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

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Oral Sessions: O3-12: Neuroimaging: Models of and Changes in Amyloid Imaging

AD were early-PiB(+). When the 1.80 AD-like cutoff was applied, 6/10 (60%) controls, 21/26 (81%) MCI and 42/45 (93%) AD subjects who were early-PiB(+) remained AD-like-PiB(+). Conclusions: Cutoffs designed to detect the very first signs of amyloid deposition in cognitively normal controls may be too liberal to accurately ascribe the underlying pathophysiology of a clinical dementia syndrome to AD. A more conservative cutoff may be necessary to increase the specificity of amyloid imaging for the identification of clinical dementia (or even MCI) syndromes caused by AD. O3-12-04

RATES OF PIB ACCUMULATION DO PLATEAU

Clifford Jack, Heather Wiste, Stephen Weigand, Prashanthi Vemuri, David Knopman, Val Lowe, Vernon Pankratz, Timothy Lesnick, Bradley Boeve, Matthew Senjem, Jeffrey Gunter, Ronald Petersen, Mayo Clinic, Rochester, Minnesota, United States. Background: A recent hypothetical model of Alzheimer’s disease (AD) biomarkers proposed that biomarker levels as function of disease stage follow a sigmoid-shaped trajectory. The basis for proposing a sigmoid shape for amyloid PET in particular was in part based on the observation that in most studies comparing PIB PET across clinical groups, the top (i.e., most abnormal values) in the distribution of cognitively normal subjects are no different than the top values in AD dementia subjects. This suggests that rates of PIB accumulation decrease as PIB accumulation reaches its highest levels. Our objective was to investigate this relationship. Methods: Subjects were enrolled in either the Mayo Clinic Study of Aging (n¼177) or the Mayo Alzheimer’s Disease Research Center (n¼15). Subjects were aged 70-92, 145 subjects were classified as cognitively normal (CN) and 47 as cognitively impaired (38 Mild Cognitive Impairment (MCI) and 9 AD dementia). All subjects had undergone 2 or more serial PIB PET exams. We measured baseline PIB SUVR and for each subject estimated a slope representing the PIB accumulation rate. We then fit regression models predicting PIB accumulation rate given baseline PIB, age, sex, education, and APOE genotype. Results: The PIB accumulation rate was strongly associated with baseline PIB (P<0.001) and had an inverted U shape (P<0.001, test of non-linearity). We observed low rates of accumulation at low baseline PIB values, rates increasing to a maximum at baseline SUVR values around 1.7-2.0, above which rates declined - reaching accumulation rates near 0 at baseline SUVR values of about 3.0. This non-linear relationship held across clinical subgroups. There was a significant interaction between APOE and clinical category (P¼0.004) such that greater rates of PIB accumulation were found in MCI/AD APOE ^Im4 carriers compared to ^Im4 non-carriers. Conclusions: Our data is consistent with a recently published hypothetical model in which rates of amyloid PET accumulation accelerate early in the disease process, reach a peak, and then decline to near 0 at the highest levels of PIB accumulation measured. This produces a sigmoid shaped trajectory of PIB level as a function of disease progression. O3-12-05

INFLUENCE OF APOE GENOTYPE ON GLOBAL AND REGIONAL AMYLOID DEPOSITION: RESULTS FROM THREE WW-ADNI [C-11]PIB DATA

Kenji Ishii1, Eisuke Haneda1, Muneyuki Sakata1, Keiichi Oda1, Jun Toyohara1, Kiichi Ishiwata1, Michio Senda2, Kengo Ito3, Ryozo Kuwano4, Takeshi Iwatsubo5, The Japanese Alzheimer’s Disease Neuroimaging Initiative, The Alzheimer’s Disease Neuroimaging Initiative, The Australian Imaging Biomarker and Lifestyle (AIBL) Flagship Study of Ageing, 1Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; 2Institute of Biomedical Research and Innovation, Kobe, Japan; 3National Center for Geriatrics and Gerontology, Obu, Japan; 4Brain Research Institute, Niigata University, Niigata, Japan; 5University of Tokyo, Tokyo, Japan. Background: Apolipoprotein E (APOE) e4 and e2 allele has been implicated as positive and negative risk factors for Alzheimer’s disease (AD), respectively. However, their detailed pathophysiological roles are not known. In this study, we evaluated the influence of APOE genotype on the global and the regional brain accumulation of 11C-Pittsburgh compound B (PiB) in three nation-wide prospective imaging studies of AD; Alzheimer’s Disease Neuroimaging Initiative (US-ADNI), Austrarian Imaging Biomarker and Lifestyle (AIBL), and Japanese Alzheimer’s Dis-

ease Neuroimaging Initiative (J-ADNI). Methods: We analyzed a total of 386 baseline 11C-PiB scan data acquired 50-70 min post-injection in all the studies. The PET images were co-registered to individual MRI data, and automated VOI analysis were performed using DARTEL template, standard set of volumes of interest, and cerebrospinal fluid volume correction. The regional (precuneus, frontal, temporal and parietal cortices) uptake was evaluated in reference to that of the cerebellum. The mean cortical uptake (mcSUVR) was regarded as the representative value of individual global cortical amyloid deposition. The cut-off mcSUVR value for PiB-positivity was set at 1.5 for all the studies. Among all the studies, the number of subjects in each APOE genotype with PiB positive or negative (PiB+/PiB-) were; e2e2 (0/1), e2e3 (4/20), e2e4 (7/3), e3e3 (71/106), e3e4 (110/31) and e4e4 (14/19). Results: In the PiB-positive subjects, 11C-PiB uptake level was significantly elevated (p<0.001) in all the regions and the whole brain in e4 carrier subjects with apparent gene dose effect. On the other hand, the regional 11C-PiB uptake in precuneus solely showed significant reduction (P<0.05) in e2 carrier subjects. Conclusions: These results suggest that APOE e4 allele has a strong effect facilitating Amyloid b (Ab) deposition in all the brain regions without regional preferences. On the other hand, ApoE e2 allele seems to have some regional weighted effect to reduce Ab deposition especially in the precuneus. Further studies are required to examine the relationship between the spatial distribution of Ab deposition and APOE genotype and their role on AD pathogenesis.

Figure. [C-11]PiB Accumulation by APOE Genotype

O3-12-06

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

Yahong Peng1, Bradley Wyman2, Kasia Lobello1, George Zubal3, Michael Ryan1, Kenneth Marek4, John Seibyl3, Mary Slomkowski1, 1Pfizer Inc., Collegeville, Pennsylvania, United States; 2Pfizer Inc., Groton, Connecticut, United States; 3Institute for Neurodegenerative Disorders, New Haven, Connecticut, United States; 4Molecular 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 ACC001 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 (1¼no plaque, 2¼minor plaque, 3¼significant plaque, 4¼unevaluable). 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

Oral Sessions: O3-13: Therapeutics/Therapeutic Strategies: Clinical Trials and Clinical Trial Design negative for 34 subjects and positive for 36 (see figure). The visual 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.

ORAL SESSIONS: O3-13 THERAPEUTICS/THERAPEUTIC STRATEGIES: CLINICAL TRIALS AND CLINICAL TRIAL DESIGN O3-13-01

CHOICE OF ENDPOINTS, META-ANALYSES AND CLINICAL JUDGMENT FOR TREATMENTS OF ALZHEIMER’S DISEASE

Matthias W. Riepe1, David Wilkinson2, Hans F€orstl3, Andreas Brieden4, Ulm University, G€ unzburg, Germany; 2Memory Assessment and Research Centre, Southampton, United Kingdom; 3Technical University Munich, Munich, Germany; 4Universit€at der Bundeswehr, Neubiberg, Germany. 1

Background: Preclinical and clinical stages of Alzheimer’s disease both take several years. Hitherto, to measure efficacy, clinical studies of Alzheimer’s disease employ a variety of instruments that are all additive scales. For a multitude of reasons the numerical results of the individual clinical studies comparing different treatments vary. Therefore, meta-analyses are performed on standardised mean differences with the intention to account for variance of the magnitude of effects in clinical studies. Methods: Endpoints to assess treatment efficacy and meta-analyses thereof pertain to the assessment of ‘cognition’, ‘behaviour’, and ‘activities of daily living’. These, however, are composites measured with additive scales. E.g., ‘cognition’, as measured with the Alzheimer’s Disease Assessment Scale (ADAScog), the Mini-Mental-Status Examination (MMSE), and the Severe Impairment Battery (SIB), comprises single cognitive functions such as memory, orientation, language, and so forth. In these scales, subdomains of ‘cognition’, e.g. memory and language, are represented in different proportions. Results: Mathematical analysis reveals that the choice of additive scales to determine treatment efficacy systematically underestimates treatment efficacy of complex diseases of long duration such as Alzheimer’s disease. Calculation of effect sizes and meta-analyses on these measures are subject to distortion by the structure of the composite measure and by the non-linearity of decline towards the endpoints being analyzed. Conclusions: With regard to both, the preclinical and the clinical stages of Alzheimer’s disease, endpoints need to be developed and used that avoid the distortion of results imposed by the inappropriateness of additive scales with an interaction of disease stage and instruments used.

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With current instruments, even meta-analyses distort rather than elucidate therapeutic efficacy. O3-13-02

PREMORBID IQ AND INTRINSIC PROGRESSION RATE EXPLAIN SUBSTANTIAL VARIANCE IN OBSERVED PROGRESSION OF ALZHEIMER’S DISEASE (AD) ON MULTIPLE MEASURES

Rachelle Doody1, Wenyaw Chan2, Valory Pavlik1, Susan Rountree1, Paul Massman3, 1Baylor College of Medicine, Houston, Texas, United States; 2University of Texas in Houston, Houston, Texas, United States; 3 University of Houston, Houston, Texas, United States. Background: We have previously standardized a method for estimating the date of onset of AD symptoms, and using this and the Mini-mental Status Examination (MMSE), developed an estimate of pre-diagnosis progression rate (preprogression rate or PPR). We have also reported that premorbid IQ predicts observed progression. In the current analysis, we examined how much of the variance in cognitive and functional decline of a large group of AD patients (N¼852) was accounted for by PPR, premorbid IQ and other predictors. Methods: We enrolled Probable AD patients (NINCDS-ADRDA) assessed at baseline and then annually with the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog), MMSE, Clinical Dementia Rating-Sum of the Boxes (CDR-SB), Progressive Self-Maintenance Scale (PSMS) and Instrumental Activities of Daily Living Scale (IADL). All had the American National Adult Reading Test (AMNART) at baseline to estimate Intelligence Quotient (IQ), Physician’s Estimate of Duration, anti-dementia drug use, and Apo E genotype. Using a longitudinal mixed effects model, we examined the percentage of variance explained by each predictor alone and in combination. Results: At baseline, 40% were progressing slowly, 14% rapidly, and 46% at an intermediate rate; and mean ADAS-Cog was 21.1 (SD¼10.1). The mean follow up was 40.7 months (SD¼27.7) and 42% were living at the time of analysis. The combination of time, time squared, AMNART, and PPR accounted for 26% of the longitudinal variance on ADAS-Cog, 37% on the CDR-SB, 43% on the MMSE, 24% on the IADL and 36% on the PSMS. Age, sex, the presence of APOE4 and AD drug persistence contributed only minimally to the variance explained (almost everyone was on drug for a majority of the disease span). Conclusions: Much of the variance in AD group progression is predicted by IQ and the preprogression rate as estimated at the time of first assessment. Since the explained variance was substantial for the outcomes commonly used in clinical trials, these variables should be taken into consideration in designing studies to test treatments or to model disease progression in symptomatic AD patients. O3-13-03

ARGO TRIAL

Teodoro del Ser1, Simon Lovestone2, Merce Boada Rovira3, Bruno Dubois4, Michael H€ull5, Juha Rinne6, Teresa Leon1, 1Noscira SA, Tres Cantos, Madrid, Spain; 2King’s College. Maudsley Hospital, London, London, United Kingdom; 3Fundacio ACE, Barcelona, Spain; 4Salp^etriere Hospital, Paris, France; 5University of Freiburg ZGGF, Freiburg, Germany; 6 University of Turku, Turku, Finland. Background: Tideglusib is an inhibitor of the glycogen synthase kinase-3 (GSK-3) enzyme which has shown promising results in transgenic models of Alzheimer’s disease (AD) as well as in a pilot clinical trial in AD patients. Objectives: ARGO trial is intended to be a proof of concept of clinical efficacy and tolerability of tideglusib in mild to moderate AD patients. Methods: ARGO is a multinational, double-blind, placebo controlled, four parallel arm clinical trial of tideglusib in mild to moderate (Mini Mental State Examination score 14 to 26) AD patients, under stable and well tolerated anticholinesterasic and/or memantine treatment. Patients will be treated with tideglusib (1000 mg o.d., 1000 mg q.o.d, or 500 mg o.d.) or placebo (ratio 2:2:1:2) for 26 weeks. The primary efficacy measure will be the change in ADAS-cog+ over 26 weeks. The secondary objectives will be safety and tolerability of the compound, functional (ADCS-ADL), cognitive (MMSE, Verbal Fluency) and behavioral (NPI, GDS) changes, quality of life (EuroQol), caregiver time (RUD) and urinary incontinence. Brain atrophy in MRI and several biomarkers in plasma and cerebrospinal fluid will be