCI subjects. Such tools may be useful for large scale drug trials in Alzheimer's disease where the early identification of subjects with MCI is critical.
Background
A developmental improvement of symptoms in attention‐deficit/hyperactivity disorder (ADHD) is frequently reported, but the underlying neurobiological substrate has not been identified. The ...aim of this study was to determine whether white matter microstructure is related to developmental improvement of ADHD symptoms.
Methods
A cross‐sectional magnetic resonance imaging (MRI) analysis was embedded in a prospective follow‐up of an adolescent cohort of ADHD and control subjects (NeuroIMAGE). Mean age at baseline was 11.9 years, mean interval of follow‐up was 5.9 years. About 75.3% of the original cohort was retained successfully. Data of 101 participants with ADHD combined type at baseline and 40 healthy controls were analysed. ADHD symptoms were measured with semistructured, investigator‐based interviews and Conners' questionnaires, on the basis of DSM‐IV criteria. Fractional anisotropy (FA) and mean diffusivity (MD) indices of white matter microstructure were measured using whole brain diffusion tensor imaging at follow‐up only. In a dimensional analysis FA and MD were related to change in ADHD symptoms. To link this analysis to DSM‐IV diagnoses, a post hoc categorical group analysis was conducted comparing participants with persistent (n = 59) versus remittent (n = 42) ADHD and controls.
Results
Over time, participants with ADHD showed improvement mainly in hyperactive/impulsive symptoms. This improvement was associated with lower FA and higher MD values in the left corticospinal tract at follow‐up. Findings of the dimensional and the categorical analysis strongly converged. Changes in inattentive symptoms over time were minimal and not related to white matter microstructure.
Conclusions
The corticospinal tract is important in the control of voluntary movements, suggesting the importance of the motor system in the persistence of hyperactive/impulsive symptoms.
Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether ...brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample.
We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered.
Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 range 8-30 yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results.
Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional.
Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research.
Autism spectrum disorder (“autism”) is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify ...and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, but its potential as a neural stratification marker has not been widely examined.
In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS (European Autism Interventions—A Multicentre Study for Developing New Medications) Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical control subjects as well as a replication dataset from ABIDE (Autism Brain Imaging Data Exchange) (513 individuals with autism, 691 neurotypical subjects) using a promising approach that moves beyond mean group comparisons. We derived gray matter voxelwise laterality values for each subject and modeled individual deviations from the normative pattern of brain laterality across age using normative modeling.
Individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language, motor, and visuospatial regions, associated with symptom severity. Language delay explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged, with individuals with autism with language delay showing more pronounced rightward deviations than individuals with autism without language delay.
Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism and indicate that atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.
Abstract In this study, we investigate whether aberrant integrity of white matter (WM) fiber tracts represents a genetically determined biological marker of schizophrenia (SZ), and its relation with ...clinical symptoms. We collected brain DTI data from 28 SZ patients, 18 first-degree relatives and 22 matched controls and used voxel-based analysis with tract-based spatial statistics (TBSS) in order to compare fractional anisotropy (FA) between groups. Mean voxel-based FA values from the entire skeleton of each group were compared. We did a multiple regression analysis, followed by single post-hoc contrasts between groups. FA values were extracted from the statistically significant areas. The results showed significantly smaller FA values for SZ patients in comparison with controls in cortico-spinal tracts, in commissural fibers, in thalamic projections, in association fibers and in cingulum bundles. A significant increase of FA in SZ patients in comparison with healthy controls was only found in the arcuate fasciculus. Relatives had intermediate values between patients and controls which were deemed significant in the comparison to patients and controls in association fibers, arcuate fasciculus and cingulum bundles. Lower FA values in association fibers were significantly associated with predisposition toward hallucinations (in SZ patients and relatives), with higher PANSS scores of positive symptoms and with duration of illness (SZ patients). Our results suggest that clinical and subclinical presentations of psychotic symptoms are associated with aberrant integrity of multiple WM tracts. This association may represent an endophenotype of schizophrenia, since it is present in unaffected relatives as well. Such endophenotypes may serve as quantitative traits for future genetic studies and as candidate markers for early and preclinical identification of subjects at risk.
Heterogeneity in the phenotypic presentation of autism spectrum disorder (ASD) is apparent in the profile and the severity of sensory features. Here, we applied factor mixture modelling (FMM) to test ...a multidimensional factor model of sensory processing in ASD. We aimed to identify homogeneous sensory subgroups in ASD that differ intrinsically in their severity along continuous factor scores. We also investigated sensory subgroups in relation to clinical variables: sex, age, IQ, social-communication symptoms, restricted and repetitive behaviours, adaptive functioning and symptoms of anxiety and attention-deficit/hyperactivity disorder.
Three hundred thirty-two children and adults with ASD between the ages of 6 and 30 years with IQs varying between 40 and 148 were included. First, three different confirmatory factor models were fit to the 38 items of the Short Sensory Profile (SSP). Then, latent class models (with two-to-six subgroups) were evaluated. The best performing factor model, the 7-factor structure, was subsequently used in two FMMs that varied in the number of subgroups: a two-subgroup, seven-factor model and a three-subgroup and seven-factor model.
The 'three-subgroup/seven-factor' FMM was superior to all other models based on different fit criteria. Identified subgroups differed in sensory severity from severe, moderate to low. Accounting for the potential confounding effects of age and IQ, participants in these sensory subgroups had different levels of social-communicative symptoms, restricted and repetitive behaviours, adaptive functioning skills and symptoms of inattention and anxiety.
Results were derived using a single parent-report measure of sensory features, the SSP, which limits the generalisability of findings.
Sensory features can be best described by three homogeneous sensory subgroups that differ in sensory severity gradients along seven continuous factor scores. Identified sensory subgroups were further differentiated by the severity of core and co-occurring symptoms, and level of adaptive functioning, providing novel evidence on the associated clinical correlates of sensory subgroups. These sensory subgroups provide a platform to further interrogate the neurobiological and genetic correlates of altered sensory processing in ASD.
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