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Cognitive impairment-related alterations in brain functional connectivity
S754
Developing Topics: P4 Posters
long-term clinical effects of early changes in CSF NFL levels and whether preventive therapies targeting axonal health will protect against the development of AD in at-risk populations.
Figure. Group Differences in CSF Total Tau, P-Tau-181, and Ab42 Levels between Participants with Detectable NFL (D-NFL) and Non-detectable NFL (ND-NFL) in CSF.
P4-272
COLUMNAR MICROSTRUCTURAL CHANGES DIFFER BETWEEN ALZHEIMER’S DISEASE, CEREBROVASCULAR DISEASE AND FRONTOTEMPORAL DEMENTIA
Steven Chance1, Susanne van Veluw2, Olaf Ansorge1, Margaret Esiri3, 1 University of Oxford, Oxford, United Kingdom; 2Rudolf Magnus Institute, UMCU, Utrecht, Netherlands; 3University of Oxford, Oxford, United Kingdom. Background: We have previously shown that the minicolumnar spacing of neurons in the cerebral cortex relates to cognitive ability, and that minicolumn thinning occurs in old age. We have suggested that this may offer an index of cognitive reserve. Further disruption of minicolumn organisation differentiates MCI from AD and demonstrates regionally selective correlations with IQ and MMSE score. The present study examined several cortical regions to see if minicolumn structure could also be used to differentiate other types of dementia: cerebrovascular disease (CVD) and frontotemporal dementia (FTD). Methods: 18 cases of dementia with cerebrovascular pathology but limited AD pathology (low Braak staging) and 12 cases of TDP-43 positive frontotemporal dementia were assessed post-mortem. These were compared with previously assessed cases: 20 normally aged controls, 18 MCI subjects, and 20 AD patients. Minicolumnar width was assessed in parahippocampal gyrus (PHG), fusiform gyrus (FG), dorsolateral prefrontal cortex (dlPFC), planum temporale (PT), and Heschl’s gyrus (HG). Overall ratings of Alzheimer’s type pathology (plaques and tangles) and vascular pathology were also determined. Results: Broadly similar regional differences were seen across all subjects with dlPFC and PHG having the widest minicolumns and HG the narrowest. In general, MCI shows thinning compared to controls and in AD this has a similar pattern, although significantly more severe. FTD showed a different pattern with the most severe thinning in dlPFC, PHG and FG but relative preservation in the superior temporal regions. CVD showed significant thinning in dlPFC and PHG, with relative preservation of the superior temporal regions, but also preservation in FG. Conclusions: The pattern of cytoarchitectural change in FTD is consistent with selective degeneration of prefrontal and medial/ventral temporal cortex, whereas in CVD the pattern may be consistent with the greater vulnerability of the vascular ’watershed’ regions. Region vulnerability measures of microstructure are being validated in post-mortem MRI of cortical areas. P4-273
COGNITIVE IMPAIRMENT-RELATED ALTERATIONS IN BRAIN FUNCTIONAL CONNECTIVITY
Arnaud Charil1, Felix Carbonell1, Andrew Reid2, Alex Zijdenbos1, Alan Evans1, Barry Bedell1, 1Biospective Inc., Montreal, Quebec, Canada; 2 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Background: Functional brain connectivity analysis has the potential to improve our understanding of the natural evolution of Alzheimer’s disease (AD) and the impact of therapy on disease progression. In order to assess the relationship between cognitive impairment and functional connectivity,
we have performed a region-of-interest (ROI)-based correlation analysis of glucose uptake/metabolism using 2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) images obtained from subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Methods: T1-weighted MRI and [18F]FDG PET images were obtained from ADNI study subjects classified as healthy controls, mild cognitive impairment (MCI) non-converters, MCI converters, and AD. Standardized uptake value ratio (SUVR) FDG PET images were generated using Biospective’s fully-automated PIANO TM pipeline. All PET volumes were registered to a customized MRI template in MNI stereotaxic space. An ROI-based Pearson correlation matrix was then constructed for each group in which gray matter density-controlled FDG SUVR values for each pair of ROIs were correlated across subjects. A false discovery rate (FDR) threshold was employed to binarize the correlation matrices, and regional normalized degree centrality measures (i.e. connectedness density) integrated over a range of correlation thresholds were computed for each group. Results: Frontal cerebral cortical ROIs and the precuneus demonstrated the highest regional normalized degree centrality in all groups. The regional normalized degree centrality in the precuneus progressively declined as cognitive impairment increased. In comparison to the other groups, the AD subjects demonstrated dramatically reduced connectedness density across all regions. All groups showed an overall decline over a two year period. Conclusions: We have employed a regional correlation analysis to examine the effects of cognitive impairment on functional brain networks. Our analysis identified substantially reduced connectivity in AD subjects relative to the other groups. While this study specifically evaluated functional connectivity based on FDG PET images, future studies will evaluate similar properties derived from restingstate BOLD and ASL perfusion MRI data. Additional data, such as graph theory-based efficiency measures, could also provide complementary information. Based on our results, correlation analysis of functional imaging data may serve as a novel imaging biomarker for the assessment of potential therapeutic agents in clinical AD studies. P4-274
SUBCORTICAL STRUCTURE CHANGES IN EARLY-ONSET VERSUS LATE-ONSET ALZHEIMER’S DISEASE: A 3-YEAR LONGITUDINAL STUDY
Hanna Cho1, Joon-Kyung Seong2, Byoung Seok Ye3, Geon Ha Kim4, Young Noh3, Hee-Jin Kim5, Cindy Yoon6, Duk Na7, Sang Won Seo8, 1 Departments of Neurology, Samsung Medical Center, Seoul, South Korea; 2 Department of Computer Science, School of Computer Science and Engineering, Soongsil University, Seoul, South Korea; 3Samsung Medical Center, Seoul, South Korea; 4Department of Neurology, Samsung Medical Center, Sungyungwan University School of Medicine, Seoul, South Korea; 5 Samsung Medical Center, Seoul, Seoul, South Korea; 6Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea; 7Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 8 Samsung Medical Center, Seoul, South Korea. Background: Patients with early-onset Alzheimer’s disease (EOAD) tend to display more diverse cognitive impairments and neurologic deficit than those with late-onset Alzheimer’s disease (LOAD), such as in attention, language, visuospatial ability, executive functions, apraxia, agnosia, and extrapyramidal symptoms, while LOAD’s predominant impairment is in memory function. To my knowledge, according to the age at onset, the study of volume changes in subcortical structures between the EOAD and LOAD has never been reported cross-sectionally or longitudinally. Methods: We prospectively recruited 36 patients with Alzheimer’s disease (14 EOAD, 22 LOAD) and 14 normal controls (NC). In this study, we aimed to assess differences in the volumes of five subcortical structures (amygdala, thalamus, putamen, globus pallidus, and caudate nucleus) and the hippocampus between EOAD and LOAD. All patients and NC were assessed with high resolution T1 weighted volume MRI at baseline and at 1- and 3-year follow-ups. Of the 50 participants, 27 patients and 13 NC completed the entire 3-year study. Results: In the cross-sectional baseline comparisons, when the LOAD and EOAD groups were directly compared, there were no regions
Developing Topics: P4 Posters
long-term clinical effects of early changes in CSF NFL levels and whether preventive therapies targeting axonal health will protect against the development of AD in at-risk populations.
Figure. Group Differences in CSF Total Tau, P-Tau-181, and Ab42 Levels between Participants with Detectable NFL (D-NFL) and Non-detectable NFL (ND-NFL) in CSF.
P4-272
COLUMNAR MICROSTRUCTURAL CHANGES DIFFER BETWEEN ALZHEIMER’S DISEASE, CEREBROVASCULAR DISEASE AND FRONTOTEMPORAL DEMENTIA
Steven Chance1, Susanne van Veluw2, Olaf Ansorge1, Margaret Esiri3, 1 University of Oxford, Oxford, United Kingdom; 2Rudolf Magnus Institute, UMCU, Utrecht, Netherlands; 3University of Oxford, Oxford, United Kingdom. Background: We have previously shown that the minicolumnar spacing of neurons in the cerebral cortex relates to cognitive ability, and that minicolumn thinning occurs in old age. We have suggested that this may offer an index of cognitive reserve. Further disruption of minicolumn organisation differentiates MCI from AD and demonstrates regionally selective correlations with IQ and MMSE score. The present study examined several cortical regions to see if minicolumn structure could also be used to differentiate other types of dementia: cerebrovascular disease (CVD) and frontotemporal dementia (FTD). Methods: 18 cases of dementia with cerebrovascular pathology but limited AD pathology (low Braak staging) and 12 cases of TDP-43 positive frontotemporal dementia were assessed post-mortem. These were compared with previously assessed cases: 20 normally aged controls, 18 MCI subjects, and 20 AD patients. Minicolumnar width was assessed in parahippocampal gyrus (PHG), fusiform gyrus (FG), dorsolateral prefrontal cortex (dlPFC), planum temporale (PT), and Heschl’s gyrus (HG). Overall ratings of Alzheimer’s type pathology (plaques and tangles) and vascular pathology were also determined. Results: Broadly similar regional differences were seen across all subjects with dlPFC and PHG having the widest minicolumns and HG the narrowest. In general, MCI shows thinning compared to controls and in AD this has a similar pattern, although significantly more severe. FTD showed a different pattern with the most severe thinning in dlPFC, PHG and FG but relative preservation in the superior temporal regions. CVD showed significant thinning in dlPFC and PHG, with relative preservation of the superior temporal regions, but also preservation in FG. Conclusions: The pattern of cytoarchitectural change in FTD is consistent with selective degeneration of prefrontal and medial/ventral temporal cortex, whereas in CVD the pattern may be consistent with the greater vulnerability of the vascular ’watershed’ regions. Region vulnerability measures of microstructure are being validated in post-mortem MRI of cortical areas. P4-273
COGNITIVE IMPAIRMENT-RELATED ALTERATIONS IN BRAIN FUNCTIONAL CONNECTIVITY
Arnaud Charil1, Felix Carbonell1, Andrew Reid2, Alex Zijdenbos1, Alan Evans1, Barry Bedell1, 1Biospective Inc., Montreal, Quebec, Canada; 2 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Background: Functional brain connectivity analysis has the potential to improve our understanding of the natural evolution of Alzheimer’s disease (AD) and the impact of therapy on disease progression. In order to assess the relationship between cognitive impairment and functional connectivity,
we have performed a region-of-interest (ROI)-based correlation analysis of glucose uptake/metabolism using 2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) images obtained from subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Methods: T1-weighted MRI and [18F]FDG PET images were obtained from ADNI study subjects classified as healthy controls, mild cognitive impairment (MCI) non-converters, MCI converters, and AD. Standardized uptake value ratio (SUVR) FDG PET images were generated using Biospective’s fully-automated PIANO TM pipeline. All PET volumes were registered to a customized MRI template in MNI stereotaxic space. An ROI-based Pearson correlation matrix was then constructed for each group in which gray matter density-controlled FDG SUVR values for each pair of ROIs were correlated across subjects. A false discovery rate (FDR) threshold was employed to binarize the correlation matrices, and regional normalized degree centrality measures (i.e. connectedness density) integrated over a range of correlation thresholds were computed for each group. Results: Frontal cerebral cortical ROIs and the precuneus demonstrated the highest regional normalized degree centrality in all groups. The regional normalized degree centrality in the precuneus progressively declined as cognitive impairment increased. In comparison to the other groups, the AD subjects demonstrated dramatically reduced connectedness density across all regions. All groups showed an overall decline over a two year period. Conclusions: We have employed a regional correlation analysis to examine the effects of cognitive impairment on functional brain networks. Our analysis identified substantially reduced connectivity in AD subjects relative to the other groups. While this study specifically evaluated functional connectivity based on FDG PET images, future studies will evaluate similar properties derived from restingstate BOLD and ASL perfusion MRI data. Additional data, such as graph theory-based efficiency measures, could also provide complementary information. Based on our results, correlation analysis of functional imaging data may serve as a novel imaging biomarker for the assessment of potential therapeutic agents in clinical AD studies. P4-274
SUBCORTICAL STRUCTURE CHANGES IN EARLY-ONSET VERSUS LATE-ONSET ALZHEIMER’S DISEASE: A 3-YEAR LONGITUDINAL STUDY
Hanna Cho1, Joon-Kyung Seong2, Byoung Seok Ye3, Geon Ha Kim4, Young Noh3, Hee-Jin Kim5, Cindy Yoon6, Duk Na7, Sang Won Seo8, 1 Departments of Neurology, Samsung Medical Center, Seoul, South Korea; 2 Department of Computer Science, School of Computer Science and Engineering, Soongsil University, Seoul, South Korea; 3Samsung Medical Center, Seoul, South Korea; 4Department of Neurology, Samsung Medical Center, Sungyungwan University School of Medicine, Seoul, South Korea; 5 Samsung Medical Center, Seoul, Seoul, South Korea; 6Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea; 7Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 8 Samsung Medical Center, Seoul, South Korea. Background: Patients with early-onset Alzheimer’s disease (EOAD) tend to display more diverse cognitive impairments and neurologic deficit than those with late-onset Alzheimer’s disease (LOAD), such as in attention, language, visuospatial ability, executive functions, apraxia, agnosia, and extrapyramidal symptoms, while LOAD’s predominant impairment is in memory function. To my knowledge, according to the age at onset, the study of volume changes in subcortical structures between the EOAD and LOAD has never been reported cross-sectionally or longitudinally. Methods: We prospectively recruited 36 patients with Alzheimer’s disease (14 EOAD, 22 LOAD) and 14 normal controls (NC). In this study, we aimed to assess differences in the volumes of five subcortical structures (amygdala, thalamus, putamen, globus pallidus, and caudate nucleus) and the hippocampus between EOAD and LOAD. All patients and NC were assessed with high resolution T1 weighted volume MRI at baseline and at 1- and 3-year follow-ups. Of the 50 participants, 27 patients and 13 NC completed the entire 3-year study. Results: In the cross-sectional baseline comparisons, when the LOAD and EOAD groups were directly compared, there were no regions