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The effects of albumin and white matter hyperintensity on cognitive function in the elderly
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Poster Presentations: P1
specificity in differentiating AD from controls with a sensitivity of 70% and specificity of 92%. Conclusions: Improved versions of the CSF Ab42 and Tau assays showed good clinical performance in differentiating AD and MCI from controls. Current results are consistent with literature reporting low levels of CSF Ab42 and high Tau in patients with AD.
P1-323
THE IMPACT OF ASSAY FORMAT ON SENSITIVITY AND MATRIX TOLERANCE FOR PLASMA BETA-AMYLOID PEPTIDE (Ab-40 AND Ab-42) MEASUREMENTS
Allison Cicero1, Pankaj Oberoi2, Sid O’Bryant3, Robert Barber4, Jill Dunty5, David Stewart2, Robert Umek2, Paula Eason2, 1Meso Scale Diagnostics, Gaithersburg, Maryland, United States; 2Meso Scale Discovery, Gaithersburg, Maryland, United States; 3University of North Texas Health Science Center, Lubbock, Texas, United States; 4University of North Texas Health Science Center, Fort Worth, Texas, United States; 5Meso Scale Discovery, Gaithersburg, Maryland, United States. Background: Ab peptides in blood can be measured with sensitive immunoassays yet absolute Ab peptide concentrations differ widely among reports. Assay format, antibody orientation, and matrix interferences contribute to assay variability. Here we describe an evaluation of multiple assay formats with respect to sensitivity and plasma matrix tolerance. Methods: Immunoassays developed by Meso Scale DiscoveryÒ (MSD) included a format that paired an N-terminal-domain binding antibody (6E10) as capture antibody with peptide-specific (Ab-40 or Ab-42) mouse monoclonal antibodies as detectors and an alternate format that paired the peptide-specific antibodies as capture antibodies with a 6E10 detector. Assay sensitivity (the lowest calibration point for which recovery was within 20% of the expected concentration and imprecision was less than 20%) was determined for each assay. Studies to evaluate matrix tolerance included dilutional linearity of pooled plasma from 5- to 80-fold dilution and spike and recovery studies with 500 pg/mL Ab-40 and Ab-42 peptides. Experimental samples were measured in duplicate using both assay orientations. Results: The Ab-42 assay with the peptide-specific capture antibody shows greater sensitivity than the assay using a 6E10 capture antibody (4.12 pg/mL vs. 37 pg/ mL). Both Ab-40 assay orientations are equally sensitive (less than 4.5 pg/mL). Ab-42 concentrations exhibit a proportional bias between the two formats, with absolute measured concentrations 60-90% lower when using the peptide capture antibody format, whereas Ab-40 concen-
trations exhibit a proportional bias of 20-40% using the peptide-specific capture orientation. Dilutional linearity is better for Ab-42 and Ab-40 assays using the 6E10 capture antibody format, falling between 80120% for all dilutions. In spike and recovery studies, Ab-42 and Ab40 recover between 80-120% using the 6E10 capture antibody format. In contrast, recovery of Ab-42 in spiked plasma diluted 5-fold is 30% using the peptide capture antibody format. A 40-fold dilution is required to eliminate plasma matrix effects, whereas a 4-fold dilution is sufficient to eliminate matrix effects in cerebrospinal fluid for the Ab-42 assay. Conclusions: This study suggests that an unidentified component in plasma interferes with binding of peptide-specific antibodies to the Ab42 C-terminus. An assay format that includes 6E10 as the capture antibody reduces the effect of this interferent.
P1-324
THE EFFECTS OF ALBUMIN AND WHITE MATTER HYPERINTENSITY ON COGNITIVE FUNCTION IN THE ELDERLY
Sang Joon Son1, Kang Soo Lee2, Chang Hyung Hong3, 1Ajou University, School of Medicine, Suwon-si, Gyeonggi-do, South Korea; 2Cha University, Seoul, South Korea; 3Ajou University School of Medicine, Suwon-si, Gyeonggi-do, South Korea. Background: Low albumin level and subcortical ischemic changes might be associated with cognitive performance in the elderly. Methods: We examined the relationship between albumin level, white matter hyperintensity (WMH) and cognitive function among 1038 old adults who were evaluated at the Clinical Research Center for Dementia of South Korea. Blood samples were drawn from all consenting subjects, and an albumin level was treated as a categorical variable based on quartile. Cognitive function was assessed by the Korean version of Mini Mental State Examination (K-MMSE). We also evaluated the severity of WMH as mild and sever level on brain MRI images. Results: After a multivariable adjustment, we could found significant differences in K-MMSE score among albumin level groups (F ¼ 6.5, P <0.001) but not between WMH mild and severe groups (t ¼ 0.2, P ¼ 0.827), independently. Interestingly, the interaction between albumin level and the severity of WMH was shown to be significantly associated with cognitive function (analysis of covariance, F ¼ 3.8, P ¼ 0.010). In post hoc tests, a higher K-MMSE score was rather observed in subjects with higher albumin level and severe WMH. Conclusions: Albumin level with severe subcortical ischemic changes appears to be related to cognitive function in old adults.
Table 1 Characteristics of subjects according to white matter hyperintensity levela White Matter Hyperintensity Level Variable Gender Physical illness
Age(years) Education(years) Illness duration(months) BMI(kg/m2) albumin(g/dl) K-MMSE GDS-15
Male Hypertension Diabetes Hyperlipidemia Cardiac disorder
Mild (N¼579)
Severe (N¼459)
X2 or t
P
179 (30.9) 262 (45.3) 85 (14.7) 93 (16.1) 42 (7.3) 70.0 6 8.5 9.9 6 5.1 41.4 6 32.0 23.7 6 3.1 4.2 6 0.3 23.2 6 5.5 4.4 6 3.7
162 (35.3) 302 (65.8) 88 (19.2) 69 (15.0) 54 (11.8) 74.8 6 6.5 8.8 6 5.1 46.3 6 37.8 24.0 6 3.3 4.1 6 0.3 23.1 6 4.9 5.5 6 4.2
2.23 43.56 3.72 0.21 6.21 -10.3 3.4 -2.2 -1.3 5.1 0.2 -4.6
0.144 <0.001 0.065 0.668 0.017 <0.001 0.001 0.028 0.179 <0.001 0.827 <0.001
Notes: BMI¼body mass index; Hb¼hemoglobin; K-MMSE¼Korean Mini Mental State Examination; GDS-15¼15-item geriatric depression scale. All values are mean6SD (continuous variables) or frequencies (N,%)(categorical variables)
a
Poster Presentations: P1
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Table 2 Characteristics of subjects according to albumin levela Albumin Level(quartile, g/dl) Variable Gender Physical illness
Male Hypertension Diabetes Hyperlipidemia Cardiac illness Mild
WMH Age(years) Education(years) Illness duration(months) BMI(kg/m2) K-MMSE GDS-15
Q1 (2.6-3.9) (N¼254)
Q2 (4.0-4.1) (N¼271)
Q3 (4.2-4.3) (N¼285)
Q4 (4.4-5.0) (N¼228)
X2 or F
P
91 (35.8) 142 (55.9) 51 (20.1) 34 (13.4) 35 (13.8) 206 (81.1) 75.2 6 7.5 9.1 6 4.9 44.1 6 31.7 23.4 6 3.4 22.2 6 5.4 5.2 6 4.2
86 (31.7) 133 (49.1) 43 (15.9) 33 (12.2) 19 (7.0) 223 (82.3) 72.6 6 6.8 9.0 6 5.5 44.1 6 33.4 24.3 6 3.2 22.9 6 5.2 5.1 6 4.0
100 (35.1) 159 (55.8) 49 (17.2) 42 (14.7) 27 (9.5) 226 (79.3) 71.2 6 8.7 9.7 6 5.1 46.2 6 38.8 23.4 6 3.1 23.4 6 4.8 4.463.7
64 (28.1) 130 (57.0) 30 (13.2) 53 (23.2) 15 (6.6) 194 (85.1) 69.2 6 8.1 10.0 6 4.9 38.9 6 33.9 24.4 6 3.0 24.2 6 5.4 4.7 6 4.0
4.2 4.2 4.3 13.6 9.8 3.0 25.3 2.3 1.8 7.2 6.5 2.2
0.243 0.243 0.228 0.003 0.021 0.395 <0.001 0.079 0.139 <0.001 <0.001 0.086
Notes. WMH¼white matter hyperintensities; BMI¼body mass index; K-MMSE¼Korean Mini Mental State Examination; GDS-15¼15-item geriatric depression scale. a All values are mean6SD (continuous variables) or frequencies (N,%)(categorical variables)
Table 3 Interactive effect on K-MMSE score between WMH and albumin levela Source
Sum of squares
df
Mean of squares
F
p
Gender Age Education Illness duration Body mass index GDS-15 Albumin level WMH level Albumin X WMH Error Total
10.2 350.0 2109.8 793.5 513.4 12.1 255.1 145.9 265.9 21987.1 533520.0
1 1 1 1 1 1 3 1 3 949 963
10.2 350.0 2109.8 793.5 513.4 12.1 85.0 145.9 88.6 23.2
0.4 15.1 91.1 34.2 22.2 0.5 3.7 6.3 3.8
0.508 0.001 <0.001 <0.001 <0.001 0.470 0.012 0.012 0.010
Notes. WMH¼white matter hyperintensities; K-MMSE¼Korean Mini Mental State Examination; GDS-15¼15-item geriatric depression scale. R Squares ¼0.182 (Adjusted R Squared ¼ 0.171) a Adjusted by gender, age, education, illness duration, BMI and depression score.
P1-325
RELATING MEMORY TO FUNCTIONAL ACTIVITIES IN NORMAL AGING, ALZHEIMER’S DISEASE AND RELATED DISORDERS USING HIERARCHICAL BAYESIAN COGNITIVE PROCESSING MODELS
James Pooley1, William Shankle2, Junko Hara3, Barry Reisberg4, Michael Lee1, 1University of California at Irvine, Irvine, California, United States; 2Medical Care Corporation, Newport Beach, California, United States; 3Shankle Clinic, Newport Beach, California, United States; 4New York University, New York, New York, United States. Backgrounds: Relating cognition to function in Alzheimer’s disease and related disorders (ADRD) is important for more meaningful interpretation of cognitive test results in clinical trials and clinical practice. Previously, Hierarchical Bayesian Cognitive Processing models (HBCP)
Poster Presentations: P1
specificity in differentiating AD from controls with a sensitivity of 70% and specificity of 92%. Conclusions: Improved versions of the CSF Ab42 and Tau assays showed good clinical performance in differentiating AD and MCI from controls. Current results are consistent with literature reporting low levels of CSF Ab42 and high Tau in patients with AD.
P1-323
THE IMPACT OF ASSAY FORMAT ON SENSITIVITY AND MATRIX TOLERANCE FOR PLASMA BETA-AMYLOID PEPTIDE (Ab-40 AND Ab-42) MEASUREMENTS
Allison Cicero1, Pankaj Oberoi2, Sid O’Bryant3, Robert Barber4, Jill Dunty5, David Stewart2, Robert Umek2, Paula Eason2, 1Meso Scale Diagnostics, Gaithersburg, Maryland, United States; 2Meso Scale Discovery, Gaithersburg, Maryland, United States; 3University of North Texas Health Science Center, Lubbock, Texas, United States; 4University of North Texas Health Science Center, Fort Worth, Texas, United States; 5Meso Scale Discovery, Gaithersburg, Maryland, United States. Background: Ab peptides in blood can be measured with sensitive immunoassays yet absolute Ab peptide concentrations differ widely among reports. Assay format, antibody orientation, and matrix interferences contribute to assay variability. Here we describe an evaluation of multiple assay formats with respect to sensitivity and plasma matrix tolerance. Methods: Immunoassays developed by Meso Scale DiscoveryÒ (MSD) included a format that paired an N-terminal-domain binding antibody (6E10) as capture antibody with peptide-specific (Ab-40 or Ab-42) mouse monoclonal antibodies as detectors and an alternate format that paired the peptide-specific antibodies as capture antibodies with a 6E10 detector. Assay sensitivity (the lowest calibration point for which recovery was within 20% of the expected concentration and imprecision was less than 20%) was determined for each assay. Studies to evaluate matrix tolerance included dilutional linearity of pooled plasma from 5- to 80-fold dilution and spike and recovery studies with 500 pg/mL Ab-40 and Ab-42 peptides. Experimental samples were measured in duplicate using both assay orientations. Results: The Ab-42 assay with the peptide-specific capture antibody shows greater sensitivity than the assay using a 6E10 capture antibody (4.12 pg/mL vs. 37 pg/ mL). Both Ab-40 assay orientations are equally sensitive (less than 4.5 pg/mL). Ab-42 concentrations exhibit a proportional bias between the two formats, with absolute measured concentrations 60-90% lower when using the peptide capture antibody format, whereas Ab-40 concen-
trations exhibit a proportional bias of 20-40% using the peptide-specific capture orientation. Dilutional linearity is better for Ab-42 and Ab-40 assays using the 6E10 capture antibody format, falling between 80120% for all dilutions. In spike and recovery studies, Ab-42 and Ab40 recover between 80-120% using the 6E10 capture antibody format. In contrast, recovery of Ab-42 in spiked plasma diluted 5-fold is 30% using the peptide capture antibody format. A 40-fold dilution is required to eliminate plasma matrix effects, whereas a 4-fold dilution is sufficient to eliminate matrix effects in cerebrospinal fluid for the Ab-42 assay. Conclusions: This study suggests that an unidentified component in plasma interferes with binding of peptide-specific antibodies to the Ab42 C-terminus. An assay format that includes 6E10 as the capture antibody reduces the effect of this interferent.
P1-324
THE EFFECTS OF ALBUMIN AND WHITE MATTER HYPERINTENSITY ON COGNITIVE FUNCTION IN THE ELDERLY
Sang Joon Son1, Kang Soo Lee2, Chang Hyung Hong3, 1Ajou University, School of Medicine, Suwon-si, Gyeonggi-do, South Korea; 2Cha University, Seoul, South Korea; 3Ajou University School of Medicine, Suwon-si, Gyeonggi-do, South Korea. Background: Low albumin level and subcortical ischemic changes might be associated with cognitive performance in the elderly. Methods: We examined the relationship between albumin level, white matter hyperintensity (WMH) and cognitive function among 1038 old adults who were evaluated at the Clinical Research Center for Dementia of South Korea. Blood samples were drawn from all consenting subjects, and an albumin level was treated as a categorical variable based on quartile. Cognitive function was assessed by the Korean version of Mini Mental State Examination (K-MMSE). We also evaluated the severity of WMH as mild and sever level on brain MRI images. Results: After a multivariable adjustment, we could found significant differences in K-MMSE score among albumin level groups (F ¼ 6.5, P <0.001) but not between WMH mild and severe groups (t ¼ 0.2, P ¼ 0.827), independently. Interestingly, the interaction between albumin level and the severity of WMH was shown to be significantly associated with cognitive function (analysis of covariance, F ¼ 3.8, P ¼ 0.010). In post hoc tests, a higher K-MMSE score was rather observed in subjects with higher albumin level and severe WMH. Conclusions: Albumin level with severe subcortical ischemic changes appears to be related to cognitive function in old adults.
Table 1 Characteristics of subjects according to white matter hyperintensity levela White Matter Hyperintensity Level Variable Gender Physical illness
Age(years) Education(years) Illness duration(months) BMI(kg/m2) albumin(g/dl) K-MMSE GDS-15
Male Hypertension Diabetes Hyperlipidemia Cardiac disorder
Mild (N¼579)
Severe (N¼459)
X2 or t
P
179 (30.9) 262 (45.3) 85 (14.7) 93 (16.1) 42 (7.3) 70.0 6 8.5 9.9 6 5.1 41.4 6 32.0 23.7 6 3.1 4.2 6 0.3 23.2 6 5.5 4.4 6 3.7
162 (35.3) 302 (65.8) 88 (19.2) 69 (15.0) 54 (11.8) 74.8 6 6.5 8.8 6 5.1 46.3 6 37.8 24.0 6 3.3 4.1 6 0.3 23.1 6 4.9 5.5 6 4.2
2.23 43.56 3.72 0.21 6.21 -10.3 3.4 -2.2 -1.3 5.1 0.2 -4.6
0.144 <0.001 0.065 0.668 0.017 <0.001 0.001 0.028 0.179 <0.001 0.827 <0.001
Notes: BMI¼body mass index; Hb¼hemoglobin; K-MMSE¼Korean Mini Mental State Examination; GDS-15¼15-item geriatric depression scale. All values are mean6SD (continuous variables) or frequencies (N,%)(categorical variables)
a
Poster Presentations: P1
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Table 2 Characteristics of subjects according to albumin levela Albumin Level(quartile, g/dl) Variable Gender Physical illness
Male Hypertension Diabetes Hyperlipidemia Cardiac illness Mild
WMH Age(years) Education(years) Illness duration(months) BMI(kg/m2) K-MMSE GDS-15
Q1 (2.6-3.9) (N¼254)
Q2 (4.0-4.1) (N¼271)
Q3 (4.2-4.3) (N¼285)
Q4 (4.4-5.0) (N¼228)
X2 or F
P
91 (35.8) 142 (55.9) 51 (20.1) 34 (13.4) 35 (13.8) 206 (81.1) 75.2 6 7.5 9.1 6 4.9 44.1 6 31.7 23.4 6 3.4 22.2 6 5.4 5.2 6 4.2
86 (31.7) 133 (49.1) 43 (15.9) 33 (12.2) 19 (7.0) 223 (82.3) 72.6 6 6.8 9.0 6 5.5 44.1 6 33.4 24.3 6 3.2 22.9 6 5.2 5.1 6 4.0
100 (35.1) 159 (55.8) 49 (17.2) 42 (14.7) 27 (9.5) 226 (79.3) 71.2 6 8.7 9.7 6 5.1 46.2 6 38.8 23.4 6 3.1 23.4 6 4.8 4.463.7
64 (28.1) 130 (57.0) 30 (13.2) 53 (23.2) 15 (6.6) 194 (85.1) 69.2 6 8.1 10.0 6 4.9 38.9 6 33.9 24.4 6 3.0 24.2 6 5.4 4.7 6 4.0
4.2 4.2 4.3 13.6 9.8 3.0 25.3 2.3 1.8 7.2 6.5 2.2
0.243 0.243 0.228 0.003 0.021 0.395 <0.001 0.079 0.139 <0.001 <0.001 0.086
Notes. WMH¼white matter hyperintensities; BMI¼body mass index; K-MMSE¼Korean Mini Mental State Examination; GDS-15¼15-item geriatric depression scale. a All values are mean6SD (continuous variables) or frequencies (N,%)(categorical variables)
Table 3 Interactive effect on K-MMSE score between WMH and albumin levela Source
Sum of squares
df
Mean of squares
F
p
Gender Age Education Illness duration Body mass index GDS-15 Albumin level WMH level Albumin X WMH Error Total
10.2 350.0 2109.8 793.5 513.4 12.1 255.1 145.9 265.9 21987.1 533520.0
1 1 1 1 1 1 3 1 3 949 963
10.2 350.0 2109.8 793.5 513.4 12.1 85.0 145.9 88.6 23.2
0.4 15.1 91.1 34.2 22.2 0.5 3.7 6.3 3.8
0.508 0.001 <0.001 <0.001 <0.001 0.470 0.012 0.012 0.010
Notes. WMH¼white matter hyperintensities; K-MMSE¼Korean Mini Mental State Examination; GDS-15¼15-item geriatric depression scale. R Squares ¼0.182 (Adjusted R Squared ¼ 0.171) a Adjusted by gender, age, education, illness duration, BMI and depression score.
P1-325
RELATING MEMORY TO FUNCTIONAL ACTIVITIES IN NORMAL AGING, ALZHEIMER’S DISEASE AND RELATED DISORDERS USING HIERARCHICAL BAYESIAN COGNITIVE PROCESSING MODELS
James Pooley1, William Shankle2, Junko Hara3, Barry Reisberg4, Michael Lee1, 1University of California at Irvine, Irvine, California, United States; 2Medical Care Corporation, Newport Beach, California, United States; 3Shankle Clinic, Newport Beach, California, United States; 4New York University, New York, New York, United States. Backgrounds: Relating cognition to function in Alzheimer’s disease and related disorders (ADRD) is important for more meaningful interpretation of cognitive test results in clinical trials and clinical practice. Previously, Hierarchical Bayesian Cognitive Processing models (HBCP)