Silke Matura

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.

Mild Cognitive Impairment in the Elderly is Associated with Volume Loss of the Cholinergic Basal Forebrain Region

BACKGROUND Cholinergic neurons within the basal forebrain are assumed to be an early (preclinical) manifestation site of pathological changes in Alzheimers disease (AD). METHODS We used morphometric magnetic resonance imaging (MRI) to detect and quantify atrophic changes in the basal forebrain of subjects suffering from amnestic mild cognitive impairment (aMCI). Three Tesla magnetic resonance (MR) data of 26 aMCI patients, 46 cognitively normal elderly control subjects (CO), and 12 patients suffering from Alzheimers dementia were analyzed, including segmentation and quantification of brain tissue as well as a segmentation of basal forebrain structures (substantia innominata [SI]). RESULTS We found the volume of the SI to be significantly different between groups in that control subjects showed the largest SI volumes, followed by aMCI and AD patients. CONCLUSIONS These results are in line with the hypothesis that cell loss within the cholinergic basal forebrain regions occurs already in the early (predementia) stage of AD. In vivo quantification of these changes might be of use as a novel neuroimaging marker of cholinergic neurodegeneration in AD.

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.

Reduced functional connectivity and asymmetry of the planum temporale in patients with schizophrenia and first-degree relatives

The planum temporale (PT) is a highly lateralized brain area associated with auditory and language processing. In schizophrenia, reduced structural and functional laterality of the PT has been suggested, which is of clinical interest because of its potential role in the generation of auditory verbal hallucinations. We investigated whether resting-state functional imaging (fMRI) of the PT reveals aberrant functional connectivity and laterality in patients with schizophrenia (SZ) and unaffected relatives, and examined possible associations between altered intrinsic functional organization of auditory networks and hallucinations. We estimated functional connectivity between bilateral PT and whole-brain in 24 SZ patients, 22 unaffected first-degree relatives and 24 matched healthy controls. The results indicated reduced functional connectivity between PT and temporal, parietal, limbic and subcortical regions in SZ patients and relatives in comparison with controls. Altered functional connectivity correlated with predisposition towards hallucinations (measured with the Revised Hallucination Scale [RHS]) in both patients and relatives. We also observed reduced functional asymmetry of the superior temporal gyrus in patients and relatives, which correlated significantly with acute severity of hallucinations in the patient group. To conclude, SZ patients and relatives showed abnormal asymmetry and aberrant connectivity in the planum temporale during resting-state, which was related to psychopathology. These results are in line with results from auditory processing and symptom-mapping studies that suggest that the PT is a central node in the generation of hallucinations. Our findings support reduced intrinsic functional hemispheric asymmetry of the auditory network as a possible trait marker in schizophrenia.

Multimodal assessments of the hippocampal formation in schizophrenia and bipolar disorder: evidences from neurobehavioral measures and functional and structural MRI

A potential clinical and etiological overlap between schizophrenia (SZ) and bipolar disorder (BD) has long been a subject of discussion. Imaging studies imply functional and structural alterations of the hippocampus in both diseases. Thus, imaging this core memory region could provide insight into the pathophysiology of these disorders and the associated cognitive deficits. To examine possible shared alterations in the hippocampus, we conducted a multi-modal assessment, including functional and structural imaging as well as neurobehavioral measures of memory performance in BD and SZ patients compared with healthy controls. We assessed episodic memory performance, using tests of verbal and visual learning (HVLT, BVMT) in three groups of participants: BD patients (n = 21), SZ patients (n = 21) and matched (age, gender, education) healthy control subjects (n = 21). In addition, we examined hippocampal resting state functional connectivity, hippocampal volume using voxel-based morphometry (VBM) and fibre integrity of hippocampal connections using diffusion tensor imaging (DTI). We found memory deficits, changes in functional connectivity within the hippocampal network as well as volumetric reductions and altered white matter fibre integrity across patient groups in comparison with controls. However, SZ patients when directly compared with BD patients were more severely affected in several of the assessed parameters (verbal learning, left hippocampal volumes, mean diffusivity of bilateral cingulum and right uncinated fasciculus). The results of our study suggest a graded expression of verbal learning deficits accompanied by structural alterations within the hippocampus in BD patients and SZ patients, with SZ patients being more strongly affected. Our findings imply that these two disorders may share some common pathophysiological mechanisms. The results could thus help to further advance and integrate current pathophysiological models of SZ and BD.

Cortical–basal ganglia imbalance in schizophrenia patients and unaffected first-degree relatives

Structural brain changes are amongst the most robust biological alterations in schizophrenia, and their investigation in unaffected relatives is important for an assessment of the contribution of genetic factors. In this cross-sectional morphometry study we investigated whether volume changes in SZ are linked with genetic vulnerability and whether these effects are separated from secondary illness effects. We compared density of grey and white matter using high-resolution 3D-anatomical MRI imaging data in 31 SZ patients, 29 first-degree relatives and 38 matched healthy controls, using Voxel-Based Morphometry (VBM) with SPM8. Volume of basal ganglia was also compared by manual segmentation. We found increased grey matter in the striatum, globus pallidus internus and thalamus and decreased grey matter in the parahippocampal and cingulate gyri both in SZ patients and relatives. Additionally, SZ patients had decreased volume of temporal, frontal and limbic grey and white matter in comparison with relatives and controls. Relatives showed intermediate values in many of these areas. Increased volume in the thalamus and parts of the basal ganglia and decreased volume of cortical areas and underlying white matter were thus associated with schizophrenia and its genetic vulnerability. These results suggest that brain morphological changes associated with SZ are in part determined by genetic risk factors and are not entirely explained by effects of medication or changes secondary to illness.

Association between symptoms of psychosis and reduced functional connectivity of auditory cortex.

We have previously reported altered functional asymmetry of the primary auditory cortex (Heschls gyrus) of patients with schizophrenia (SZ) and their relatives during auditory processing. In this study, we investigated whether schizophrenia patients have altered intrinsic functional organization of Heschls gyrus (HG) during rest. Using functional magnetic resonance imaging (fMRI), we measured functional connectivity between bilateral HG and the whole brain in 24 SZ patients, 22 unaffected first-degree relatives and 24 matched healthy controls. SZ patients and relatives showed altered functional asymmetry in HG and altered connectivity between temporal and limbic areas in the auditory network during resting-state in comparison with healthy controls. These changes in functional connectivity correlated with predisposition towards hallucinations in patients and relatives and with acute positive symptoms in patients. The results are in line with the results from task-related and symptom-mapping studies that investigated the neural correlates of positive symptoms, and suggest that individual psychopathology is associated with aberrant intrinsic organization of auditory regions in schizophrenia. This might be evidence that reduced hemispheric lateralization and reduced functional connectivity of the auditory network are trait markers of schizophrenia.

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.

Recognition memory is associated with altered resting- state functional connectivity in people at genetic risk for Alzheimer's disease

The apolipoprotein E ε4 (ApoE ε4) allele not only represents the strongest single genetic risk factor for sporadic Alzheimers disease, but also imposes independent effects on brain function in healthy individuals where it has been shown to promote subtle memory deficits and altered intrinsic functional brain network connectivity. Based on previous work showing a potential relevance of the default mode network (DMN) functional connectivity for episodic memory function, we hypothesized that the ApoE ε4 genotype would affect memory performance via modulation of the DMN. We assessed 63 healthy individuals (50–80 years old), of which 20 carried the ε4 allele. All participants underwent resting‐state functional magnetic resonance imaging (fMRI), high‐resolution 3D anatomical MRI imaging and neuropsychological assessment. Functional connectivity analysis of resting‐state activity was performed with a predefined seed region located in the left posterior cingulate cortex (PCC), a core region of the DMN. ApoE ε4 carriers performed significantly poorer than non‐carriers in wordlist recognition and cued recall. Furthermore, ε4 carriers showed increased connectivity relative to ε4 non‐carriers between the PCC seed region and left‐hemispheric middle temporal gyrus (MTG). There was a positive correlation between recognition memory scores and resting‐state connectivity in the left MTG in ε4 carriers. These results can be interpreted as compensatory mechanisms strengthening the cross‐links between DMN core areas and cortical areas involved in memory processing.

Expanded Temporal Binding Windows in People with Mild Cognitive Impairment

Previous studies investigating mild cognitive impairment (MCI) have focused primarily on cognitive, memory, attention, and executive function deficits. There has been relatively little research on the perceptual deficits people with MCI may exhibit. This is surprising given that it has been suggested that sensory and cognitive functions share a common cortical framework [1]. In the following study, we presented the sound-induced flash illusion (SiFi) to a group of participants with mild cognitive impairment (MCI) and healthy controls (HC). The SiFi is an audio-visual illusion whereby two-beeps and one-flash are presented. Participants tend to perceive two flashes when the time-interval between the auditory beeps is small [2, 3]. Participants with MCI perceived significantly more illusions compared to HC over longer auditory time-intervals. This suggests that MCIs integrate more (arguably irrelevant) audiovisual information compared to HCs. By incorporating perceptual tasks into a clinical diagnosis it may be possible to gain a more comprehensive understanding into the disease, as well as provide a more accurate diagnose to those who may have a language impairment.