- Email: [email protected]
A specific relationship between hippocampal CA1 subfield atrophy and episodic memory encoding in amnestic mild cognitive impairment
CP: Preconference for Physicians and Clinicians uptake ratios were calculated within a ROI including frontal, temporoparietal, and retrosplenial cortices (FLR-ROI), using the cerebellum as reference region. Based on a FLR-threshold of 1.15, subjects were divided into PIBpositive (+) and -negative (-). Three age-matched groups were studied: A) 12 PIB(-) cognitively normal elderly controls, B) 12 PIB(+) cognitively normal elderly controls and C) 13 PIB(+) MCI-patients. Voxel-based and ROI-based statistical analyses were performed. The overlap between hypometabolism and WBC-abnormalities in MCI was used to define a ROI to extract values for correlation analysis between different modalities. Results: Group comparison between MCI and PIB(-) controls revealed significant hypometabolism and regionally overlapping WBC-reductions in MCI in posterior cingulate cortex/precuneus (typical cortical hubs, see figure 1). PIB-FLR values were negatively correlated with FDG-values (r ¼ -0.67) and WBC-values (r ¼ -0.42) and a linear positive correlation was found between FDG and WBC-values (r ¼ 0.51) across the entire population (groups A, B and C). These results survived correction for age and grey matter density. Conclusions: These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer-pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.
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disruption of a hippocampo-parieto-frontal network probably involving structural connectivity damage. The present study addresses these issues by assessing the relationships between encoding versus retrieval deficits, and hippocampal subfields GM atrophy as well as whole brain white matter (WM) atrophy, in MCI patients. Methods: Twenty-two aMCI patients underwent T1-weighted MRI scans. MRI data were segmented into GM and WM, then spatially normalized, modulated and smoothed. Resulting images were entered in positive correlation analyses with episodic encoding and retrieval performances at the Encoding-Storage-Retrieval task (Chetelat et al., Brain 2003 for details), setting the significance level at p(uncorrected) < 0.005. To assess subregional hippocampal atrophy, the resulting GM SPM-T maps were then superimposed onto the 3D representation of the hippocampi using the Anatomist/BrainVISA software, as already used (Chetelat et al., Neuropsychologia 2008) and validated (La Joie et al., NeuroImage 2010) elsewhere. Results: Episodic encoding impairment specifically correlated with CA1 subfield GM atrophy (Figure 1B), in reference to hippocampal MRI atlas obtained from manual delineation (La Joie et al., NeuroImage 2010 - Figure 1A), but not with WM atrophy. In contrast, the weak correlation of retrieval scores with hippocampal GM did not point to a particular subfield (Figure 1C), while it was strong with WM, especially in medial parietal and frontal areas (Figure 1D). Conclusions: In a MCI patients, encoding impairment appears specifically related to GM atrophy of the CA1 hippocampal subfield, consistently with the predominant encoding deficits
A SPECIFIC RELATIONSHIP BETWEEN HIPPOCAMPAL CA1 SUBFIELD ATROPHY AND EPISODIC MEMORY ENCODING IN AMNESTIC MILD COGNITIVE IMPAIRMENT
Marine Fouquet1, Beatrice Desgranges1, Renaud La Joie1, Denis Riviere2, Brigitte Landeau1, Florence Mezenge1, Vincent de La Sayette1, Fausto Viader1, Jean-Franc¸ois Mangin2, Jean-Claude Baron3, Francis Eustache1, Ga€el Chetelat1, 1INSERM-EPHE-UCBN U923, Caen, France; 2CEA - LNAO, Gif-sur-Yvette, France; 3University of Cambridge, Cambridge, United Kingdom. Background: The brain substrates of episodic memory deficits in patients with Mild Cognitive Impairment (MCI) who best represent the predementia stage of Alzheimer’s disease, offer potentially useful therapeutic targets. Episodic encoding deficits were found to be subtended mainly by hippocampal gray matter (GM) atrophy, but it remains to determine which hippocampal subfield(s) are involved. In contrast, retrieval deficits seem to result from the
Figure 1. (A) Schematic representation of the hippocampal subfields on 3D surface superior and inferior views obtained from manual delineation (La Joie et al., NeuroImage 2010). Superimposition of the SPM-T maps of the correlation between GM volume and encoding (B) as well as retrieval (C) scores in aMCI patients. (D) Representation of the significant correlation [p(uncorrected)<0.005] between WM volume and retrieval scores in aMCI patients.
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and predominant CA1 atrophy in MCI. In contrast, episodic retrieval deficits seem to be underlain by more distributed tissue losses, consistent with a disruption of a hippocampo-parieto-frontal network. Overall, the specific involvement of the CA1 hippocampal subfield atrophy in episodic encoding deficits in aMCI patients emphasizes this particular subfield as a potential future therapeutic target. IC-P-164
PATTERNS OF 18F-FDG PET IN DIFFERENT SUBTYPES OF ALZHEIMER’ DISEASE
No. females (%) No. of APOE e4 carrier (%) Median age, yr. (min, max) Education, yr. (min, max) Median Short Test score (min, max)
CN e4-
AD
n ¼ 56
n ¼ 28
21 (38) 0 79 (64, 91) 14 (8, 20) 36 (30, 38)
10 (36) 0.87 19 (68) — 78 (62, 92) 0.52 16 (8, 20) 0.36 25 (15, 34) <0.001
Age Cohort P-value n ¼ 341 141 (41) n/a 82 (60, 94) 13 (7, 20) 35 (27, 38)
Cathleen Haense1, Shailendra Segobin1, Jenny Pridham2, Jose AntonRodriguez1, Cheryl Stopford2, Julie Snowden2, Karl Herholz3, 1The University of Manchester, Manchester, United Kingdom; 2Salford Royal NHS Foundation Trust, Salford, United Kingdom; 3University of Manchester, Manchester, United Kingdom. Background: Alzheimer’s disease (AD) is thought to follow a predictable course, with episodic memory loss being the earliest and defining characteristic and other cognitive deficits emerging later, reflecting spread of pathology from medial temporal lobes into neocortex. Heterogeneity in the clinical presentation of AD challenges this staging model. This preliminary study of 15 AD patients examines the relationship between clinical phenotype and 18F-FDG PET imaging abnormalities. It addresses too the anatomical substrate for working memory deficits in AD, a dissociable component of memory commonly assumed to reflect impaired frontal lobe function. Methods: Patients were classified, on the basis of their neuropsychological performance, into three cognitive groups (amnestic AD, multi-domain AD, visual AD), each consisting of 5 patients and comparable in their demographic data. They underwent PET imaging with 18F-FDG. Image data were corrected for patient movement using centroid data and analysed using a brain atlas to assess cerebral metabolic rates of glucose consumption (CMRglc). Results: Compared to multi-domain and visual patients a significantly lower glucose metabolism in left hippocampus was found in amnestic patients which was reflected by their poorer performance in episodic memory tests. The groups also presented significant metabolic differences in the parietal cortex, especially in the left inferior parietal lobule, with a lower CMRglc in the visual and multi-domain group compared to the amnestic group. These two groups also showed a trend towards poorer performance in working memory tasks. The left and right middle and inferior occipital gyri were metabolically more impaired in the visual group. No metabolic differences were found for frontal cortex, temporal cortex and basal ganglia between the groups. Conclusions: There were topographical differences in glucose metabolism reflecting differences in patients’ clinical presentation. Interestingly, poorer performance on working memory tasks was associated with reduced glucose metabolism in inferior parietal lobule. No group differences in CMRglc were evident in frontal cortex. The findings challenge the view that working memory deficits in AD are primarily related to impaired frontal lobe function and highlight the important role of the inferior parietal lobule in underpinning working memory in AD.
IC-P-165
Figure 1. The age effect on the independent component analysis of the posterior (left) and anterior (right) default mode networks (DMN) in a large population-based cohort of cognitively normal control (corrected clusterlevel p< 0.05).
AGE-RELATED CHANGES IN THE DEFAULT MODE NETWORK ARE MORE ADVANCED IN ALZHEIMER’S DISEASE
David Jones, Mary Machulda, Prashanthi Vemuri, Eric McDade, Guang Zeng, Mathew Senjem, Jeffrey Gunter, Scott Przybelski, Ramesh Avula, David Knopman, Bradley Boeve, Ronald Petersen, Clifford Jack, Mayo Clinic, Rochester, Minnesota, United States. Background: Age is the largest risk factor for Alzheimer’s disease (AD). Intrinsic connectivity networks (ICN) demonstrate changes related to AD and advancing age. Whether age-related changes are similar to AD related changes is unknown. We hypothesize that reciprocal age-related changes in posterior DMN (pDMN) and anterior DMN (aDMN) are similar to those seen in AD. To test this hypothesis we performed two
Figure 2. Independent component analysis of porterior (left) and anterior (right) default mode networks (DMN) in Alzheimer’s disesse (AD) and matched controls. The spatial extent of the aDMN and PDMN is displsayed in the top row (cyan) using a redering of a one sample t-test for the entire group (FDR corrected p< 0.05). Regions displaying greater connectivity in the AD group are in red, while regions displaying less connectivity in AD are in blue (corrected cluster-level p < 0.05).
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disruption of a hippocampo-parieto-frontal network probably involving structural connectivity damage. The present study addresses these issues by assessing the relationships between encoding versus retrieval deficits, and hippocampal subfields GM atrophy as well as whole brain white matter (WM) atrophy, in MCI patients. Methods: Twenty-two aMCI patients underwent T1-weighted MRI scans. MRI data were segmented into GM and WM, then spatially normalized, modulated and smoothed. Resulting images were entered in positive correlation analyses with episodic encoding and retrieval performances at the Encoding-Storage-Retrieval task (Chetelat et al., Brain 2003 for details), setting the significance level at p(uncorrected) < 0.005. To assess subregional hippocampal atrophy, the resulting GM SPM-T maps were then superimposed onto the 3D representation of the hippocampi using the Anatomist/BrainVISA software, as already used (Chetelat et al., Neuropsychologia 2008) and validated (La Joie et al., NeuroImage 2010) elsewhere. Results: Episodic encoding impairment specifically correlated with CA1 subfield GM atrophy (Figure 1B), in reference to hippocampal MRI atlas obtained from manual delineation (La Joie et al., NeuroImage 2010 - Figure 1A), but not with WM atrophy. In contrast, the weak correlation of retrieval scores with hippocampal GM did not point to a particular subfield (Figure 1C), while it was strong with WM, especially in medial parietal and frontal areas (Figure 1D). Conclusions: In a MCI patients, encoding impairment appears specifically related to GM atrophy of the CA1 hippocampal subfield, consistently with the predominant encoding deficits
A SPECIFIC RELATIONSHIP BETWEEN HIPPOCAMPAL CA1 SUBFIELD ATROPHY AND EPISODIC MEMORY ENCODING IN AMNESTIC MILD COGNITIVE IMPAIRMENT
Marine Fouquet1, Beatrice Desgranges1, Renaud La Joie1, Denis Riviere2, Brigitte Landeau1, Florence Mezenge1, Vincent de La Sayette1, Fausto Viader1, Jean-Franc¸ois Mangin2, Jean-Claude Baron3, Francis Eustache1, Ga€el Chetelat1, 1INSERM-EPHE-UCBN U923, Caen, France; 2CEA - LNAO, Gif-sur-Yvette, France; 3University of Cambridge, Cambridge, United Kingdom. Background: The brain substrates of episodic memory deficits in patients with Mild Cognitive Impairment (MCI) who best represent the predementia stage of Alzheimer’s disease, offer potentially useful therapeutic targets. Episodic encoding deficits were found to be subtended mainly by hippocampal gray matter (GM) atrophy, but it remains to determine which hippocampal subfield(s) are involved. In contrast, retrieval deficits seem to result from the
Figure 1. (A) Schematic representation of the hippocampal subfields on 3D surface superior and inferior views obtained from manual delineation (La Joie et al., NeuroImage 2010). Superimposition of the SPM-T maps of the correlation between GM volume and encoding (B) as well as retrieval (C) scores in aMCI patients. (D) Representation of the significant correlation [p(uncorrected)<0.005] between WM volume and retrieval scores in aMCI patients.
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CP: Preconference for Physicians and Clinicians
and predominant CA1 atrophy in MCI. In contrast, episodic retrieval deficits seem to be underlain by more distributed tissue losses, consistent with a disruption of a hippocampo-parieto-frontal network. Overall, the specific involvement of the CA1 hippocampal subfield atrophy in episodic encoding deficits in aMCI patients emphasizes this particular subfield as a potential future therapeutic target. IC-P-164
PATTERNS OF 18F-FDG PET IN DIFFERENT SUBTYPES OF ALZHEIMER’ DISEASE
No. females (%) No. of APOE e4 carrier (%) Median age, yr. (min, max) Education, yr. (min, max) Median Short Test score (min, max)
CN e4-
AD
n ¼ 56
n ¼ 28
21 (38) 0 79 (64, 91) 14 (8, 20) 36 (30, 38)
10 (36) 0.87 19 (68) — 78 (62, 92) 0.52 16 (8, 20) 0.36 25 (15, 34) <0.001
Age Cohort P-value n ¼ 341 141 (41) n/a 82 (60, 94) 13 (7, 20) 35 (27, 38)
Cathleen Haense1, Shailendra Segobin1, Jenny Pridham2, Jose AntonRodriguez1, Cheryl Stopford2, Julie Snowden2, Karl Herholz3, 1The University of Manchester, Manchester, United Kingdom; 2Salford Royal NHS Foundation Trust, Salford, United Kingdom; 3University of Manchester, Manchester, United Kingdom. Background: Alzheimer’s disease (AD) is thought to follow a predictable course, with episodic memory loss being the earliest and defining characteristic and other cognitive deficits emerging later, reflecting spread of pathology from medial temporal lobes into neocortex. Heterogeneity in the clinical presentation of AD challenges this staging model. This preliminary study of 15 AD patients examines the relationship between clinical phenotype and 18F-FDG PET imaging abnormalities. It addresses too the anatomical substrate for working memory deficits in AD, a dissociable component of memory commonly assumed to reflect impaired frontal lobe function. Methods: Patients were classified, on the basis of their neuropsychological performance, into three cognitive groups (amnestic AD, multi-domain AD, visual AD), each consisting of 5 patients and comparable in their demographic data. They underwent PET imaging with 18F-FDG. Image data were corrected for patient movement using centroid data and analysed using a brain atlas to assess cerebral metabolic rates of glucose consumption (CMRglc). Results: Compared to multi-domain and visual patients a significantly lower glucose metabolism in left hippocampus was found in amnestic patients which was reflected by their poorer performance in episodic memory tests. The groups also presented significant metabolic differences in the parietal cortex, especially in the left inferior parietal lobule, with a lower CMRglc in the visual and multi-domain group compared to the amnestic group. These two groups also showed a trend towards poorer performance in working memory tasks. The left and right middle and inferior occipital gyri were metabolically more impaired in the visual group. No metabolic differences were found for frontal cortex, temporal cortex and basal ganglia between the groups. Conclusions: There were topographical differences in glucose metabolism reflecting differences in patients’ clinical presentation. Interestingly, poorer performance on working memory tasks was associated with reduced glucose metabolism in inferior parietal lobule. No group differences in CMRglc were evident in frontal cortex. The findings challenge the view that working memory deficits in AD are primarily related to impaired frontal lobe function and highlight the important role of the inferior parietal lobule in underpinning working memory in AD.
IC-P-165
Figure 1. The age effect on the independent component analysis of the posterior (left) and anterior (right) default mode networks (DMN) in a large population-based cohort of cognitively normal control (corrected clusterlevel p< 0.05).
AGE-RELATED CHANGES IN THE DEFAULT MODE NETWORK ARE MORE ADVANCED IN ALZHEIMER’S DISEASE
David Jones, Mary Machulda, Prashanthi Vemuri, Eric McDade, Guang Zeng, Mathew Senjem, Jeffrey Gunter, Scott Przybelski, Ramesh Avula, David Knopman, Bradley Boeve, Ronald Petersen, Clifford Jack, Mayo Clinic, Rochester, Minnesota, United States. Background: Age is the largest risk factor for Alzheimer’s disease (AD). Intrinsic connectivity networks (ICN) demonstrate changes related to AD and advancing age. Whether age-related changes are similar to AD related changes is unknown. We hypothesize that reciprocal age-related changes in posterior DMN (pDMN) and anterior DMN (aDMN) are similar to those seen in AD. To test this hypothesis we performed two
Figure 2. Independent component analysis of porterior (left) and anterior (right) default mode networks (DMN) in Alzheimer’s disesse (AD) and matched controls. The spatial extent of the aDMN and PDMN is displsayed in the top row (cyan) using a redering of a one sample t-test for the entire group (FDR corrected p< 0.05). Regions displaying greater connectivity in the AD group are in red, while regions displaying less connectivity in AD are in blue (corrected cluster-level p < 0.05).