- Email: [email protected]
EPISODIC MEMORY IN MILD COGNITIVE IMPAIRMENT INVERSELY CORRELATES WITH THE PATIENT CONTRIBUTION TO CEREBRAL BLOOD FLOW NETWORK MODULARITY
Poster Presentations: Monday, July 17, 2017 Background: Three different 18F-labeled radiotracers for b-amyloid PET are available, which demonstrated similar performance as 11C-PiB. The leaflets of the three tracers indicate 3 different visual criteria for PET reporting based on controlled trials, but it’s not yet verified in clinical practice if these criteria are equivalent in term of diagnostic accuracy or if there is a reading criteria better than an other. The aim of this study is to determine the inter-rater variabilityof the visual interpretation of 18F-Florbetapir PET/CT among 6 independent readers for 3 different visual criteria recommended by the 3 companies. We studied the intra-reader variability. Methods: We analyzed 252 18F-Florbetapir PET/CT (228 patients with cognitive impairment and 24 normal cognitive control), obtained from subjects participating at INDIA-FBP study and performed in 2 PET centers. Six independent blinded readers (2 experts in amyloid imaging and 4 who followed reading educational programs but without direct clinical experience) examined each PET-scan three times according to 3 different visual reading criteria, classifying them with a subjective confidence level of 5 point score (4:definitely positive; 3:doubt positive; 2:doubt; 1:doubt negative or 0:definitely negative) and then attributing a numeric score for each region analyzed that formed anoverallobjective score. We compared the mean of the results obtained by the 2 experts readers (considered as “gold standard”) with those obtained by the others 4 readers. Results: Substantial to almost perfect agreement was observed for visual interpretation by the six readers’ confidence level (mean weighted Kappa) for all 3 radiotracers: mwK¼0.82 for 18F-Florbetapir lecture; mwK¼0.84 for 18F-Florbetaben; mwK¼0.85 for 18F-Flutemetamol. Overall objective score showed a low inter-readers variability: mwK¼0.73 for 18F-Florbetapir lecture; mwK¼0.82 for 18F-Florbetaben and mean Spearman’s rho¼0.82 for 18F-Flutemetamol. Comparison between the “gold standard” showed a high confidence level: wK ranging 0.80-0.94. Intra-rater agreement has Spearman’s rho ranging 0.89-1.00 (p<0.001) about confidence level and Spearman’srho ranging 0.75-0.90 (p<0.001) about overall score. Conclusions: There is a high inter-rater and intra-reader agreement using the three different visual criteria for amyloid images. All the criteria proposed are useful and valid to determine the positivity or negativity of amyloid deposition and when compared with a “gold standard” there aren’t statistical differences between the three criteria.
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tricular (LV) mass index, LV hypertrophy (LVH), cardiac index, LV ejection fraction (LVEF), and myocardial contraction fraction. A neuroradiologist used a combination of T1 and T2weighted FLAIR images to manually code perivascular spaces in the basal ganglia and centrum semiovale. Regression models related cardiac measures, hypertension, and anti-hypertensive medication use to perivascular spaces adjusting for age, sex, race/ethnicity, and education. Results: The presence of LVH (b¼4.92, p¼0.004), decreased cardiac index (b¼0.66, p¼0.02), and decreased myocardial contraction fraction (b¼0.19, p¼0.03) were each individually associated with increased perivascular spaces in the basal ganglia. LVH (b¼4.53, p¼0.006) and increased LV mass index (b¼1.01, p¼0.03) were associated with perivascular spaces in the centrum semiovale. Associations persisted when anti-hypertensive medication usage was added to the models (all p-values<0.04). Conclusions: Poorer cardiovascular health markers are associated with increased presence of perivascular spaces in this relatively healthy cardiac aging cohort. Abnormalities in cardiac structure versus function measures may relate to perivascular spaces in different brain regions, perhaps due to temporal differences in the development of LVH versus decreased cardiac index and myocardial contraction fraction abnormalities. Future longitudinal investigation of cardiovascular abnormalities and incident perivascular spaces is needed. Funding: Alzheimer’s Association IIRG-08-88733, R01-AG034962, R01-HL111516, K24AG046373, K23-AG030962, K01-AG049164-02, UL1-TR000445
P2-387
EPISODIC MEMORY IN MILD COGNITIVE IMPAIRMENT INVERSELY CORRELATES WITH THE PATIENT CONTRIBUTION TO CEREBRAL BLOOD FLOW NETWORK MODULARITY
Carlos A. Sanchez Catas us1,2, Antoon Willemsen1, Ronald Boellaard1, Luis Juarez Orozco1, Juan Samper-Noa3, Angel Aguila-Ruiz2, Peter Paul De Deyn1, Rudi Dierckx1, Lester Melie-Garcia3,4, Yasser Iturria Medina3,5, 1 University Medical Center Groningen, Groningen, Netherlands; 2 Center for Neurological Restoration (CIREN), Havana, Cuba; 3 Cuban Neuroscience Center, Havana, Cuba; 4Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland; 5McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, QC, Canada. Contact e-mail: [email protected] Background: Cerebral blood flow (CBF) SPECT is an interesting meth-
P2-386
ABNORMAL CARDIAC STRUCTURE AND FUNCTION MEASURES ARE ASSOCIATED WITH INCREASED PERIVASCULAR SPACES IN OLDER ADULTS
Brittany C. Schneider1, Dandan Liu1, Francis E. Cambronero2, Katie E. Osborn2, Kimberly R. Pechman2, Elizabeth A. Gordon2, Faizan Badami2, Timothy J. Hohman2, Katherine A. Gifford2, L. Taylor Davis2, Angela L. Jefferson2, Vanderbilt Memory & Alzheimer’s Center, 1Vanderbilt University School of Medicine, Nashville, TN, USA; 2Vanderbilt University Medical Center, Nashville, TN, USA. Contact e-mail: [email protected] Background: Small vessel disease (SVD) is associated with incident cognitive decline and dementia, and neuroimaging markers of SVD have been associated with abnormal cardiovascular health. Research on perivascular spaces, an emerging marker of SVD, is sparse. Our study cross-sectionally investigated associations between cardiovascular health and perivascular spaces. Methods: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n¼328, 7367 years) underwent echocardiography and cardiac MRI to measure left ven-
odology to study connectivity in mild cognitive impairment (MCI) as it is a neuroimaging biomarker of neuronal injury of MCI due to Alzheimer disease (AD) and accessible worldwide. In this context, connectivity is a concept grounded on a group-based correlation network whose topology is analyzed using graph theory [Melie-Garcıa et al., 2103]. However, topological metrics derived from the CBF correlation (CBFcorr) network cannot be used to support diagnosis and prognosis individually. Recently, methods to extract the individual patient contribution to the metrics of a group-based correlation network were published [Saggar et al., 2015] but not yet applied to MCI . To clarify whether this approach could be useful for MCI, we investigated whether the episodic memory of amnestic MCI patients correlates with individual patient contributions to topological metrics of the group-based CBFcorrnetwork. Methods: We first investigated topological metrics of the CBFcorrnetwork constructed using 24 amnestic MCI patients, by comparing with one corresponding to 26 controls. We focused on the global network modularity which seems to be more sensitive to the AD process compared with more used metrics [Pereira et al., 2016]. We also analyzed the global and mean local efficiencies that are typically used as metrics of network integration and
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Poster Presentations: Monday, July 17, 2017
segregation, respectively. Metrics that showed significant differences were then used for the individual patient contribution analysis. This latter analysis was performed by extracting the patient contribution to a metric for the network constructed using healthy controls plus the patient. The Rey Complex Figure test was used for episodic memory assessment. Results: The global network modularity was increased while global efficiency decreased in the MCI network compared with the control network. Most important, only the individual patient contribution to the global network modularity showed a significant negative correlation with episodic memory as shown in the figure. Conclusions: Episodic memory in MCI inversely correlates with the patient contribution to CBF network modularity, which warrants further research to develop a CBF connectivity-based biomarker at the individual level as episodic memory decline is the hallmark and major symptom in patients that progress to AD dementia. P2-388
INTRINSIC CONNECTIVITY NETWORKS IN POSTERIOR CORTICAL ATROPHY: A ROLE FOR THE PULVINAR?
Carolyn A. Fredericks1, Jesse Brown2, Jersey Deng3, Rik Ossenkoppele4, Katherine Rankin5, Joel H. Kramer6, Bruce L. Miller6, Gil D. Rabinovici6, William W. Seeley7, 1 Stanford Hospital and Clinics, Palo Alto, CA, USA; 2UCSF, San Francisco, CA, USA; 3University of California, San Francisco, CA, USA; 4Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; 5UCSF, San Francisco, CA, USA; 6 Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA; 7University of California, San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Amnestic Alzheimer’s disease (AD) is characterized by
disrupted default mode network (DMN) connectivity with corresponding increased salience network (SN) connectivity. Posterior cortical atrophy (PCA) is an uncommon AD variant presenting with progressive visuospatial symptoms, and the relationships between functional networks in PCA are unknown. We hypothesized that PCA patients would show early decreased integrity within the visual network, with corresponding increases in SN connectivity, despite relative preservation of DMN. As the medial and lateral pulvinar are anatomically interconnected with SN, DMN, and visual structures, we further hypothesized that the pulvinar nucleus might play a key role in these networks. Methods: 26 individuals diagnosed with PCA (all amyloid-positive or with AD-consistent CSF) and 64 matched controls were recruited through UCSF Memory and Aging Center research programs. Each completed a standardized neuropsychological battery, structural imaging, and task-free fMRI. We used voxel-based morphometry (VBM) to assess structural atrophy. For fMRI, time series from seeds for networks of interest were regressed across the whole brain and fitted to a secondlevel regression model for group effects analysis. Functional data analyses were atrophy-corrected using the BPM toolbox. Results: PCA patients show relatively preserved memory in the early stages
of illness despite poor visuospatial performance; like others with AD, they also show preserved social sensitivity. As expected, VBM revealed highly significant parieto-occipital atrophy (Figure 1). PCA patients showed widespread decreased connectivity within the visual network, increased connectivity between some structures in SN, and increased connectivity between key nodes of the DMN compared to controls. Medial pulvinar connectivity mirrored SN connectivity, while lateral pulvinar connectivity mirrored DMN connectivity (Figure 2). Conclusions:Individuals with PCA show relatively preserved connectivity in SN and DMN despite widespread parietooccipital atrophy and decreased visual network connectivity. The striking similarity of medial and lateral pulvinar-derived connectivity maps to SN and DMN suggests an important role for the pulvinar within these networks, particularly given the close anatomic relationship between medial pulvinar and SN, and lateral pulvinar and DMN and visual regions. Thalamic subnuclei are well-poised to serve as network switches, and different subnuclei may be differentially implicated in different subtypes of AD.
P2-389
LONGITUDINAL ASSESSMENT OF Ab ACCUMULATION WITH FLUTEMETAMOL
Christopher C. Rowe1, Vincent Dore1,2, Pierrick Bourgeat3, Robert Williams4, David Ames5, Olivier Salvado6, Colin L. Masters7, Victor L. L. Villemagne1,4, 1Austin Health, Melbourne, Australia; 2CSIRO, Melbourne, Australia; 3CSIRO, Brisbane, Australia; 4The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 5The University of Melbourne, Melbourne, Australia; 6Commonwealth Scientific and Industrial Research Organisation, Brisbane, Australia; 7The Florey Institute of Neuroscience and Mental Health, Parkville, Australia. Contact e-mail: [email protected] Background: We investigated if longitudinal Ab imaging with
18
Fflutemetamol (FLUTE) PET can detect change over time in Ab burden as previously shown with 11C-PiB in participants of the AIBL study. Methods: FLUTE-PET was performed in 264 AIBL volunteers who had not previously had Ab imaging: 186 healthy controls (HC; 73.365.7 yo), 60 subjects with Mild Cognitive Impairment (MCI; 74.566.1 yo), and 18 Alzheimer’s disease patients (AD; 74.667.2 yo). Follow-up scans at 18 and 36 months were obtained in 107 participants. Results were expressed as Centiloids (CL), generated using the CL cortical and whole cerebellum masks. Rates of Ab deposition were derived from the slope of the linear regression plots of those participants with three studies. Change was expressed as the yearly rates of Ab accumulaton or as yearly % difference from baseline. Results: At 36-month follow-up, positive rates of Ab accumulation were observed in 70/88 (80%) of HC, 8/12 (67%) of MCI, and 3/7 (43%) of AD. We compared the rates of Ab deposition using 2 or 3 points in the same participants. The mean rates of Ab deposition were -0.5064.6 (CV 9.2) and 1.0863.3 (CV 3.1), when using just the first 2 points or all 3 points, respectively. A significant increase (5.3 CL or 3%/yr, p¼0.0008) was observed at 36-month follow-up in participants with high FLUTE retention at baseline. These increases were very similar to those observed in participants with high PiB retention during a similar 36-month interval (7.1 CL or 4%/yr). Finally, rates of Ab accumulation were marginally significantly faster in APOE4 carriers compared to non-carriers, (2.5663.4 CL/yr vs. 0.9563.8 CL/yr, respectively, p¼0.048). Conclusions: As we have shown with PiB, Ab deposition is a slow process. FLUTE expressed in the universal language of Centiloids is a useful tool to detect changes in Ab deposition over time.
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tricular (LV) mass index, LV hypertrophy (LVH), cardiac index, LV ejection fraction (LVEF), and myocardial contraction fraction. A neuroradiologist used a combination of T1 and T2weighted FLAIR images to manually code perivascular spaces in the basal ganglia and centrum semiovale. Regression models related cardiac measures, hypertension, and anti-hypertensive medication use to perivascular spaces adjusting for age, sex, race/ethnicity, and education. Results: The presence of LVH (b¼4.92, p¼0.004), decreased cardiac index (b¼0.66, p¼0.02), and decreased myocardial contraction fraction (b¼0.19, p¼0.03) were each individually associated with increased perivascular spaces in the basal ganglia. LVH (b¼4.53, p¼0.006) and increased LV mass index (b¼1.01, p¼0.03) were associated with perivascular spaces in the centrum semiovale. Associations persisted when anti-hypertensive medication usage was added to the models (all p-values<0.04). Conclusions: Poorer cardiovascular health markers are associated with increased presence of perivascular spaces in this relatively healthy cardiac aging cohort. Abnormalities in cardiac structure versus function measures may relate to perivascular spaces in different brain regions, perhaps due to temporal differences in the development of LVH versus decreased cardiac index and myocardial contraction fraction abnormalities. Future longitudinal investigation of cardiovascular abnormalities and incident perivascular spaces is needed. Funding: Alzheimer’s Association IIRG-08-88733, R01-AG034962, R01-HL111516, K24AG046373, K23-AG030962, K01-AG049164-02, UL1-TR000445
P2-387
EPISODIC MEMORY IN MILD COGNITIVE IMPAIRMENT INVERSELY CORRELATES WITH THE PATIENT CONTRIBUTION TO CEREBRAL BLOOD FLOW NETWORK MODULARITY
Carlos A. Sanchez Catas us1,2, Antoon Willemsen1, Ronald Boellaard1, Luis Juarez Orozco1, Juan Samper-Noa3, Angel Aguila-Ruiz2, Peter Paul De Deyn1, Rudi Dierckx1, Lester Melie-Garcia3,4, Yasser Iturria Medina3,5, 1 University Medical Center Groningen, Groningen, Netherlands; 2 Center for Neurological Restoration (CIREN), Havana, Cuba; 3 Cuban Neuroscience Center, Havana, Cuba; 4Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland; 5McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, QC, Canada. Contact e-mail: [email protected] Background: Cerebral blood flow (CBF) SPECT is an interesting meth-
P2-386
ABNORMAL CARDIAC STRUCTURE AND FUNCTION MEASURES ARE ASSOCIATED WITH INCREASED PERIVASCULAR SPACES IN OLDER ADULTS
Brittany C. Schneider1, Dandan Liu1, Francis E. Cambronero2, Katie E. Osborn2, Kimberly R. Pechman2, Elizabeth A. Gordon2, Faizan Badami2, Timothy J. Hohman2, Katherine A. Gifford2, L. Taylor Davis2, Angela L. Jefferson2, Vanderbilt Memory & Alzheimer’s Center, 1Vanderbilt University School of Medicine, Nashville, TN, USA; 2Vanderbilt University Medical Center, Nashville, TN, USA. Contact e-mail: [email protected] Background: Small vessel disease (SVD) is associated with incident cognitive decline and dementia, and neuroimaging markers of SVD have been associated with abnormal cardiovascular health. Research on perivascular spaces, an emerging marker of SVD, is sparse. Our study cross-sectionally investigated associations between cardiovascular health and perivascular spaces. Methods: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n¼328, 7367 years) underwent echocardiography and cardiac MRI to measure left ven-
odology to study connectivity in mild cognitive impairment (MCI) as it is a neuroimaging biomarker of neuronal injury of MCI due to Alzheimer disease (AD) and accessible worldwide. In this context, connectivity is a concept grounded on a group-based correlation network whose topology is analyzed using graph theory [Melie-Garcıa et al., 2103]. However, topological metrics derived from the CBF correlation (CBFcorr) network cannot be used to support diagnosis and prognosis individually. Recently, methods to extract the individual patient contribution to the metrics of a group-based correlation network were published [Saggar et al., 2015] but not yet applied to MCI . To clarify whether this approach could be useful for MCI, we investigated whether the episodic memory of amnestic MCI patients correlates with individual patient contributions to topological metrics of the group-based CBFcorrnetwork. Methods: We first investigated topological metrics of the CBFcorrnetwork constructed using 24 amnestic MCI patients, by comparing with one corresponding to 26 controls. We focused on the global network modularity which seems to be more sensitive to the AD process compared with more used metrics [Pereira et al., 2016]. We also analyzed the global and mean local efficiencies that are typically used as metrics of network integration and
P778
Poster Presentations: Monday, July 17, 2017
segregation, respectively. Metrics that showed significant differences were then used for the individual patient contribution analysis. This latter analysis was performed by extracting the patient contribution to a metric for the network constructed using healthy controls plus the patient. The Rey Complex Figure test was used for episodic memory assessment. Results: The global network modularity was increased while global efficiency decreased in the MCI network compared with the control network. Most important, only the individual patient contribution to the global network modularity showed a significant negative correlation with episodic memory as shown in the figure. Conclusions: Episodic memory in MCI inversely correlates with the patient contribution to CBF network modularity, which warrants further research to develop a CBF connectivity-based biomarker at the individual level as episodic memory decline is the hallmark and major symptom in patients that progress to AD dementia. P2-388
INTRINSIC CONNECTIVITY NETWORKS IN POSTERIOR CORTICAL ATROPHY: A ROLE FOR THE PULVINAR?
Carolyn A. Fredericks1, Jesse Brown2, Jersey Deng3, Rik Ossenkoppele4, Katherine Rankin5, Joel H. Kramer6, Bruce L. Miller6, Gil D. Rabinovici6, William W. Seeley7, 1 Stanford Hospital and Clinics, Palo Alto, CA, USA; 2UCSF, San Francisco, CA, USA; 3University of California, San Francisco, CA, USA; 4Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; 5UCSF, San Francisco, CA, USA; 6 Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA; 7University of California, San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Amnestic Alzheimer’s disease (AD) is characterized by
disrupted default mode network (DMN) connectivity with corresponding increased salience network (SN) connectivity. Posterior cortical atrophy (PCA) is an uncommon AD variant presenting with progressive visuospatial symptoms, and the relationships between functional networks in PCA are unknown. We hypothesized that PCA patients would show early decreased integrity within the visual network, with corresponding increases in SN connectivity, despite relative preservation of DMN. As the medial and lateral pulvinar are anatomically interconnected with SN, DMN, and visual structures, we further hypothesized that the pulvinar nucleus might play a key role in these networks. Methods: 26 individuals diagnosed with PCA (all amyloid-positive or with AD-consistent CSF) and 64 matched controls were recruited through UCSF Memory and Aging Center research programs. Each completed a standardized neuropsychological battery, structural imaging, and task-free fMRI. We used voxel-based morphometry (VBM) to assess structural atrophy. For fMRI, time series from seeds for networks of interest were regressed across the whole brain and fitted to a secondlevel regression model for group effects analysis. Functional data analyses were atrophy-corrected using the BPM toolbox. Results: PCA patients show relatively preserved memory in the early stages
of illness despite poor visuospatial performance; like others with AD, they also show preserved social sensitivity. As expected, VBM revealed highly significant parieto-occipital atrophy (Figure 1). PCA patients showed widespread decreased connectivity within the visual network, increased connectivity between some structures in SN, and increased connectivity between key nodes of the DMN compared to controls. Medial pulvinar connectivity mirrored SN connectivity, while lateral pulvinar connectivity mirrored DMN connectivity (Figure 2). Conclusions:Individuals with PCA show relatively preserved connectivity in SN and DMN despite widespread parietooccipital atrophy and decreased visual network connectivity. The striking similarity of medial and lateral pulvinar-derived connectivity maps to SN and DMN suggests an important role for the pulvinar within these networks, particularly given the close anatomic relationship between medial pulvinar and SN, and lateral pulvinar and DMN and visual regions. Thalamic subnuclei are well-poised to serve as network switches, and different subnuclei may be differentially implicated in different subtypes of AD.
P2-389
LONGITUDINAL ASSESSMENT OF Ab ACCUMULATION WITH FLUTEMETAMOL
Christopher C. Rowe1, Vincent Dore1,2, Pierrick Bourgeat3, Robert Williams4, David Ames5, Olivier Salvado6, Colin L. Masters7, Victor L. L. Villemagne1,4, 1Austin Health, Melbourne, Australia; 2CSIRO, Melbourne, Australia; 3CSIRO, Brisbane, Australia; 4The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 5The University of Melbourne, Melbourne, Australia; 6Commonwealth Scientific and Industrial Research Organisation, Brisbane, Australia; 7The Florey Institute of Neuroscience and Mental Health, Parkville, Australia. Contact e-mail: [email protected] Background: We investigated if longitudinal Ab imaging with
18
Fflutemetamol (FLUTE) PET can detect change over time in Ab burden as previously shown with 11C-PiB in participants of the AIBL study. Methods: FLUTE-PET was performed in 264 AIBL volunteers who had not previously had Ab imaging: 186 healthy controls (HC; 73.365.7 yo), 60 subjects with Mild Cognitive Impairment (MCI; 74.566.1 yo), and 18 Alzheimer’s disease patients (AD; 74.667.2 yo). Follow-up scans at 18 and 36 months were obtained in 107 participants. Results were expressed as Centiloids (CL), generated using the CL cortical and whole cerebellum masks. Rates of Ab deposition were derived from the slope of the linear regression plots of those participants with three studies. Change was expressed as the yearly rates of Ab accumulaton or as yearly % difference from baseline. Results: At 36-month follow-up, positive rates of Ab accumulation were observed in 70/88 (80%) of HC, 8/12 (67%) of MCI, and 3/7 (43%) of AD. We compared the rates of Ab deposition using 2 or 3 points in the same participants. The mean rates of Ab deposition were -0.5064.6 (CV 9.2) and 1.0863.3 (CV 3.1), when using just the first 2 points or all 3 points, respectively. A significant increase (5.3 CL or 3%/yr, p¼0.0008) was observed at 36-month follow-up in participants with high FLUTE retention at baseline. These increases were very similar to those observed in participants with high PiB retention during a similar 36-month interval (7.1 CL or 4%/yr). Finally, rates of Ab accumulation were marginally significantly faster in APOE4 carriers compared to non-carriers, (2.5663.4 CL/yr vs. 0.9563.8 CL/yr, respectively, p¼0.048). Conclusions: As we have shown with PiB, Ab deposition is a slow process. FLUTE expressed in the universal language of Centiloids is a useful tool to detect changes in Ab deposition over time.