Richard Margolin

Brain metabolism as measured with positron emission tomography: Serial assessment in a patient with familial Alzheimer's disease

This paper presents, for the first time, repeated assessments of cerebral metabolism and neuropsychological competence in early Alzheimers disease. Regional cerebral metabolic rates for glucose were measured with positron emission tomography and 18F-fluoro-2-deoxy-D-glucose on three occasions at 8-month intervals, in a 57-year-old man with Alzheimers disease of 21/2 years duration and with a family history of neuropathologically confirmed Alzheimers disease. Data were compared with mean cerebral metabolic rates from 12 healthy men. No differences in regional cerebral metabolic rates for glucose were found on the initial patient scan, whereas metabolism on the second and third scans was reduced significantly in the parietal lobes and bilaterally in some parietal lobe regions. Memory loss was demonstrable at the first scan, but then and at later scans, other aspects of cognitive performance remained within normal limits (Wechsler Adult Intelligence Scale, Boston Naming Test, Two-dimensional Block Construction). The results show that memory loss can precede a measurable reduction of cerebral metabolism in early Alzheimers disease, but that later reductions in parietal lobe metabolism may not be accompanied by additional measurable neuropsychological deficits.

Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

Objective: To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using 11C-Pittsburgh compound B (11C-PiB)-PET. Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aβ over 71 weeks using an 11C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. Results: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in 11C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = −0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = −0.068; p = 0.027; 1.0 mg/kg vs placebo δ = −0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results. Conclusions: The 11C-PiB-PET imaging results demonstrated reduction of fibrillar Aβ accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aβ species were inadequately targeted.

Safety, tolerability and immunogenicity of an immunotherapeutic vaccine (vanutide cridificar [ACC-001]) and the QS-21 adjuvant in Japanese individuals with mild-to-moderate Alzheimer's disease: A phase IIa, multicenter, randomized, adjuvant and placebo clinical trial

P1-338 SAFETY, TOLERABILITYAND IMMUNOGENICITY OFAN IMMUNOTHERAPEUTIC VACCINE (VANUTIDE CRIDIFICAR [ACC-001]) AND THE QS-21 ADJUVANT IN JAPANESE INDIVIDUALS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE: A PHASE IIA, MULTICENTER, RANDOMIZED, ADJUVANTAND PLACEBO CLINICALTRIAL Heii Arai, Hideo Suzuki, Tamotsu Yoshiyama, Kasia Lobello, Yahong Peng, Enchi Liu, Nzeera Ketter, Richard Margolin, Nicholas Jackson, Yoko Fujimoto, Juntendo University School of Medicine, Tokyo, Japan; Pfizer Japan Inc., Tokyo, Japan; Pfizer Japan Inc., Tokyo, Japan; Pfizer Inc., Collegeville, Pennsylvania, United States; Pfizer Inc., Collegeville, Pennsylvania, United States; Janssen Alzheimer Immunotherapy Research & Development, LLC, South San Francisco, California, United States; Janssen Alzheimer Immunotherapy Research & Development, LLC, South San Francisco, California, United States; Janssen Alzheimer Immunotherapy, South San Francisco, California, United States; Pfizer Inc., Pearl River, New York, United States. Contact e-mail: heii@juntendo.ac.jp

EVALUATION OF CEREBRAL GRAY MATTER AND PONS AS REFERENCE REGIONS FOR AMYLOID PET: RESULTS FROM A BAPINEUZUMAB SUBCUTANEOUS PHASE 2 TRIAL

ensure comparability and spatial correlations were assessed both voxelwise and using regions of interest (ROIs) from the AAL atlas. Results: Developmental effects showed reductions in GMwith advancing age that were highly correlated with both metabolism and A. All three maps (Figure, top row) showed significant spatial correlation, on a voxelwise level (GM-FDG, r 1⁄4 0.264; FDG-Ab, r1⁄4 0.546; GM-Ab, r1⁄4 0.336, all p<0.001; Figure, middle row) or with AAL ROIs (pruning-FDG, r 1⁄4 0.563; FDG-Ab, r 1⁄4 0.634; pruning-Ab, r 1⁄4 0.641, all p<0.001; Figure, bottom row). Conclusions: The regions that are prone to Ab already share common features in early life: they are very metabolically active in young adults and also show age-related gray matter reduction (“pruning”) in childhood. While these topographical correlations do not define causal relationships, they support theories that synaptic activity influences Ab deposition. In particular, these data suggest that early life pruning may result in neural systems in association cortex that are metabolically stressed and thereby susceptible to Ab deposition.

Discordance for hippocampal atrophy and amyloid burden in amnestic mild cognitive impairment may identify distinct subgroups of patients

P3-081 CHANGES IN THE VETERANS AFFAIRS SAINT LOUIS UNIVERSITY MENTAL STATUS (SLUMS) EXAM SCORES OVER 7.5 YEARS’ FOLLOW-UP AND RELATED OUTCOMES: THE INFLUENCE OF REVERSIBLE COGNITIVE IMPAIRMENTAND CORRECTION OF SENSORY LOSS Dulce Cruz-Oliver, TheodoreMalmstrom, Nina Tumosa, JohnMorley, 1 Saint Louis University School of Medicine, St. Louis, Missouri, United States; Geriatric Research Education and Clinical Centers, St Louis VAMC, Jefferson Barracks, St. Louis, Missouri, United States; Saint Louis University Medical Center, St. Louis, Missouri, United States.

The impact of gradient field distortion on the calculation of brain atrophy in Alzheimer's disease, derived from volumetric MRI using the boundary shift integral

P1-335 THE IMPACT OF GRADIENT FIELD DISTORTION ON THE CALCULATION OF BRAIN ATROPHY IN ALZHEIMER’S DISEASE, DERIVED FROM VOLUMETRIC MRI USING THE BOUNDARY SHIFT INTEGRAL Steven Einstein, Sylvain Bouix, Casper Nielsen, Shona Clegg, Andrea Les, Howard Simon, Derek Hill, Richard Margolin, Reisa Sperling, Nick Fox, Enchi Liu, Gerald Novak, Janssen Alzheimer Immunotherapy, South San Francisco, California, United States; Brigham and Women’s Hospital, Boston, Massachusetts, United States; University College London, London, United Kingdom; University College London, London, United Kingdom; IXICO Ltd, London, United Kingdom; Synarc, Newark, California, United States; IXICO Ltd., London, United Kingdom; Brigham and Women’s Hospital, Boston, Massachusetts, United States; University College London, London, United Kingdom. Contact e-mail: seinstei@janimm.com