Pharmacologic and pharmacokinetic equivalence studies of GE-067 to PiB

P262

Poster Presentations P2

Preto at University of Sa˜o Paulo, Ribeira˜o Preto, Brazil. Contact e-mail: [email protected] Background: Diabetes mellitus (DM) and pre-Diabetes (PD) have been identified as risk factors for dementia not only of vascular type but also to Alzheimer’s Disease (AD). The aim of this study was to investigate the association between PD, DM, AD and structural and metabolic cerebral lesions using cerebral Quantitative Magnetic Resonance Imaging (MRI) and neuropsychological evaluation, considering the influence of Systemic Hypertension (SH). Methods: 64 Volunteers, both sexes, 60-75 years old, were divided in groups: AD(n¼10), DM(n¼13), DM+SH(n¼12), PD(n¼ 9), PD+SH(n¼10), and healthy controls (HC)(n¼10). Gray (GMP) and and White Matter Percentage(WMP), Brain Parenchyma Fraction(BPF), Gray (GMR) and White Matter Relaxometry(WMR) and Gray (GMMTR) and White Matter Magnetization Transfer Ratio(WMMTR), were compared using ANOVA. Results: AD was different from HC by GMP(p<0,01), BPF(p<0,01), GMR(p<0,01), WMR(p<0,01), GMMTR(p<0,02) and WMMTR(p<0,01). DM+SH was different from HC by BPF(p<0,01), GMR(p<0,01), WMR(p<0,01), GMMTR(p<0,01) and WMMTR(p<0,03). WMMTR differentiated DM from HC(p<0,01). GMR differentiated AD from DM+SH(p<0,04). GMP(p<0,01), GMR(p<0,01) and WMR(p<0,02) differentiated AD from DM. PD/PD+SH were differentiated from AD by: GMP (PD/PD+SH; p<0,01), GMR (PD+SH; p<0,02) and (PD; p<0,01); WMR (PD; p<0,01); GMMTR (PD+SH; p<0,03) and (PD; p<0,04) and WMMTR (PD+SH; p<0,02) and (PD; p<0,04). DM+SH presented cognitive dysfunction on attention and executive functions (Stroop Test). Conclusions: Lesions present in AD are no t only cortical ones but also white matter subcortical lesions of vascular type. Quantitative MRI has greater sensibility in diagnosing histological cerebral lesions and is useful to investigate myelin integrity. Quantitative MRI is useful to differentiate patients with AD from healthy controls and the findings suggest an association between PD, DM and AD. P2-007

PHARMACOLOGIC AND PHARMACOKINETIC EQUIVALENCE STUDIES OF GE-067 TO PIB

Chester A. Mathis, Milos D. Ikonomovic, Neal S. Mason, Manik L. Debnath, Ronald L. Hamilton, Julie C. Price, Brian J. Lopresti, Steven T. DeKosky, William E. Klunk, University of Pittsburgh, Pittsburgh, PA, USA. Contact e-mail: [email protected] Background: Extensive preclinical in vitro studies and in vivo human imaging studies of Pittsburgh Compound B (PiB) to amyloid-beta (Ab) have been performed. We compared the in vitro pharmacologic and in vivo pharmacokinetic properties of a new F-18-labeled PiB analogue (termed GE-067 or [F18]3’F-PiB) to those of PiB. Methods: The first level of comparison was an inhibition study in which cold GE-067 and PiB were used to compete with both [3H]PiB and [3H]GE-067 in homogenates from Alzheimer’s disease (AD) frontal cortex. A second level of comparison utilized post-mortem samples from 14 brain areas from an AD patient who had undergone a PiB PET study prior to death (Ikonomovic et al., Brain 2008). [3H]PiB and [3H]GE067 binding measures were correlated to Ab plaque load and ELISA measures in the 14 brain areas. Finally, we compared the in vivo pharmacokinetics of [C-11]PiB to [F-18]GE-067 in the brains of 2 elderly control subjects and 2 AD subjects using positron emission tomography (PET) imaging. Results: The Ki of GE-067 in homogenates from AD frontal cortex was nearly identical, whether the labeled tracer was [3H]PiB (Ki¼1.9 nM) or [3H]GE067 (Ki¼2.4 nM). In addition, cold GE-067 blocked 100% of [3H]PiB specific binding to the homogenates, and the same held true for cold PiB vs. [3H]GE-067. The correlation of [3H]PiB and [3H]GE-067 binding in postmortem homogenates from the 14 brain areas of the AD subject was very strong (r¼0.99). The amount of [3H]GE-067 bound to these brain homogenates correlated closely with the Ab content of these homogenates (r¼0.92), as did [3H]PiB binding (r¼0.94). In PET imaging studies, GE-067 entered human brain readily with uptake at 5 min in all subjects nearly identical to PiB. In the cortical gray regions of all subjects, GE-067 PET measure values (SUVR 90-120’) were similar (within 20%) to PiB PET values (SUVR 40-90’), while in sub-cortical white matter, w25% higher non-specific binding was observed for GE-067 than for PiB. Conclusions: Taken

together, these in vitro and in vivo bridging studies suggest strongly that the in vivo binding of GE-067 reflects Ab deposition in a manner highly similar to PiB. P2-008

CONTRIBUTIONS OF RIGID AND ELASTIC SPATIAL TRANSFORMATION STEPS TO ANALYSIS OF ALZHEIMER-RELATED METABOLIC CHANGES USING AUTOMATED REGIONAL QUANTIFICATION OF BRAIN PET SCANS

Erin Siu, Thalia Wong, Magnus Dahlbom, Daniel H. S. Silverman, University of California, Los Angeles, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: Software tools for regional quantification of brain images can be useful adjuncts in interpreting PET scans and quantifying metabolic changes occurring in individuals over time. Automated quantification methods generally rely on initial transformation of scans into template space, but relative contributions of different steps of that process have not been well-defined. Methods: 102 brain FDG PET scans were examined _ 36 from 18 Normal subjects (N) and 16 from 8 AD subjects (AD) all recruited for the Alzheimer’s disease Neuroimaging Initiative, then studied at baseline and 2 years later, used for assessment of metabolic decline; and 50 from 50 subjects with mild decline in cognition (MDC) used for assessment of baseline hypometabolism associated with early cognitive changes. All scans were quantified after conforming each to a normal template by both of two approaches: an iterative elastic (E, nonlinear) transformation into template space, or a two-step process involving initial rigid (linear) pre-registration of each scan with template prior to application of the E transformation algorithm (RE). Mean activities in 47 standardized volumes of interest (VOIs) were measured in each scan, and normalized to pontine activity. Results: For the 50 scans from MDC subjects, activities of 22 VOIs changed after rigid pre-registration, 3 becoming less hypometabolic and 19 more profoundly hypometabolic, with 14/ 19 VOIs occurring in Alzheimer-related regions. Both E and RE methods found 9 VOIs demonstrating metabolic decline with a significance level by paired t-test of t > 2.0 in AD; in N, only 1 (by E) or 2 (by RE) such VOIs occurred. With RE of AD, all 9 VOIs were in the temporal lobe. With E, 6 of the 9 VOIs were in the temporal lobe while 2 of the remaining 3 were in medial anterior frontocortical regions, suggesting a greater atrophy-related influence on VOI values when rigid pre-registration is omitted. Moreover, 7 VOIs after RE had t > 3.0 (highest 5.6) whereas only 2 sVOI’s after E (highest 3.3) did. Conclusions: Initial rigid pre-registration preceding elastic transformation to template space increased significance of both baseline hypometabolism and longitudinal metabolic decline in regions of the brain implicated in AD-related hypometabolism and its progression. P2-009

TEST-RETEST VARIABILITY STUDIES IN ALZHEIMER’S DISEASE AND NORMAL AGEING OF THE NEW AMYLOID IMAGING AGENT [18F]BAY 94-9172

Christopher C. Rowe1, Svetlana Pejoska1, Rachel S. Mulligan1, Gordon Chan1, Lueder Fels2, Helena Kusi2, Gareth Jones1, Cornelia Reininger2, Beate Rohde2, Barbara Putz2, Graeme O’Keefe1, Colin L. Masters3, Victor L. Villemagne1, 1Austin Hospital, Heidelberg, VIC, Australia; 2Bayer Schering Pharma, Berlin, Germany; 3The Mental Health Research Institute of Victoria, Parkville, VIC, Australia. Contact e-mail: [email protected] Background: Ab deposition can be examined in vivo using [18F]BAY 949172 and PET. In order to assess the response to anti-Ab therapy it is important to know the test-retest variability of amyloid imaging PET scans. The aim of the present study was to assess test-retest variability of 18FBAY94-9172 PET studies in Alzheimer’s disease (AD) patients and agematched healthy controls (HC). Methods: Test and retest static [18F]BAY 94-9172 scans (30 min duration) were acquired in 7 AD patients and 8 age-matched healthy controls, 2-4 weeks apart (median 3 weeks). Volumes of interest (VOI) were defined on the co-registered