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Semantic memory impairment in Alzheimer's disease and frontotemporal dementia is associated with semantic network degradation
S72
CP: Preconference for Physicians and Clinicians
between arterial calcifications (stratified by gender), cognition and brain tissue volumes were assessed with linear regression, adjusted for relevant confounders. Results: Higher CT-assessed calcification load in all vessel beds was associated with worse cognitive scores in all domains. Adjustment for total brain volume attenuated these associations, except for the associations between extracranial and intracranial carotid artery calcifications and motor speed in men. A higher load of extracranial carotid artery calcifications in men and intracranial carotid artery calcifications in women was significantly associated with smaller total brain volume and smaller white matter volume. In women, aortic calcifications were strongly associated with smaller grey matter volume. Calcifications in any vessel bed were not associated with hippocampal volume. Adjustment for cardiovascular risk factors or carotid plaque did not change these associations. Conclusions: A higher arterial calcification load is associated with worse cognitive function. Furthermore, calcification load in specific vessel beds is associated with smaller total brain volume, white matter volume and grey matter volume. The association between arterial calcification load and cognitive function is partly mediated by its effect on brain tissue volumes. IC-P-160
THE NEURAL CORRELATES OF VERBAL EPISODIC MEMORY ENCODING IN PRODROMAL PROBABLE ALZHEIMER’S DISEASE AT THE STAGE OF AMNESTIC MILD COGNITIVE IMPAIRMENT: AN FMRI STUDY
Thomas Dannhauser1, Sukhi Shergill2, Zuzana Walker1, 1University College London, London, United Kingdom; 2The Institute of Psychiatry at King’s College London, London, United Kingdom. Background: Amnestic Mild Cognitive Impairment (AMCI) is a high-risk state for future Alzheimer’s dementia (AD) and is characterised by episodic memory deficits. Verbal episodic memory tests are commonly used in clinical settings and isolated verbal memory deficits, as found in AMCI, are highly predictive of progression to AD; however, not everyone with AMCI progress to AD. The fMRI correlates of verbal episodic memory impairment in AMCI that converts to probable AD have not been determined. Methods: We studied verbal episodic memory with fMRI in a group of AMCI patients (n ¼ 22) and they were followed for a minimum of 3 years to identify those that progressed to probable AD (n ¼ 12). The prodromal AD (pAD) group was compared to healthy elderly controls (n ¼ 10) on a verbal episodic memory paradigm that is sensitive to the effect of semantic elaboration. Encoding success was measured on a recognition task. Results: Recognition rates were lower in pAD and were associated with semantic elaboration failure evident from decreased false recognition rates for semantically related distractors. The pAD group demonstrated (1) hyperactivation in right temporal (BA 21, 22, 41, 42, insula) basal ganglia (caudate, putamen), anterior cingulate (BA 24, 32) and thalamic areas, and (2) decreased deactivation in bilateral posterior cingulate (BA 23, 31), medial parietal (BA 7) and visual (BA 18) areas. Altered activation correlated negatively with recognition success, and with out-of-scanner measures of verbal memory and global cognitive performance. Conclusions: The behavioural results indicate that impaired semantic processing, and therefore executive failure, contributes to amnesia in prodromal AD at the stage of AMCI. Functional results indicate hyperactivation in areas that process language, working memory and attention, and this may be due to compensatory efforts. Decreased deactivation in medial posterior default network areas suggest impaired cognitive down-regulation of non-task areas, supporting the notion that functional changes appear early in the course of AD in this area.
IC-P-161
SEMANTIC MEMORY IMPAIRMENT IN ALZHEIMER’S DISEASE AND FRONTOTEMPORAL DEMENTIA IS ASSOCIATED WITH SEMANTIC NETWORK DEGRADATION
Kimiko Domoto-Reilly1, Daisy Sapolsky1, Michael Brickhouse1, Mark Hollenbeck1, Brad Dickerson2, 1Massachusetts General Hospital, Charlestown, Massachusetts, United States; 2MGH/Harvard Medical School, Charlestown, Massachusetts, United States. Background: Semantic memory deficits in early AD are typically subtle, and overshadowed by other cognitive impairments such as problems with episodic memory. FTD, in contrast, can sometimes cause early, prominent semantic impairment. Ongoing debate regarding the localization of semantic memory has focused on whether there is a distributed set of brain regions with convergence zones in association cortices, or whether the anterior temporal lobes form a “hub” for centralizing conceptual processing. We performed a series of analyses to address this issue. First, we examined ADNI data to determine the correlation between regional cortical atrophy and degree of semantic impairment in early AD. Our group has previously demonstrated that AD affects a “signature set” of cortical regions, overlapping with the default mode network. We hypothesized that, if semantic memory is subserved primarily by a distributed set of brain regions, the degree of semantic impairment in AD would correlate with the degree of atrophy distributed throughout this large-scale network. In contrast, if access to semantic memory requires a temporal pole hub, patients with greater semantic impairment would have greater atrophy in a pattern more consistent with a temporopolar network. Second, we analyzed FTD patients to identify brain regions associated with prominent semantic impairment. Methods: We extracted Boston Naming Test data from mild AD patients in ADNI. Cortical thickness analysis was performed, identifying areas in which cortical thinning was correlated with naming impairment, controlling for age, sex, education, and MMSE score. We performed a similar analysis of FTD patients (all subtypes). We then compared the thinning maps associated with semantic impairment between the two diseases. Results: Naming impairment correlated strongly with left-lateralized anterior and lateral temporal cortical thinning, and not with thinning in the overall AD signature. This pattern was very similar in FTD. Conclusions: The basis for naming deficits in early AD appears to be neurodegeneration of temporal regions associated with lexico-semantic abilities. Semantic impairment in FTD follows a similar pattern: atrophy prominently affecting the ventral language network, with relative dorsal sparing. These findings provide further support that neurodegenerative diseases may target specific cognitive-behavioral brain networks, but demonstrate that distinct diseases may affect a single network. IC-P-162
NEURONAL DYSFUNCTION AND DISCONNECTION OF CORTICAL HUBS IN NONDEMENTED SUBJECTS WITH ELEVATED AMYLOID-BURDEN
Alex Drzezga1, Alex Becker2, Koene van Dijk2, Aish Sreenivasan2, Tanveer Talukdar2, Caroline Sullivan2, Aaron Schultz2, Jorge Sepulcre2, Deepti Putcha2, Douglas Greve2, Keith Johnson2, Reisa Sperling3, 1 Technische Universit€at M€unchen, Munich, Germany; 2Harvard Medical School, Charlestown, Massachusetts, United States; 3Brigham and Women’s. Background: In Alzheimer’s disease (AD) and mild cognitive impairment (MCI) specific patterns of cerebral hypometabolism and disrupted functional connectivity have been reported. New functional MRI-methods allow the identification of cortical hubs, i.e. regions with high functional wholebrain connectivity (WBC), without restriction to specific networks. Aim of this study was to assess changes in cerebral metabolism and WBC in relation to ß-amyloid-load in prodromal and preclinical stages of AD. Methods: Thirty-seven elderly subjects underwent resting state BOLDfMRI to measure WBC, [18F]FDG PET for assessment of cerebral glucose metabolism and [11C]PIB PET for evaluation of amyloid-plaque load. PIB-
CP: Preconference for Physicians and Clinicians
between arterial calcifications (stratified by gender), cognition and brain tissue volumes were assessed with linear regression, adjusted for relevant confounders. Results: Higher CT-assessed calcification load in all vessel beds was associated with worse cognitive scores in all domains. Adjustment for total brain volume attenuated these associations, except for the associations between extracranial and intracranial carotid artery calcifications and motor speed in men. A higher load of extracranial carotid artery calcifications in men and intracranial carotid artery calcifications in women was significantly associated with smaller total brain volume and smaller white matter volume. In women, aortic calcifications were strongly associated with smaller grey matter volume. Calcifications in any vessel bed were not associated with hippocampal volume. Adjustment for cardiovascular risk factors or carotid plaque did not change these associations. Conclusions: A higher arterial calcification load is associated with worse cognitive function. Furthermore, calcification load in specific vessel beds is associated with smaller total brain volume, white matter volume and grey matter volume. The association between arterial calcification load and cognitive function is partly mediated by its effect on brain tissue volumes. IC-P-160
THE NEURAL CORRELATES OF VERBAL EPISODIC MEMORY ENCODING IN PRODROMAL PROBABLE ALZHEIMER’S DISEASE AT THE STAGE OF AMNESTIC MILD COGNITIVE IMPAIRMENT: AN FMRI STUDY
Thomas Dannhauser1, Sukhi Shergill2, Zuzana Walker1, 1University College London, London, United Kingdom; 2The Institute of Psychiatry at King’s College London, London, United Kingdom. Background: Amnestic Mild Cognitive Impairment (AMCI) is a high-risk state for future Alzheimer’s dementia (AD) and is characterised by episodic memory deficits. Verbal episodic memory tests are commonly used in clinical settings and isolated verbal memory deficits, as found in AMCI, are highly predictive of progression to AD; however, not everyone with AMCI progress to AD. The fMRI correlates of verbal episodic memory impairment in AMCI that converts to probable AD have not been determined. Methods: We studied verbal episodic memory with fMRI in a group of AMCI patients (n ¼ 22) and they were followed for a minimum of 3 years to identify those that progressed to probable AD (n ¼ 12). The prodromal AD (pAD) group was compared to healthy elderly controls (n ¼ 10) on a verbal episodic memory paradigm that is sensitive to the effect of semantic elaboration. Encoding success was measured on a recognition task. Results: Recognition rates were lower in pAD and were associated with semantic elaboration failure evident from decreased false recognition rates for semantically related distractors. The pAD group demonstrated (1) hyperactivation in right temporal (BA 21, 22, 41, 42, insula) basal ganglia (caudate, putamen), anterior cingulate (BA 24, 32) and thalamic areas, and (2) decreased deactivation in bilateral posterior cingulate (BA 23, 31), medial parietal (BA 7) and visual (BA 18) areas. Altered activation correlated negatively with recognition success, and with out-of-scanner measures of verbal memory and global cognitive performance. Conclusions: The behavioural results indicate that impaired semantic processing, and therefore executive failure, contributes to amnesia in prodromal AD at the stage of AMCI. Functional results indicate hyperactivation in areas that process language, working memory and attention, and this may be due to compensatory efforts. Decreased deactivation in medial posterior default network areas suggest impaired cognitive down-regulation of non-task areas, supporting the notion that functional changes appear early in the course of AD in this area.
IC-P-161
SEMANTIC MEMORY IMPAIRMENT IN ALZHEIMER’S DISEASE AND FRONTOTEMPORAL DEMENTIA IS ASSOCIATED WITH SEMANTIC NETWORK DEGRADATION
Kimiko Domoto-Reilly1, Daisy Sapolsky1, Michael Brickhouse1, Mark Hollenbeck1, Brad Dickerson2, 1Massachusetts General Hospital, Charlestown, Massachusetts, United States; 2MGH/Harvard Medical School, Charlestown, Massachusetts, United States. Background: Semantic memory deficits in early AD are typically subtle, and overshadowed by other cognitive impairments such as problems with episodic memory. FTD, in contrast, can sometimes cause early, prominent semantic impairment. Ongoing debate regarding the localization of semantic memory has focused on whether there is a distributed set of brain regions with convergence zones in association cortices, or whether the anterior temporal lobes form a “hub” for centralizing conceptual processing. We performed a series of analyses to address this issue. First, we examined ADNI data to determine the correlation between regional cortical atrophy and degree of semantic impairment in early AD. Our group has previously demonstrated that AD affects a “signature set” of cortical regions, overlapping with the default mode network. We hypothesized that, if semantic memory is subserved primarily by a distributed set of brain regions, the degree of semantic impairment in AD would correlate with the degree of atrophy distributed throughout this large-scale network. In contrast, if access to semantic memory requires a temporal pole hub, patients with greater semantic impairment would have greater atrophy in a pattern more consistent with a temporopolar network. Second, we analyzed FTD patients to identify brain regions associated with prominent semantic impairment. Methods: We extracted Boston Naming Test data from mild AD patients in ADNI. Cortical thickness analysis was performed, identifying areas in which cortical thinning was correlated with naming impairment, controlling for age, sex, education, and MMSE score. We performed a similar analysis of FTD patients (all subtypes). We then compared the thinning maps associated with semantic impairment between the two diseases. Results: Naming impairment correlated strongly with left-lateralized anterior and lateral temporal cortical thinning, and not with thinning in the overall AD signature. This pattern was very similar in FTD. Conclusions: The basis for naming deficits in early AD appears to be neurodegeneration of temporal regions associated with lexico-semantic abilities. Semantic impairment in FTD follows a similar pattern: atrophy prominently affecting the ventral language network, with relative dorsal sparing. These findings provide further support that neurodegenerative diseases may target specific cognitive-behavioral brain networks, but demonstrate that distinct diseases may affect a single network. IC-P-162
NEURONAL DYSFUNCTION AND DISCONNECTION OF CORTICAL HUBS IN NONDEMENTED SUBJECTS WITH ELEVATED AMYLOID-BURDEN
Alex Drzezga1, Alex Becker2, Koene van Dijk2, Aish Sreenivasan2, Tanveer Talukdar2, Caroline Sullivan2, Aaron Schultz2, Jorge Sepulcre2, Deepti Putcha2, Douglas Greve2, Keith Johnson2, Reisa Sperling3, 1 Technische Universit€at M€unchen, Munich, Germany; 2Harvard Medical School, Charlestown, Massachusetts, United States; 3Brigham and Women’s. Background: In Alzheimer’s disease (AD) and mild cognitive impairment (MCI) specific patterns of cerebral hypometabolism and disrupted functional connectivity have been reported. New functional MRI-methods allow the identification of cortical hubs, i.e. regions with high functional wholebrain connectivity (WBC), without restriction to specific networks. Aim of this study was to assess changes in cerebral metabolism and WBC in relation to ß-amyloid-load in prodromal and preclinical stages of AD. Methods: Thirty-seven elderly subjects underwent resting state BOLDfMRI to measure WBC, [18F]FDG PET for assessment of cerebral glucose metabolism and [11C]PIB PET for evaluation of amyloid-plaque load. PIB-