Laurence O'Dwyer

Reduced Hippocampal Volume in Healthy Young ApoE4 Carriers: An MRI Study

The E4 allele of the ApoE gene has consistently been shown to be related to an increased risk of Alzheimers 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 FMRIBs 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.

Multiple Indices of Diffusion Identifies White Matter Damage in Mild Cognitive Impairment and Alzheimer’s Disease

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 Alzheimers 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.

Using support vector machines with multiple indices of diffusion for automated classification of mild cognitive impairment.

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 Alzheimers disease where the early identification of subjects with MCI is critical.

Association between white matter fiber integrity and subclinical psychotic symptoms in schizophrenia patients and unaffected relatives

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.

Differential effects of the ApoE4 genotype on brain structure and function.

The apolipoprotein E ε4 allele is a well established genetic risk factor for sporadic Alzheimers disease. It is associated with structural and functional brain changes in healthy young, middle-aged and elderly subjects. In the current study, we assessed the impact of the ApoE genotype on brain macro- and microstructure, cognitive functioning and brain activity in fifty healthy young subjects (25 ApoE ε4 (ε4+) carriers and 25 non-carriers (ε4-), mean age 26.4±4.6years). We used diffusion tensor imaging (DTI) and voxel based morphometry (VBM) to assess brain structure, an extensive neuropsychological battery to test cognitive functioning and event-related functional magnetic resonance imaging (fMRI) to capture brain activity during episodic memory encoding and retrieval. ApoE ε4 carriers differed from non-carriers in fMRI activations but not in cognitive performance nor in brain micro- and macrostructure. These results suggest functional alterations in the episodic memory network that are modulated by the ε4 allele and might precede clinical or structural neurodegeneration.

Using Diffusion Tensor Imaging and Mixed-Effects Models to Investigate Primary and Secondary White Matter Degeneration in Alzheimer's Disease and Mild Cognitive Impairment

White matter (WM) degeneration in Alzheimers disease (AD) and mild cognitive impairment (MCI) may be a key indicator of early damage in AD. Here, we analyzed WM diffusion tensor data using Tract-Based Spatial Statistics in conjunction with mixed-effects models. Four indices of diffusion were assessed in 61 healthy control, 19 non-amnestic MCIs, 14 amnestic MCIs, and 9 AD patients. The aim of the study was to use advanced mixed-effects models to investigate the retrogenesis hypothesis of AD, which suggests that tracts that are late to myelinate in ontogenetic development are the earliest to be affected in AD. Our results show that a number of late-myelinating pathways, including the parahippocampal region and the inferior longitudinal fasciculus, were predominantly affected by changes in WM volume. Conversely, early-myelinating pathways were found to be affected by a combination of both WM and gray matter (GM) atrophy. A model of the entire WM structure of the brain returned GM models for two indices of diffusion, suggesting that more complex regional landscapes of diffusion lie hidden beneath a global analysis of the entire brain. Our results warn against an explanation of white matter damage that points simply to one of two mechanisms: secondary degeneration or direct damage of myelin. We suggest that tracts may be affected by both mechanisms, with the balance depending on whether tracts are early or late-myelinating. A greater understanding of the pattern of WM changes in AD may prove useful for the early detection of AD.

Association of microstructural white matter abnormalities with cognitive dysfunction in geriatric patients with major depression.

Major depression disorder (MDD) is one of the most common causes of disability in people over 60years of age. Previous studies have linked affective and cognitive symptoms of MDD to white matter (WM) disruption in limbic-cortical circuits. However, the relationship between clinical cognitive deficits and loss of integrity in particular WM tracts is poorly understood. Fractional anisotropy (FA) as a measure of WM integrity was investigated in 17 elderly MDD subjects in comparison with 18 age-matched controls using tract-based spatial statistics (TBSS) and correlated with clinical and cognitive parameters. MDD patients revealed significantly reduced FA in the right posterior cingulate cluster (PCC) compared with controls. FA in the right PCC (but not in the left PCC) showed a significant positive correlation with performance in a verbal naming task, and showed a non-significant trend toward a correlation with verbal fluency and episodic memory performance. In control subjects, no correlations were found between cognitive tasks and FA values either in the right or left PCC. Results provide additional evidence supporting the neuronal disconnection hypothesis in MDD and suggest that cognitive deficits are related to the loss of integrity in WM tracts associated with the disorder.

White Matter Differences between Healthy Young ApoE4 Carriers and Non-Carriers Identified with Tractography and Support Vector Machines

The apolipoprotein E4 (ApoE4) is an established risk factor for Alzheimers disease (AD). Previous work has shown that this allele is associated with functional (fMRI) changes as well structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess the diffusion characteristics and the white matter (WM) tracts of healthy young (20–38 years) ApoE4 carriers and non-carriers. No significant differences in diffusion indices were found between young carriers (ApoE4+) and non-carriers (ApoE4−). There were also no significant differences between the groups in terms of normalised GM or WM volume. A feature selection algorithm (ReliefF) was used to select the most salient voxels from the diffusion data for subsequent classification with support vector machines (SVMs). SVMs were capable of classifying ApoE4 carrier and non-carrier groups with an extremely high level of accuracy. The top 500 voxels selected by ReliefF were then used as seeds for tractography which identified a WM network that included regions of the parietal lobe, the cingulum bundle and the dorsolateral frontal lobe. There was a non-significant decrease in volume of this WM network in the ApoE4 carrier group. Our results indicate that there are subtle WM differences between healthy young ApoE4 carriers and non-carriers and that the WM network identified may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age.

Patterns of autobiographical memory in bipolar disorder examined by psychometric and functional neuroimaging methods

Abstract This is the first study to combine psychometric and functional neuroimaging methods to study altered patterns of autobiographical memory in bipolar disorder (BD). All participants were interviewed with an expanded version of the Bielefelder Autobiographical Memory Inventory (Bielefelder Autobiographisches Gedächtnis Inventar 2004;Lisse: Swets and Zeitlinger). We then acquired functional magnetic resonance imaging data during a task of individually designed autobiographical recall. Compared with healthy controls, BD patients reported a stronger emotionality of autobiographical memories and more frequent recollections of autobiographical events during their everyday life. Furthermore, they failed to deactivate areas in the cuneus and lingual gyrus and showed decreased activation in the inferior frontal and precentral areas compared with the control group. More frequent intrusions from a person’s past, which had a neural correlate in the lack of deactivation in some default mode network areas in BD patients, may contribute to manic or depressive symptoms.

Corrigendum to “Association between white matter fiber integrity and subclinical psychotic symptoms in schizophrenia patients and unaffected relatives” [Schizophr. Res. 140 (2012) 129–135]

a Laboratory of Neuroscience, Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe Univ., Frankfurt/Main, Germany b Brain Imaging Center, Goethe Univ., Frankfurt/Main, Germany c School of Psychology, Cardiff University, United Kingdom d MRC Centre for Neuropsychiatric Genetics & Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, United Kingdom