- Email: [email protected]
FOUR DIMENSIONAL ARTERIAL BLOOD FLOW METRICS IN THE INTERNAL CAROTID ARTERY PREDICT COGNITIVE PERFORMANCE AND ARE ASSOCIATED WITH CSF BIOMARKERS IN PATIENTS WITH MCI
Poster Presentations: Saturday, July 23, 2016
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callosum, bilateral parahippocampal tract), Ab42 classification detected no difference in MCI-int vs MCI-neg. Conversely, for the Ab42/p-tau classification MCI-int showed significant atrophy in the right hippocampus. DT MRI reported reduced FA in the right parahippocampal tract of MCI-int for both Ab42/t-tau and Ab42/ p-tau classifications. Conclusions: Patients classified as MCI-int by the two ratios had structural features more similar to MCI-pos than MCI-neg. Indeed, they reported significant differences in areas already affected in MCI-pos and might therefore indicate early AD. Conversely, Ab42 classification did not detect any significant difference in MCI-int, possibly being less sensitive to early AD changes either indicating a pathologically heterogeneous group. PharmaCog is funded by the EU-FP7 for the Innovative Medicine Initiative (grant n 115009). IC-P-123
FOUR DIMENSIONAL ARTERIAL BLOOD FLOW METRICS IN THE INTERNAL CAROTID ARTERY PREDICT COGNITIVE PERFORMANCE AND ARE ASSOCIATED WITH CSF BIOMARKERS IN PATIENTS WITH MCI
Sara Elizabeth Berman1,2,3, Leonardo A. Rivera4, Annie M. Racine2,3,5,6, Lindsay R. Clark3, Christopher R. Nicholas3,7, Cynthia M. Carlsson3,7,8, Barbara B. Bendlin3,7,8, Howard A. Rowley3, Kaj Blennow9, Henrik Zetterberg9,10, Sanjay Asthana3,7,8, Patrick Turski3, Oliver Wieben4, Sterling C. Johnson3,7,8,11, 1University of Wisconsin School of Medicine and Public Health: Medical Scientist Training Program, Madison, WI, USA; 2 Neuroscience Training Program, University of Wisconsin, Madison, WI, USA; 3Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 4 University of Wisconsin-Madison, Madison, WI, USA; 5Institute on Aging, University of Wisconsin, Madison, WI, USA; 6Neuroscience and Public Policy Program, University of Wisconsin, Madison, WI, USA; 7Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI, USA; 8Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA;
Figure 1. PC VIPR angiogram (Adapted from Berman et al. 2015). Green planes denote locations of measurements taken to analyze arterial health metrics of the Circle of Willis. Planes marked with arrows represent the distal petrous portion of the ICA (left and right), the average of which was used as a metric of ICA flow in this abstract.
Figure 2. Graphical representation of significant relationships (from Table 1) between ICA mean flow and cognitive performance. ICA mean flow is on the x-axis, and cognitive scores adjusted for covariates (age, gender, interval between MRI and neuropsychological testing, and years of education) are on the y-axis. For all congnitive tests, with the exception of Trails B, higher scores indicate better cognitive performance. 9 Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 10University College London, Institute of Neurology, London, United Kingdom; 11Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, USA. Contact e-mail: seberman@ medicine.wisc.edu
Background: It is becoming increasingly recognized that there is a
vascular contribution to the pathogenesis of Alzheimer’s disease (AD). We use a unique four-dimensional MRI technique, (termed Phase Contrast Vastly undersampled Isotropic PRojection imaging, PC VIPR), that allows us to examine volumetric blood flow in the arteries of the Circle of Willis. Reduced flow is believed to be indicative of suboptimal vascular health. Methods: 38 Mild Cognitive Impairment (MCI) participants (diagnosed via clinical consensus conference; mean age 73.3368.45 years, 42% female, 50% APOE ε4+), underwent a comprehensive neuroimaging protocol (including PC VIPR) and a standard neuropsychological battery. A subset of participants also underwent lumbar puncture (LP) for CSF analysis. To investigate the relationship between arterial flow and cognition, we ran linear regressions with cognitive performance as the outcome, flow measured in the distal petrous portion of the ICA as the predictor variable (Figure 1), and age, sex, years of education, and interval between MRI scan and neuropsychological testing as covariates. Cut-offs for biomarker positivity resulting from an ROC analysis of AD cases and controls in the Wisconsin ADRC sample were used to identify subsets of MCIs as biomarker positive or negative on CSF Aß42 (cut-off for positivity¼below 477 ng/L) and CSF total-tau/Aß42 (cut-off ratio for positivity¼above 0.9). ANCOVA models controlling for age, sex, and interval between MRI and LP were run to determine the relationship between biomarker positivity and arterial health. Results: Lower ICA mean flow predicted worse performance on Trails B, Animal Naming, WAIS-Digit Symbol, and RAVLT learning total trials 1-5 (p<0.05) but not Boston Naming or RAVLT long delay (Table 1,
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Poster Presentations: Saturday, July 23, 2016 TX, USA; 5University of Pennsylvania, Philadelphia, PA, USA; 6University of Minnesota, Minneapolis, MN, USA; 7University of Alabama, Birmingham, AL, USA; 8Kaiser Permanente, Oakland, CA, USA. Contact e-mail: [email protected]
Figure 3. Boxplots depicting the comparison of ICA mean flow in biomarker positive vs. biomarker negative individuals with MCI. Biomarker positivity status for amyloid and the ratio of total-tau to amyloid is denoted on the y-axis, while ICA mean flow adjusted for age, sex, and interval between MRI and LP is on the y-axis. Amyloid negative subjects have high Ab-42 in the CSF, while amyloid positive subjects have low Ab-42 in the CSF.
Table 1 Relationship between ICA mean flow and cross-sectional cognitive performance. RAVLT ¼ Rey Auditory Verbal Learning Test, WAIS ¼ Wechsler Adult Intelligence Scale. ICA mean flow is the predictor variable in the linear regression, cognitive test performance is the outcome, and age, sex, years of education and interval between MRI and cognitive test date are included as covariates. The Animal Naming Test and Trails B were log transformed and one outlier was removed from the Boston Naming Test to correct for deviations from normality. One subject did not complete the RAVLT test. For all cognitive tests, with the exception of Trails B, higher scores indicate better cognitive performance. Beta
T-Statistic p-value
Animal Naming Test (Log Transformed) 0.490 3.350 Boston Naming Test 0.224 1.435 RAVLT Learning Total 0.331 2.177 RAVLT Long Delay Total 0.076 0.446 Trails B (Log Transformed) -0.373 -2.536 WAIS-Digit Symbol 0.388 2.835
p ¼ 0.002 p ¼ 0.161 p ¼ 0.037 p ¼ 0.659 p ¼ 0.016 p ¼ 0.008
Figure 2). Patients who were Aß42 or total-tau/Aß42 positive had significantly lower ICA mean flow than did subjects with negative biomarker profiles (p0.05; Figure 3). Conclusions: Mean ICA arterial flow predicted cognitive performance in MCI subjects and biomarker positivity was associated with perturbed flow. This suggests an increasing role for vascular health as a contributing factor in the etiopathogenesis of AD, and could represent a window of opportunity to intervene in the disease process. It also exemplifies a role for novel 4D flow imaging in better understanding cerebrovascular related AD pathology.
IC-P-124
PLASMA CLUSTERIN IS ASSOCIATED WITH ADVULNERABLE BRAIN REGIONS IN MIDDLE-AGE ADULTS: THE CARDIA BRAIN MRI STUDY
Thaddeus J. Haight1, R. N. Bryan2, Russell Tracy3, Myriam Fornage4, Osorio Meirelles1, Melissa Richard4, Christos Davatzikos2, Ilya Nasrallah5, David R. Jacobs, Jr,6, Cora Lewis7, Pamela Schreiner6, Stephen Sidney8, Lenore J. Launer1, 1National Institute on Aging, Bethesda, MD, USA; 2 Center for Biomedical Image Computing and Analytics / University of Pennsylvania, Philadelphia, PA, USA; 3University of Vermont, Colchester, VT, USA; 4University of Texas Health Science Center at Houston, Houston,
Background: A gene regulating clusterin has been shown to increase the risk for Alzheimer’s disease (AD). Studies of older persons with higher plasma clusterin (PC) have reported increased prevalence of AD and faster clinical progression. In the context of identifying early biomarkers of risk, it is of interest to investigate the association of PC with characteristics of AD, which include vulnerable brain regions, in middle age individuals from the community. Methods: Subjects were 639 cognitively normal individuals (mean age 50 6 3.5 SD) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI Study. PC (mean 255 6 31 ng/ml) was quantified with sandwich ELISA using samples prepared by standard protocol. PC was investigated in association with brain regions affected early in AD, as described by Braak staging: entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and larger brain structures affected in later Braak staging were examined for comparison. Preliminary analyses suggested curvilinear relationships between PC and volumes of the smaller structures (Figure 1), therefore, we fit quadratic models to assess their associations, adjusting for age, sex, race, intracranial volume, C-reactive protein, diabetes, and dyslipidemia. Results: Higher PC had a negative nonlinear association with lower ECV (combined left and right side), as indicated by Figure 1 which documents the quadratic model fit and concordance with decile means, that was influenced by highest PC levels (p<0.025), adjusted for covariates. Similar relationships were observed between PC and HV, although the relationship was stronger for the left-side HV than the rightside. After adjustment, the association was non-significant. Associations between PC and MTLV were strongest for the left-side: higher PC was associated with lower MTLV, and this negative non-linear association was influenced by highest PC levels (p<0.045), adjusted for covariates. There were no significant
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callosum, bilateral parahippocampal tract), Ab42 classification detected no difference in MCI-int vs MCI-neg. Conversely, for the Ab42/p-tau classification MCI-int showed significant atrophy in the right hippocampus. DT MRI reported reduced FA in the right parahippocampal tract of MCI-int for both Ab42/t-tau and Ab42/ p-tau classifications. Conclusions: Patients classified as MCI-int by the two ratios had structural features more similar to MCI-pos than MCI-neg. Indeed, they reported significant differences in areas already affected in MCI-pos and might therefore indicate early AD. Conversely, Ab42 classification did not detect any significant difference in MCI-int, possibly being less sensitive to early AD changes either indicating a pathologically heterogeneous group. PharmaCog is funded by the EU-FP7 for the Innovative Medicine Initiative (grant n 115009). IC-P-123
FOUR DIMENSIONAL ARTERIAL BLOOD FLOW METRICS IN THE INTERNAL CAROTID ARTERY PREDICT COGNITIVE PERFORMANCE AND ARE ASSOCIATED WITH CSF BIOMARKERS IN PATIENTS WITH MCI
Sara Elizabeth Berman1,2,3, Leonardo A. Rivera4, Annie M. Racine2,3,5,6, Lindsay R. Clark3, Christopher R. Nicholas3,7, Cynthia M. Carlsson3,7,8, Barbara B. Bendlin3,7,8, Howard A. Rowley3, Kaj Blennow9, Henrik Zetterberg9,10, Sanjay Asthana3,7,8, Patrick Turski3, Oliver Wieben4, Sterling C. Johnson3,7,8,11, 1University of Wisconsin School of Medicine and Public Health: Medical Scientist Training Program, Madison, WI, USA; 2 Neuroscience Training Program, University of Wisconsin, Madison, WI, USA; 3Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 4 University of Wisconsin-Madison, Madison, WI, USA; 5Institute on Aging, University of Wisconsin, Madison, WI, USA; 6Neuroscience and Public Policy Program, University of Wisconsin, Madison, WI, USA; 7Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI, USA; 8Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA;
Figure 1. PC VIPR angiogram (Adapted from Berman et al. 2015). Green planes denote locations of measurements taken to analyze arterial health metrics of the Circle of Willis. Planes marked with arrows represent the distal petrous portion of the ICA (left and right), the average of which was used as a metric of ICA flow in this abstract.
Figure 2. Graphical representation of significant relationships (from Table 1) between ICA mean flow and cognitive performance. ICA mean flow is on the x-axis, and cognitive scores adjusted for covariates (age, gender, interval between MRI and neuropsychological testing, and years of education) are on the y-axis. For all congnitive tests, with the exception of Trails B, higher scores indicate better cognitive performance. 9 Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 10University College London, Institute of Neurology, London, United Kingdom; 11Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, USA. Contact e-mail: seberman@ medicine.wisc.edu
Background: It is becoming increasingly recognized that there is a
vascular contribution to the pathogenesis of Alzheimer’s disease (AD). We use a unique four-dimensional MRI technique, (termed Phase Contrast Vastly undersampled Isotropic PRojection imaging, PC VIPR), that allows us to examine volumetric blood flow in the arteries of the Circle of Willis. Reduced flow is believed to be indicative of suboptimal vascular health. Methods: 38 Mild Cognitive Impairment (MCI) participants (diagnosed via clinical consensus conference; mean age 73.3368.45 years, 42% female, 50% APOE ε4+), underwent a comprehensive neuroimaging protocol (including PC VIPR) and a standard neuropsychological battery. A subset of participants also underwent lumbar puncture (LP) for CSF analysis. To investigate the relationship between arterial flow and cognition, we ran linear regressions with cognitive performance as the outcome, flow measured in the distal petrous portion of the ICA as the predictor variable (Figure 1), and age, sex, years of education, and interval between MRI scan and neuropsychological testing as covariates. Cut-offs for biomarker positivity resulting from an ROC analysis of AD cases and controls in the Wisconsin ADRC sample were used to identify subsets of MCIs as biomarker positive or negative on CSF Aß42 (cut-off for positivity¼below 477 ng/L) and CSF total-tau/Aß42 (cut-off ratio for positivity¼above 0.9). ANCOVA models controlling for age, sex, and interval between MRI and LP were run to determine the relationship between biomarker positivity and arterial health. Results: Lower ICA mean flow predicted worse performance on Trails B, Animal Naming, WAIS-Digit Symbol, and RAVLT learning total trials 1-5 (p<0.05) but not Boston Naming or RAVLT long delay (Table 1,
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Poster Presentations: Saturday, July 23, 2016 TX, USA; 5University of Pennsylvania, Philadelphia, PA, USA; 6University of Minnesota, Minneapolis, MN, USA; 7University of Alabama, Birmingham, AL, USA; 8Kaiser Permanente, Oakland, CA, USA. Contact e-mail: [email protected]
Figure 3. Boxplots depicting the comparison of ICA mean flow in biomarker positive vs. biomarker negative individuals with MCI. Biomarker positivity status for amyloid and the ratio of total-tau to amyloid is denoted on the y-axis, while ICA mean flow adjusted for age, sex, and interval between MRI and LP is on the y-axis. Amyloid negative subjects have high Ab-42 in the CSF, while amyloid positive subjects have low Ab-42 in the CSF.
Table 1 Relationship between ICA mean flow and cross-sectional cognitive performance. RAVLT ¼ Rey Auditory Verbal Learning Test, WAIS ¼ Wechsler Adult Intelligence Scale. ICA mean flow is the predictor variable in the linear regression, cognitive test performance is the outcome, and age, sex, years of education and interval between MRI and cognitive test date are included as covariates. The Animal Naming Test and Trails B were log transformed and one outlier was removed from the Boston Naming Test to correct for deviations from normality. One subject did not complete the RAVLT test. For all cognitive tests, with the exception of Trails B, higher scores indicate better cognitive performance. Beta
T-Statistic p-value
Animal Naming Test (Log Transformed) 0.490 3.350 Boston Naming Test 0.224 1.435 RAVLT Learning Total 0.331 2.177 RAVLT Long Delay Total 0.076 0.446 Trails B (Log Transformed) -0.373 -2.536 WAIS-Digit Symbol 0.388 2.835
p ¼ 0.002 p ¼ 0.161 p ¼ 0.037 p ¼ 0.659 p ¼ 0.016 p ¼ 0.008
Figure 2). Patients who were Aß42 or total-tau/Aß42 positive had significantly lower ICA mean flow than did subjects with negative biomarker profiles (p0.05; Figure 3). Conclusions: Mean ICA arterial flow predicted cognitive performance in MCI subjects and biomarker positivity was associated with perturbed flow. This suggests an increasing role for vascular health as a contributing factor in the etiopathogenesis of AD, and could represent a window of opportunity to intervene in the disease process. It also exemplifies a role for novel 4D flow imaging in better understanding cerebrovascular related AD pathology.
IC-P-124
PLASMA CLUSTERIN IS ASSOCIATED WITH ADVULNERABLE BRAIN REGIONS IN MIDDLE-AGE ADULTS: THE CARDIA BRAIN MRI STUDY
Thaddeus J. Haight1, R. N. Bryan2, Russell Tracy3, Myriam Fornage4, Osorio Meirelles1, Melissa Richard4, Christos Davatzikos2, Ilya Nasrallah5, David R. Jacobs, Jr,6, Cora Lewis7, Pamela Schreiner6, Stephen Sidney8, Lenore J. Launer1, 1National Institute on Aging, Bethesda, MD, USA; 2 Center for Biomedical Image Computing and Analytics / University of Pennsylvania, Philadelphia, PA, USA; 3University of Vermont, Colchester, VT, USA; 4University of Texas Health Science Center at Houston, Houston,
Background: A gene regulating clusterin has been shown to increase the risk for Alzheimer’s disease (AD). Studies of older persons with higher plasma clusterin (PC) have reported increased prevalence of AD and faster clinical progression. In the context of identifying early biomarkers of risk, it is of interest to investigate the association of PC with characteristics of AD, which include vulnerable brain regions, in middle age individuals from the community. Methods: Subjects were 639 cognitively normal individuals (mean age 50 6 3.5 SD) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI Study. PC (mean 255 6 31 ng/ml) was quantified with sandwich ELISA using samples prepared by standard protocol. PC was investigated in association with brain regions affected early in AD, as described by Braak staging: entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and larger brain structures affected in later Braak staging were examined for comparison. Preliminary analyses suggested curvilinear relationships between PC and volumes of the smaller structures (Figure 1), therefore, we fit quadratic models to assess their associations, adjusting for age, sex, race, intracranial volume, C-reactive protein, diabetes, and dyslipidemia. Results: Higher PC had a negative nonlinear association with lower ECV (combined left and right side), as indicated by Figure 1 which documents the quadratic model fit and concordance with decile means, that was influenced by highest PC levels (p<0.025), adjusted for covariates. Similar relationships were observed between PC and HV, although the relationship was stronger for the left-side HV than the rightside. After adjustment, the association was non-significant. Associations between PC and MTLV were strongest for the left-side: higher PC was associated with lower MTLV, and this negative non-linear association was influenced by highest PC levels (p<0.045), adjusted for covariates. There were no significant