- Email: [email protected]
Novel tau fragments are present in human CSF
P276
Poster Presentations: P2
sensitivity, performance, and inter-lot reproducibility and was able to measure differences in A b 1-42 levels between normal and AD samples. The results show an average LLOD (66 runs, 3 lots) of 0.35 pg/mL with a quantitative range of 3 to 2000 pg/mL. The precision, accuracy, and total error were determined from human CSF control samples with typical inter- and intra-plate precision < 12% CV. Dilution linearity and spike recovery testing demonstrated minimal matrix effects at 1:8 dilution of CSF and accurate quantitation of A b 1-42 peptide over the range of the assay. The assay exhibited tolerance of CSF contamination with hemolyzed blood and showed no significant cross-reactivity to closely related A b peptides, suggesting the assay was highly specific for A b 1-42. Conclusions: A new assay was developed and analytically validated to measure A b 1-42 in human CSF. The A b 1-42 assay had good analytical performance characteristics, inter-lot consistency, and the ability to distinguish A b 1-42 levels between normal and AD CSF samples. This assay will support ongoing efforts to standardize AD biomarker testing.
P2-037
DEVELOPMENT AND ANALYTICAL VALIDATION OF A NOVEL ASSAY FOR MEASUREMENT OF TOTAL TAU IN HUMAN CSF
Jill Dunty1, Flora Berisha2, Leonid Dzantiev1, Adam Simon3, Carol Gleason4, Oitak (Allen) Wong4, Mwanatumu Mbwana1, Sara Hapip1, Qian Ning1, Franklin Braffett1, Sarah Robles1, George Green4, Robert Neely5, Holly Soares6, James Wilbur1, Pankaj Oberoi1, David Stewart1, Paul Rhyne4, 1Meso Scale Discovery, Gaithersburg, Maryland, United States; 2Bristol Myers Squibb, Lawrenceville, New Jersey, United States; 3AJ Simon Enterprises LLC, Yardley, Pennsylvania, United States; 4Bristol-Myers Squibb Company, Princeton, New Jersey, United States; 5Bristol-Myers Squibb, Princeton, New Jersey, United States; 6 Bristol-Myers Squibb, Wallingford, New Jersey, United States. Background: Measurement of Alzheimer’s disease (AD) biomarkers in clinical cerebrospinal fluid (CSF) samples has been challenging with existing assays due to inter-lot variability, matrix interferences, and inconsistent quantitation. Here we describe the development and analytical validation of an assay to measure Total Tau in human CSF using Fit-forPurpose and CLSI principles. Elements of assay development and performance are presented as well as results of multi-lot validation. Methods: Monoclonal antibodies were evaluated and selected based on sensitivity, specificity, affinity, and performance characteristics in human CSF. Critical reagents were subjected to biochemical and functional characterization to verify purity, integrity, and lot-to-lot consistency. The assay was developed with MSD’s MULTI-ARRAYÒ technology and optimized to minimize CSF matrix effects and interferences. Analytical validation was assessed across three independent kit lots to verify performance including sensitivity, accuracy, and precision using matrix-based validation samples. Tests were conducted by multiple analysts over multiple runs and days. Dilution linearity and spike recovery were measured using well-curated normal and AD CSF samples. Results: The assay demonstrated good sensitivity, performance, and inter-lot reproducibility and differentiated between normal and AD CSF samples. The average LLOD determined from 54 runs over three independent kit lots was 10 pg/mL with a quantitative range of 30 to 8000 pg/mL. The precision, accuracy, and total error were determined from matrix-based controls with typical precision of <10% CV (inter-plate) and <5% CV (intra-plate). Dilution linearity and spike recovery testing demonstrated quantitation of Tau protein over the range of the assay and minimal interference from human CSF matrix. Furthermore, the assay detected 6 isoforms of human Tau and was tolerant of significant CSF contamination with hemolyzed blood. Data also showed that the assay measured elevated levels of Tau in AD samples compared to healthy samples. Conclusions: A new assay was developed and analytically validated to measure Tau in human CSF. The result is an assay with good analytical performance characteristics and lot to lot reproducibility with the ability to distinguish Tau levels between healthy and AD CSF samples. This assay will support ongoing efforts to standardize testing of biomarkers for AD and other tauopathies.
P2-038
LATENT VARIABLES OFFER A COST-EFFECTIVE APPROACH TO DEMENTIA CASE-FINDING
Donald Royall1, Raymond Palmer2, 1UTHSCSA Psychiatry, San Antonio, Texas, United States; 2UTHSCSA, San Antonio, Texas, United States. Background: Structural equation models can explicitly distinguish dementia-relevant variance in cognitive task performance. The resulting latent variable (ie, “d” for dementia) represents an “error free” continuously varying endophenotype. Here, we derive d’s serum biomarkers among participants of the Texas Alzheimer’s Research and Care Consortium (TARCC). Methods: We began with O’Bryant et al’s (2010) panel of 24 dementia-related biomarkers. All analyses were performed on statistically transformed data obtained from Rules Based Medicine (RBM) (Austin, TX). All observed variables were adjusted for age, education, gender, and RBM processing batch. Subjects included n ¼ 805 Alzheimer’s Disease (AD) cases and controls (n ¼ 655). First, we constructed three latent variables; “d”, ie, the cognitive correlates of Instrumental Activities of Daily Living (IADL), “DEP”, ie, the cognitive correlates of depressive symptoms, and “g’”, ie, the residual shared variance in cognitive performance. Next, we simultaneously assessed d, DEP and g’ as potential mediators of each biomarker’s association with blindly adjudicated TARCC diagnoses. Next, we selected analytes related to dementia status through d, and used them as indicators of a fourth latent construct (i.e., d’s biomarkers). Finally, we culled this set to achieve the most parsimonious combination that accurately replicated TARCC diagnoses. Results: Eleven serum analytes were significantly related to diagnosis through d. These were reduced to three, i.e., TNF- b, Mip-1 a and thrombopoetin which explained 87% of the variance in adjudicated diagnoses. Model fit was acceptable (CMIN/df ¼ 5.96, P ¼ 0.001; CFI ¼ 0.948; RMSEA ¼ 0.058). The resulting latent construct (i.e., the biomarkers of d) predicted dementia status (r ¼ -0.83) and achieved an Area Under the Curve (AUC) of 0.869 (S ¼ 0.80, SP ¼ 0.80). If caregiver rated IADL, also strongly related to d, is added as an indicator, the AUC increases to 0.91 (Figure 1). Conclusions: This study illustrates how a latent variable approach to dementia case finding can result in an endophenotype that is highly predictive of clinical diagnoses. d’s biomarkers may offer an objective and cost-effect alternative to clinical dementia assessment. Although a diagnostic “blood test” for AD may be achievable by this approach, it remains necessary to demonstrate its specificity for AD.
P2-039
NOVEL TAU FRAGMENTS ARE PRESENT IN HUMAN CSF
Jere Meredith1, Randall Slemmon2, Valerie Guss1, Anthony Lanzetti1, Sethu Sankaranarayanan3, Holly Soares1, Kaj Blennow4, Charlie Albright1, Michael Ahlijanian1, 1Bristol-Myers Squibb, Wallingford, Connecticut, United States; 2Johnson & Johnson, Titusville, New Jersey, United States; 3 Bristol-Myers Squibb, Wallingford, New Jersey, United States; 4 Sahlgrenska Academy at the University of Gothenburg, M€olndal, Sweden. Background: CSF Ab42, Tau and p181Tau are widely accepted diagnostic biomarkers of Alzheimer’s disease (AD). Results from numerous studies
Poster Presentations: P2 demonstrate that CSF Tau levels are w2X higher in mild-to-moderate AD compared to age-matched controls. In addition, this increase in CSF Tau is detected prior to the onset of clinical symptoms, and thus is predictive of the conversion from predementia (MCI) to clinical disease. Despite the importance as a diagnostic biomarker, the molecular nature of Tau present in CSF is not known. Methods: We have employed CSF denaturation coupled with reverse-phase HPLC in order to enrich and concentrate Tau and to further characterize the CSF Tau profile. Individual fractions from pooled AD and control CSF samples were analyzed by SDS-PAGE/Western blot (WB) using various anti-Tau antibodies or by using in-house, research-grade Tau ELISAs. Results: Multiple fragments of Tau, with apparent MW sizes ranging from w15 kD to 40 kD, were identified by WB using an antibody that recognizes the mid-domain of Tau, but not an isotype control IgG. A subset of these bands was recognized using an antibody specific for the N-terminal of Tau. In contrast, relatively low levels of C-terminal-containing fragments were detected as demonstrated using a C-terminal specific antibody. Tau ELISA results confirmed the WB data and demonstrated that differences in Tau levels between AD and control CSF are more prominent in specific fractions, corresponding to certain apparent molecular weight Tau fragments. Conclusions: Our results demonstrate the existence of multiple Tau fragments in CSF and suggest that a subset of these fragments are increased in AD CSF. These particular Tau fragments may have utility as disease and/or pharmacodynamic biomarkers. P2-040
PLASMA CERAMIDE CONCENTRATIONS ARE ASSOCIATED WITH CHANGE IN VERBAL MEMORY PERFORMANCE IN PATIENTS UNDERTAKING CARDIAC REHABILITATION
Krista Lanctot1, Mahwesh Saleem1, Veera Vankata Ratnam Bandaru2, Nathan Herrmann1, Walter Swardfager1, Michelle Mielke3, Norman Haughey2, Paul Oh4, 1Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 2Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; 3Mayo Clinic, Rochester, Minnesota, United States; 4Toronto Rehabilitation Institute, Toronto, Ontario, Canada. Background: Coronary artery disease (CAD) and related risk factors have been associated with increased risks of mild cognitive impairment and progression to dementia. A decline in verbal memory performance is a key marker of cognitive impairment in CAD, although deterioration may be mitigated in individuals undertaking exercise interventions. Accumulating evidence suggests that long-chain ceramides may play a role in pathological neurodegeneration by mediating cell death mechanisms. Higher concentrations of ceramides have been associated with the development and progression of CAD but their relationship with memory performance has not been assessed in this population. Methods: Patients with CAD were interviewed at entry and completion of cardiac rehabilitation (CR). The California Verbal Learning Test 2 nd ed. (CVLT-II) was administered at entry and after 1 year to assess memory. Z-scores were calculated from the long-delay free recall (LDFR) outcome of the CVLT-II word list based on age, gender and education matched norms. Baseline plasma ceramide (d18:0/16:0-d18:0/26:1) concentrations were measured from fasting plasma samples using HPLCcoupled electrospray ionization tandem mass spectrometry. Repeated measures general linear models were used to determine the association between baseline plasma ceramides and the change in LDFR Z-scores between the baseline and follow-up time points, controlling for age and body mass index (BMI). Pearson correlations were used to determine the direction of the associations using one-year LDFR change Z-scores. Results: Patients with CAD (n ¼ 34, mean age 62 6 9 years, 85% male, total education 17 6 3 years) showed improved verbal memory performance after 1 year of CR (mean change LDFR Z-score ¼ 0.88 6 0.76). Higher baseline d18:1/22:0 (F 1,30 ¼ 5.140, P ¼ 0.027) and d18:1/24:0 (F 1,30 ¼ 4.157, P ¼ 0.050) concentrations were significantly associated with less improvement in verbal memory performance over 1 year of CR. Conclusions: Higher baseline d18:1/22:0 and d18:1/24:0 concentrations predicted less improvement in verbal memory performance over 1 year of CR. These preliminary findings suggest that plasma ceramides may be possible biomarkers of cognitive response to CR in CAD patients. The need for a prospective longitudinal study
P277
to explore the association between ceramides and cognitive function in CAD patients who are likely to have aberrant ceramide metabolism is strongly supported. P2-041
VISUAL CONTRAST SENSITIVITY AS A NOVEL BIOMARKER: DISCRIMINATIVE ANALYSIS USING ELASTIC NET TO CLASSIFY ALZHEIMER’S DISEASE, MCI AND OLDER ADULTS WITH COGNITIVE COMPLAINTS
Jingwen Yan1, Taiyong Li2, Brenna McDonald3, Shannon Risacher3, Darrell WuDunn4, Martin Farlow5, Susan M. Pepin6, Laura Flashman7, Heather Wishart6, Robert Santulli7, Andrew Saykin8, Li Shen3, 1Indiana University, Indianapolis, Indiana, United States; 2Southwestern University of Finance and Economics, Chengdu, China; 3Indiana University School of Medicine, Indianapolis, Indiana, United States; 4Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States; 5Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, United States; 6Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, United States; 7Dartmouth Medical School, Lebanon, New Hampshire, United States; 8 Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, United States. Background: Visual deficits in contrast sensitivity, assessed using frequency doubling technology (FDT), have been studied in Alzheimer’s disease (AD), and been related to brain atrophy measures and cognitive functioning [1,2]. This study aims to examine the effectiveness of advanced classification methodology for classifying early and prodromal stages of disease (AD, mild cognitive impairment (MCI), older adults with cognitive complaints, healthy controls) using visual contrast sensitivity test data. Methods: Participants (n ¼ 77) included those with mild AD (n ¼ 9), amnestic MCI (n ¼ 27), older adults with informant-verified cognitive complaints but no significant
Figure 1. Visual field maps of classifier weights of 110 regional measures: (a) HC vs AD, (b) CC vs AD, and (c) MCI vs AD. Blue (red) indicates decreased (increased) level in cases.
Poster Presentations: P2
sensitivity, performance, and inter-lot reproducibility and was able to measure differences in A b 1-42 levels between normal and AD samples. The results show an average LLOD (66 runs, 3 lots) of 0.35 pg/mL with a quantitative range of 3 to 2000 pg/mL. The precision, accuracy, and total error were determined from human CSF control samples with typical inter- and intra-plate precision < 12% CV. Dilution linearity and spike recovery testing demonstrated minimal matrix effects at 1:8 dilution of CSF and accurate quantitation of A b 1-42 peptide over the range of the assay. The assay exhibited tolerance of CSF contamination with hemolyzed blood and showed no significant cross-reactivity to closely related A b peptides, suggesting the assay was highly specific for A b 1-42. Conclusions: A new assay was developed and analytically validated to measure A b 1-42 in human CSF. The A b 1-42 assay had good analytical performance characteristics, inter-lot consistency, and the ability to distinguish A b 1-42 levels between normal and AD CSF samples. This assay will support ongoing efforts to standardize AD biomarker testing.
P2-037
DEVELOPMENT AND ANALYTICAL VALIDATION OF A NOVEL ASSAY FOR MEASUREMENT OF TOTAL TAU IN HUMAN CSF
Jill Dunty1, Flora Berisha2, Leonid Dzantiev1, Adam Simon3, Carol Gleason4, Oitak (Allen) Wong4, Mwanatumu Mbwana1, Sara Hapip1, Qian Ning1, Franklin Braffett1, Sarah Robles1, George Green4, Robert Neely5, Holly Soares6, James Wilbur1, Pankaj Oberoi1, David Stewart1, Paul Rhyne4, 1Meso Scale Discovery, Gaithersburg, Maryland, United States; 2Bristol Myers Squibb, Lawrenceville, New Jersey, United States; 3AJ Simon Enterprises LLC, Yardley, Pennsylvania, United States; 4Bristol-Myers Squibb Company, Princeton, New Jersey, United States; 5Bristol-Myers Squibb, Princeton, New Jersey, United States; 6 Bristol-Myers Squibb, Wallingford, New Jersey, United States. Background: Measurement of Alzheimer’s disease (AD) biomarkers in clinical cerebrospinal fluid (CSF) samples has been challenging with existing assays due to inter-lot variability, matrix interferences, and inconsistent quantitation. Here we describe the development and analytical validation of an assay to measure Total Tau in human CSF using Fit-forPurpose and CLSI principles. Elements of assay development and performance are presented as well as results of multi-lot validation. Methods: Monoclonal antibodies were evaluated and selected based on sensitivity, specificity, affinity, and performance characteristics in human CSF. Critical reagents were subjected to biochemical and functional characterization to verify purity, integrity, and lot-to-lot consistency. The assay was developed with MSD’s MULTI-ARRAYÒ technology and optimized to minimize CSF matrix effects and interferences. Analytical validation was assessed across three independent kit lots to verify performance including sensitivity, accuracy, and precision using matrix-based validation samples. Tests were conducted by multiple analysts over multiple runs and days. Dilution linearity and spike recovery were measured using well-curated normal and AD CSF samples. Results: The assay demonstrated good sensitivity, performance, and inter-lot reproducibility and differentiated between normal and AD CSF samples. The average LLOD determined from 54 runs over three independent kit lots was 10 pg/mL with a quantitative range of 30 to 8000 pg/mL. The precision, accuracy, and total error were determined from matrix-based controls with typical precision of <10% CV (inter-plate) and <5% CV (intra-plate). Dilution linearity and spike recovery testing demonstrated quantitation of Tau protein over the range of the assay and minimal interference from human CSF matrix. Furthermore, the assay detected 6 isoforms of human Tau and was tolerant of significant CSF contamination with hemolyzed blood. Data also showed that the assay measured elevated levels of Tau in AD samples compared to healthy samples. Conclusions: A new assay was developed and analytically validated to measure Tau in human CSF. The result is an assay with good analytical performance characteristics and lot to lot reproducibility with the ability to distinguish Tau levels between healthy and AD CSF samples. This assay will support ongoing efforts to standardize testing of biomarkers for AD and other tauopathies.
P2-038
LATENT VARIABLES OFFER A COST-EFFECTIVE APPROACH TO DEMENTIA CASE-FINDING
Donald Royall1, Raymond Palmer2, 1UTHSCSA Psychiatry, San Antonio, Texas, United States; 2UTHSCSA, San Antonio, Texas, United States. Background: Structural equation models can explicitly distinguish dementia-relevant variance in cognitive task performance. The resulting latent variable (ie, “d” for dementia) represents an “error free” continuously varying endophenotype. Here, we derive d’s serum biomarkers among participants of the Texas Alzheimer’s Research and Care Consortium (TARCC). Methods: We began with O’Bryant et al’s (2010) panel of 24 dementia-related biomarkers. All analyses were performed on statistically transformed data obtained from Rules Based Medicine (RBM) (Austin, TX). All observed variables were adjusted for age, education, gender, and RBM processing batch. Subjects included n ¼ 805 Alzheimer’s Disease (AD) cases and controls (n ¼ 655). First, we constructed three latent variables; “d”, ie, the cognitive correlates of Instrumental Activities of Daily Living (IADL), “DEP”, ie, the cognitive correlates of depressive symptoms, and “g’”, ie, the residual shared variance in cognitive performance. Next, we simultaneously assessed d, DEP and g’ as potential mediators of each biomarker’s association with blindly adjudicated TARCC diagnoses. Next, we selected analytes related to dementia status through d, and used them as indicators of a fourth latent construct (i.e., d’s biomarkers). Finally, we culled this set to achieve the most parsimonious combination that accurately replicated TARCC diagnoses. Results: Eleven serum analytes were significantly related to diagnosis through d. These were reduced to three, i.e., TNF- b, Mip-1 a and thrombopoetin which explained 87% of the variance in adjudicated diagnoses. Model fit was acceptable (CMIN/df ¼ 5.96, P ¼ 0.001; CFI ¼ 0.948; RMSEA ¼ 0.058). The resulting latent construct (i.e., the biomarkers of d) predicted dementia status (r ¼ -0.83) and achieved an Area Under the Curve (AUC) of 0.869 (S ¼ 0.80, SP ¼ 0.80). If caregiver rated IADL, also strongly related to d, is added as an indicator, the AUC increases to 0.91 (Figure 1). Conclusions: This study illustrates how a latent variable approach to dementia case finding can result in an endophenotype that is highly predictive of clinical diagnoses. d’s biomarkers may offer an objective and cost-effect alternative to clinical dementia assessment. Although a diagnostic “blood test” for AD may be achievable by this approach, it remains necessary to demonstrate its specificity for AD.
P2-039
NOVEL TAU FRAGMENTS ARE PRESENT IN HUMAN CSF
Jere Meredith1, Randall Slemmon2, Valerie Guss1, Anthony Lanzetti1, Sethu Sankaranarayanan3, Holly Soares1, Kaj Blennow4, Charlie Albright1, Michael Ahlijanian1, 1Bristol-Myers Squibb, Wallingford, Connecticut, United States; 2Johnson & Johnson, Titusville, New Jersey, United States; 3 Bristol-Myers Squibb, Wallingford, New Jersey, United States; 4 Sahlgrenska Academy at the University of Gothenburg, M€olndal, Sweden. Background: CSF Ab42, Tau and p181Tau are widely accepted diagnostic biomarkers of Alzheimer’s disease (AD). Results from numerous studies
Poster Presentations: P2 demonstrate that CSF Tau levels are w2X higher in mild-to-moderate AD compared to age-matched controls. In addition, this increase in CSF Tau is detected prior to the onset of clinical symptoms, and thus is predictive of the conversion from predementia (MCI) to clinical disease. Despite the importance as a diagnostic biomarker, the molecular nature of Tau present in CSF is not known. Methods: We have employed CSF denaturation coupled with reverse-phase HPLC in order to enrich and concentrate Tau and to further characterize the CSF Tau profile. Individual fractions from pooled AD and control CSF samples were analyzed by SDS-PAGE/Western blot (WB) using various anti-Tau antibodies or by using in-house, research-grade Tau ELISAs. Results: Multiple fragments of Tau, with apparent MW sizes ranging from w15 kD to 40 kD, were identified by WB using an antibody that recognizes the mid-domain of Tau, but not an isotype control IgG. A subset of these bands was recognized using an antibody specific for the N-terminal of Tau. In contrast, relatively low levels of C-terminal-containing fragments were detected as demonstrated using a C-terminal specific antibody. Tau ELISA results confirmed the WB data and demonstrated that differences in Tau levels between AD and control CSF are more prominent in specific fractions, corresponding to certain apparent molecular weight Tau fragments. Conclusions: Our results demonstrate the existence of multiple Tau fragments in CSF and suggest that a subset of these fragments are increased in AD CSF. These particular Tau fragments may have utility as disease and/or pharmacodynamic biomarkers. P2-040
PLASMA CERAMIDE CONCENTRATIONS ARE ASSOCIATED WITH CHANGE IN VERBAL MEMORY PERFORMANCE IN PATIENTS UNDERTAKING CARDIAC REHABILITATION
Krista Lanctot1, Mahwesh Saleem1, Veera Vankata Ratnam Bandaru2, Nathan Herrmann1, Walter Swardfager1, Michelle Mielke3, Norman Haughey2, Paul Oh4, 1Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 2Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; 3Mayo Clinic, Rochester, Minnesota, United States; 4Toronto Rehabilitation Institute, Toronto, Ontario, Canada. Background: Coronary artery disease (CAD) and related risk factors have been associated with increased risks of mild cognitive impairment and progression to dementia. A decline in verbal memory performance is a key marker of cognitive impairment in CAD, although deterioration may be mitigated in individuals undertaking exercise interventions. Accumulating evidence suggests that long-chain ceramides may play a role in pathological neurodegeneration by mediating cell death mechanisms. Higher concentrations of ceramides have been associated with the development and progression of CAD but their relationship with memory performance has not been assessed in this population. Methods: Patients with CAD were interviewed at entry and completion of cardiac rehabilitation (CR). The California Verbal Learning Test 2 nd ed. (CVLT-II) was administered at entry and after 1 year to assess memory. Z-scores were calculated from the long-delay free recall (LDFR) outcome of the CVLT-II word list based on age, gender and education matched norms. Baseline plasma ceramide (d18:0/16:0-d18:0/26:1) concentrations were measured from fasting plasma samples using HPLCcoupled electrospray ionization tandem mass spectrometry. Repeated measures general linear models were used to determine the association between baseline plasma ceramides and the change in LDFR Z-scores between the baseline and follow-up time points, controlling for age and body mass index (BMI). Pearson correlations were used to determine the direction of the associations using one-year LDFR change Z-scores. Results: Patients with CAD (n ¼ 34, mean age 62 6 9 years, 85% male, total education 17 6 3 years) showed improved verbal memory performance after 1 year of CR (mean change LDFR Z-score ¼ 0.88 6 0.76). Higher baseline d18:1/22:0 (F 1,30 ¼ 5.140, P ¼ 0.027) and d18:1/24:0 (F 1,30 ¼ 4.157, P ¼ 0.050) concentrations were significantly associated with less improvement in verbal memory performance over 1 year of CR. Conclusions: Higher baseline d18:1/22:0 and d18:1/24:0 concentrations predicted less improvement in verbal memory performance over 1 year of CR. These preliminary findings suggest that plasma ceramides may be possible biomarkers of cognitive response to CR in CAD patients. The need for a prospective longitudinal study
P277
to explore the association between ceramides and cognitive function in CAD patients who are likely to have aberrant ceramide metabolism is strongly supported. P2-041
VISUAL CONTRAST SENSITIVITY AS A NOVEL BIOMARKER: DISCRIMINATIVE ANALYSIS USING ELASTIC NET TO CLASSIFY ALZHEIMER’S DISEASE, MCI AND OLDER ADULTS WITH COGNITIVE COMPLAINTS
Jingwen Yan1, Taiyong Li2, Brenna McDonald3, Shannon Risacher3, Darrell WuDunn4, Martin Farlow5, Susan M. Pepin6, Laura Flashman7, Heather Wishart6, Robert Santulli7, Andrew Saykin8, Li Shen3, 1Indiana University, Indianapolis, Indiana, United States; 2Southwestern University of Finance and Economics, Chengdu, China; 3Indiana University School of Medicine, Indianapolis, Indiana, United States; 4Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States; 5Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, United States; 6Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, United States; 7Dartmouth Medical School, Lebanon, New Hampshire, United States; 8 Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, United States. Background: Visual deficits in contrast sensitivity, assessed using frequency doubling technology (FDT), have been studied in Alzheimer’s disease (AD), and been related to brain atrophy measures and cognitive functioning [1,2]. This study aims to examine the effectiveness of advanced classification methodology for classifying early and prodromal stages of disease (AD, mild cognitive impairment (MCI), older adults with cognitive complaints, healthy controls) using visual contrast sensitivity test data. Methods: Participants (n ¼ 77) included those with mild AD (n ¼ 9), amnestic MCI (n ¼ 27), older adults with informant-verified cognitive complaints but no significant
Figure 1. Visual field maps of classifier weights of 110 regional measures: (a) HC vs AD, (b) CC vs AD, and (c) MCI vs AD. Blue (red) indicates decreased (increased) level in cases.