Comparison of visual and quantitative florbetapir-PET reads in subjects with early Alzheimer's disease for assessing amyloid burden

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Alzheimer’s Imaging Consortium Posters: IC-P

Ab-status groups are detectable 7-9 years before neuroimaging. Collectively, these findings provide evidence that Ab deposition is not a benign process in the oldest old. IC-P-064

TAU IMMUNOTHERAPY IMPROVES AXONAL TRANSPORT AS DETECTED IN VIVO BY MANGANESE-ENHANCED MAGNETIC RESONANCE IMAGING

Benjamin Little, Umer Khan, Anne Bertrand, Hameetha Rajamohamedsait, Lindsay Hill, Dung Minh Hoang, Youssef Zaim Wadghiri, Einar M. Sigurdsson, New York University School of Medicine, New York, New York, United States. Background: Immunotherapy targeting hyperphosphorylated tau is a promising prospect to mitigate the neurodegenerative effects of tauopathies. Assessing the effectiveness of such immunotherapies often involves sacrifice of the animal. However, Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) permits the longitudinal study of neuronal function with minimal risk to the animal. We hypothesize that tract-tracing MEMRI in a mouse model of tau pathology should enable non-invasive monitoring of various tau targeting therapies aimed at improving neuronal integrity. Methods: Twenty-five homozygous JNPL3 tangle transgenic mice underwent MEMRI at 6 months of age. Thirteen of the mice received tau immunotherapy with Tau379-408[P-Ser396,404] in alum adjuvant from 3 months of age, and twelve controls received an adjuvant alone. Imaging studies were performed on a 7-T micro-MRI. Mice were imaged pre-injection, then injected in one nostril with a solution of 2.5 M MnCl 2, under isoflurane anesthesia. Image sets were acquired at 1, 4, 8, 12, 24, 36 and 48 hours, and finally at 7 days (Fig 1). The datasets were processed using ImageJ. Normalized measurements for each mouse were plotted and fitted to a tract tracing bolus model using MATLAB. Fitting enabled the estimation of the timing (Pt) and intensity (Pv) of the bolus peak of Mn, and maximal slope of uptake (Sv). Results: A significant increase in maximal slope of manganese uptake, Sv, was observed in the mitral cell layer (35%, P <.005) and glomerular layer (36%, P <0.02) in treated JNPL3 mice compared to identical controls. There was also a significant increase in bolus peak value, Pv, in the mitral layer in the treated group (7%, P ¼ 0.02). Furthermore, in the immunized mice, there was a strong trend for a decrease in the time to peak value, Pt (-9%P ¼ 0.10), in the mitral cell layer, compared to the controls. Conclusions: Utilizing MEMRI’s non-invasive, longitudinal measurements from 1 hour to 7 days, allowed us to detect substantial improvements in neu-

Figure 1. (Row 1: 1, 4, 8, 12 hours j Row 2: 24, 36, 48 hours, 7 days)

ronal transport following tau immunotherapy. We are analyzing tau pathology in olfactory sections from these mice to assess the correlation of these benefits with clearance of tau lesions, which we have shown previously to occur with this treatment. IC-P-065

COMPARISON OF VISUAL AND QUANTITATIVE FLORBETAPIR-PET READS IN SUBJECTS WITH EARLY ALZHEIMER’S DISEASE FOR ASSESSING AMYLOID BURDEN

Bradley Wyman1, Yahong Peng2, Kasia Lobello2, George Zubal3, Michael Ryan2, Kenneth Marek4, John Seibyl5, Mary Slomkowski2, 1Pfizer Inc., Groton, Connecticut, United States; 2Pfizer Inc., Collegeville, Pennsylvania, United States; 3Institute for Neurodegenerative Disorders, New Haven, Pennsylvania, United States; 4Molecular NeuroImaging, New Haven, Connecticut, United States; 5Molecular NeuroImaging, New Haven, Connecticut, United States. Background: For studies of beta amyloid (Ab) reducing compounds it is important to select subjects with sufficient brain Ab load during screening. Florbetapir -PET imaging allows the visualization or quantitative assessment of Ab. Quantitative methods are objective but may require an MRI and centralized processing which can lengthen screening timelines. This study compares the quantitative results to the visual assessment of the screening images in the ongoing B2571010 study of a novel potential Ab reducing compound ACC-001 in subjects with early AD. Methods: Visual assessments were conducted independently by two experienced readers trained in the visual read protocol. The readers graded the Ab load in 8 cortical regions, on a 4 point scale (1 ¼ no plaque, 2 ¼ minor plaque, 3 ¼ significant plaque, 4 ¼ unevaluable). The overall visual score was determined by the highest score in any one of 4 key regions (frontal, posterior cingulate gyrus, lateral temporal, and parietal). For this comparison a score of 3 was considered amyloid positive.Quantitative assessments were done by co-registering the PET and MRI images to the MNI template then regionally segmenting to create grey matter PET images for volume of interest sampling. The average SUVr was calculated over 6 cortical regions (frontal, posterior and anterior cingulum, lateral temporal, parietal and occipital) using the cerebellar cortex as the reference region. Subjects with an SUVr 1.45 were considered amyloid positive. Results: A total of 96 early AD subjects were screened. Both the visual and quantitative assessments were negative for 34 subjects and positive for 36 (see Figure). The visual

Alzheimer’s Imaging Consortium Posters: IC-P assessments were negative and quantitative assessments were positive in 14 subjects. The visual assessments were positive and quantitative assessments were negative in 12 subjects. Conclusions: In this population, 26 of 96 subjects had discordant reads between the two methods. This may be a result of averaging regions in the quantitative assessment while only 1 region was required to be positive for the visual assessment. The quantitative threshold could be modified or visual assessment scores of 2 could be also considered positive but these alternative approaches would predominantly shift the balance between false positives and false negatives without substantially changing the discordant pairs.

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20% in some cases. Significant differences were found between HRRT sites and between HR+ sites. Differences between 3 scanner types were reduced when pons was used as reference. Modeling showed potential to compensate for inter-scanner differences. Conclusions: Amyloid values measured using 11C-PiB must be evaluated in the context of the scanner used to collect data, particularly when the SUVR value is close to a positivity threshold. In longitudinal studies, within-subject data must be reconciled to account for variability in SUVR values that arise from change in the scanner, changes in acquisition on the same camera, and impact of different corrections applied to the emission data.

Figure 1. Scatter Plot of Quantitative SUVr vs. Visual Assessment

IC-P-066

WHEN AN AMYLOID PET THRESHOLD OF 1.5 BECOMES 1.4 AND LONGITUDINAL ACCUMULATION IS NOT WHAT IT APPEARS: INTERPRETING AND RECONCILING VALUES AMIDST SCANNER VARIABILITY

Dawn Matthews1, Randolph Andrews2, Lisa Mosconi3, Mark Schmidt4, 1 Abiant, Inc./ADM Diagnostics LLC, Grayslake, Illinois, United States; 2 Abiant, Inc./ADM Diagnostics, LLC, Grayslake, Illinois, United States; 3 Abiant, Inc./ADM Diagnostics, LLC, Grayslake, Illinois, and NYU School of Medicine, New York, New York, United States; 4Janssen Research and Development, Beerse, Belgium. Background: Measurement of amyloid burden using 11C-PiB has been incorporated as an endpoint in Alzheimer’s Disease clinical research and therapeutic trials. Studies of Normal, MCI, and AD populations have been used to establish thresholds for amyloid positivity, impacting subject inclusion in trials and contributing to diagnosis. Yet, these values are highly dependent upon several factors including the scanner. Methods: One hundred eighty-seven PiB scans from 94 ADNI subjects were evaluated from five scanner models: HR+ (76 scans), HRRT (42), GE Advance (32), GE Discovery (15), and Biograph HiRez (22). Using 50-70 minute summed images, values were sampled at 27 individual slices of gray matter cerebellum, 27 slices of subcortical white matter, 5 regions of interest (anterior cingulate, posterior cingulate/precuneus, frontal cortex, lateral temporal cortex, parietal cortex), and 8 additional reference regions including combinations of gray and white matter cerebellum and pons. Standardized Uptake Value Ratio (SUVR) values were compared across scanner models using PIB- and PIB+ scans together and separated into subgroups, and across sites within scanner model. A subgroup of subjects each having scans from both a GE Advance and HR+ scanner was evaluated. Differences between scanners were mathematically modeled and tested to predict cross-scanner equivalent values. Results: Significant SUVR differences were found across scanner models. Using PiB- and PiB- scans combined, average white matter referenced to gray matter cerebellum SUVRs ranked: HR+ >GE Advance ¼ GE Discovery >BiographHiRez >HRRT(site-specific). Differences between HR+ and all other scanner models were significant (P <0.03 vs. Discovery to P <0.00001 vs. HRRT-site 1) and

Figure 1. Relationship between SUVRs for reference regions of varied intensity levels. HR+ values are higher, and a similar increase was seen in cortical average SUVR, potentially resulting from scanner differences rather than amyloid increase.

IC-P-067

3T MAGNETIC RESONANCE SPECTROSCOPY OF THE POSTERIOR CINGULATE FOLLOWING RIVASTIGMINE TREATMENT IN ALZHEIMER’S DISEASE

Jacob Penner1, Matthew Smith2, Jennie Wells2, Marybelle Campbell2, Michael Borrie2, Robert Bartha1, 1Robarts Research Institute, Western University, London, Ontario, Canada; 2Lawson Health Research Institute, London, Ontario, Canada. Background: Rivastigmine is a cholinesterase inhibitor used for the treatment of Alzheimer disease (AD) that provides positive effects on cognition, behaviour, and function. Proton Magnetic Resonance Spectroscopy (1 H MRS) has been previously used to monitor metabolic changes in brain tissue following cholinesterase inhibitor treatment in subjects with AD. The purpose of this study was to compare metabolic changes in the posterior cingulate to changes in cognition in subjects with AD following rivastigmine treatment. Methods: Five subjects with AD (3 males, age 70 6 11 years) were recruited. Cognition was measured with the MMSE and the ADAS-cog performed before beginning rivastigmine treatment via the Exelon Patch (4.6 mg/24 hours for the first month, 9.5 mg/24 hours thereafter), and again after four months of treatment. All MR imaging and spectroscopic data were acquired on a 3T Siemens whole-body MRI. T 2 -weighted images (0.7x0.7x4 mm 3 resolution, TR ¼ 6s, TE ¼ 84 ms) were acquired for MRS voxel placement. MRS data were acquired from an 8 cm 3 volume of interest (TR ¼ 2s, TE ¼ 135 ms) in the posterior cingulate at baseline and after four months of treatment. N