- Email: [email protected]
Glycosylation of serum protein as a new diagnostic marker for Alzheimer's disease
S506
Poster Presentations P3
2 University of Southern California, Los Angeles, CA, USA; 3The Weizmann Institute of Science, Rehovot, Israel. Contact e-mail: [email protected]
Background: A definite diagnosis of Alzheimer’s disease (AD) is determined following brain autopsy by detection of hallmark pathologies of the disease: an extracellular aggregates of amyloid-b (Ab) peptides, termed as Ab plaques, and an intracellular neurofibrillary tangles. Presently, noninvasive monitoring of Ab plaques in the brains of living patients is, however, inadequate due to restricted resolution and specificity. We, thus, hypothesized that the eyes can serve as a window to the brain for direct and noninvasive imaging of AD. Methods: To this end, we used APPswe/PS1dE9 double-transgenic AD mice, which faithfully represent some of the key pathologies found in the human disease. We investigated presence and formation of amyloid plaques in retinas from these AD mice, as well as estimated the correlation between retinal amyloid plaques and the plaque pathology in the brain. Lastly, we evaluated responsiveness of retinal plaques to an immune-based therapy and the ability to image them in live mice. Results: Here, we detected Ab plaques in retinal samples of AD mice, and found that Ab plaques appear in the retina significantly earlier than in the brain. Retinal plaques accumulated during disease progression, and in good correlation with brain pathology. Moreover, retinal Ab plaque number and size were significantly reduced following an immune-based therapy, which we found to be effective in reducing plaques in the brain. Systemic administration of a natural compound that binds and labels Ab plaques, allowed in vivo noninvasive visualization of retinal Ab plaques in live AD mice, with high resolution and specificity. Conclusions: These studies establish the potential of direct retinal Ab plaque imaging in live subjects as a promising tool for early AD diagnosis, prognosis and assessment of therapies. P3-189
ASSOCIATION BETWEEN GENE EXPRESSION OF PERIPHERAL BLOOD OXIDATIVE STRESS MARKERS AND ALZHEIMER’S DISEASE: THE NUN STUDY
Jon D. Wilson, Bharat Thyragarajan, Myron D. Gross, University of Minnesota, Fairview Hospital, Minneapolis, MN, USA. Contact e-mail: wils1355@ umn.edu Background: There is increasing evidence that oxidative stress plays an important role in the pathogenesis of several neurodegenerative disorders, including Alzheimer’s disease. Circulating concentrations of both SOD1 and HMOX1 protein have been associated with oxidative stress in neurons. We performed a case control study of 22 participants with clinical dementia and 22 controls within the Nun Study Cohort to evaluate the association between Copper-Zinc Superoxide Dismutase (SOD1) and Heme Oxygenase 1 (HMOX1) expression in peripheral blood and clinical dementia. Methods: The Nun Study cohort was begun with 678 sisters who were at least 75 years of age at enrollment. We randomly selected twenty-two individuals with severe clinical dementia, and twenty-two normal individuals from the Nun Study for evaluation. RNA was extracted with the RNeasy method from peripheral blood samples collected in PaxGENE tubes. The mRNA was used to assess relative expression of SOD1 and HMOX1 using Taqman gene expression assays (Applied Biosystems Inc.). The 18s ribosomal RNA was used as a housekeeping gene to standardize gene expression levels across all samples. Relative gene expression (copy fold change) was calculated using the Pfaffl method. Results: Expression of SOD1 was lower in cases as compared to controls (mean 6 SD: 0.68 6 0.26 vs. 0.77 6 0.15 respectively; p ¼ 0.13). In contrast, expression of HMOX1 was higher in cases as compared to controls (mean 6 SD: 1.00 6 0.23 vs. 0.84 6 0.23 respectively; p ¼ 0.17). Assay variability, based on 8 blinded duplicates, was 5.8% for both SOD1 and HMOX1 genes. Conclusions: This pilot study demonstrates the feasibility of utilizing expression levels of SOD1 and HMOX1 in peripheral blood and testing as risk factors for Alzheimer’s disease. Though the results were not statistically significant in this study with limited sample size, the direction of effect observed is consistent with previous studies that have shown associations between HMOX1, and SOD1 protein concentrations and Alzheimer’s disease. Future studies with larger samples will be needed to fully
evaluate oxidative stress markers in peripheral blood as risk factors for Alzheimer’s disease. P3-190
A NOVEL DIAGNOSTIC AND PROGNOSTIC FLUID BIOMARKER FOR EARLY ALZHEIMER’S DISEASE: YKL-40
Rebecca Craig-Schapiro1, Richard J. Perrin1, Catherine M. Roe2, Elizabeth A. Grant2, Deborah Carter2, Nigel J. Cairns2, Mark A. Mintun2, Elaine R. Peskind3, Ge Li3, Douglas R. Galasko4, Christopher M. Clark5, Joseph F. Quinn6, Gina D’Angelo2, James P. Malone2, R. Reid Townsend2, John C. Morris2, Anne M. Fagan2, David M. Holtzman2, 1Washington University in St. Louis, St. Louis, MO, USA; 2Washington University in St. Louis, St. Louis, MO, USA; 3University of Washington, Seattle, WA, USA; 4 University of California San Diego, San Diego, CA, USA; 5University of Pennsylvania, Philadelphia, PA, USA; 6Oregon Health Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: Clinicopathological studies suggest that Alzheimer’s disease (AD) pathology begins w10-20 years before the resulting cognitive impairment draws medical attention. Currently, AD diagnosis relies upon clinical assessment, without a definitive confirmatory laboratory test. Biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression would, therefore, be invaluable for patient care and efficient clinical trial design. Methods: To discover such AD biomarkers, we used two-dimensional difference gel electrophoresis and tandem mass spectrometry to identify cerebrospinal fluid (CSF) proteins that are increased or decreased in subjects with early AD relative to age-matched cognitively normal controls. YKL-40 (chitinase 3-like 1), a secreted 40-kDa glycoprotein of poorly understood function, was found to be significantly more abundant in AD CSF. To confirm this finding, we measured YKL-40 concentrations in the original cohort of CSF samples by enzyme-linked immunosorbent assay (ELISA). Results: Mean CSF YKL-40 levels were significantly higher in subjects with mild AD (N ¼ 23, Clinical Dementia Rating [CDR] 1) relative to age-matched controls (N ¼ 24, CDR 0). Subsequent evaluation of YKL-40 by ELISA in a larger, independent set of CSF samples (N ¼ 292) confirmed that YKL-40 is more abundant in the CSF of those with very mild and mild AD-type dementia. Importantly, CSF YKL-40 levels also predicted risk of developing dementia (conversion from CDR 0 to CDR>0) and of dementia progression from CDR 0.5 to 1; subjects with high CSF YKL40 values (327 ng/mL, corresponding to the upper tertile) converted and progressed faster than subjects with lower CSF YKL-40 values. In plasma, mean levels of YKL-40, evaluated in 237 subjects of the larger cohort, were significantly higher in the CDR>0 groups vs. the CDR 0 group. Plasma and CSF YKL-40 levels were correlated, with levels roughly 5-fold higher in CSF than in plasma. In an immunohistological study of human AD brain tissue, we detected YKL-40 within astrocytes in the vicinity of a subset of amyloid plaques, implicating YKL-40 as part of a neuroinflammatory response to Ab deposition. Conclusions: Together, these data suggest that YKL-40, as a putative indicator of neuroinflammation, has potential utility as a diagnostic and prognostic biomarker for the earliest stages of AD. P3-191
GLYCOSYLATION OF SERUM PROTEIN AS A NEW DIAGNOSTIC MARKER FOR ALZHEIMER’S DISEASE
Miyako Taniguchi1, Minoru Kouduki1, Yuka Okayama2, Mai Okazaki1, Daiki Jimbo1, Masashi Inoue1, Katsuya Urakami1, 1Tottori University, Yonago, Japan; 2Tottori University Hospital, Yonago, Japan. Contact e-mail: miyako@ med.tottori-u.ac.jp Background: We previously discovered that a few glycoproteins in the cerebrospinal fluid of Alzheimer’s disease patients (AD) had less lectin-binding activities. Especially one of them showed high diagnostic sensitivity and specificity for the AD against other non-AD groups even tauopathies. In this study, we examined the some serum glycoproteins as a new diagnostic marker for AD. Methods: We investigated serum samples obtained from
Poster Presentations P3 30 AD patients and 30 non-demented controls (NDC). The AD subjects were diagnosed according to NINCDS-ADRDA and DSM-IV criteria. We measured the glycosylation of serum glycproteins using lectin blot analysis and improved lectin enzyme-linked immunosorbent assay. The study was approved by the Tottori University Ethical Committee and informed consent was obtained from each patient or their relatives prior to inclusion in the study. The study was performed in accordance with the Helsinki Declaration. Results: We identified several kinds of sugar chain in some serum glycoproteins were altered in AD patients compared with NDC groups. And these changes were observed in early stage of AD. Conclusions: These data implicate glycosylation changes in AD patients are potential biological markers to diagnose with serum. Moreover, the aberrations are prospective to detect the initial phase of AD. P3-192
CONFORMATIONALLY ALTERED P53 AS A PERIPHERAL MARKER FOR MILD ALZHEIMER’S DISEASE
Manuel Mene´ndez-Gonza´lez1, Renee Ribacoba1, Marta Martı´nez-Rivera1, Antonello Novelli2, Maurizio Memo3, 1Hospital A´lvarez-Buylla, Mieres, Spain; 2Universidad de Oviedo, Oviedo, Spain; 3Hospital A´lvarez-Buylla, University of Brescia, Italy. Contact e-mail: [email protected] Background: The identification of biological markers of mild Alzheimer’s disease (AD) can be extremely useful to improve diagnostic accuracy and/ or to monitor the efficacy of putative therapies. In this regard, peripheral cells may be of great importance because of their easy accessibility. Previous studies suggest conformationally altered p53 may be overexpressed in mononuclear cells from AD patients. Methods: We measured the mononuclear cells expresion of a conformationally altered p53 in 50 patients with mild Alzheimer’s disease, 50 patients with mild cognitive impairment and age-matched 60 controls. Two independent methods to evaluate the differential expression of a conformational mutant p53 were developed. Mononuclear cells were analyzed by immunoprecipitation or by flow cytometric analysis, following incubation with a conformation-specific p53 antibody, which discriminates unfolded p53 tertiary structure. Patients with mild cognitive impairment were followed for 1 year. Results: Mononuclear cells from mild AD patients express a statistically significantly higher amount of mutant-like p53 compared to mononuclear cells from controls. Mononuclear cells from MCI patients who converted to AD also tended to express a higher (not statistically significant) amount of mutant-like p53 compared to patients with MCI who did not convert. Conclusions: This study support the possibility of using the conformational mutant p53 as a new putative marker in the early diagnosis of Alzheimer’s disease. P3-193
THE PLASMA Ab42/Ab40 RATIO: A PROMISING BIOMARKER FOR COGNITIVE DECLINE
Andrea L. Weston1, Nanjiang Hou1, Neill Graff-Radford2, Suzanne Satterfield3, Tamara Harris4, Lewis Kuller5, Eleanor Simonsick6, Hilsa Ayonayon1, Jingzhong Dong7, Linda Younkin2, Steven Younkin2, Kristine Yaffe1 for the Health ABC Study 1University of California San Francisco, San Francisco, CA, USA; 2Mayo Clinic, Jacksonville, FL, USA; 3 University of Tennessee, Memphis, TN, USA; 4National Institute on Aging, Bethesda, MD, USA; 5University of Pittsburgh, Pittsburgh, PA, USA; 6National Institute on Aging, Baltimore, MD, USA; 7Wake Forest University, Winston-Salem, NC, USA. Contact e-mail: [email protected] Background: Although some studies have found lower plasma levels of Amyloid-b (Ab) 42 and Ab42/Ab40 plasma ratio associated with incident dementia, findings have been mixed. This study investigates the association between the Ab42/Ab40 plasma ratio and cognitive decline over nine years in a biracial cohort of adults aged 70-79. We also evaluate the association in selected subgroups. Methods: We studied 997 participants in the Health ABC study. Cognitive function was measured serially with the Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). The Ab42/Ab40 ratio (measured with Innogenetics INNO-BIA assays at Mayo Clinic, Jacksonville, FL) was categorized into ‘‘low’’ ‘‘medium’’ and ‘‘high’’ tertile. We used mixed effects repeated measures
S507
models to determine the association between tertile and nine-year decline in cognitive function. We stratified models by race, sex, education and APOEe4 and tested for interactions. Results: At baseline, average age was 74.0 years, 55.2% were female, and 54.0% were Black. After adjustment for age, race, sex, education, and diabetes, lower Ab42/Ab40 was associated with greater 9-year cognitive decline, on the 3MS (Low -6.58 6 0.63 points, Medium -6.32 6 0.60, High -3.58 6 0.62, p ¼ 0.01) and on the DSST (-6.57 6 0.68 points, -6.81 6 0.66, -4.41 6 0.67, p ¼ 0.02). In stratified adjusted models, the association between the Ab42/Ab40 ratio and decline over 9 years was stronger in blacks compared to whites (3MS: inter-tertile difference [low-high] -3.23 points for blacks vs. -1.84 points for whites, p for interaction <0.001; DSST: -3.43 vs. -1.34, p < 0.001), and in those with less education (3MS: -3.55 for
P3-194
REGIONAL DIFFERENCES IN AMYLOID LOAD AND CORTICAL CHOLINERGIC PLASTICITY DURING THE PROGRESSION OF ALZHEIMER’S DISEASE
Milos Ikonomovic1, Eric Abrahamson1, William Klunk1, Chester Mathis1, William Paljug1, Manik Debnath1, Stephen Scheff2, Elliott Mufson3, Steven DeKosky4, 1University of Pittsburgh, Pittsburgh, PA, USA; 2University of Kentucky, Lexington, KY, USA; 3Rush University, Chicago, IL, USA; 4 University of Virginia, Charlottesville, VA, USA. Contact e-mail: ikono [email protected] Background: Cholinergic activity is up-regulated in the superior frontal cortex (SFC) but remains stable in other cortical regions in mild cognitive impairment (MCI). The relation between cortical cholinergic activity and amyloid pathology across clinical stages of Alzheimer’s disease (AD) remains unclear; this is clinically relevant given the diagnostic potential of amyloid imaging and the established role of cholinergic neurotransmission dysfunction in AD. Methods: SFC and posterior medial parietal cortex (precuneus) were harvested postmortem from subjects with clinical diagnoses of MCI, no cognitive impairment (NCI), or mild-moderate AD (mAD). Samples were evaluated for choline acetyltransferase (ChAT) activity, and for amyloid load by a [H-3]PiB (Pittsburgh Compound-B) binding assay. Results: Precuneus [H-3]PiB binding distinguished clinical groups (NCImAD)), while SFC ChAT activity was significantly increased in the MCI group relative to both NCI and mAD (NCImAD). In the precuneus, [H-3]PiB binding correlated inversely with regional ChAT activity (r ¼ -0.65, p < 0.0001); MMSE scores correlated inversely with [H-3]PiB binding (r ¼ - 0.86, p < 0.0001) and directly with ChAT activity levels (r ¼ 0.61, p < 0.001). In the SFC, there was a weak inverse correlation of [H-3]PiB binding with ChAT activity (r ¼ -0.37; p < 0.05). MMSE scores correlated weakly with ChAT activity (r ¼ 0.36; p < 0.05) and strongly with [H-3]PiB binding in the SFC (r ¼ -0.70; p < 0.0001). Conclusions: PiB binding in the SFC differentiates mAD, but not MCI, from NCI subjects. SFC ChAT activity is increased in MCI, while in mAD it is comparable to control levels. In contrast, PiB binding in the precuneus differentiates the three clinical groups. Despite the significantly increased precuneus PiB binding in MCI, precuneus ChAT activity was stable, and decreased only when PiB binding reached levels seen in mAD. The present observations of up-regulated SFC ChAT activity before PiB binding reaches levels seen in mAD, and of stable precuneus ChAT activity despite high levels of PiB binding in MCI, suggest that amyloid may not be a necessary precondition of cholinergic enzyme changes in prodromal AD.
Poster Presentations P3
2 University of Southern California, Los Angeles, CA, USA; 3The Weizmann Institute of Science, Rehovot, Israel. Contact e-mail: [email protected]
Background: A definite diagnosis of Alzheimer’s disease (AD) is determined following brain autopsy by detection of hallmark pathologies of the disease: an extracellular aggregates of amyloid-b (Ab) peptides, termed as Ab plaques, and an intracellular neurofibrillary tangles. Presently, noninvasive monitoring of Ab plaques in the brains of living patients is, however, inadequate due to restricted resolution and specificity. We, thus, hypothesized that the eyes can serve as a window to the brain for direct and noninvasive imaging of AD. Methods: To this end, we used APPswe/PS1dE9 double-transgenic AD mice, which faithfully represent some of the key pathologies found in the human disease. We investigated presence and formation of amyloid plaques in retinas from these AD mice, as well as estimated the correlation between retinal amyloid plaques and the plaque pathology in the brain. Lastly, we evaluated responsiveness of retinal plaques to an immune-based therapy and the ability to image them in live mice. Results: Here, we detected Ab plaques in retinal samples of AD mice, and found that Ab plaques appear in the retina significantly earlier than in the brain. Retinal plaques accumulated during disease progression, and in good correlation with brain pathology. Moreover, retinal Ab plaque number and size were significantly reduced following an immune-based therapy, which we found to be effective in reducing plaques in the brain. Systemic administration of a natural compound that binds and labels Ab plaques, allowed in vivo noninvasive visualization of retinal Ab plaques in live AD mice, with high resolution and specificity. Conclusions: These studies establish the potential of direct retinal Ab plaque imaging in live subjects as a promising tool for early AD diagnosis, prognosis and assessment of therapies. P3-189
ASSOCIATION BETWEEN GENE EXPRESSION OF PERIPHERAL BLOOD OXIDATIVE STRESS MARKERS AND ALZHEIMER’S DISEASE: THE NUN STUDY
Jon D. Wilson, Bharat Thyragarajan, Myron D. Gross, University of Minnesota, Fairview Hospital, Minneapolis, MN, USA. Contact e-mail: wils1355@ umn.edu Background: There is increasing evidence that oxidative stress plays an important role in the pathogenesis of several neurodegenerative disorders, including Alzheimer’s disease. Circulating concentrations of both SOD1 and HMOX1 protein have been associated with oxidative stress in neurons. We performed a case control study of 22 participants with clinical dementia and 22 controls within the Nun Study Cohort to evaluate the association between Copper-Zinc Superoxide Dismutase (SOD1) and Heme Oxygenase 1 (HMOX1) expression in peripheral blood and clinical dementia. Methods: The Nun Study cohort was begun with 678 sisters who were at least 75 years of age at enrollment. We randomly selected twenty-two individuals with severe clinical dementia, and twenty-two normal individuals from the Nun Study for evaluation. RNA was extracted with the RNeasy method from peripheral blood samples collected in PaxGENE tubes. The mRNA was used to assess relative expression of SOD1 and HMOX1 using Taqman gene expression assays (Applied Biosystems Inc.). The 18s ribosomal RNA was used as a housekeeping gene to standardize gene expression levels across all samples. Relative gene expression (copy fold change) was calculated using the Pfaffl method. Results: Expression of SOD1 was lower in cases as compared to controls (mean 6 SD: 0.68 6 0.26 vs. 0.77 6 0.15 respectively; p ¼ 0.13). In contrast, expression of HMOX1 was higher in cases as compared to controls (mean 6 SD: 1.00 6 0.23 vs. 0.84 6 0.23 respectively; p ¼ 0.17). Assay variability, based on 8 blinded duplicates, was 5.8% for both SOD1 and HMOX1 genes. Conclusions: This pilot study demonstrates the feasibility of utilizing expression levels of SOD1 and HMOX1 in peripheral blood and testing as risk factors for Alzheimer’s disease. Though the results were not statistically significant in this study with limited sample size, the direction of effect observed is consistent with previous studies that have shown associations between HMOX1, and SOD1 protein concentrations and Alzheimer’s disease. Future studies with larger samples will be needed to fully
evaluate oxidative stress markers in peripheral blood as risk factors for Alzheimer’s disease. P3-190
A NOVEL DIAGNOSTIC AND PROGNOSTIC FLUID BIOMARKER FOR EARLY ALZHEIMER’S DISEASE: YKL-40
Rebecca Craig-Schapiro1, Richard J. Perrin1, Catherine M. Roe2, Elizabeth A. Grant2, Deborah Carter2, Nigel J. Cairns2, Mark A. Mintun2, Elaine R. Peskind3, Ge Li3, Douglas R. Galasko4, Christopher M. Clark5, Joseph F. Quinn6, Gina D’Angelo2, James P. Malone2, R. Reid Townsend2, John C. Morris2, Anne M. Fagan2, David M. Holtzman2, 1Washington University in St. Louis, St. Louis, MO, USA; 2Washington University in St. Louis, St. Louis, MO, USA; 3University of Washington, Seattle, WA, USA; 4 University of California San Diego, San Diego, CA, USA; 5University of Pennsylvania, Philadelphia, PA, USA; 6Oregon Health Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: Clinicopathological studies suggest that Alzheimer’s disease (AD) pathology begins w10-20 years before the resulting cognitive impairment draws medical attention. Currently, AD diagnosis relies upon clinical assessment, without a definitive confirmatory laboratory test. Biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression would, therefore, be invaluable for patient care and efficient clinical trial design. Methods: To discover such AD biomarkers, we used two-dimensional difference gel electrophoresis and tandem mass spectrometry to identify cerebrospinal fluid (CSF) proteins that are increased or decreased in subjects with early AD relative to age-matched cognitively normal controls. YKL-40 (chitinase 3-like 1), a secreted 40-kDa glycoprotein of poorly understood function, was found to be significantly more abundant in AD CSF. To confirm this finding, we measured YKL-40 concentrations in the original cohort of CSF samples by enzyme-linked immunosorbent assay (ELISA). Results: Mean CSF YKL-40 levels were significantly higher in subjects with mild AD (N ¼ 23, Clinical Dementia Rating [CDR] 1) relative to age-matched controls (N ¼ 24, CDR 0). Subsequent evaluation of YKL-40 by ELISA in a larger, independent set of CSF samples (N ¼ 292) confirmed that YKL-40 is more abundant in the CSF of those with very mild and mild AD-type dementia. Importantly, CSF YKL-40 levels also predicted risk of developing dementia (conversion from CDR 0 to CDR>0) and of dementia progression from CDR 0.5 to 1; subjects with high CSF YKL40 values (327 ng/mL, corresponding to the upper tertile) converted and progressed faster than subjects with lower CSF YKL-40 values. In plasma, mean levels of YKL-40, evaluated in 237 subjects of the larger cohort, were significantly higher in the CDR>0 groups vs. the CDR 0 group. Plasma and CSF YKL-40 levels were correlated, with levels roughly 5-fold higher in CSF than in plasma. In an immunohistological study of human AD brain tissue, we detected YKL-40 within astrocytes in the vicinity of a subset of amyloid plaques, implicating YKL-40 as part of a neuroinflammatory response to Ab deposition. Conclusions: Together, these data suggest that YKL-40, as a putative indicator of neuroinflammation, has potential utility as a diagnostic and prognostic biomarker for the earliest stages of AD. P3-191
GLYCOSYLATION OF SERUM PROTEIN AS A NEW DIAGNOSTIC MARKER FOR ALZHEIMER’S DISEASE
Miyako Taniguchi1, Minoru Kouduki1, Yuka Okayama2, Mai Okazaki1, Daiki Jimbo1, Masashi Inoue1, Katsuya Urakami1, 1Tottori University, Yonago, Japan; 2Tottori University Hospital, Yonago, Japan. Contact e-mail: miyako@ med.tottori-u.ac.jp Background: We previously discovered that a few glycoproteins in the cerebrospinal fluid of Alzheimer’s disease patients (AD) had less lectin-binding activities. Especially one of them showed high diagnostic sensitivity and specificity for the AD against other non-AD groups even tauopathies. In this study, we examined the some serum glycoproteins as a new diagnostic marker for AD. Methods: We investigated serum samples obtained from
Poster Presentations P3 30 AD patients and 30 non-demented controls (NDC). The AD subjects were diagnosed according to NINCDS-ADRDA and DSM-IV criteria. We measured the glycosylation of serum glycproteins using lectin blot analysis and improved lectin enzyme-linked immunosorbent assay. The study was approved by the Tottori University Ethical Committee and informed consent was obtained from each patient or their relatives prior to inclusion in the study. The study was performed in accordance with the Helsinki Declaration. Results: We identified several kinds of sugar chain in some serum glycoproteins were altered in AD patients compared with NDC groups. And these changes were observed in early stage of AD. Conclusions: These data implicate glycosylation changes in AD patients are potential biological markers to diagnose with serum. Moreover, the aberrations are prospective to detect the initial phase of AD. P3-192
CONFORMATIONALLY ALTERED P53 AS A PERIPHERAL MARKER FOR MILD ALZHEIMER’S DISEASE
Manuel Mene´ndez-Gonza´lez1, Renee Ribacoba1, Marta Martı´nez-Rivera1, Antonello Novelli2, Maurizio Memo3, 1Hospital A´lvarez-Buylla, Mieres, Spain; 2Universidad de Oviedo, Oviedo, Spain; 3Hospital A´lvarez-Buylla, University of Brescia, Italy. Contact e-mail: [email protected] Background: The identification of biological markers of mild Alzheimer’s disease (AD) can be extremely useful to improve diagnostic accuracy and/ or to monitor the efficacy of putative therapies. In this regard, peripheral cells may be of great importance because of their easy accessibility. Previous studies suggest conformationally altered p53 may be overexpressed in mononuclear cells from AD patients. Methods: We measured the mononuclear cells expresion of a conformationally altered p53 in 50 patients with mild Alzheimer’s disease, 50 patients with mild cognitive impairment and age-matched 60 controls. Two independent methods to evaluate the differential expression of a conformational mutant p53 were developed. Mononuclear cells were analyzed by immunoprecipitation or by flow cytometric analysis, following incubation with a conformation-specific p53 antibody, which discriminates unfolded p53 tertiary structure. Patients with mild cognitive impairment were followed for 1 year. Results: Mononuclear cells from mild AD patients express a statistically significantly higher amount of mutant-like p53 compared to mononuclear cells from controls. Mononuclear cells from MCI patients who converted to AD also tended to express a higher (not statistically significant) amount of mutant-like p53 compared to patients with MCI who did not convert. Conclusions: This study support the possibility of using the conformational mutant p53 as a new putative marker in the early diagnosis of Alzheimer’s disease. P3-193
THE PLASMA Ab42/Ab40 RATIO: A PROMISING BIOMARKER FOR COGNITIVE DECLINE
Andrea L. Weston1, Nanjiang Hou1, Neill Graff-Radford2, Suzanne Satterfield3, Tamara Harris4, Lewis Kuller5, Eleanor Simonsick6, Hilsa Ayonayon1, Jingzhong Dong7, Linda Younkin2, Steven Younkin2, Kristine Yaffe1 for the Health ABC Study 1University of California San Francisco, San Francisco, CA, USA; 2Mayo Clinic, Jacksonville, FL, USA; 3 University of Tennessee, Memphis, TN, USA; 4National Institute on Aging, Bethesda, MD, USA; 5University of Pittsburgh, Pittsburgh, PA, USA; 6National Institute on Aging, Baltimore, MD, USA; 7Wake Forest University, Winston-Salem, NC, USA. Contact e-mail: [email protected] Background: Although some studies have found lower plasma levels of Amyloid-b (Ab) 42 and Ab42/Ab40 plasma ratio associated with incident dementia, findings have been mixed. This study investigates the association between the Ab42/Ab40 plasma ratio and cognitive decline over nine years in a biracial cohort of adults aged 70-79. We also evaluate the association in selected subgroups. Methods: We studied 997 participants in the Health ABC study. Cognitive function was measured serially with the Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). The Ab42/Ab40 ratio (measured with Innogenetics INNO-BIA assays at Mayo Clinic, Jacksonville, FL) was categorized into ‘‘low’’ ‘‘medium’’ and ‘‘high’’ tertile. We used mixed effects repeated measures
S507
models to determine the association between tertile and nine-year decline in cognitive function. We stratified models by race, sex, education and APOEe4 and tested for interactions. Results: At baseline, average age was 74.0 years, 55.2% were female, and 54.0% were Black. After adjustment for age, race, sex, education, and diabetes, lower Ab42/Ab40 was associated with greater 9-year cognitive decline, on the 3MS (Low -6.58 6 0.63 points, Medium -6.32 6 0.60, High -3.58 6 0.62, p ¼ 0.01) and on the DSST (-6.57 6 0.68 points, -6.81 6 0.66, -4.41 6 0.67, p ¼ 0.02). In stratified adjusted models, the association between the Ab42/Ab40 ratio and decline over 9 years was stronger in blacks compared to whites (3MS: inter-tertile difference [low-high] -3.23 points for blacks vs. -1.84 points for whites, p for interaction <0.001; DSST: -3.43 vs. -1.34, p < 0.001), and in those with less education (3MS: -3.55 for
P3-194
REGIONAL DIFFERENCES IN AMYLOID LOAD AND CORTICAL CHOLINERGIC PLASTICITY DURING THE PROGRESSION OF ALZHEIMER’S DISEASE
Milos Ikonomovic1, Eric Abrahamson1, William Klunk1, Chester Mathis1, William Paljug1, Manik Debnath1, Stephen Scheff2, Elliott Mufson3, Steven DeKosky4, 1University of Pittsburgh, Pittsburgh, PA, USA; 2University of Kentucky, Lexington, KY, USA; 3Rush University, Chicago, IL, USA; 4 University of Virginia, Charlottesville, VA, USA. Contact e-mail: ikono [email protected] Background: Cholinergic activity is up-regulated in the superior frontal cortex (SFC) but remains stable in other cortical regions in mild cognitive impairment (MCI). The relation between cortical cholinergic activity and amyloid pathology across clinical stages of Alzheimer’s disease (AD) remains unclear; this is clinically relevant given the diagnostic potential of amyloid imaging and the established role of cholinergic neurotransmission dysfunction in AD. Methods: SFC and posterior medial parietal cortex (precuneus) were harvested postmortem from subjects with clinical diagnoses of MCI, no cognitive impairment (NCI), or mild-moderate AD (mAD). Samples were evaluated for choline acetyltransferase (ChAT) activity, and for amyloid load by a [H-3]PiB (Pittsburgh Compound-B) binding assay. Results: Precuneus [H-3]PiB binding distinguished clinical groups (NCI