- Email: [email protected]
Serum Granulocyte Colony Stimulating Factor and Alzheimer's Disease
Poster Presentations P2 P2-018
ASSOCIATION STUDY OF RECENTLY REPORTED AD RISK VARIANTS WITH CEREBROSPINAL FLUID AD BIOMARKER LEVELS
Matthew Bailey1, John Kauwe1, Carlos Cruchaga2, David McKean1, Kevin Mayo2, Sarah Bertelsen2, Tony Hinrichs2, Anne Fagan2, David Holtzman2, Alison Goate3, 1Brigham Young University, Provo, Utah, United States; 2Washington University School of Medicine, St. Louis, Missouri, United States; 3Washington University, St. Louis, Missouri, United States. Background: Two large scale GWAS of late onset Alzheimer’s disease have identified several novel risk loci (Naj et al in press, Hollingworth et al in press). While significant and replicable association for these variants has been shown, the biological mechanisms for risk are still largely unknown. The purpose of this study is to evaluate the SNPs from these recent reports for association with cerebrospinal fluid biomarkers for AD to provide insight into possible biological mechanisms by which these SNPs influence Alzheimer’s disease. Methods: CSF Aß42 and tau levels were measured in 957 samples including 356 samples the Knight ADRC, 391 from the Alzheimer’s Disease Neuroimaging Initiative and 210 from the University of Washington. Analyses were restricted to individuals with European American Ancestry. The samples were genotyped using Illumina BeadChips. Approximately 275,000 SNPs were directly genotyped in all series. CSF Aß42 levels are not normally distributed required analysis in each series separately. Analyses were performed using linear regression with age, principle components from stratification analyses and/or APOE genotype as covariates. Empirical P-values for each SNP were generated using ten million permutations. Metaanalysis of the three series was performed using METAL. CSF tau levels were standardized to a mean of zero in each series. The combined sample was then analyzed using linear regression including age, principal components from EigenStrat analysis and series as covariates. Results: We had genotypes for 5 of the 13 SNPs reported in the two studies. We failed to detect significant association with CSF Aß42, tau or ptau levels in our sample of 850 individuals. Power to detect a 5% difference between the genotype groups assuming an additive model with Alpha ¼ 0.05 and a minor allele frequency of 0.10 is 0.97. Conclusions: Our study was designed to detect associations between specific biomarkers and biological mechanisms. This study does not address replication o ¼ of case-control associations. Given our statistical power it is unlikely that there are strong additive effects between these five variants and CSF biomarker levels. We will soon obtain genotypes for the remaining SNPs and analyses of the complete set of variants will be reported at the meeting. P2-019
MEMORY DECLINE AND CEREBROSPINAL FLUID BIOMARKERS IN MCI 1
2
2
lation between biological markers of AD pathology and memory impairment. In this study, CSF biomarkers support early AD diagnosis based on the Free and Cued Selective Reminding Test. P2-020
Ines Baldeiras , Raquel Lemos , Catarina Cunha , Maria Helena Ribeiro , Beatriz Santiago2, Catarina Oliveira1, Isabel Santana2, 1Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 2Neurology Department, Coimbra University Hospital, Coimbra, Portugal. Background: The International Working Group on Alzheimer’s disease (AD; Dubois 2007) developed new research criteria for AD. These include the evidence of significant episodic memory impairment, assessed by the Free and Cued Selective Reminding Test (FCSRT), associated with at least one biological footprint of the disease. In this study we evaluated the relation between Cerebrospinal fluid (CSF) markers, namely amyloid-b1-42 peptide (Ab42), total tau (t-tau) and phosphorylated tau (p-tau) protein and the FCSRT scores in Mild Cognitive Impairment (MCI). Methods: A group of 18 MCI patients was studied and their performance on the Immediate Recall (IR) and on the Delayed Recall (DR) for FCSRT was compared. CSF levels of Ab42, t-tau and p-tau were determined by sandwich ELISA (Innogenetics). Results: Both t-tau and p-tau CSF levels were significantly inversely correlated with IR and DR scores for FCSRT, the correlation being slightly better for the DR. The results of the FCSRT allowed us to divide the initial MCI group into MCI (n ¼ 10) and prodromal AD (n ¼ 8) (cut-off scores 2SD, based on a control population). CSF t-tau and ptau were significantly higher in the prodromal AD group, while Ab42 levels were similar in MCI and prodromal AD. Conclusions: The results show a re-
SERUM GRANULOCYTE COLONY STIMULATING FACTOR AND ALZHEIMER’S DISEASE
Robert Barber1, Sid O’Bryant2, Joan Reisch3, Rachelle Doody4, Thomas Fairchild1, Perrie Adams3, Donald Royall5, Ramon Diaz-Arrastia3, 1 University of North Texas Health Science Center, Fort Worth, Texas, United States; 2Texas Tech Health Science Center, Lubbock, Texas, United States; 3 University of Texas Southwestern Medical Center, Dallas, Texas, United States; 4Baylor College of Medicine, Houston, Texas, United States; 5 UTHSCSA Psychiatry, San Antonio, Texas, United States. Background: Granulocyte colony stimulating factor (GCSF) promotes the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. Additionally, GCSF acts as a neurotrophic factor, by increasing neuroplasticity and suppressing apoptosis. Alzheimer’s disease (AD) is the most common form of age-related dementia and one of the most serious health problems in the world. Due to the role of GCSF as a neurotrophic factor, we sought to determine if peripheral GCSF levels were related to Alzheimer’s disease risk or severity. Methods: We analyzed levels of GCSF as part of a multiplex assay of serum proteins in 197 patients diagnosed with AD and 200 cognitively normal controls enrolled in a longitudinal study of Alzheimer’s disease being conducted by the Texas Alzheimer’s Research and Care Consortium (TARCC). Data were analyzed by regression analysis with adjustment for age, years of education, gender and carriage of the ApoE4 allele. Results: Serum GCSF was significantly lower among individuals diagnosed with probable Alzheimer’s disease, relative to cognitively normal controls (ß ¼ -0.124; p ¼ 0.001). However, among AD participants alone, higher serum GCSF was significantly associated with increased disease severity, as indicated by higher scores on the Global Clinical Dementia Rating Scale (ß ¼ 0.170; p ¼ 0.018) and lower scores on the Mini-Mental Status Exam (ß ¼ -0.176; p ¼ 0.016). Conclusions: A significantly lower level of serum GCSF was observed among Alzheimer’s patients, relative to cognitively normal individuals. However, among Alzheimer’s patients, increased GCSF was associated with greater disease severity. This relationship suggests that GCSF is dysregulated early in the disease process and that the elevation in GCSF observed in more advanced Alzheimer’s disease may represent a compensatory response to neuronal damage.
P2-021 1
S313
VARIABLE EFFECTS OF THE GAMMASECRETASE INHIBITOR ELND006 ON Ab ACROSS DIFFERENT COMPARTMENTS (BRAIN, ISF, CSF, AND PLASMA) FOLLOWING SUSTAINED EXPOSURE VIA SUBCUTANEOUS OSMOTIC PUMPS IN WILD-TYPE MICE
Elizabeth Brigham1, Angelina Wong2, Gullapalli Rampurna2, Kevin Quinn2, Grace Kwong2, Christopher Willits2, Angie Wadsworth2, Lilibeth Dofiles2, Florentino San Pablo2, David Chian2, Pamela Santiago2, Jennifer Hoffman2, John Cirrito3, Jessica Restivo4, Erich Goldbach2, Ruth Motter2, William Wallace2, Gene Kinney2, Daniel Ness1, 1Elan Pharmaceuticals, South San Francisco, California, United States; 2Elan, South San Francisco, California, United States; 3Washington University, St Louis, Missouri, United States; 4Washington Unviersity, St Louis, Missouri, United States. Background: ELND006 is a potent gamma-secretase inhibitor which demonstrates in vitro substrate selectivity towards inhibiting APP cleavage compared to Notch and has been evaluated in Phase 1 human clinical trials. Preclinical PK/PD models are essential in assisting in clinical development, including dose selection. To more effectively model the extended human half-life observed in Phase 1, we established a wildtype mouse model in which ELND006 was continuously infused via a subcutaneous Alzet minipump and Aß levels in the CSF, interstitial fluid (ISF), brain and plasma
ASSOCIATION STUDY OF RECENTLY REPORTED AD RISK VARIANTS WITH CEREBROSPINAL FLUID AD BIOMARKER LEVELS
Matthew Bailey1, John Kauwe1, Carlos Cruchaga2, David McKean1, Kevin Mayo2, Sarah Bertelsen2, Tony Hinrichs2, Anne Fagan2, David Holtzman2, Alison Goate3, 1Brigham Young University, Provo, Utah, United States; 2Washington University School of Medicine, St. Louis, Missouri, United States; 3Washington University, St. Louis, Missouri, United States. Background: Two large scale GWAS of late onset Alzheimer’s disease have identified several novel risk loci (Naj et al in press, Hollingworth et al in press). While significant and replicable association for these variants has been shown, the biological mechanisms for risk are still largely unknown. The purpose of this study is to evaluate the SNPs from these recent reports for association with cerebrospinal fluid biomarkers for AD to provide insight into possible biological mechanisms by which these SNPs influence Alzheimer’s disease. Methods: CSF Aß42 and tau levels were measured in 957 samples including 356 samples the Knight ADRC, 391 from the Alzheimer’s Disease Neuroimaging Initiative and 210 from the University of Washington. Analyses were restricted to individuals with European American Ancestry. The samples were genotyped using Illumina BeadChips. Approximately 275,000 SNPs were directly genotyped in all series. CSF Aß42 levels are not normally distributed required analysis in each series separately. Analyses were performed using linear regression with age, principle components from stratification analyses and/or APOE genotype as covariates. Empirical P-values for each SNP were generated using ten million permutations. Metaanalysis of the three series was performed using METAL. CSF tau levels were standardized to a mean of zero in each series. The combined sample was then analyzed using linear regression including age, principal components from EigenStrat analysis and series as covariates. Results: We had genotypes for 5 of the 13 SNPs reported in the two studies. We failed to detect significant association with CSF Aß42, tau or ptau levels in our sample of 850 individuals. Power to detect a 5% difference between the genotype groups assuming an additive model with Alpha ¼ 0.05 and a minor allele frequency of 0.10 is 0.97. Conclusions: Our study was designed to detect associations between specific biomarkers and biological mechanisms. This study does not address replication o ¼ of case-control associations. Given our statistical power it is unlikely that there are strong additive effects between these five variants and CSF biomarker levels. We will soon obtain genotypes for the remaining SNPs and analyses of the complete set of variants will be reported at the meeting. P2-019
MEMORY DECLINE AND CEREBROSPINAL FLUID BIOMARKERS IN MCI 1
2
2
lation between biological markers of AD pathology and memory impairment. In this study, CSF biomarkers support early AD diagnosis based on the Free and Cued Selective Reminding Test. P2-020
Ines Baldeiras , Raquel Lemos , Catarina Cunha , Maria Helena Ribeiro , Beatriz Santiago2, Catarina Oliveira1, Isabel Santana2, 1Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 2Neurology Department, Coimbra University Hospital, Coimbra, Portugal. Background: The International Working Group on Alzheimer’s disease (AD; Dubois 2007) developed new research criteria for AD. These include the evidence of significant episodic memory impairment, assessed by the Free and Cued Selective Reminding Test (FCSRT), associated with at least one biological footprint of the disease. In this study we evaluated the relation between Cerebrospinal fluid (CSF) markers, namely amyloid-b1-42 peptide (Ab42), total tau (t-tau) and phosphorylated tau (p-tau) protein and the FCSRT scores in Mild Cognitive Impairment (MCI). Methods: A group of 18 MCI patients was studied and their performance on the Immediate Recall (IR) and on the Delayed Recall (DR) for FCSRT was compared. CSF levels of Ab42, t-tau and p-tau were determined by sandwich ELISA (Innogenetics). Results: Both t-tau and p-tau CSF levels were significantly inversely correlated with IR and DR scores for FCSRT, the correlation being slightly better for the DR. The results of the FCSRT allowed us to divide the initial MCI group into MCI (n ¼ 10) and prodromal AD (n ¼ 8) (cut-off scores 2SD, based on a control population). CSF t-tau and ptau were significantly higher in the prodromal AD group, while Ab42 levels were similar in MCI and prodromal AD. Conclusions: The results show a re-
SERUM GRANULOCYTE COLONY STIMULATING FACTOR AND ALZHEIMER’S DISEASE
Robert Barber1, Sid O’Bryant2, Joan Reisch3, Rachelle Doody4, Thomas Fairchild1, Perrie Adams3, Donald Royall5, Ramon Diaz-Arrastia3, 1 University of North Texas Health Science Center, Fort Worth, Texas, United States; 2Texas Tech Health Science Center, Lubbock, Texas, United States; 3 University of Texas Southwestern Medical Center, Dallas, Texas, United States; 4Baylor College of Medicine, Houston, Texas, United States; 5 UTHSCSA Psychiatry, San Antonio, Texas, United States. Background: Granulocyte colony stimulating factor (GCSF) promotes the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. Additionally, GCSF acts as a neurotrophic factor, by increasing neuroplasticity and suppressing apoptosis. Alzheimer’s disease (AD) is the most common form of age-related dementia and one of the most serious health problems in the world. Due to the role of GCSF as a neurotrophic factor, we sought to determine if peripheral GCSF levels were related to Alzheimer’s disease risk or severity. Methods: We analyzed levels of GCSF as part of a multiplex assay of serum proteins in 197 patients diagnosed with AD and 200 cognitively normal controls enrolled in a longitudinal study of Alzheimer’s disease being conducted by the Texas Alzheimer’s Research and Care Consortium (TARCC). Data were analyzed by regression analysis with adjustment for age, years of education, gender and carriage of the ApoE4 allele. Results: Serum GCSF was significantly lower among individuals diagnosed with probable Alzheimer’s disease, relative to cognitively normal controls (ß ¼ -0.124; p ¼ 0.001). However, among AD participants alone, higher serum GCSF was significantly associated with increased disease severity, as indicated by higher scores on the Global Clinical Dementia Rating Scale (ß ¼ 0.170; p ¼ 0.018) and lower scores on the Mini-Mental Status Exam (ß ¼ -0.176; p ¼ 0.016). Conclusions: A significantly lower level of serum GCSF was observed among Alzheimer’s patients, relative to cognitively normal individuals. However, among Alzheimer’s patients, increased GCSF was associated with greater disease severity. This relationship suggests that GCSF is dysregulated early in the disease process and that the elevation in GCSF observed in more advanced Alzheimer’s disease may represent a compensatory response to neuronal damage.
P2-021 1
S313
VARIABLE EFFECTS OF THE GAMMASECRETASE INHIBITOR ELND006 ON Ab ACROSS DIFFERENT COMPARTMENTS (BRAIN, ISF, CSF, AND PLASMA) FOLLOWING SUSTAINED EXPOSURE VIA SUBCUTANEOUS OSMOTIC PUMPS IN WILD-TYPE MICE
Elizabeth Brigham1, Angelina Wong2, Gullapalli Rampurna2, Kevin Quinn2, Grace Kwong2, Christopher Willits2, Angie Wadsworth2, Lilibeth Dofiles2, Florentino San Pablo2, David Chian2, Pamela Santiago2, Jennifer Hoffman2, John Cirrito3, Jessica Restivo4, Erich Goldbach2, Ruth Motter2, William Wallace2, Gene Kinney2, Daniel Ness1, 1Elan Pharmaceuticals, South San Francisco, California, United States; 2Elan, South San Francisco, California, United States; 3Washington University, St Louis, Missouri, United States; 4Washington Unviersity, St Louis, Missouri, United States. Background: ELND006 is a potent gamma-secretase inhibitor which demonstrates in vitro substrate selectivity towards inhibiting APP cleavage compared to Notch and has been evaluated in Phase 1 human clinical trials. Preclinical PK/PD models are essential in assisting in clinical development, including dose selection. To more effectively model the extended human half-life observed in Phase 1, we established a wildtype mouse model in which ELND006 was continuously infused via a subcutaneous Alzet minipump and Aß levels in the CSF, interstitial fluid (ISF), brain and plasma