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Effect of Apolipoprotein E on cortical thickness and resting-state brain function in Alzheimer's disease
Poster Presentations P1 P1-388
ARE SNPS ASSOCIATED WITH ALZHEIMER’S DISEASE ALSO ASSOCIATED WITH COGNITION AND STRUCTURAL BRAIN CHANGES IN A RELATIVELY YOUNG POPULATION?
Benjamin Verhaaren, Meike Vernooij, Andre Uitterlinden, Albert Hofman, Wiro Niessen, Aad van der Lugt, Monique Breteler, Mohammad Arfan Ikram, Erasmus Medical Center, Rotterdam, Netherlands. Background: Six genetic loci (APOE, CLU, PICALM, EXOC3L2, BIN1 and CR1) have been associated with Alzheimer’s disease (AD) in genome-wide association studies. AD has a long preclinical phase with cognitive decline and during which Alzheimer pathology and cerebral small vessel disease can be visualized on structural MRI. It is unclear how these loci exert their effect and relate to cognition and preclinical MRI markers of AD. In a population-based study of relatively young persons we investigated how these genetic loci associated with cognitive performance. In addition, we explored whether putative effects would be mediated by AD pathology and cerebral small vessel disease as seen on MRI. Methods: In 677 non-demented individuals (mean age: 67 yrs) from the populationbased Rotterdam Study, we genotyped reported significant SNPs from each locus (rs2075650, rs11136000, rs3851179, rs597668, rs744373 and rs3818361). All persons underwent cognitive testing, using a standardized test battery, and underwent MRI-scanning from which volumetric measures of grey matter, white matter, hippocampus and white matter lesions were obtained. Brain infarcts and cerebral microbleeds were rated visually. Persons with cortical infarcts were excluded. We investigated each SNP separately for its association with cognition and MRI-markers. Subsequently, we performed analyses with summary risk scores based on the six SNPs. These scores were constructed by weighting the number of risk alleles within an individual by the reported effect size for dementia. All analyses were adjusted for relevant confounders. Results: We found that rs744373 (BIN1) strongly associated with poorer memory performance (p ¼ 0.003, Bonferroni adjusted). None of the loci were significantly related to any of the MRI markers. Summary risk scores of the six loci together were neither associated with cognition nor with brain markers. Conclusions: In this study among a relatively young population, the BIN1 locus was strongly associated with poorer memory performance, while no associations with brain MRI markers were found. We hypothesize that BIN1 exerts its influence on the development of AD via mechanisms not visualized by structural MRI (e.g. amyloid-deposition or tau-pathology). Furthermore, we hypothesize that the effects of the other loci on AD possibly manifest at higher age. P1-389
EFFECT OF APOLIPOPROTEIN E ON CORTICAL THICKNESS AND RESTING-STATE BRAIN FUNCTION IN ALZHEIMER’S DISEASE
Xiao Wang1, Jinhui Wang2, Yi He2, Huiying Li2, Huishu Yuan3, Alan Evans4, Xin Yu2, Yong He2, Huali Wang2, 1Peking University Institute of Mental Health, Beijing, China; 2Beijing Normal University, Beijing, China; 3Peking University Third Hospital, Beijing, China; 4Montreal Neurological Institute, Montreal, Quebec, Canada. Background: The APOE e4 allele is a risk factor of Alzheimer’s disease (AD) and may be associated with anatomical and functional brain changes. This study aimed to investigate the effects of APOE4 allele on the cortical thickness and spontaneous brain activity in AD. Methods: Fifty-seven mild AD patients (MMSE ¼ 21.263.5) were prospectively recruited at Dementia Care Research Center, Peking University Institute of Mental Health, and stratified into APOE4 carriers (e3/e4 and e4/e4, n ¼ 21) and non-carriers (e3/e3, n ¼ 36). All subjects completed an MRI examination with a standard multi-modality imaging protocol and the cross-cultural neuropsychological battery test (CCNB). High-resolution 3D T1 structural images were acquired with 3DMPRAGE sequence. Resting-state functional MR (R-fMRI) images were collected using an echo-planar imaging (EPI) sequence. T1-weighted MRI data were analyzed with the Constrained Laplacian Anatomic Segmentation using Proximity (CLASP) algorithm to generate measures of cortical thickness. R-fMRI data were analyzed using amplitude of low-frequency (range 0.010.1Hz) fluctuations (ALFF) method in REST (www.restfmri.net). Results:
S237
APOE e4-carriers and non-carriers were matched for age, gender, the duration of illness, and years of education. Relative to the non-carriers, the e4-carriers had significantly lower scores in MMSE and 5-min delayed recall of objects (P < 0.05). No significant differences in executive function were noted between e4-carriers and non-carriers (P>0.05). Compared with the non-carriers, the e4-carriers displayed reduced cortical thickness in the right medial temporal gyrus, right lingual gyrus and right middle frontal gyrus (P < 0.001, Figure 1a). Relating to the R-fMRI data, the e4-carriers exhibited decreased ALFF in the right medial temporal gyrus and higher ALFF in the components of ‘’default mode network’’ (DMN), involving prefrontal, anterior and posterior cingulate, lateral parietal; and basal ganglia) (P < 0.05, Figure 1b). Conclusions: APOE e4-carriers displayed greater impairment on measures of memory retention, which was corroborated by the cortical thinning and decreased spontaneous activity of medial temporal gyrus. Increased DMN co-activation among APOE4-carriers relative to non-carriers may represent the compensatory mechanism of brain function. The convergent cognitive and multimodal MRI findings in AD provide evidences that APOE genotype modulates the clinical phenotype and brain structure and function in AD. P1-390
ADDENBROOKE’S COGNITIVE EXAMINATIONREVISED AND MINI MENTAL STATE EXAMINATION IN PATIENTS WITH DIFFERENT TYPES OF COGNITIVE IMPAIRMENT
Luısa Alves, Olga Ribeiro, Paulo Bugalho, Isabel Carmo, Hospital de Egas Moniz, Lisboa, Portugal. Background: The Addenbrooke’s Cognitive Examination-Revised (ACER) is a test battery containing the Mini Mental State Examination (MMSE), but also a wider set of tests, which potentially allows a higher sensitivity in the differentiation between different types of cognitive impairment. Our aim was to compare the performance of the ACE-R and the MMSE in the detection of different types of cognitive dysfunction in a series of patients from our Memory Clinic. Methods: Thirty-four patients (15 males) with cognitive complaints were classified into different types of cognitive dysfunction according to current clinical criteria. The patients were divided into three groups: Subjective Memory Complaints (SMC), Frontal Type Deficit (FD) and Memory Type Deficit (MD). Patient distribution was the following: 10 had SMC, 15 had MD (4 had Alzheimer Disease and 11 had Mnestic Mild Cognitive Impairment) and 9 had FD (5 had FrontoTemporal Lobar Degeneration, 2 had Vascular Dementia and 2 had Executive Mild Cognitive Impairment). We compared the scores and sub-scores of the MMSE and the ACE-R between the three groups. Results: Significant differences were found in the total score, memory and verbal fluency subscores of the ACE-R both between the SMC group and the FD group and between the SMC group and the MD group. Significant differences between the SMC and the FD groups were also found in the language and visuospatial sub-scores of the ACE-R. The total score of MMSE could only differentiate between the SMC and the FD groups. There were also significant differences between the SMC and the FD groups in the visuospatial and orientation subscores of the MMSE. The memory sub-score of the MMSE could only distinguish between the SMC and the MD groups. Conclusions: Our findings show superiority of the ACE-R in relation to the MMSE, demonstrating its better capacity in distinguishing between subjective memory complaints and different types of cognitive dysfunction. The memory and the verbal fluency sub-scores of ACE-R were significantly different both between the SMC and the FD groups and between the SMC and the MD groups, suggesting their high sensitivity to detect cognitive impairment, in particular memory deficit. P1-391
NORMATIVE DATA OF FULD OBJECT MEMORY EVALUATION FOR BRAZILIAN ELDERLY POPULATION
Eduardo Nakano1, Renata Avila2, Cassio Bottino2, 1University Of Brasilia, Brasilia, Brazil; 2University of Sao Paulo, Sao Paulo, Brazil. Background: Memory Evaluation was designed to assess several aspects of learning and retrieval in elderly persons and also provides information about tactile recognition, right-left discrimination, and verbal fluency. This study aims to present normative data for Fuld Object Memory Evaluation test
ARE SNPS ASSOCIATED WITH ALZHEIMER’S DISEASE ALSO ASSOCIATED WITH COGNITION AND STRUCTURAL BRAIN CHANGES IN A RELATIVELY YOUNG POPULATION?
Benjamin Verhaaren, Meike Vernooij, Andre Uitterlinden, Albert Hofman, Wiro Niessen, Aad van der Lugt, Monique Breteler, Mohammad Arfan Ikram, Erasmus Medical Center, Rotterdam, Netherlands. Background: Six genetic loci (APOE, CLU, PICALM, EXOC3L2, BIN1 and CR1) have been associated with Alzheimer’s disease (AD) in genome-wide association studies. AD has a long preclinical phase with cognitive decline and during which Alzheimer pathology and cerebral small vessel disease can be visualized on structural MRI. It is unclear how these loci exert their effect and relate to cognition and preclinical MRI markers of AD. In a population-based study of relatively young persons we investigated how these genetic loci associated with cognitive performance. In addition, we explored whether putative effects would be mediated by AD pathology and cerebral small vessel disease as seen on MRI. Methods: In 677 non-demented individuals (mean age: 67 yrs) from the populationbased Rotterdam Study, we genotyped reported significant SNPs from each locus (rs2075650, rs11136000, rs3851179, rs597668, rs744373 and rs3818361). All persons underwent cognitive testing, using a standardized test battery, and underwent MRI-scanning from which volumetric measures of grey matter, white matter, hippocampus and white matter lesions were obtained. Brain infarcts and cerebral microbleeds were rated visually. Persons with cortical infarcts were excluded. We investigated each SNP separately for its association with cognition and MRI-markers. Subsequently, we performed analyses with summary risk scores based on the six SNPs. These scores were constructed by weighting the number of risk alleles within an individual by the reported effect size for dementia. All analyses were adjusted for relevant confounders. Results: We found that rs744373 (BIN1) strongly associated with poorer memory performance (p ¼ 0.003, Bonferroni adjusted). None of the loci were significantly related to any of the MRI markers. Summary risk scores of the six loci together were neither associated with cognition nor with brain markers. Conclusions: In this study among a relatively young population, the BIN1 locus was strongly associated with poorer memory performance, while no associations with brain MRI markers were found. We hypothesize that BIN1 exerts its influence on the development of AD via mechanisms not visualized by structural MRI (e.g. amyloid-deposition or tau-pathology). Furthermore, we hypothesize that the effects of the other loci on AD possibly manifest at higher age. P1-389
EFFECT OF APOLIPOPROTEIN E ON CORTICAL THICKNESS AND RESTING-STATE BRAIN FUNCTION IN ALZHEIMER’S DISEASE
Xiao Wang1, Jinhui Wang2, Yi He2, Huiying Li2, Huishu Yuan3, Alan Evans4, Xin Yu2, Yong He2, Huali Wang2, 1Peking University Institute of Mental Health, Beijing, China; 2Beijing Normal University, Beijing, China; 3Peking University Third Hospital, Beijing, China; 4Montreal Neurological Institute, Montreal, Quebec, Canada. Background: The APOE e4 allele is a risk factor of Alzheimer’s disease (AD) and may be associated with anatomical and functional brain changes. This study aimed to investigate the effects of APOE4 allele on the cortical thickness and spontaneous brain activity in AD. Methods: Fifty-seven mild AD patients (MMSE ¼ 21.263.5) were prospectively recruited at Dementia Care Research Center, Peking University Institute of Mental Health, and stratified into APOE4 carriers (e3/e4 and e4/e4, n ¼ 21) and non-carriers (e3/e3, n ¼ 36). All subjects completed an MRI examination with a standard multi-modality imaging protocol and the cross-cultural neuropsychological battery test (CCNB). High-resolution 3D T1 structural images were acquired with 3DMPRAGE sequence. Resting-state functional MR (R-fMRI) images were collected using an echo-planar imaging (EPI) sequence. T1-weighted MRI data were analyzed with the Constrained Laplacian Anatomic Segmentation using Proximity (CLASP) algorithm to generate measures of cortical thickness. R-fMRI data were analyzed using amplitude of low-frequency (range 0.010.1Hz) fluctuations (ALFF) method in REST (www.restfmri.net). Results:
S237
APOE e4-carriers and non-carriers were matched for age, gender, the duration of illness, and years of education. Relative to the non-carriers, the e4-carriers had significantly lower scores in MMSE and 5-min delayed recall of objects (P < 0.05). No significant differences in executive function were noted between e4-carriers and non-carriers (P>0.05). Compared with the non-carriers, the e4-carriers displayed reduced cortical thickness in the right medial temporal gyrus, right lingual gyrus and right middle frontal gyrus (P < 0.001, Figure 1a). Relating to the R-fMRI data, the e4-carriers exhibited decreased ALFF in the right medial temporal gyrus and higher ALFF in the components of ‘’default mode network’’ (DMN), involving prefrontal, anterior and posterior cingulate, lateral parietal; and basal ganglia) (P < 0.05, Figure 1b). Conclusions: APOE e4-carriers displayed greater impairment on measures of memory retention, which was corroborated by the cortical thinning and decreased spontaneous activity of medial temporal gyrus. Increased DMN co-activation among APOE4-carriers relative to non-carriers may represent the compensatory mechanism of brain function. The convergent cognitive and multimodal MRI findings in AD provide evidences that APOE genotype modulates the clinical phenotype and brain structure and function in AD. P1-390
ADDENBROOKE’S COGNITIVE EXAMINATIONREVISED AND MINI MENTAL STATE EXAMINATION IN PATIENTS WITH DIFFERENT TYPES OF COGNITIVE IMPAIRMENT
Luısa Alves, Olga Ribeiro, Paulo Bugalho, Isabel Carmo, Hospital de Egas Moniz, Lisboa, Portugal. Background: The Addenbrooke’s Cognitive Examination-Revised (ACER) is a test battery containing the Mini Mental State Examination (MMSE), but also a wider set of tests, which potentially allows a higher sensitivity in the differentiation between different types of cognitive impairment. Our aim was to compare the performance of the ACE-R and the MMSE in the detection of different types of cognitive dysfunction in a series of patients from our Memory Clinic. Methods: Thirty-four patients (15 males) with cognitive complaints were classified into different types of cognitive dysfunction according to current clinical criteria. The patients were divided into three groups: Subjective Memory Complaints (SMC), Frontal Type Deficit (FD) and Memory Type Deficit (MD). Patient distribution was the following: 10 had SMC, 15 had MD (4 had Alzheimer Disease and 11 had Mnestic Mild Cognitive Impairment) and 9 had FD (5 had FrontoTemporal Lobar Degeneration, 2 had Vascular Dementia and 2 had Executive Mild Cognitive Impairment). We compared the scores and sub-scores of the MMSE and the ACE-R between the three groups. Results: Significant differences were found in the total score, memory and verbal fluency subscores of the ACE-R both between the SMC group and the FD group and between the SMC group and the MD group. Significant differences between the SMC and the FD groups were also found in the language and visuospatial sub-scores of the ACE-R. The total score of MMSE could only differentiate between the SMC and the FD groups. There were also significant differences between the SMC and the FD groups in the visuospatial and orientation subscores of the MMSE. The memory sub-score of the MMSE could only distinguish between the SMC and the MD groups. Conclusions: Our findings show superiority of the ACE-R in relation to the MMSE, demonstrating its better capacity in distinguishing between subjective memory complaints and different types of cognitive dysfunction. The memory and the verbal fluency sub-scores of ACE-R were significantly different both between the SMC and the FD groups and between the SMC and the MD groups, suggesting their high sensitivity to detect cognitive impairment, in particular memory deficit. P1-391
NORMATIVE DATA OF FULD OBJECT MEMORY EVALUATION FOR BRAZILIAN ELDERLY POPULATION
Eduardo Nakano1, Renata Avila2, Cassio Bottino2, 1University Of Brasilia, Brasilia, Brazil; 2University of Sao Paulo, Sao Paulo, Brazil. Background: Memory Evaluation was designed to assess several aspects of learning and retrieval in elderly persons and also provides information about tactile recognition, right-left discrimination, and verbal fluency. This study aims to present normative data for Fuld Object Memory Evaluation test