Neural substrates of self-reference effect deficits in beta-amyloid–positive individuals with MCI and Alzheimer’s disease

Alzheimer’s Imaging Consortium Poster Presentations: IC-P assessments and MRI scan. The intrinsic connectivity of bilateral hippocampus (seed regions) was measured by the R-fMRI approach at a 3.0 T GE scanner. The correlation coefficient maps of individual participant were generated by cross-correlating each voxel timecourse with the average time course of seed regions. Fisher’s Z-transformation was then performed in the resulting datasets, and data normalized to a standard Talairach space. Voxelwise 2 3 2 ANCOVA analysis was used to examine the main effects and interactive effects of LLD and MCI on the HFC networks in the four groups, after controlling for age, gender, education and gray matter volumes. Results: The main effects of depression on the bilateral HFC was seen in the regions previously implicated in mood regulation, including bilateral dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), thalamus, and dorsal striatum; main effects of MCI on the bilateral HFCs were seen in the default mode, executive control and salience network-related regions (Fig 1a representing right HFC); The interactive effects of depression and MCI on the right HFC network were identified in the bilateral ventromedial PFC, dorsal anterior cingulate cortex, right DLPFC and middle occipital gyrus (Fig 1b). Conclusions: Divergent hippocampal network abnormalities were associated with LLD and MCI, whereas shared and interactive effects of these disorders were also identified. The presence of specific medial temporal lobe-based network dysfunction may increase the vulnerability of individuals with LLD and/or MCI to progress to AD.

IC-P-201

FRACTIONAL ANISOTROPY DIFFERENCES IN ATTENTION AND DEFAULT-MODE NETWORK AREAS BETWEEN HEALTHY AGING AND ALZHEIMER’S DISEASE

Angela Luedke1, Juan Fernandez-Ruiz2, Angela Tam1, Angeles Garcia1, Queen’s University, Kingston, Ontario, Canada; 2National University of Mexico, Distrito Federal, Mexico. Contact e-mail: [email protected] 1

Background: Compared to healthy aging, Alzheimer’s disease (AD) patients show gray matter atrophy in the precuneus and posterior cingulate cortex (PCC), as well as functional disruption of the default mode network (DMN) and deficits in selective attention. In healthy aging, increased activation of the inferior frontal gyrus (IFG) during selective attention tasks suggests increased prefrontal cortex recruitment to maintain inhibitory functioning. Conversely, IFG activation is decreased in selective attention tasks in AD patients. White matter integrity is also frequently affected in AD, especially in frontal areas. We investigated differences in fractional anisotropy (FA), a measure of white matter integrity, within the precuneus, PCC and IFG in healthy controls (HC) and AD, which may help explain the pathological decline in selective attention in AD. Methods: This pilot study included healthy elderly and mild AD patients. Diffusion tensor imaging (DTI) data was collected in 30 directions using a Siemens 3T scanner. A 3D MPRAGE anatomical scan was co-registered to the diffusion data for 3D analysis.Diffusion-weighted imaging data was transformed into common Talaraich space and spherical predetermined regions of interest (ROI’s) were placed individually at the right and left PCC (radius 4.5mm), precuneus (radius 7.5mm) and IFG (radius 8mm) for both groups. Mean FA values for each ROI were computed. A MANOVA was applied to test the effect of group on mean FA values for all ROI’s. Results: There was a significant effect of group (AD vs. HC) on mean FA values in the ROI’s, Wilks L ¼ 0.1, F(6,7) ¼ 10.03, p< .05. Separate univariate ANOVA’s revealed a significant difference between HC and AD for the right precuneus F(1,12) ¼ 5.07, p< .05 and the right inferior frontal gyrus F(1, 12) ¼ 6.45, p< .05. Conclusions: Our pilot study confirms that FA is altered in AD compared to healthy aging in frontal and DMN regions. Our next step will be to correlate cognitive and behavioural scores with FA to further understand the relationship between white matter pathology and cognitive deficits in AD. IC-P-202

METABOLIC ABNORMALITIES IN ALZHEIMER’S DISEASE AND SEMANTIC DEMENTIA INVOLVE DISTINCT FUNCTIONAL NETWORKS OVERLAPPING IN THE HIPPOCAMPUS

Renaud La Joie1, Beatrice Desgranges2, Audrey Perrotin2, Brigitte Landeau3, Alexandre Bejanin4, Alice Pelerin3, Florence Mezenge3, Serge Belliard5,

P113

Vincent de La Sayette1, Francis Eustache2, Gael Chetelat6, 1Unite INSERM / EPHE/UCBN/CHU Caen U1077, Caen, France; 2INSERM, Universite de Caen Basse-Normandie, Ecole Pratique des Hautes Etudes, CHU de Caen, Caen, France; 3INSERM-EPHE-UCBN U1077, Caen, France; 4 INSERM-APHE-UCBN U1077, Caen, France; 5Unite INSERM / EPHE / UCBN / CHU Caen U1077, CAEN, France; 6Inserm-EPHE-UCBN U1077, Caen, France. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) and semantic dementia (SD) are two neurodegenerative disorders characterized by distinct neuropsychological deficits. Despite common temporal atrophy, the impairment of different brain networks have been emphasized (Nestor et al., 2006; Selley et al., 2009). Combining FDG-PET in patients and resting-state fMRI in healthy elderly, we aimed at assessing the differences and potential similarities between the brain networks that are impaired in AD versus SD. Methods: FDG-PET data from 21 patients with AD and 13 patients with SD were corrected for partial volume effects, spatially normalized into MNI space using corresponding MRIs and scaled to the mean cerebellar cortex value. Voxelwise analyses allowed to identify the main peaks of metabolism differences between AD and SD. These peaks served to define seeds for functional connectivity analyses performed using resting-state fMRI in 51 healthy elderly. This procedure allowed comparing the brain networks which hypometabolic regions in AD versus SD belong to and assess their relationships with cognitive performances. Results: Compared to SD, AD patients showed lower brain metabolism in the right precuneus and angular cortex and greater metabolism in the left parahippocampus, subgenual cortex and anterior cingulate (Fig 1a). In the healthy elderly, these seeds revealed five networks of functionally-connected brain areas, that all converged to a single area of overlap located in the anterior hippocampus (Fig 1b).Interestingly, verbal episodic memory performances correlated with the connectivity between this anterior hippocampus region and both seeds showing greater hypometabolism in AD (the precuneus: r¼0.34, p¼0.02; and the right angular cortex: r¼0.31, p¼0.035) but not with the seeds showing greater hypometabolism in SD (all r<0.1, p>0.2). Conclusions: Differences in the pattern of cortical hypometabolism in AD and SD were found in distinct brain networks that however overlap in the anterior hippocampus. Yet, in the normal brain, only the connectivity between the hippocampus and regions that are hypometabolic in AD correlates with episodic memory performances while hippocampal connectivity with SD sensitive regions does not. This finding probably accounts for the stronger alteration of episodic memory in AD as compared to SD in spite of comparable hippocampal atrophy in both diseases.

IC-P-203

NEURAL SUBSTRATES OF SELF-REFERENCE EFFECT DEFICITS IN BETA-AMYLOID–POSITIVE INDIVIDUALS WITH MCI AND ALZHEIMER’S DISEASE

Malo Gaubert1, Gael Chetelat2, Nastassja Morel3, Nicolas Villain2, Brigitte Landeau2, Florence Mezenge4, Audrey Perrotin2, Vincent de La Sayette2, Francis Eustache2, Beatrice Desgranges2, Geraldine Rauchs2, 1 INSERM, Universite de Caen Basse-Normandie, Ecole Pratique des

P114

Alzheimer’s Imaging Consortium Poster Presentations: IC-P

Hautes Etudes, CHU de Caen, CATI, Caen, France; 2INSERM, Universite de Caen Basse-Normandie, Ecole Pratique des Hautes Etudes, CHU de Caen, Caen, France; 3INSERM, Universite de Caen Basse-Normandie, Ecole Pratique des Hautes Etudes, CHU de Caen, CAEN, France; 4Inserm EPHE-UCBN U1077, Caen, France. Contact e-mail: [email protected] Background: Self-referential processing of personality trait words is generally associated with better remembering compared to words processed in a semantic condition, an effect called self-reference effect (SRE). Previous works suggest that SRE is subserved by neural activity during encoding in several cortical areas including the medial prefrontal cortex (MPFC). Alzheimer’s disease (AD) is characterized by early memory deficits and Ab deposits that predominate in the prefrontal cortex. The goal of the present study was to assess whether SRE was altered in AD and to highlight the neural basis of this effect using fMRI in mild cognitive impairment (MCI) and AD patients with Ab deposits. Methods: We used an fMRI event-related self-referential paradigm in 16 patients (8 MCI and 8 AD) with a florbetapir-positive scan and 27 healthy elderly with a florbetapir-negative scan. The neural activity associated with self-reference processing compared to a semantic control condition during both encoding and retrieval was compared between groups and correlated with behavioral measures of memory and SRE. Results are reported at p<0.005 (uncorrected). Results: Greater memory performance was found after self-related than after semantic processing in controls (p<0.001) but not in patients (p>0.05; condition x group interaction p¼0.01). In both groups, self-related processing was associated with increased activity during encoding in a common brain network involving midline cortical structures. Memory performance correlated with selfrelated activity in the hippocampus during both encoding and retrieval in the patients. SRE score was related to MPFC activity during encoding in controls. In patients, no such relationship was found with SRE, and self-related activity during encoding was decreased in the MPFC and posterior cingulate cortex (PCC) compared to controls. Conclusions: While the PCC and the hippocampus may have a more general role in self and memory processes, the positive effect of self-reference processing on memory appears to be subserved by increased activity in the MPFC. In AD patients, this effect is lost as self-reference processing does not improve memory performance, and this abnormality seems to be due to impaired MPFC activity.

IC-P-204

NEUROANATOMICAL CORRELATES OF THE BEHAVIORAL AND PSYCHIATRIC SYMPTOMS IN ALZHEIMER’S DISEASE: A VOXEL-BASED MORPHOMETRY STUDY

Xiaochen Hu1, Beate Newport2, Dix Meiberth3, Frank Jessen3, 1University of Bonn, Bonn, Germany; 2German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 3University of Bonn, Bonn, Germany. Contact e-mail: [email protected] Background: Behavioural and psychiatric symptoms (BPS) are frequently observed in the clinical course of Alzheimer’s disease (AD). However, previous studies on neuroanatomical underpinnings of BPS in AD have revealed inconsistent results, which might be biased by the image pre-processing steps and the small samples. The current study aimed to assess the relationship between regional grey matter volume (GMV) atrophy and BPS in a large sample of 424 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants. Methods: Structural MRI images and the scores of neuropsychiatric inventory questionnaire (NPI-Q) of altogether 85 AD, 208 patients with mild cognitive impairment (MCI), and 131 healthy controls (HC) were collected from the ADNI website. In contrast to the previous studies in this field, we used improved image pre-processing strategies, including the new segmentation and DARTEL normalization tools from SPM8. Voxel-based multiple regression analyses were used to characterize the association between GMVatrophy and each NPI-Q symptoms across the whole sample, with age, gender and total intracranial volume as covariates of non-interest. The results were exclusively masked with regions directly related to general cognitive deterioration, as expressed by the correlation

with the Mini-Mental-State-Examination (MMSE). A statistic threshold of p<0.05 (cluster level family wise error corrected) was applied. Results: Agitation was associated with GMV loss in the bilateral precuneus, the left frontal and insula cortices. Depression was related to GMV decreases in the left frontal cortex. Aberrant motor behaviour was associated with GMV atrophy in bilateral medial orbitofrontal cortices, bilateral putamen and the right inferior frontal gyrus. Conclusions: The current study has shown the neuroanatomical underpinnings of specific BPS by using advanced VBM techniques within a large public available database (ADNI). Our results contribute to the poor understanding of the pathology of BPS in AD.

IC-P-205

STRUCTURAL MRI MEASURES IN ALZHEIMER’S DISEASE AND EFFECTS OF ETHNICITY

Linda Zhang1, Raymond Tak-Fai Cheung1, Henry Ka Fung Mak1, Leung-wing Chu2, 1University of Hong Kong, Hong Kong, Hong Kong; 2 The University of Hong Kong, Hong Kong, Hong Kong. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) affects populations worldwide, and there are increasing numbers of AD-focused international neuroimaging studies. For these global cohorts, ethnicity may be a confounding factor. Morphometric differences have been found between European and Japanese brains, though the implications for common AD neuroimaging biomarkers, such as hippocampal volume and cortical thickness, are unknown and should be investigated. Methods: 65 local Chinese participants (33 AD, 32 elderly controls) were recruited, and a matching Caucasian cohort was downloaded from ADNI. All participants underwent T1-weighted MPRAGE scanning with ADNI’s protocol in 3T Philips Achieva scanners, and the raw images were processed using FreeSurfer v5.1. Cortical thickness was compared between groups with FreeSurfer’s GLM analysis tools. Hippocampal volumes were corrected for intracranial volume and analysed using multivariate GLM, with age, gender and years of education as covariates. Results: There were no significant differences between the two ethnicities for age, gender, MMSE and ADAS-cog scores, but local Chinese had significantly fewer years of education than Caucasians (4.863.8 vs. 15.863.3). Several clusters in the bilateral cingulate and precuneus regions showed cortical thinning in Chinese patients whereas Caucasian patients only had thinning in the inferior temporal regions compared to their respective controls. Between ethnicities, clusters in the left parietal area were thicker in Caucasian patients, whereas Chinese controls had thicker paracentral cortices than Caucasian controls. When combined, patients had cortical thinning in the bilateral temporal regions (all results significant at p<0.01). Controls had larger relative hippocampal volumes than patients (0.2760.05 vs. 0.1960.04), and Chinese subjects had larger relative hippocampal volumes than Caucasian subjects, regardless of diagnosis (0.2860.05 vs. 0.2360.03 for controls, 0.2060.04 vs. 0.1760.02 for patients). Conclusions: Chinese subjects have larger relative hippocampal volumes than Caucasian subjects, but Chinese AD patients also display a greater degree of hippocampal atrophy and cortical thinning. As none of these trends are reflected in the cognitive test scores, this may be indicative of a protective effect