Encoding of novel complex visual scenes in presymptomatic Alzheimer\'s disease

P104

Oral Sessions: O1-11: Therapeutics/Therapeutic Strategies: Gamma-Secretase Inhibition/Modulation

of cholinergic cells to amyloid pathology or a negative effect of cholinergic decline on cortical amyloid clearance.

O1-10-06

ENCODING OF NOVEL COMPLEX VISUAL SCENES IN PRESYMPTOMATIC ALZHEIMER’S DISEASE

Yakeel Quiroz1, Kim Willment2, Martha Muniz1, Adriana Ruiz3, Gabriel Castrillon4, Francisco Lopera3, Chantal Stern1, 1Center for Memory and Brain, Boston University, Boston, Massachusetts, United States; 2 Brigham and Women’s Hospital, Boston, Massachusetts, United States; 3 Grupo de Neurociencias, Universidad de Antioquia, Medellin, Colombia; 4 Instituto de Alta Tecnologia Medica, Medellin, Colombia. Background: Medial temporal lobe regions, including the hippocampus and entorhinal cortex, are pathologically affected during the early phases of Alzheimer’s disease (AD). Our goal was to examine whether functional MRI could be used to detect early pre-clinical functional changes in medial temporal lobe regions in pre-symptomatic individuals carrying the E280A Presenilin 1 (PSEN1) mutation. Our participants were recruited from the world’s largest known autosomal dominant early-onset AD (EOAD) kindred, located in Antioquia, Colombia. Methods: 16 presenilin 1 (PSEN1) presymptomatic mutation carriers (M age ¼ 34.14 years SD ¼ 5.36) and 18 noncarriers (M age ¼ 34.27 years, SD ¼ 5.37) were studied using functional MRI. Subjects were matched for age, sex, education, and neuropsychological performance. During fMRI scanning, subjects performed a novel picture encoding task adapted from Stern et al. (1996) which reliably activates MTL regions and has been used previously in subjects with mild cognitive impairment (Dickerson et al. 2004). Subjects performed a force-choice recognition test following encoding. Subjects were scanned using a Phillips Achieva 1.5T scanner, and analysis was carried out using SPM8. Results: Both groups performed similarly on the postscan recognition memory task. All subjects showed activation in the posterior hippocampus and parahippocampal gyrus during the encoding of novel scenes. Carriers showed a greater extent of activation within the left hippocampus than noncarriers. Carriers also showed lesser extent of activation within posterior parietal regions compared to noncarriers. Conclusions: PSEN1 presymptomatic carriers demonstrated greater extent of activation within the hippocampal formation during picture encoding compared to noncarriers. Our findings are consistent with previous studies that have reported changes in fMRI activation during presymptomatic stages of AD and suggest that functional changes within MTL regions occur well before the onset of cognitive symptoms.

ORAL SESSIONS: O1-11 THERAPEUTICS/THERAPEUTIC STRATEGIES: GAMMA-SECRETASE INHIBITION/MODULATION O1-11-01

SATORI GAMMA-SECRETASE MODULATORS ARE EFFICACIOUS IN WILD-TYPE RODENTS FOLLOWING EITHER ACUTE OR STEADY-STATE DOSING

Robyn Loureiro, Timothy McKee, Jo Ann Dumin, Vladislav Zarayskiy, Wesley Austin, Brian Bronk, Nathan Fuller, Jed Hubbs, Ruichao Shen, Jeffrey Ives, Barbara Tate, Satori Pharmaceuticals, Cambridge, Massachusetts, United States. Background: Modulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Ab42 peptide while sparing the production of other Ab species, is a promising therapeutic approach for the treatment of Alzheimer’s disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing A b 42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Ab42 and Ab38 while sparing Ab40 and total Ab levels (AAIC 2011 poster #P1-028). In vivo, the lead compounds demonstrate similar pharmacology. Methods: Sprague Dawley rats were dosed via oral gavage either in a single acute dose or once a day dosing for six days. Brain Ab levels were measured

24 hours post final dose for effects on Ab 38, Ab 40 and Ab 42 using a sensitive plate based ELISA system (MSD). The brain and plasma exposure were assessed by LC/MS/MS. Results: Notably, SPI-1865, is able to robustly and selectively reduce both Ab42 and Ab38 while sparing Ab40 in vivo, similar to the results in in vitro systems. This effect was shown to be dose responsive and long lasting. Conclusions: Taken together, the Satori lead compounds are Ab42 selective, brain penetrant, and dose responsive at achievable exposure levels. With this profile, these unique compounds are promising new therapies for Alzheimer’s Disease.

O1-11-02

RANDOMIZED, DOUBLE-BLINDED, PLACEBOCONTROLLED STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF AVAGACESTAT (BMS 708163) IN HEALTHY JAPANESE AND NON-JAPANESE SUBJECTS

Randy Dockens1, Ellen Chung2, Oleksandr Sverdlov2, Holly Soares3, Bing He1, Michael Furlong2, Gary Tong2, 1Bristol-Myers Squibb, Pennington, New Jersey, United States; 2Bristol-Myers Squibb, Princeton, New Jersey, United States; 3Bristol-Myers Squibb, Wallingford, Connecticut, United States. Background: Avagacestat is a selective g-secretase inhibitor being assessed for the treatment of Alzheimer’s Disease. The current study was designed to assess the safety and tolerability of multiple oral doses of avagacestat in healthy male subjects. Methods: This was a randomized, double-blinded, placebo-controlled, multiple-dose study in healthy Japanese and nonJapanese young male subjects. Ten subjects were to receive either avagacestat 125 mg (n ¼ 6) or matching placebo (n ¼ 4) within each population. The primary objective was to assess safety and tolerability. Secondary assessments included avagacestat pharmacokinetic parameters, plasma Ab40 concentrations, and cerebrospinal fluid (CSF) concentrations of Ab38, Ab40, and Ab42. Results: Twenty-two subjects were randomized. There were no deaths or serious adverse events (SAEs).One subject in the avagacestat group discontinued due to orthostatic tachycardia, cognitive impairment, headache, and anxiety on Day 3. Six gastrointestinal AEs were reported in 5 subjects (4/ 14 avagacestat; 1/8 placebo). Most other types of AEs occurred with similar frequency between groups. The pharmacokinetic profile of avagacestat was similar between Japanese and non-Japanese subjects. Avagacestat was rapidly absorbed, with peak plasma concentrations achieved at 1-2 hours post-dose. The plasma concentration of avagacestat declined in a biphasic manner with the mean terminal elimination half-life values ranging from 32-36 hours. At steady state, the geometric mean Cmax value of avagacestat was approximately 30% higher in Japanese subjects; however, the geometric mean AUC(TAU) values were similar among the Japanese and non-Japanese subjects. Avagacestat decreased the mean plasma Ab40 concentration at 2 and 4 hours post-dose (mean maximal reduction 66%-77% (Day 1) and 36%40% (Day 14) of baseline), in both Japanese and non-Japanese groups. However, the plasma Ab40 concentration returned to baseline levels at 6-8 and 12 hours post-dose (Days 1, and 14, respectively), and then surpassed baseline levels subsequently. By Day 13, avagacestat was associated with a significant effect on CSF Ab, with mean maximal reductions ranging from 22%-56% of baseline. Conclusions: Avagacestat appeared to be safe and well tolerated at daily doses of 125 mg for 14 days. Pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Changes in plasma and CSF amyloid fragments suggest successful targeting of g-secretase activity.

O1-11-03

ENDOGENOUS CHOLESTEROL METABOLITES AS POTENTIAL ALZHEIMER’S THERAPEUTICS

Kevin Felsenstein1, Joo-In Jung2, Thomas Ladd1, Ashleigh Price1, Brenda Moore1, Yufei Tang3, Gideon Shapiro4, Guenther Hochhaus3, Todd Golde1, 1University of Florida College of Medicine, Gainesville, Florida, United States; 2University of Florida, Gainesville, Florida, United