- Email: [email protected]
Low-frequency variant imputation identifies rare variant candidate loci in a gwas of late-onset Alzheimer’s disease in the igap consortium
Developing Topics: Clinical Trial Results
open-label human trial have suggested that deep brain stimulation (DBS) directed at cognitive circuits may improve symptoms and possibly slow disease progression. The ADvance trial (Clinicaltrials.gov: NCT01608061) was designed to examine DBS targeting the fornix (DBS-f) as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebocontrolled, delayed-start, multicenter clinical trial conducted at 6 sites in the US and 1 site in Canada. Forty-two patients with very mild AD who met entry criteria received bilateral DBS implants with leads placed anterior to the columns of the fornix. After being randomized 1:1 in a double-blind fashion to DBS “off” or DBS “on” groups for the initial 12 months, participants had their devices turned “on” for the remainder of the study. Post-implantation, patients return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months), and safety monitoring. The primary efficacy outcome measures include: Alzheimer’s Disease Assessment Scale (ADAS-cog-13), Clinical Dementia Rating sum of boxes (CDR-SB), and cerebral glucose metabolism measured with positron emission tomography (18FDG-PET). Results: Implanted subjects (mean age ¼68.2 years; 55% male) had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD 5.2) and 3.9 (SD 1.6), respectively. During the oral presentation, we will present unmasked efficacy and safety results for the 12month double-blind phase of the study. Conclusions: ADvance was successful in enrolling a group of early AD patients for this novel application of DBS. The study is strengthened by rigorous independent subject selection, a double-blind placebo-controlled design, and an extensive open-label follow up period.
studies, genomic sequencing, mutant genotyping and expression studies to identify the causal variant. Results: We identified a loss-of-function (LOF) mutation, p.Glu643del, in the tank-binding kinase 1 gene (TBK1) that segregated in the FTD-ALS family. Mutation analysis of TBK1 in the patient cohort identified another 5 patients carrying the p.Glu643del mutation as well as 5 patients with different LOF mutations resulting in an overall mutation frequency of 1.7% (11/629) of which 1.1% in FTD patients (5/460), 3.4% in ALS patients (5/147) and 4.5% in FTD-ALS patients (1/22). In the Belgian patient cohort, TBK1 LOF mutations are the third most frequent cause of FTD after C9orf72 and GRN and the second most frequent cause of ALS after C9orf72. Of two mutation carriers, brain and spinal cord pathology was characterized by TDP-43 positive inclusions while TBK1 staining showed variable cytoplasmic immunoreactivity without staining of the TDP-43 positive inclusions. Further, we confirmed that the LOF mutations lead to loss of transcript and/or that in blood and in brain of carriers there is a significant loss of TBK1 protein. Conclusions: We identified LOF mutations in FTD, FTD-ALS, and in ALS patients as recently reported in two studies of ALS patients and families. These findings extend the role of TBK1 to include FTD and reiterate that FTD and ALS belong to the same disease continuum. Decreased expression of TBK1 in brain suggests haploinsufficiency as an underlying disease mechanism. Several FTLD and ALS proteins are in the same pathway as TBK1 stressing a role for autophagy and inflammation in neurodegeneration.
DT-02-02 DT-01-06
WITHDRWAN
DEVELOPING TOPICS: GENES, PROTEINS, AND RISK DT-02 DT-02-01
LOSS-OF-FUNCTION MUTATIONS IN TBK1 ARE FREQUENTLY ASSOCIATED WITH FRONTOTEMPORAL LOBAR DEGENERATION IN A BELGIAN PATIENT COHORT
Ilse Gijselinck1, Sara Van Mossevelde1, Anne Sieben1, Bavo Heeman1, Sebastiaan Engelborghs2, Mathieu Vandenbulcke3, Ivy Cuijt1, Marleen Van den Broeck1, Karin Peeters1, Maria Mattheijssens1, Rik Vandenberghe4, Peter De Jonghe1, Patrick Cras2, Peter P. De Deyn2, Jean-Jacques Martin2, Marc Cruts1, Christine Van Broeckhoven1, 1VIB/University of Antwerp, Antwerp, Belgium; 2University of Antwerp, Antwerp, Belgium; 3Alzheimer Research Centre, KU Leuven, Leuven, Belgium; 4Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium. Contact e-mail: christine. [email protected] Background: In the Belgian FTD cohort, mutations in known FTD genes accounted for 34% of the familial FTD patients and 88% of familial FTD-ALS patients with several families with autosomal dominant inheritance remaining genetically unresolved. We aimed to identify new causal FTD genes using whole-genome-sequencing in a 4-generations FTD-ALS family and mutation analysis in cohort of 483 unrelated FTD and FTDALS patients and 147 ALS patients. Methods: In the FTD-ALS family, we obtained whole genome sequences of 3 patients and used bioinformatics to identify shared variants that were predicted to affect the protein. We followed up by segregation
P333
LOW-FREQUENCY VARIANT IMPUTATION IDENTIFIES RARE VARIANT CANDIDATE LOCI IN A GWAS OF LATE-ONSET ALZHEIMER’S DISEASE IN THE IGAP CONSORTIUM
Brian W. Kunkle1, Benjamin Grenier-Boley2, Maria Vronskaya3, Vincent Chouraki4, Sven J. van der Lee5, Kara L. Hamilton-Nelson1, A.M. Toeglhofer6, Rebecca Sims3, Johanna Jakobsdottir7, Joshua C. Bis8, Beth A. Dombroski9, Eden R. Martin1, Richard Mayeux10, Lindsay A. Farrer11, Cornelia M. van Duijn12, Jonathan L. Haines13, Julie Williams3, Sudha Seshadri14, Philippe Amouyel15, Gerard D. Schellenberg9, Margaret A. PericakVance1, The International Genomics of Alzheimer’s Project (IGAP), 1 University of Miami, Miami, FL, USA; 2Institut Pasteur de Lille, Lille, France; 3Cardiff University, Cardiff, United Kingdom; 4Boston University School of Medicine, Boston, MA, USA; 5Erasmus Medical Center, Rotterdam, Netherlands; 6University of Graz, Graz, Austria; 7Icelandic Heart Association, Kopavogur, Iceland; 8University of Washington, Seattle, WA, USA; 9University of Pennsylvania, Philadelphia, PA, USA; 10 Columbia University, New York, NY, USA; 11Boston University, Boston, MA, USA; 12Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, Netherlands; 13Case Western Reserve University, Cleveland, OH, USA; 14The Framingham Heart Study, Framingham, MA, USA; 15Universite Lille 2, Lille, France. Contact e-mail: bkunkle@med. miami.edu Background: The largest Alzheimer disease (AD) Genome-wide Association Studies (GWAS) to date, conducted by the International Genomics of Alzheimer’s Project (IGAP) in 2013, identified 19 susceptibility loci, in addition to APOE, for Late-onset Alzheimer disease (LOAD). Following up these analyses, IGAP conducted a GWAS focused on rare (MAF<¼0.01) and low-frequency variants (MAF<¼0.05) using 38 datasets (including 17
P334
Developing Topics: Clinical Trial Results
new datasets), increasing our discovery sample to 21,433 cases and 44,340 controls. Methods: All datasets were imputed to a 1000 Genomes reference panel (Phase 1 v3, March 2012) of over 37 million variants, many of which are low-frequency single nucleotide variants (SNV) and indels. Single-variant-based association analysis was conducted adjusting for age, sex and population substructure. Individual datasets were analyzed with the score test for case-control datasets and general estimating equations (with generalized linear mixed model for rare variants) for family-based analyses. Within-study results were meta-analyzed in METAL. Gene-based testing was conducted on summary statistics using VEGAS. Results: Imputation produced approximately nine million high-quality low-frequency variants for analyses. Twenty-five loci were genomewide significant at P5310-8, including five novel loci. Three of these novel loci are driven by significant low-frequency variants, while two are associations of common intergenic variants between the genes USP6NL and ECHDC3 at Chr10: 10:11720308 (P¼2.91x10-9) and the genes CYYR1 and ADAMTS1 at Chr21: 28,156,856 (P¼1.44x10-8). Previously reported rare and low-frequency variants in TREM2 and SORL1 were also significantly associated, while low-frequency SNVs in the common loci BIN1 (MAF¼0.026) and CLU (MAF¼0.029) show suggestive significance (P5310-7). Twelve additional loci produced signals with suggestive significance, seven driven by low-frequency or rare variants and five driven by common variants. Genotyping to confirm imputation quality, and replication genotyping using the Sequenom MassArray are underway. Gene-based analyses identified 13 significantly associated genes (Bonferroni P2.83x10-6), four of which are novel loci driven by nominally significant low-frequency variants. Conclusions: Using an imputation set with a large number of rare variants we identified several novel candidate loci for LOAD, giving support to the hypothesis that rare and low-frequency variant imputation can identify novel associations with disease.
DT-02-03
A RANDOMIZED, CONTROLLED, MULTICENTER, INTERNATIONAL STUDY OF THE IMPACT OF FLORBETAPIR (18F) PET AMYLOID IMAGING ON PATIENT MANAGEMENT AND OUTCOME
Michael J. Pontecorvo1, Andew Siderowf1, Michael Grundman2, Bruno Dubois3, Flavio Nobili4, Carl H. Sadowsky5, Murali Doraiswamy6, Stephen Salloway7, Anne McGeehan1, Mark Lowrey1, Abigail Dudek1, Matthew Flitter1, Grazia Dell’Agnello8, Antoine Chevrette9, Walter Deberdt9, Anupa Arora1, Michael D. Devous, Sr.,1, Mark A. Mintun1, 1Avid Radiopharmaceuticals, Philadelphia, PA, USA; 2Global R&D Partners, San Diego, CA, USA; 3APHP- Groupe Hospitalier Pitie Salpetriere, Paris, France; 4University of Genoa, Genoa, Italy; 5Nova SE University, West Palm Beach, FL, USA; 6Duke University, Durham, NC, USA; 7 Butler Hospital & Alpert Medical School of Brown University, Providence, RI, USA; 8Eli Lilly Italia, Sesto Fiorentino, Italy; 9Eli Lilly France, Paris, France. Contact e-mail: [email protected] Background: Previous studies of PET amyloid imaging impact on
patient diagnosis and treatment have been limited in size or design (retrospective or hypothetical outcomes, lacking a control group that does not receive PET results). This is the first prospective, multicenter, randomized, controlled study of amyloid
PET impact on actual patient diagnosis, management and outcomes. Methods: Physicians in France, Italy and the US identified patients seeking diagnosis for MCI or dementia, where AD was considered a possible cause (<85% certain). They recorded a working diagnosis, and a management plan including any planned diagnostic and neuropsychological testing, plans for follow-up and referral visits, and any medication planned to improve cognition. Patients underwent a florbetapir PET scan and were then randomized to either immediate or delayed (1 year) feedback regarding PET amyloid status (positive: Ab+, negative: Ab-). Patients returned after 3 months and the physician updated the diagnosis and recorded a summary of actual management, including neuropsychological and diagnostic testing actually performed, follow-up/referral visits that occurred and medications actually used to treat cognitive impairment since the post-scan visit. Patients returned one year post baseline for assessment of patient and caregiver outcomes including change in cognitive status (ADAScog), health outcomes/resource utilization, mood, function and quality of life. Analyses examined the impact of immediate feedback versus delayed feedback of amyloid status for diagnosis and management changes at 3 months, and outcome measures at 12 months. Results: A total of 618 subjects were randomized to the immediate (308) or to the delayed (310) amyloid PET feedback arms, including 174 subjects in France, 221 in Italy and 223 in the US. 599 completed the 3 month and 560 completed the oneyear follow-up visits. Analyses are currently ongoing. Preliminary results indicate that the percentage of patients for whom the actual management composite recorded at 3 months was different from the baseline management plan (protocol specified primary outcome) was significantly greater for the group that received immediate feedback regarding amyloid status than for those with delayed feedback. Conclusions: This randomized controlled trial supports the hypothesis that knowledge of amyloid status as determined by florbetapir PET imaging alters patient management.
DT-02-04
TAU KINETICS IN THE HUMAN CNS
Chihiro Sato, Kwasi Mawuenyega, Nicolas Barthelemy, Bruce W. Patterson, Tom Kasten, Jennifer Jockel-Balsarotti, Robert Chott, Kevin E. Yarasheski, Timothy M. Miller, Randall Bateman, Washington University School of Medicine, St. Louis, MO, USA. Contact e-mail: satoc@ neuro.wustl.edu Background: We developed a stable isotope labeled amino acid administration paradigm, Stable Isotope Labeling Kinetics (SILK). We recently developed and used the tau SILK method to quantify tau protein kinetics in the human central nervous system (CNS). Methods: Normal participants (n¼6) ingested 13C6Leucine (10g, 10 days) and its in vivo incorporation kinetics into cerebrospinal fluid (CSF) tau protein were quantified after immunoprecipitation, trypsin digestion, and mass spectrometry analysis of specific Leu-containing tau peptides. Results: In the normal human CNS, tau had a half-life of approximately 20 days. This half-life and turnover rate is much slower than other previously measured CNS proteins, such as amyloid beta (t1/ 2 w8 hours), and Apolipoprotein E (t1/2 w12 hours). Conclusions: We have developed a method to measure tau kinetics in human CNS that will be useful to test the hypothesis
open-label human trial have suggested that deep brain stimulation (DBS) directed at cognitive circuits may improve symptoms and possibly slow disease progression. The ADvance trial (Clinicaltrials.gov: NCT01608061) was designed to examine DBS targeting the fornix (DBS-f) as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebocontrolled, delayed-start, multicenter clinical trial conducted at 6 sites in the US and 1 site in Canada. Forty-two patients with very mild AD who met entry criteria received bilateral DBS implants with leads placed anterior to the columns of the fornix. After being randomized 1:1 in a double-blind fashion to DBS “off” or DBS “on” groups for the initial 12 months, participants had their devices turned “on” for the remainder of the study. Post-implantation, patients return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months), and safety monitoring. The primary efficacy outcome measures include: Alzheimer’s Disease Assessment Scale (ADAS-cog-13), Clinical Dementia Rating sum of boxes (CDR-SB), and cerebral glucose metabolism measured with positron emission tomography (18FDG-PET). Results: Implanted subjects (mean age ¼68.2 years; 55% male) had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD 5.2) and 3.9 (SD 1.6), respectively. During the oral presentation, we will present unmasked efficacy and safety results for the 12month double-blind phase of the study. Conclusions: ADvance was successful in enrolling a group of early AD patients for this novel application of DBS. The study is strengthened by rigorous independent subject selection, a double-blind placebo-controlled design, and an extensive open-label follow up period.
studies, genomic sequencing, mutant genotyping and expression studies to identify the causal variant. Results: We identified a loss-of-function (LOF) mutation, p.Glu643del, in the tank-binding kinase 1 gene (TBK1) that segregated in the FTD-ALS family. Mutation analysis of TBK1 in the patient cohort identified another 5 patients carrying the p.Glu643del mutation as well as 5 patients with different LOF mutations resulting in an overall mutation frequency of 1.7% (11/629) of which 1.1% in FTD patients (5/460), 3.4% in ALS patients (5/147) and 4.5% in FTD-ALS patients (1/22). In the Belgian patient cohort, TBK1 LOF mutations are the third most frequent cause of FTD after C9orf72 and GRN and the second most frequent cause of ALS after C9orf72. Of two mutation carriers, brain and spinal cord pathology was characterized by TDP-43 positive inclusions while TBK1 staining showed variable cytoplasmic immunoreactivity without staining of the TDP-43 positive inclusions. Further, we confirmed that the LOF mutations lead to loss of transcript and/or that in blood and in brain of carriers there is a significant loss of TBK1 protein. Conclusions: We identified LOF mutations in FTD, FTD-ALS, and in ALS patients as recently reported in two studies of ALS patients and families. These findings extend the role of TBK1 to include FTD and reiterate that FTD and ALS belong to the same disease continuum. Decreased expression of TBK1 in brain suggests haploinsufficiency as an underlying disease mechanism. Several FTLD and ALS proteins are in the same pathway as TBK1 stressing a role for autophagy and inflammation in neurodegeneration.
DT-02-02 DT-01-06
WITHDRWAN
DEVELOPING TOPICS: GENES, PROTEINS, AND RISK DT-02 DT-02-01
LOSS-OF-FUNCTION MUTATIONS IN TBK1 ARE FREQUENTLY ASSOCIATED WITH FRONTOTEMPORAL LOBAR DEGENERATION IN A BELGIAN PATIENT COHORT
Ilse Gijselinck1, Sara Van Mossevelde1, Anne Sieben1, Bavo Heeman1, Sebastiaan Engelborghs2, Mathieu Vandenbulcke3, Ivy Cuijt1, Marleen Van den Broeck1, Karin Peeters1, Maria Mattheijssens1, Rik Vandenberghe4, Peter De Jonghe1, Patrick Cras2, Peter P. De Deyn2, Jean-Jacques Martin2, Marc Cruts1, Christine Van Broeckhoven1, 1VIB/University of Antwerp, Antwerp, Belgium; 2University of Antwerp, Antwerp, Belgium; 3Alzheimer Research Centre, KU Leuven, Leuven, Belgium; 4Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium. Contact e-mail: christine. [email protected] Background: In the Belgian FTD cohort, mutations in known FTD genes accounted for 34% of the familial FTD patients and 88% of familial FTD-ALS patients with several families with autosomal dominant inheritance remaining genetically unresolved. We aimed to identify new causal FTD genes using whole-genome-sequencing in a 4-generations FTD-ALS family and mutation analysis in cohort of 483 unrelated FTD and FTDALS patients and 147 ALS patients. Methods: In the FTD-ALS family, we obtained whole genome sequences of 3 patients and used bioinformatics to identify shared variants that were predicted to affect the protein. We followed up by segregation
P333
LOW-FREQUENCY VARIANT IMPUTATION IDENTIFIES RARE VARIANT CANDIDATE LOCI IN A GWAS OF LATE-ONSET ALZHEIMER’S DISEASE IN THE IGAP CONSORTIUM
Brian W. Kunkle1, Benjamin Grenier-Boley2, Maria Vronskaya3, Vincent Chouraki4, Sven J. van der Lee5, Kara L. Hamilton-Nelson1, A.M. Toeglhofer6, Rebecca Sims3, Johanna Jakobsdottir7, Joshua C. Bis8, Beth A. Dombroski9, Eden R. Martin1, Richard Mayeux10, Lindsay A. Farrer11, Cornelia M. van Duijn12, Jonathan L. Haines13, Julie Williams3, Sudha Seshadri14, Philippe Amouyel15, Gerard D. Schellenberg9, Margaret A. PericakVance1, The International Genomics of Alzheimer’s Project (IGAP), 1 University of Miami, Miami, FL, USA; 2Institut Pasteur de Lille, Lille, France; 3Cardiff University, Cardiff, United Kingdom; 4Boston University School of Medicine, Boston, MA, USA; 5Erasmus Medical Center, Rotterdam, Netherlands; 6University of Graz, Graz, Austria; 7Icelandic Heart Association, Kopavogur, Iceland; 8University of Washington, Seattle, WA, USA; 9University of Pennsylvania, Philadelphia, PA, USA; 10 Columbia University, New York, NY, USA; 11Boston University, Boston, MA, USA; 12Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, Netherlands; 13Case Western Reserve University, Cleveland, OH, USA; 14The Framingham Heart Study, Framingham, MA, USA; 15Universite Lille 2, Lille, France. Contact e-mail: bkunkle@med. miami.edu Background: The largest Alzheimer disease (AD) Genome-wide Association Studies (GWAS) to date, conducted by the International Genomics of Alzheimer’s Project (IGAP) in 2013, identified 19 susceptibility loci, in addition to APOE, for Late-onset Alzheimer disease (LOAD). Following up these analyses, IGAP conducted a GWAS focused on rare (MAF<¼0.01) and low-frequency variants (MAF<¼0.05) using 38 datasets (including 17
P334
Developing Topics: Clinical Trial Results
new datasets), increasing our discovery sample to 21,433 cases and 44,340 controls. Methods: All datasets were imputed to a 1000 Genomes reference panel (Phase 1 v3, March 2012) of over 37 million variants, many of which are low-frequency single nucleotide variants (SNV) and indels. Single-variant-based association analysis was conducted adjusting for age, sex and population substructure. Individual datasets were analyzed with the score test for case-control datasets and general estimating equations (with generalized linear mixed model for rare variants) for family-based analyses. Within-study results were meta-analyzed in METAL. Gene-based testing was conducted on summary statistics using VEGAS. Results: Imputation produced approximately nine million high-quality low-frequency variants for analyses. Twenty-five loci were genomewide significant at P5310-8, including five novel loci. Three of these novel loci are driven by significant low-frequency variants, while two are associations of common intergenic variants between the genes USP6NL and ECHDC3 at Chr10: 10:11720308 (P¼2.91x10-9) and the genes CYYR1 and ADAMTS1 at Chr21: 28,156,856 (P¼1.44x10-8). Previously reported rare and low-frequency variants in TREM2 and SORL1 were also significantly associated, while low-frequency SNVs in the common loci BIN1 (MAF¼0.026) and CLU (MAF¼0.029) show suggestive significance (P5310-7). Twelve additional loci produced signals with suggestive significance, seven driven by low-frequency or rare variants and five driven by common variants. Genotyping to confirm imputation quality, and replication genotyping using the Sequenom MassArray are underway. Gene-based analyses identified 13 significantly associated genes (Bonferroni P2.83x10-6), four of which are novel loci driven by nominally significant low-frequency variants. Conclusions: Using an imputation set with a large number of rare variants we identified several novel candidate loci for LOAD, giving support to the hypothesis that rare and low-frequency variant imputation can identify novel associations with disease.
DT-02-03
A RANDOMIZED, CONTROLLED, MULTICENTER, INTERNATIONAL STUDY OF THE IMPACT OF FLORBETAPIR (18F) PET AMYLOID IMAGING ON PATIENT MANAGEMENT AND OUTCOME
Michael J. Pontecorvo1, Andew Siderowf1, Michael Grundman2, Bruno Dubois3, Flavio Nobili4, Carl H. Sadowsky5, Murali Doraiswamy6, Stephen Salloway7, Anne McGeehan1, Mark Lowrey1, Abigail Dudek1, Matthew Flitter1, Grazia Dell’Agnello8, Antoine Chevrette9, Walter Deberdt9, Anupa Arora1, Michael D. Devous, Sr.,1, Mark A. Mintun1, 1Avid Radiopharmaceuticals, Philadelphia, PA, USA; 2Global R&D Partners, San Diego, CA, USA; 3APHP- Groupe Hospitalier Pitie Salpetriere, Paris, France; 4University of Genoa, Genoa, Italy; 5Nova SE University, West Palm Beach, FL, USA; 6Duke University, Durham, NC, USA; 7 Butler Hospital & Alpert Medical School of Brown University, Providence, RI, USA; 8Eli Lilly Italia, Sesto Fiorentino, Italy; 9Eli Lilly France, Paris, France. Contact e-mail: [email protected] Background: Previous studies of PET amyloid imaging impact on
patient diagnosis and treatment have been limited in size or design (retrospective or hypothetical outcomes, lacking a control group that does not receive PET results). This is the first prospective, multicenter, randomized, controlled study of amyloid
PET impact on actual patient diagnosis, management and outcomes. Methods: Physicians in France, Italy and the US identified patients seeking diagnosis for MCI or dementia, where AD was considered a possible cause (<85% certain). They recorded a working diagnosis, and a management plan including any planned diagnostic and neuropsychological testing, plans for follow-up and referral visits, and any medication planned to improve cognition. Patients underwent a florbetapir PET scan and were then randomized to either immediate or delayed (1 year) feedback regarding PET amyloid status (positive: Ab+, negative: Ab-). Patients returned after 3 months and the physician updated the diagnosis and recorded a summary of actual management, including neuropsychological and diagnostic testing actually performed, follow-up/referral visits that occurred and medications actually used to treat cognitive impairment since the post-scan visit. Patients returned one year post baseline for assessment of patient and caregiver outcomes including change in cognitive status (ADAScog), health outcomes/resource utilization, mood, function and quality of life. Analyses examined the impact of immediate feedback versus delayed feedback of amyloid status for diagnosis and management changes at 3 months, and outcome measures at 12 months. Results: A total of 618 subjects were randomized to the immediate (308) or to the delayed (310) amyloid PET feedback arms, including 174 subjects in France, 221 in Italy and 223 in the US. 599 completed the 3 month and 560 completed the oneyear follow-up visits. Analyses are currently ongoing. Preliminary results indicate that the percentage of patients for whom the actual management composite recorded at 3 months was different from the baseline management plan (protocol specified primary outcome) was significantly greater for the group that received immediate feedback regarding amyloid status than for those with delayed feedback. Conclusions: This randomized controlled trial supports the hypothesis that knowledge of amyloid status as determined by florbetapir PET imaging alters patient management.
DT-02-04
TAU KINETICS IN THE HUMAN CNS
Chihiro Sato, Kwasi Mawuenyega, Nicolas Barthelemy, Bruce W. Patterson, Tom Kasten, Jennifer Jockel-Balsarotti, Robert Chott, Kevin E. Yarasheski, Timothy M. Miller, Randall Bateman, Washington University School of Medicine, St. Louis, MO, USA. Contact e-mail: satoc@ neuro.wustl.edu Background: We developed a stable isotope labeled amino acid administration paradigm, Stable Isotope Labeling Kinetics (SILK). We recently developed and used the tau SILK method to quantify tau protein kinetics in the human central nervous system (CNS). Methods: Normal participants (n¼6) ingested 13C6Leucine (10g, 10 days) and its in vivo incorporation kinetics into cerebrospinal fluid (CSF) tau protein were quantified after immunoprecipitation, trypsin digestion, and mass spectrometry analysis of specific Leu-containing tau peptides. Results: In the normal human CNS, tau had a half-life of approximately 20 days. This half-life and turnover rate is much slower than other previously measured CNS proteins, such as amyloid beta (t1/ 2 w8 hours), and Apolipoprotein E (t1/2 w12 hours). Conclusions: We have developed a method to measure tau kinetics in human CNS that will be useful to test the hypothesis