Souvenir II trial - EEG and MEG

Poster Presentations P2 combined all groups of DAT patients together and re-grouped them into three cohorts (equal sample size) according to their rates of change in ADAS-Cog total scores. Patients with most positive rates of change in ADAS-cog total scores (i.e., worsening) showed significantly more rapid hippocampal atrophy as compared with to patients that showed the most negative rates of change in ADAS-Cog total scores (i.e., improving), and patients with intermediate, near-zero, rates of change in ADAS-cog total scores (i.e., stable) (trend). Conclusions: The rate of hippocampal degeneration may be altered in DAT patients who respond to treatment with memantine or donepezil as compared to patients who are treated with these drugs but who do not respond. However, we were not able to detect drug-specific changes in hippocampal degeneration. Cognitive improvement and slowing of disease progression in AD as a result of drug treatment may be dependent upon neuroanatomical factors that influence who will respond to treatment. Improving our understanding of these factors way lead to the development of more effective therapies. P2-194

SOUVENIR II TRIAL - EEG AND MEG

Hanneke de Waal1, Marieke Lansbergen2, E. C. W. van Straaten1, Philip Scheltens1, Rico Wieggers2, Patrick Kamphuis2, Cornelis Stam1, 1 Alzheimer Centre, VU University Medical Centre, Amsterdam, Netherlands; 2Nutricia Advanced Medical Nutrition, Danone Research, Centre for Specialised Nutrition, Wageningen, Netherlands. Background: One of the important hallmarks of Alzheimer’s disease (AD) is the loss of synaptic connections, causing disruption in neuronal communication. Previous work has demonstrated that nutrients such as DHA, EPA, UMP, choline, vitamins B6, B12, folate, phospholipids (PLs), vitamins C, E, and selenium act synergistically in improving synapse formation. The multinutrient drink Souvenaid Ò, containing these specific nutrients (Fortasyn TM Connect), is developed to improve synapse formation in AD patients. A recent Proof-of-Concept study (’Souvenir I’) with 225 drug-naive mild AD patients showed that Souvenaid improved memory performance. In animal studies the administration of these nutrients has led to increased neurite out growth and dendritic spine density. In humans, the electrical activity generated by neuronal communication at the synapse can be measured indirectly by ‘functional connectivity’ studies using electro encephalography (EEG) or magneto-encephalography (MEG). The Souvenir II study is the first trial to use EEG and MEG as biomarker to explore changes in functional connectivity after nutritional intervention with Souvenaid. 1 Souvenaid and Fortasyn are registered trademarks of N.V. Nutricia. Methods: The Souvenir II study (NTR1975) is a 24-week double blind randomised placebo-controlled study in drug-naive mild AD patients (MMSE ¼ 20)in 27 European centres. Patients are randomly allocated to receive either Souvenaid or a control product. Primary outcome measure is the memory domain score resulting from a neuropsychological test battery (NTB). Resting state EEG and MEG data are recorded at baseline and after 12 and 24 weeks intervention. Outcomes of interest are relative power in 6 frequency bands (delta, theta, alpha1, alpha2, beta, and gamma), Phase Lag Index (PLI) as connectivity measure, and clustering coefficient and path length in network analysis. Results: Enrolment for the Souvenir II study was completed in December 2010. A total number of 259 patients were randomised. EEG was recorded in 220 patients. MEG was recorded in a subset of patients. Conclusions: The multi-nutrient drink Souvenaid contains a specific combination of nutrients, developed to improve synapse formation in AD patients. In the Souvenir II study, EEG and MEG measurements are used to provide information regarding the effects of Souvenaid on changes in functional connectivity as a measure of synaptic formation. The EEG and MEG results are expected to be available in 2012-2013. P2-195

CEREBRAL MICROBLEEDS IN A PHASE 2 CLINICAL TRIAL OF MILD-TO-MODERATE ALZHEIMER’S DISEASE WITH THE GAMMA SECRETASE INHIBITOR BMS-708163

Howard Feldman1, Vlad Coric1, Reisa Sperling2, Steven Greenberg3, Richard Bronen4, A. Gregory Sorensen5, Stephen Salloway6,

S375

Chahin Pachai7, Stephen Kaplita1, Mark Meadowcroft1, Charles Albright1, Robert Berman1, 1Bristol-Myers Squibb, Wallingford, Connecticut, United States; 2Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States; 3Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States; 4Yale University School of Medicine, New Haven, Connecticut, United States; 5Massachusetts General Hospital, Boston, Massachusetts, United States; 6Butler Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States; 7BioClinica Inc., Newtown, Pennsylvania, United States. Background: Clinical trials of Aß lowering treatment in AD have directed attention to the prevalence/incidence of cerebral microbleeds (CMBs). The clinical significance of CMBs in AD and their possible association with amyloid lowering treatment needs investigation. This study determined the prevalence, incidence and risk factors for CMBs in a phase 2 dose finding and safety study of BMS-708163, a gamma secretase inhibitor designed for selective inhibition of amyloid beta (Aß) synthesis. Methods: Post-hoc analysis of a phase 2, six month placebo controlled multiple dose arm study of BMS-708163 in mild-to-moderate AD (MMSE 16-26, Hachinski score &< 4). This analysis included n ¼ 175 subjects having centrally read MRI scans at baseline and week 24. The MRI protocol included a sagittal millimetric 3D T1 sequence, and axial T2*, T2 FLAIR and T2 Spin Echo sequences with 5 mm contiguous slices and no gap. CMBs were defined as focal T2* hypointensities of <10 mm. Analytic methods included descriptive statistics, with Fisher’s Exact test, t-tests and Analysis of Covariance for comparison tests. Results: At baseline, 26% of subjects had CMBs, 19% having one CMB and 7% having > 2 (range up to 122). Risk factors included a history of stroke and Apo E genotype. The incident rate of CMBs was 14% without significant differences (p>0.4) amongst the treatment arms (10% placebo, 13-19% across BMS-708163 treatment groups). The risk of incident CMBs was associated with the presence of baseline lesions. Of subjects with incident CMBs, 50% had 1, while 17% had >3 new lesions. There were no significant differences on clinical outcomes between the incident CMB + and CMB - groups nor within the aggregated BMS-708163 treatment group evaluated by incident CMB status (p>0.14 at Week 24). Conclusions: The prevalence rate and risk factors of CMBs in this trial (history of stroke, ApoE genotype) are consistent with other clinic studies, while the incident rate is higher. Treatment with BMS-708163 did not appear to be associated with an increased risk of incident CMBs, or with adverse clinical effects. However, this study sample is limited in size. More data are needed to further evaluate these potential relationships. P2-196

A NOVEL MRI-COMPATIBLE BRAIN VENTRICLE PHANTOM FOR VALIDATION OF LATERAL VENTRICLE SEGMENTATION PROGRAMS

Amanda Khan1, Robert Ta1, John Drozd1, Robert Moreland2, Michael Borrie3, Robert Bartha1, 1Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada; 2Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada; 3Lawson Health Research Institute, London, Ontario, Canada. Background: Patients with Alzheimer’s Disease (AD) demonstrate an increase in ventricle volume as brain tissues atrophy. Software has been developed to quantify ventricular volume using magnetic resonance imaging (MRI) scans. However, they are rarely validated using known standards. The next generation of clinical trials will benefit from ventricle volumetry, to distinguish between disease-modifying effects and symptomatic relief. The purpose of this study was to construct a physical phantom that could be used as a gold standard to validate ventricle segmentation algorithms. Methods: A typical AD subject from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database with a lateral ventricle volume of 48.8 cm3 was identified. Using this subject’s MRI and ITK-SNAP, a mesh of the