- Email: [email protected]
Clusterin: An early biomarker for Alzheimer's disease?
P198
Poster Presentations: P1
Bradley Folley8, David Casey9, Andrew Budson10, 1Neuronetrix, Louisville, Kentucky, United States; 2UK MRISC, Lexington, Kentucky, United States; 3 University of Kentucky, Lexington, Kentucky, United States; 4Williams University, Bennington, Vermont, United States; 5Nova SE University, West Palm Beach, Florida, United States; 6Duke University, Durham, North Carolina, United States; 7University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 8Norton Healthcare, Louisville, Kentucky, United States; 9University of Louisville Department of Psychiatry and Behavioral Sciences, Louisville, Kentucky, United States; 10Boston University Alzheimer’s Disease Center, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: Event-related potentials (ERPs) are part of the EEG response that is generated by sensory and cognitive processing of external stimuli. As such, they provide a real-time physiological measure of fundamental cognitive processes. The waveform generated as a result of an ERP test is altered in individuals affected by Alzheimer’s disease (AD). However, the promise of this technique as a diagnostic tool for AD has not reached widespread clinical application. Primary reasons have been the lack of standardization of ERPs acquisition and data analysis techniques across clinical sites, and the impracticality of running ERP tests in clinical environments on real patients. These limitations have been overcome by integrating the complex hardware and software subsystems into an inexpensive, easy to use, handheld system for automated ERP testing and analysis. The goal of the current study is to determine whether ERPs collected with standardized methods and in outpatient settings can be a useful biomarker for early detection of AD. Methods: 100 subjects with probable mild AD and 100 age-matched controls are being recruited at seven clinical sites across the US. Study subjects complete a two-deviant auditory oddball paradigm administered with an integrated ERP system in an outpatient setting. Features collected during the tests, such as wavelet coefficients and peaks latency and amplitude, are used to train an ensemble of classifiers to discriminate subjects with mild AD from cognitively normal controls. Results: Data from 65 controls and 41 AD subjects have been analyzed to date. Preliminary classification results provide a prediction accuracy of 78%, sensitivity of 0.80, specificity of 0.77, and an area under the ROC curve of 0.787. Signal-to-noise ratio was high throughout the tests administered to date, and comparison of test results at different clinical sites showed little inter-site variability. Data analysis including the remaining study subjects is ongoing. Conclusions: The use of an integrated hardware/ software ERP system addresses the main limitations that have hindered a widespread adoption of ERPs in clinical settings. Preliminary data from our study suggest that a classification approach to the analysis of features generated during ERP testing is an effective tool for early diagnosis of AD.
P1-132
FINANCIAL LITERACY IS ASSOCIATED WITH FUNCTIONAL CONNECTIVITY BETWEEN ANTERIOR AND POSTERIOR BRAIN REGIONS
S. Duke Han1, Patricia Boyle1, Konstantinos Arfanakis2, Debra Fleischman1, David Bennett3, 1Rush University Medical Center, Chicago, Illinois, United States; 2Illinois Institute of Technology, Chicago, Illinois, United States; 3Rush University Medical Center, Chicago, Illinois, United States. Contact e-mail: [email protected] Background: Literacy has been shown to be a neurocognitive protective factor in aging, and financial literacy is important for beneficial financial decision-making in old age. Reduced functional connectivity between anterior and posterior regions of the Default Mode Network has been associated with worse cognitive outcomes in aging. We tested the hypothesis that higher financial literacy would be associated with greater functional connectivity of anterior and posterior brain regions in older persons without dementia. Methods: One hundred and thirty-nine participants with-
out dementia (mean age¼82.08, mean education¼15.70, male/ female¼27/112, mean MMSE¼28.58) from the Rush Memory and Aging Project, a clinical-pathological cohort study of aging and dementia, were scanned using resting-state functional MRI. Financial literacy was assessed using a series of questions imbedded as part of an ongoing decision making study. A 4 mm radius spherical seed region of interest (ROI) was prescribed in the posterior cingulate cortex (x¼0, y¼53, z¼26) after removal of 6 head motion parameters, white matter signal, global mean signal, and cerebrospinal fluid as nuisance variables. Results: After adjusting for age, education, sex, and global cognition, and correcting for multiple comparisons, analyses revealed significant associations (AlphaSim cluster level p<0.05, voxelwise p<0.004) such that functional connectivity values between the posterior cingulate and the right ventromedial prefrontal cortex (t¼4.7917), left postcentral gyrus (t¼3.3051), right precuneus (t¼3.5919), and right postcentral gyrus (t¼3.5262) were positively associated with higher financial literacy. Interestingly, functional connectivity values between the posterior cingulate and left caudate were inversely associated with financial literacy (t¼-3.7011). Conclusions: Greater financial literacy is associated with stronger functional connectivity between anterior and posterior regions typically associated with the Default Mode Network. Financial literacy may also be associated with functional connectivity between the posterior cingulate and basal ganglia structures, although this relationship is less clear. Results suggest specific functional brain network properties may be associated with differing levels of financial literacy among older adults.
P1-133
CLUSTERIN: AN EARLY BIOMARKER FOR ALZHEIMER’S DISEASE?
Karin van Dijk1, Wesley Jongbloed2, Wilma van de Bergh1, Philip Scheltens2, Sandra Mulder2, Piet Eikelenboom1, Marinus A. Blankenstein2, Wiesje Van der Flier3, Rob Veerhuis2, 1VU University Medical Center, Amsterdam, Netherlands; 2VU University Medical Center, Amsterdam, Netherlands; 3VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: Clusterin is a protein that is involved in the earliest pathological stages of Alzheimer’s disease (AD), and may serve as an early marker for AD diagnosis. In this study we investigated whether clusterin concentrations in cerebrospinal fluid (CSF) as well as in plasma 1) serve as a diagnostic marker for AD and 2) predict disease progression, and 3) relate to ADbiomarkers in CSF. Methods: Plasma and CSF was obtained from 67 controls (6468 y.o.; MMSE 30; male/female 24/43), 50 MCI (6869 y.o.; MMSE 26.5; male/female 30/20) and 107 AD patients (6569 y.o.; MMSE 21; male/female 54/53). Diagnosis and cognitive status (MMSE) were acquired at baseline and, on average, two years later. Cognitive decline was calculated as follow-up minus baseline MMSE-score and divided by the time (in years) between baseline and follow-up MMSE. Clusterin, amyloid beta 42 (A b 42), Tau and hyperphosphorylated Tau (pTau) concentrations were determined in baseline CSF samples, clusterin also in baseline plasma. Results: Clusterin levels differed between MCI and healthy controls in plasma, but not in CSF. MCI patients that progressed to AD had 20610 percent (1668mg/mL) higher levels of clusterin in plasma than MCI patients that remained stable at follow-up (t-test;p¼0.06). Higher baseline plasma clusterin levels were associated with faster cognitive decline over time (r ¼-0.49; p ¼0.001). Additionally, only in the group of MCI patients, plasma and CSF levels were related (r¼0.35; p¼ 0.01). In all groups, clusterin levels in CSF were associated to CSF Tau (r¼0.24;p<0.001) and pTau (r¼ 0.31;p<0.001), and to amyloid beta levels in MCI patients only (r¼ 0.29;p¼0.04). Conclusions: Plasma clusterin levels are associated with cognitive decline and progression to AD and elevated plasma levels seem to predict more aggressive cognitive decline in MCI patients. CSF levels of clusterin relate to Tau and pTau levels in CSF, markers of neurodegeneration. Whether the observed correlation between CSF and plasma clusterin
Poster Presentations: P1 levels results from blood-brain barrier damage, or a local as well as peripheral response to early AD pathology, is subject of investigation.
P1-134
PERCEPTION OF ODOR EPISODIC MEMORY (POEM) TEST AS A CANDIDATE BIOMARKER FOR EARLY ALZHEIMER’S DISEASE
Alefiya Albers1, Kathleen Kelly2, Josephine Asafu-Adjei3, Rebecca Betensky3, Lloyd Hastings4, Mark Albers5, 1Endicott College, Beverly, Massachusetts, United States; 2Massachusetts General Hospital, Boston, Massachusetts, United States; 3Harvard School of Public Health, Boston, Massachusetts, United States; 4Osmic Enterprises, Cincinnati, Ohio, United States; 5Massachusetts General Hospital, Charlestown, Massachusetts, United States. Contact e-mail: [email protected] Background: Pathological aggregates of amyloid beta and neurofibrillary tangles accumulate in the olfactory bulb and entorhinal cortex in autopsy specimens of cognitively healthy individuals. Examination of human olfactory function has provided reproducible evidence of odor identification deficits in the prodromal and dementia stages of Alzheimer’s Disease (AD). Most of these studies have been conducted with a scratch and sniff smell test with limited sensitivity and specificity. We evaluate a novel olfactory battery in a well-studied aged cohort across a spectrum of cognitively healthy to probable AD. We aim to identify asymptomatic individuals at-risk for preclinical AD with improved acumen. Methods: We deployed a customizable, portable olfactometer to conduct 12-item odor discrimination, 20-item identification of olfactory percepts, and a novel 20-item Perception of Odor Episodic Memory (POEM) tests. The subjects (n ¼ 133) were recruited from the Massachusetts ADRC longitudinal cohort that include cognitively normal elderly subjects, cognitively impaired subjects who do not reach criteria for a diagnosis of Mild Cognitive Impairment (MCI), subjects diagnosed with amnestic MCI, and those with a probable diagnosis of AD. Results: The POEM test significantly differentiates between diagnostic categories (p < 0.001) and provides a broad distribution of performance among the cognitively healthy cohort, facilitating identification of hypothesized individuals at risk due to poor performance. Moreover, for the identification of olfactory percept task there are significant effects of diagnostic category and age, and we find a significant interaction between diagnostic category and age (p < 0.02). These results are congruent with previous findings that performance of odor identification varies significantly as a function of diagnosis after controlling for age and gender. The performance of the odor discrimination task, a test of more basic olfactory function, was not significant across diagnostic categories. Further analyses will incorporate other known and proposed risk factors for AD including ApoE genotype, entorhinal and hippocampal volumes, and amyloid status. Conclusions: Together, these results indicate that probing episodic memory of olfactory percepts and identification of odor percepts may serve as a cost-effective, functional biomarker for preclinical AD that is non-invasive and cost-effective with less educational and cultural bias.
P1-135
QUANTITATIVE ALTERATION OF P3-ALC PEPTIDES IN CSF OF PEOPLE WITH ALZHEIMER’S DISEASE
Saori Hata1, Chiori Omori1, Madoka Kaneko1, Masaaki Waragai2, Katsuya Urakami3, Miyako Taniguchi3, Takeshi Ikeuchi4, Hiroyasu Akatsu5, Toshiharu Suzuki1, 1Hokkaido University, Sapporo, Japan; 2Higashi Matsudo Municipal Hospital, Matsudo, Japan; 3Tottori University, Yonago, Japan; 4Niigata University, Niigata, Japan; 5Choju Medical Institute, Toyohashi, Japan. Contact e-mail: shata@pharm. hokudai.ac.jp Background: Alcadein (Alc) proteins comprise a family of evolutionarily conserved, type I membrane proteins that are predominantly expressed in neuronal tissues with the Alzheimer’s amyloid-b precursor protein (APP). Successive cleavage of Alc by APP a-secretase and g-
P199
secretases generates non-aggregatable p3-Alc (corresponding to the APP fragment, p3). p3-Alc peptides are detectable in both cerebrospinal fluid (CSF) and plasma. Qualitative alteration of p3-Alc peptides were detected in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD), however quantity of p3-Alc peptides in CSF of AD patients remains unclear. Methods: We developed the sandwich enzyme-linked immunosorbent assay (ELISA) systems that specifically detect the p3-Alc peptides. We determined the levels of p3-Alc peptides in CSF using this sandwich ELISA system. Results: We quantified the levels of p3-Alc in CSF from subjects in four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from several independent cohorts. The levels of p3-Alc peptides were altered in CSF of AD patients. Moreover, Ab40 correlated with levels of p3-Alc peptides in all cohorts. Conclusions: In this study, we indicated that multiple g-secretase product peptides were coordinately altered in concentration in the CSF of sporadic AD subjects. We propose a model in which CSF p3-Alc can serve as a either (1) a nonaggregatable surrogate marker for g-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alc and Ab40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of g-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in Ab metabolism.
P1-136
RELATIONSHIP BETWEEN BACE ACTIVITY, INFLAMMATION AND STANDARD CSF BIOMARKERS OF ALZHEIMER’S DISEASE
Daniel Alcolea1, Maria Carmona-Iragui1, Marc Suarez-Calvet1, Maria Belen Sanchez-Saudinos1, Isabel Sala1, Sofıa Anton-Aguirre1, Rafael Blesa1, Juan Fortea1, Alberto Lleo1, 1Hospital de Sant Pau - IIB Sant Pau - CIBERNED, Barcelona, Spain. Contact e-mail: dalcolea@santpau. cat Background: BACE1 (beta-site APP-cleaving enzyme 1) is involved in the proteolytic cleavage of APP that generates Abeta42 and sAPPbeta. BACE1 activity (BACE-act) is known to increase in the AD brain and is known to be up-regulated under inflammatory conditions. Methods: We studied 150 subjects: 20 cognitively normal controls (GDS1), 20 with subjective cognitive impairment (GDS2), 35 with amnestic mild cognitive impairment (aMCI), 45 with Alzheimer’s dementia (AD) and 30 with other dementias (OD). All subjects underwent formal neuropsychological evaluation and lumbar puncture. We used commercial ELISA kits to measure CSF Abeta42, Tau, PTau (Innogenetics), sAPPbeta (IBL) and YKL-40 (Quidel). CSF BACE-act was measured using a beta-secretase fluorogenic substrate (Calbiochem). Group comparisons (ANOVA) and Pearson correlations were determined between different biomarkers. Results: Overall, there was no correlation between BACE-act and YKL-40. BACE-act was not significantly different among the clinical groups. In the whole sample BACE-act showed a mild positive correlation with Abeta42 (r¼0.22 p¼0.006) and sAPPbeta (r¼0.28 p¼0.001). BACE-act correlated with sAPPbeta (r¼0.34 p¼0.001) in subjects with low levels of Abeta42 (<550pg/ml) but not in the group with normal Abeta42 (r¼0.08 p¼0.54).YKL-40 levels showed a gradual increase in clinical stages. In the whole cohort YKL-40 showed a positive correlation with Tau (r¼0.45 p<0.001) and P-Tau (r¼0.49 p<0.001), as well as with sAPPbeta (r¼0.20 p¼0.015). Across clinical groups, YKL40 positively correlated with Tau and P-Tau in the groups of aMCI, AD and OD, but not in the GDS1 or GDS2 groups. The correlation between YKL-40 and sAPPbeta was found in aMCI and AD but not in GDS1, GDS2 or OD. Conclusions: Globally we did not find any correlation between BACE-act and YKL-40 in our sample BACE-act only correlates with sAPPbeta in the group with abnormal Abeta42 levels.YKL-40, on the other hand, correlates with CSF neurodegeneration biomarkers in
Poster Presentations: P1
Bradley Folley8, David Casey9, Andrew Budson10, 1Neuronetrix, Louisville, Kentucky, United States; 2UK MRISC, Lexington, Kentucky, United States; 3 University of Kentucky, Lexington, Kentucky, United States; 4Williams University, Bennington, Vermont, United States; 5Nova SE University, West Palm Beach, Florida, United States; 6Duke University, Durham, North Carolina, United States; 7University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 8Norton Healthcare, Louisville, Kentucky, United States; 9University of Louisville Department of Psychiatry and Behavioral Sciences, Louisville, Kentucky, United States; 10Boston University Alzheimer’s Disease Center, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: Event-related potentials (ERPs) are part of the EEG response that is generated by sensory and cognitive processing of external stimuli. As such, they provide a real-time physiological measure of fundamental cognitive processes. The waveform generated as a result of an ERP test is altered in individuals affected by Alzheimer’s disease (AD). However, the promise of this technique as a diagnostic tool for AD has not reached widespread clinical application. Primary reasons have been the lack of standardization of ERPs acquisition and data analysis techniques across clinical sites, and the impracticality of running ERP tests in clinical environments on real patients. These limitations have been overcome by integrating the complex hardware and software subsystems into an inexpensive, easy to use, handheld system for automated ERP testing and analysis. The goal of the current study is to determine whether ERPs collected with standardized methods and in outpatient settings can be a useful biomarker for early detection of AD. Methods: 100 subjects with probable mild AD and 100 age-matched controls are being recruited at seven clinical sites across the US. Study subjects complete a two-deviant auditory oddball paradigm administered with an integrated ERP system in an outpatient setting. Features collected during the tests, such as wavelet coefficients and peaks latency and amplitude, are used to train an ensemble of classifiers to discriminate subjects with mild AD from cognitively normal controls. Results: Data from 65 controls and 41 AD subjects have been analyzed to date. Preliminary classification results provide a prediction accuracy of 78%, sensitivity of 0.80, specificity of 0.77, and an area under the ROC curve of 0.787. Signal-to-noise ratio was high throughout the tests administered to date, and comparison of test results at different clinical sites showed little inter-site variability. Data analysis including the remaining study subjects is ongoing. Conclusions: The use of an integrated hardware/ software ERP system addresses the main limitations that have hindered a widespread adoption of ERPs in clinical settings. Preliminary data from our study suggest that a classification approach to the analysis of features generated during ERP testing is an effective tool for early diagnosis of AD.
P1-132
FINANCIAL LITERACY IS ASSOCIATED WITH FUNCTIONAL CONNECTIVITY BETWEEN ANTERIOR AND POSTERIOR BRAIN REGIONS
S. Duke Han1, Patricia Boyle1, Konstantinos Arfanakis2, Debra Fleischman1, David Bennett3, 1Rush University Medical Center, Chicago, Illinois, United States; 2Illinois Institute of Technology, Chicago, Illinois, United States; 3Rush University Medical Center, Chicago, Illinois, United States. Contact e-mail: [email protected] Background: Literacy has been shown to be a neurocognitive protective factor in aging, and financial literacy is important for beneficial financial decision-making in old age. Reduced functional connectivity between anterior and posterior regions of the Default Mode Network has been associated with worse cognitive outcomes in aging. We tested the hypothesis that higher financial literacy would be associated with greater functional connectivity of anterior and posterior brain regions in older persons without dementia. Methods: One hundred and thirty-nine participants with-
out dementia (mean age¼82.08, mean education¼15.70, male/ female¼27/112, mean MMSE¼28.58) from the Rush Memory and Aging Project, a clinical-pathological cohort study of aging and dementia, were scanned using resting-state functional MRI. Financial literacy was assessed using a series of questions imbedded as part of an ongoing decision making study. A 4 mm radius spherical seed region of interest (ROI) was prescribed in the posterior cingulate cortex (x¼0, y¼53, z¼26) after removal of 6 head motion parameters, white matter signal, global mean signal, and cerebrospinal fluid as nuisance variables. Results: After adjusting for age, education, sex, and global cognition, and correcting for multiple comparisons, analyses revealed significant associations (AlphaSim cluster level p<0.05, voxelwise p<0.004) such that functional connectivity values between the posterior cingulate and the right ventromedial prefrontal cortex (t¼4.7917), left postcentral gyrus (t¼3.3051), right precuneus (t¼3.5919), and right postcentral gyrus (t¼3.5262) were positively associated with higher financial literacy. Interestingly, functional connectivity values between the posterior cingulate and left caudate were inversely associated with financial literacy (t¼-3.7011). Conclusions: Greater financial literacy is associated with stronger functional connectivity between anterior and posterior regions typically associated with the Default Mode Network. Financial literacy may also be associated with functional connectivity between the posterior cingulate and basal ganglia structures, although this relationship is less clear. Results suggest specific functional brain network properties may be associated with differing levels of financial literacy among older adults.
P1-133
CLUSTERIN: AN EARLY BIOMARKER FOR ALZHEIMER’S DISEASE?
Karin van Dijk1, Wesley Jongbloed2, Wilma van de Bergh1, Philip Scheltens2, Sandra Mulder2, Piet Eikelenboom1, Marinus A. Blankenstein2, Wiesje Van der Flier3, Rob Veerhuis2, 1VU University Medical Center, Amsterdam, Netherlands; 2VU University Medical Center, Amsterdam, Netherlands; 3VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: Clusterin is a protein that is involved in the earliest pathological stages of Alzheimer’s disease (AD), and may serve as an early marker for AD diagnosis. In this study we investigated whether clusterin concentrations in cerebrospinal fluid (CSF) as well as in plasma 1) serve as a diagnostic marker for AD and 2) predict disease progression, and 3) relate to ADbiomarkers in CSF. Methods: Plasma and CSF was obtained from 67 controls (6468 y.o.; MMSE 30; male/female 24/43), 50 MCI (6869 y.o.; MMSE 26.5; male/female 30/20) and 107 AD patients (6569 y.o.; MMSE 21; male/female 54/53). Diagnosis and cognitive status (MMSE) were acquired at baseline and, on average, two years later. Cognitive decline was calculated as follow-up minus baseline MMSE-score and divided by the time (in years) between baseline and follow-up MMSE. Clusterin, amyloid beta 42 (A b 42), Tau and hyperphosphorylated Tau (pTau) concentrations were determined in baseline CSF samples, clusterin also in baseline plasma. Results: Clusterin levels differed between MCI and healthy controls in plasma, but not in CSF. MCI patients that progressed to AD had 20610 percent (1668mg/mL) higher levels of clusterin in plasma than MCI patients that remained stable at follow-up (t-test;p¼0.06). Higher baseline plasma clusterin levels were associated with faster cognitive decline over time (r ¼-0.49; p ¼0.001). Additionally, only in the group of MCI patients, plasma and CSF levels were related (r¼0.35; p¼ 0.01). In all groups, clusterin levels in CSF were associated to CSF Tau (r¼0.24;p<0.001) and pTau (r¼ 0.31;p<0.001), and to amyloid beta levels in MCI patients only (r¼ 0.29;p¼0.04). Conclusions: Plasma clusterin levels are associated with cognitive decline and progression to AD and elevated plasma levels seem to predict more aggressive cognitive decline in MCI patients. CSF levels of clusterin relate to Tau and pTau levels in CSF, markers of neurodegeneration. Whether the observed correlation between CSF and plasma clusterin
Poster Presentations: P1 levels results from blood-brain barrier damage, or a local as well as peripheral response to early AD pathology, is subject of investigation.
P1-134
PERCEPTION OF ODOR EPISODIC MEMORY (POEM) TEST AS A CANDIDATE BIOMARKER FOR EARLY ALZHEIMER’S DISEASE
Alefiya Albers1, Kathleen Kelly2, Josephine Asafu-Adjei3, Rebecca Betensky3, Lloyd Hastings4, Mark Albers5, 1Endicott College, Beverly, Massachusetts, United States; 2Massachusetts General Hospital, Boston, Massachusetts, United States; 3Harvard School of Public Health, Boston, Massachusetts, United States; 4Osmic Enterprises, Cincinnati, Ohio, United States; 5Massachusetts General Hospital, Charlestown, Massachusetts, United States. Contact e-mail: [email protected] Background: Pathological aggregates of amyloid beta and neurofibrillary tangles accumulate in the olfactory bulb and entorhinal cortex in autopsy specimens of cognitively healthy individuals. Examination of human olfactory function has provided reproducible evidence of odor identification deficits in the prodromal and dementia stages of Alzheimer’s Disease (AD). Most of these studies have been conducted with a scratch and sniff smell test with limited sensitivity and specificity. We evaluate a novel olfactory battery in a well-studied aged cohort across a spectrum of cognitively healthy to probable AD. We aim to identify asymptomatic individuals at-risk for preclinical AD with improved acumen. Methods: We deployed a customizable, portable olfactometer to conduct 12-item odor discrimination, 20-item identification of olfactory percepts, and a novel 20-item Perception of Odor Episodic Memory (POEM) tests. The subjects (n ¼ 133) were recruited from the Massachusetts ADRC longitudinal cohort that include cognitively normal elderly subjects, cognitively impaired subjects who do not reach criteria for a diagnosis of Mild Cognitive Impairment (MCI), subjects diagnosed with amnestic MCI, and those with a probable diagnosis of AD. Results: The POEM test significantly differentiates between diagnostic categories (p < 0.001) and provides a broad distribution of performance among the cognitively healthy cohort, facilitating identification of hypothesized individuals at risk due to poor performance. Moreover, for the identification of olfactory percept task there are significant effects of diagnostic category and age, and we find a significant interaction between diagnostic category and age (p < 0.02). These results are congruent with previous findings that performance of odor identification varies significantly as a function of diagnosis after controlling for age and gender. The performance of the odor discrimination task, a test of more basic olfactory function, was not significant across diagnostic categories. Further analyses will incorporate other known and proposed risk factors for AD including ApoE genotype, entorhinal and hippocampal volumes, and amyloid status. Conclusions: Together, these results indicate that probing episodic memory of olfactory percepts and identification of odor percepts may serve as a cost-effective, functional biomarker for preclinical AD that is non-invasive and cost-effective with less educational and cultural bias.
P1-135
QUANTITATIVE ALTERATION OF P3-ALC PEPTIDES IN CSF OF PEOPLE WITH ALZHEIMER’S DISEASE
Saori Hata1, Chiori Omori1, Madoka Kaneko1, Masaaki Waragai2, Katsuya Urakami3, Miyako Taniguchi3, Takeshi Ikeuchi4, Hiroyasu Akatsu5, Toshiharu Suzuki1, 1Hokkaido University, Sapporo, Japan; 2Higashi Matsudo Municipal Hospital, Matsudo, Japan; 3Tottori University, Yonago, Japan; 4Niigata University, Niigata, Japan; 5Choju Medical Institute, Toyohashi, Japan. Contact e-mail: shata@pharm. hokudai.ac.jp Background: Alcadein (Alc) proteins comprise a family of evolutionarily conserved, type I membrane proteins that are predominantly expressed in neuronal tissues with the Alzheimer’s amyloid-b precursor protein (APP). Successive cleavage of Alc by APP a-secretase and g-
P199
secretases generates non-aggregatable p3-Alc (corresponding to the APP fragment, p3). p3-Alc peptides are detectable in both cerebrospinal fluid (CSF) and plasma. Qualitative alteration of p3-Alc peptides were detected in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD), however quantity of p3-Alc peptides in CSF of AD patients remains unclear. Methods: We developed the sandwich enzyme-linked immunosorbent assay (ELISA) systems that specifically detect the p3-Alc peptides. We determined the levels of p3-Alc peptides in CSF using this sandwich ELISA system. Results: We quantified the levels of p3-Alc in CSF from subjects in four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from several independent cohorts. The levels of p3-Alc peptides were altered in CSF of AD patients. Moreover, Ab40 correlated with levels of p3-Alc peptides in all cohorts. Conclusions: In this study, we indicated that multiple g-secretase product peptides were coordinately altered in concentration in the CSF of sporadic AD subjects. We propose a model in which CSF p3-Alc can serve as a either (1) a nonaggregatable surrogate marker for g-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alc and Ab40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of g-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in Ab metabolism.
P1-136
RELATIONSHIP BETWEEN BACE ACTIVITY, INFLAMMATION AND STANDARD CSF BIOMARKERS OF ALZHEIMER’S DISEASE
Daniel Alcolea1, Maria Carmona-Iragui1, Marc Suarez-Calvet1, Maria Belen Sanchez-Saudinos1, Isabel Sala1, Sofıa Anton-Aguirre1, Rafael Blesa1, Juan Fortea1, Alberto Lleo1, 1Hospital de Sant Pau - IIB Sant Pau - CIBERNED, Barcelona, Spain. Contact e-mail: dalcolea@santpau. cat Background: BACE1 (beta-site APP-cleaving enzyme 1) is involved in the proteolytic cleavage of APP that generates Abeta42 and sAPPbeta. BACE1 activity (BACE-act) is known to increase in the AD brain and is known to be up-regulated under inflammatory conditions. Methods: We studied 150 subjects: 20 cognitively normal controls (GDS1), 20 with subjective cognitive impairment (GDS2), 35 with amnestic mild cognitive impairment (aMCI), 45 with Alzheimer’s dementia (AD) and 30 with other dementias (OD). All subjects underwent formal neuropsychological evaluation and lumbar puncture. We used commercial ELISA kits to measure CSF Abeta42, Tau, PTau (Innogenetics), sAPPbeta (IBL) and YKL-40 (Quidel). CSF BACE-act was measured using a beta-secretase fluorogenic substrate (Calbiochem). Group comparisons (ANOVA) and Pearson correlations were determined between different biomarkers. Results: Overall, there was no correlation between BACE-act and YKL-40. BACE-act was not significantly different among the clinical groups. In the whole sample BACE-act showed a mild positive correlation with Abeta42 (r¼0.22 p¼0.006) and sAPPbeta (r¼0.28 p¼0.001). BACE-act correlated with sAPPbeta (r¼0.34 p¼0.001) in subjects with low levels of Abeta42 (<550pg/ml) but not in the group with normal Abeta42 (r¼0.08 p¼0.54).YKL-40 levels showed a gradual increase in clinical stages. In the whole cohort YKL-40 showed a positive correlation with Tau (r¼0.45 p<0.001) and P-Tau (r¼0.49 p<0.001), as well as with sAPPbeta (r¼0.20 p¼0.015). Across clinical groups, YKL40 positively correlated with Tau and P-Tau in the groups of aMCI, AD and OD, but not in the GDS1 or GDS2 groups. The correlation between YKL-40 and sAPPbeta was found in aMCI and AD but not in GDS1, GDS2 or OD. Conclusions: Globally we did not find any correlation between BACE-act and YKL-40 in our sample BACE-act only correlates with sAPPbeta in the group with abnormal Abeta42 levels.YKL-40, on the other hand, correlates with CSF neurodegeneration biomarkers in