Kevin Ong

Amyloid Imaging with 18 F-Florbetaben in Alzheimer Disease and Other Dementias

Amyloid imaging with 18F-labeled radiotracers will allow widespread use, facilitating research, diagnosis, and therapeutic development for Alzheimer disease. The purpose of the study program was to compare cortical amyloid deposition using 18F-florbetaben and PET in controls and subjects with mild cognitive impairment (MCI), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), vascular dementia (VaD), Parkinson disease (PD), and Alzheimer disease (AD). Methods: One hundred nine subjects in 3 clinical studies at Austin Health were reviewed: 32 controls, 20 subjects with MCI, and 30 patients with AD, 11 with FTLD, 7 with DLB, 5 with PD, and 4 with VaD underwent PET after intravenous injection of 300 MBq of 18F-florbetaben. Standardized uptake value ratios (SUVR) using the cerebellar cortex as a reference region were calculated between 90 and 110 min after injection. Results: When compared with the other groups, AD patients demonstrated significantly higher SUVRs (P < 0.0001) in neocortical areas. Most AD patients (96%) and 60% of MCI subjects showed diffuse cortical 18F-florbetaben retention. In contrast, only 9% of FTLD, 25% of VaD, 29% of DLB, and no PD patients and 16% of controls showed cortical binding. Although there was a correlation between Mini Mental State Examination and β-amyloid burden in the MCI group, no correlation was observed in controls, FTLD or AD. Conclusion: 18F-florbetaben had high sensitivity for AD, clearly distinguished patients with FTLD from AD, and provided results comparable to those reported with 11C-Pittsburgh Compound B in a variety of neurodegenerative diseases.

Aβ imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study

Background We assessed the clinical utility of β-amyloid (Aβ) imaging with 18F-florbetaben (FBB) in mild cognitive impairment (MCI) by evaluating its prognostic accuracy for progression to Alzheimers disease (AD), comparing semiquantitative with visual scan assessment, and exploring the relationships among Aβ, hippocampal volume (HV) and memory over time. Methods 45 MCI underwent FBB positron emission tomography, MRI and neuropsychological assessment at baseline and 2 years and clinical follow-up at 4 years. Positive FBB (FBB+), defined by a cortical to cerebellar cortex standardised uptake value ratio (SUVR) ≥1.45, was compared with visual assessment by five readers. Amnestic MCI (aMCI) was defined by a composite episodic memory (EM) Z-score of <−1.5. Results At baseline, 24 (53%) MCI were FBB+. Majority reads agreed with SUVR classification (κ 0.96). In 2 years, 18 (75%) FBB+ progressed to AD compared with 2 (9.5%) FBB−, yielding a predictive accuracy of 83% (95% CI 61% to 94%). Four FBB− developed non-AD dementia. Predictive accuracies of HV (58% (95% CI 42% to 73%)) and aMCI status (73% (95% CI 58% to 81%)) were lower. Combinations did not improve accuracy. By 4 years, 21 (87.5%) FBB+ had AD whereas 5 (24%) FBB− had non-AD dementia yielding a predictive accuracy of 94% (95% CI 74% to 99%). While the strong baseline association between FBB SUVR and EM declined over 2 years, the association between EM and HV became stronger. FBB SUVR increased 2.2%/year in FBB+ with no change in FBB−. Conclusions 18F-florbetaben Aβ imaging facilitates accurate detection of prodromal AD. As neurodegeneration progresses, and in contrast with the early stages of the disease, hippocampal atrophy and not Aβ, seems to drive memory decline. Trial registration number NCT01138111.

18F-florbetaben Aβ imaging in mild cognitive impairment

Introduction18F-florbetaben and positron emission tomography were used to examine the relationships between β-amyloid (Aβ) deposition, cognition, hippocampal volume, and white matter hyperintensities in mild cognitive impairment (MCI).MethodsForty-five MCI participants were evaluated. A neocortical standardized uptake value ratio threshold ≥ 1.45 was used to discriminate high from low Aβ burden. Correlations were adjusted for age, gender and years of education.ResultsHigh Aβ burden was found in 53% of MCI. Regression analyses showed standardized uptake value ratio (r = -0.51, P = 0.0015) and hippocampal volume (r = 0.60, P = 0.024) both contributing to episodic memory impairment in independent fashion. White matter hyperintensities correlated with nonmemory cognition, and this correlation was particularly associated with Aβ burden.ConclusionHigher Aβ deposition in MCI is associated with more severe memory impairment and is contributing to early amnestic symptoms independent of hippocampal atrophy.

En Attendant Centiloid

Aims: Test the robustness of a linear regression transformation of semiquantitative values from different Aβ tracers into a single continuous scale. Study Design: Retrospective analysis. Place and Duration of Study: PET imaging data acquired in Melbourne and Perth, Australia, between August 2006 and May 2014. Methodology: Aβ imaging in 633 participants was performed with four different radiotracers: flutemetamol (n=267), florbetapir (n=195), florbetaben (n=126) and NAV4694 (n=45). SUVR were generated with the methods recommended for each tracer, and classified as high (Aβ+) or low (Aβ-) based on their respective thresholds. Linear regression transformation based on reported head-to-head comparisons of each tracer with PiB was applied to each tracer result. Each tracer native classification was compared with the classification derived from the transformed data into PiB-like SUVR units (or BeCKeT: Before the Centiloid Kernel Transformation) using 1.50 as a cut-off. Results: Misclassification after transformation to PiB-like SUVR compared to native classification was extremely low with only 3/267 (1.1%) of flutemetamol, 1/195 (0.5%) of florbetapir, 1/45 (2.2%) of NAV4694, and 1/126 (0.8%) of florbetaben cases assigned into the wrong category. When misclassification occurred (<1% of all cases) it was restricted to an extremely narrow margin (±0.02 BeCKeT) around the 1.50 BeCKeT threshold. Conclusion: While a definitive transformation into centesimal units is being established, application of linear regression transformations provide an interim, albeit robust, way of converting results from different Aβ imaging tracers into more familiar PiB-like SUVR units.

Prediction of Amyloid-β Pathology in Amnestic Mild Cognitive Impairment with Neuropsychological Tests

Assessment of disease biomarkers, particularly the in vivo assessment of amyloid-β (Aβ) burden with positron emission tomography (PET), is gradually becoming central to the diagnosis of mild cognitive impairment (MCI) due to Alzheimers disease (AD). However, the incorporation of biomarker evidence to the diagnostic process is currently restricted mainly to research settings. The identification of memory measures that are associated with Aβ is of clinical relevance as this may enhance the confidence in making a diagnosis of MCI due to AD in clinical settings. Forty one persons with amnestic MCI underwent Aβ imaging with (18)F-Florbetaben PET, magnetic resonance imaging, and a comprehensive neuropsychological assessment. All measures of episodic memory were significantly correlated with Aβ burden, but regression analyses revealed a strong and selective association between story recall and Aβ over and beyond the effects of age, education, global cognition, hippocampal volume, or other memory tests. Analyses of sensitivity and specificity of memory measures to detect high versus low Aβ scans suggested that word-list recall performed better when high sensitivity was preferred, whereas story recall performed better when high specificity was preferred. In conclusion, a measure of story recall may increase the confidence in making a diagnosis of MCI due to AD in clinical settings.

Assessment of Aβ Deposition in Mild Cognitive Impairment with 18F-Florbetaben

IC-P-059 ASSESSMENT OF Ab DEPOSITION IN MILD COGNITIVE IMPAIRMENT WITH 18FFLORBETABEN Kevin Ong, Victor L. Villemagne, Narelle Langdon, Gerhard Holl, Cornelia Reininger, Barbara Putz, Gareth Jones, Rachel Mulligan, Svetlana Pejoska, Beate Rohde, Colin L. Masters, Christopher C. Rowe, Austin Hospital, Melbourne, VIC, Australia; The Mental Health Research Institute, Melbourne, VIC, Australia; Bayer Schering Pharma, Berlin, Germany. Contact e-mail: kevin.ong@petnm.unimelb.edu.au

Conversion from mild cognitive impairment to Alzheimer's disease over 12 months: Predictive value of Aβ imaging with 18F-Florbetaben

in mild cognitive impairment patients subsequently diagnosed with probable Alzheimer’s disease (Olichney et al., 2008), and a feedback-locked P300 which we believe is reflective of participants’ confidence in their category learning. Younger adults showed similar patterns for the late positive complex and P300 event-related potentials as in our original study (Morrison, Reber, and Paller, 2009). Because of the previously described differences in accuracy between the rule and no-rule subgroups, we examined event-related potentials separately in these two subgroups. The rule subgroup showed a larger late positive complex for correct than incorrect trials, similar in magnitude to that observed for younger adults. The no-rule subgroup showed no late positive complex differences between correct and incorrect trials. The rule subgroup also showed a feedback P300 difference for correct/incorrect trials, but it was smaller than that in younger adults, suggesting decreased rule-learning confidence (despite similar accuracy across groups). The no-rule subgroup showed event-related potentials characteristic of chance performance, with no differences between correct and incorrect trials in the feedback-locked P300, paralleling the lack of an effect on the stimulus-locked late positive complex.There were no significant differences in the control task between younger and older adults. Rule and norule older adults also performed similarly showing performance approximately equal to the asymptotic categorization performance for the rule-subgroup during the primary task. This suggests that no-rule subgroup categorization performance was likely reflecting deficits in long-term memory or executive functions. Conclusions: Preliminary results in this study showed that a simple rule-based category-learning task elicited differential performance and event-related potential findings as a function of age. We focused on findings from a group of older adults known to have long-term memory within the normal range on standard neuropsychological tests. Yet, some members of this group were successful in learning to categorize stimuli and some were not. We thus identified two distinct subgroups of healthy older individuals, one subgroup with category learning similar to college students and the other with dramatic deficits. Event-related potentialss recorded during categorization confirmed this stratification. Specifically a stimulus-locked late positive complex believed to index long-term memory was preserved in older adults who learned to categorize, but not in the others. Secondly a feedback-locked P300 believed to reflect the degree to which the participant is confident in their category learning showed a graded decrement. P300 differences for feedback on correct versus incorrect trials were greatest in amplitude in younger adults, intermediate in rulelearning older adults, and smallest in those older adults who failed to learn to categorize. The current study suggests that rule-based category learning, a task utilizing long-termmemory and executive functions, may be an effective means for identifying individuals at increased risk for mild cognitive impairment and probable Alzheimer’s disease. Event-related potentials recorded during this task may provide a more sensitive measure of changes in cognition compared to simple neuropsychological tests by measuring neural function even when participants perform well, thus providing an objective measure of confidence in learning. Future work will be directed at testing patients with mild cognitive impairment and Alzheimer’s disease using this paradigm.

HIGHER AB BURDEN IN HEALTHY APOE-E4 CARRIERS IS ASSOCIATED WITH SUBJECTIVE MEMORY COMPLAINTS: RESULTS FROM THE FLUTEMETAMOL AND PIB AIPL COHORTS

IC-P-074 HIGHER Ab BURDEN IN HEALTHYAPOE-E4 CARRIERS IS ASSOCIATEDWITH SUBJECTIVE MEMORY COMPLAINTS: RESULTS FROM THE FLUTEMETAMOL AND PIB AIBL COHORTS Christopher Cleon Rowe, Vincent Dore, Pierrick Bourgeat, Rachel Buckley, Robyn Veljanovski, Olivier Salvado, Kevin Ong, Robert Williams, Alan Rembach, Lance Macaulay, David Ames, Colin LouisMasters, Victor L. Villemagne, Austin Hospital, Melbourne, Australia; CSIRO, Brisbane, Australia; CSIRO, Herston, Australia; University of Melbourne, Victoria, Australia; Austin Health, Melbourne, Australia; Austin Health, Heidelberg, Australia; Melbourne Brain Centre Imaging Unit (Parkville), Parkville, Australia; Mental Health Research Institute, Melbourne, Australia; CSIRO, Parkville, Australia; National Ageing Research Institute Inc. (NARI), Parkville, Australia; Florey Institute, UoM, Parkville, Australia. Contact e-mail: christopher.rowe@ austin.org.au

REPETITIVE PHENOMENA IS SPECIFIC FOR ALZHEIMER'S DISEASE

Background: During the development and validation of neuropsychological measures for native English speakers, normative data are typically collected from healthy normal individuals across an age range (e.g. 1890 years-old) and from a specified geographic region (usually the USA). However, these norms may not be valid across geographically/culturally different populations. The purpose of this investigation was to compare, within a large Australian cohort, published norms against those derived from a, within-study, large sub-cohort of healthy individuals, as well as to examine the impact of a variety of demographic, clinical and biomarker variables on normative standards.Methods: Data from the Australian Imaging, Biomarkers and Lifestyle Study were used to compare three different normalisation procedures: (i) published population norms; (ii) norms derived from within-study participants who remained healthy over 3-years; (iii) norms derived from within-study amyloid negative (PiB-PETSUVR<1.5) participants who remained healthy over 3 years. The published norms were age, education and/or gender corrected. Multiple linear regressions were used to derive norms from within-study, with covariates including age, education, gender, premorbid IQ, and depressive symptomatology. Deviations from the raw data were assessed. Efficacy of the norms was examined cross-sectionally with receiver operating characteristics for separating a well defined HC population (3-years stable, amyloid negative) from diseased populations (AD, MCI or amyloid positive HC). Results: There was generally good alignment between the normed and raw data. Differences in the normed data were exacerbated in more diseased groups (AD>MCI>HC). There was a general, expected, increase in efficacy for stratifying more severely diseased participants (AD>MCI>amyloid positive HC). A systematic trend shows that population norms are not as effective as the within-study derived norms for differ-

18F-Florbetaben-pet imaging in the differential diagnosis of dementia

movement or special nutrition (Mediterranean Diet) could be consider to be potential preventive strategies. A few studies support also the protective effects of cognitively stimulating activities like reading or playing chess. They seem to reduce the dementia risk by enhancing cognitive reserve. Methods: The AKTIVA-program was developed, implemented and evaluated to determine the effects of a cognitive intervention training, based on the concept of cognitively stimulating activities. It can be understood as a manual for a cognitively stimulating design in everyday life and represents an individual approach of prevention. Participants were informed about their individual possibilities of prevention and were systematically instructed and reinforced to increase cognitive stimulating activities as part of their daily routines. Initially the study consisted of 307 older persons (170 female, 72 6 7 years). The intervention was evaluated with a randomized, controlled pre-post-follow-up design. Participants were randomly assigned to 1 of 3 conditions: AKTIVA-intervention (N 1⁄4 126), AKTIVA-intervention plus nutritionand sport-guidance (N 1⁄4 84), no-intervention control-group (N 1⁄4 97). Outcome measures were among others cognitive function, assessment of memory-performance and participation in leisure activities. Results: Data of 208 persons were analyzed (dropouts N 1⁄4 67, exclusions N 1⁄4 32). Significant training effects were found for sub-assembly groups of the sample. Older Persons ( 75 years) showed enhanced speed of information processing (by Trail-Making-Test Version A) (F 1⁄4 4.17*, p < .05) and younger participants showed an improvement in subjective memory decline (by Memory Complaint Questionnaire) (F1⁄4 2.55*, p< .05). Furthermore, significant outcomes in leisure activities (reading, take a walk, meet friends) were found. Conclusions: Participation at the AKTIVA-intervention enhances activityfrequencies of leisure activities and has positive effects on outcome measures for sub-assembly groups. Further research is necessary to identify long-term intervention-benefits. Results of the one-year follow-up will be also presented at the congress.