Rachel S. Mulligan

Relationship between nicotinic receptors and cognitive function in early Alzheimer’s disease: A 2-[18F]fluoro-A-85380 PET study

Neuronal nicotinic acetylcholine receptors (nAChRs) are critical for higher order cognitive processes. Post-mortem studies suggest reductions in nAChRs (particularly the alpha(4)beta(2) subtype) with ageing and in Alzheimers disease (AD). This study aimed to; (1) quantify nAChR distribution in vivo with 2-[18F]fluoro-A-85380 (2-FA) in 15 early AD patients compared to 14 age-matched, healthy controls (HC) and (2) correlate nAChR distribution with cognitive performance in both groups. All participants were non-smokers and underwent cognitive testing along with a dynamic PET scan after injection of 200 MBq of 2-FA. Brain regional 2-FA binding was assessed through a simplified estimation of Distribution Volume (DV(S)). The AD group differed significantly from HC on all cognitive measures employed, with impairments on measures of attention, working memory, language, executive function, visuospatial ability, verbal learning and verbal memory (p<.05). Contrary to post-mortem data this study found no evidence of in vivo nAChR loss in early AD despite significant cognitive impairment. Furthermore, no correlation between nAChR and cognitive performance was found for either group. The findings of the current study suggest preservation of nAChRs early in AD supporting previous studies. It is possible that while the clinical 2-FA PET method described here may be insensitive in detecting changes in early AD, such changes may be detected in more advanced stages of the illness.

The relationship between nicotinic receptors and cognitive functioning in healthy aging: An in vivo positron emission tomography (PET) study with 2‐[18F]fluoro‐A‐85380

Extensive experimental and neuropathological evidence supports the general hypothesis that decline in the basal forebrain cholinergic system contributes significantly to age‐related cognitive impairment. Postmortem studies suggest reductions in neuronal nicotinic acetylcholine receptors (nAChRs, particularly the α4β2 subtype) with aging. This study aimed to determine the distribution of α4β2‐subtype nAChRs in vivo by 2‐FA PET in healthy subjects (aged 21–83) and to establish whether there is an age‐related decline in nAChRs. Furthermore, the relationship between PET measures of 2‐FA binding and neurobehavioral measures of cognitive function was investigated. All participants were nonsmokers and underwent extensive cognitive testing and a PET scan after injection of 2‐FA (200 MBq). Brain regional 2‐FA binding was assessed through a simplified estimation of distribution volume (DVS). As expected, increasing age was associated with poorer cognitive performance, particularly on tasks assessing episodic memory and attentional processes. No significant age‐related differences in regional nAChR DVS were found. Furthermore, no significant correlations were found between cognitive measures and nAChR DVS. These results are consistent with recent studies suggesting the stability of cholinergic markers during senescence. It is plausible that changes in α4β2 nAChRs do occur with advancing age, but are beyond detection by the clinical 2‐FA PET approach adopted here. However, this approach may be appropriate for use in pathologies considered to undergo extensive nAChR loss such as Alzheimers disease and Parkinsons disease. Synapse 63:752–763, 2009.

Standardized Expression of 18F-NAV4694 and 11C-PiB β-Amyloid PET Results with the Centiloid Scale.

A common quantitative output value for PET measures of β-amyloid (Aβ) binding across tracers and methods would allow better comparison of data across sites and application of universal diagnostic and prognostic values. A method has recently been developed that generates a unit of measurement called the centiloid. We applied this method to 2-[2-18F-fluoro-6-(methylamino)-3-pyridinyl]-1-benzofuran-5-ol (18F-NAV4694) and 11C-Pittsburgh compound B (11C-PiB) Aβ images to derive the scaling factor required to express tracer binding in centiloids. Methods: Fifty-five participants, including 10 young controls (33 ± 7 y old), underwent both 11C-PiB and 18F-NAV4694 imaging no more than 3 mo apart, with the images acquired 50–70 min after tracer injection. The images were spatially normalized and analyzed using the standard centiloid method and regions (cortex and whole-cerebellum reference) downloaded from the Global Alzheimer Association Interactive Network website. Results: SUV ratios (SUVRs) showed a strong correlation in tracer binding (18F-NAV4694 SUVR = 1.09 × 11C-PiB SUVR – 0.08, R2 = 0.99). The equation to convert 18F-NAV4694 to centiloids [100 × (18F-NAV4694 SUVR – 1.028)/1.174] was similar to a published equation for 11C-PiB [100 × (11C-PiB SUVR – 1.009)/1.067]. In the young controls, the variance ratio (18F-NAV4694 centiloid SD divided by 11C-PiB centiloid SD) was 0.85. Conclusion: The results for both 11C-PiB and 18F-NAV4694 can now be expressed in centiloids, an important step that should allow better clinical and research use of Aβ imaging. The standard centiloid method also showed that 18F-NAV4694 has slightly higher Aβ binding and lower variance than 11C-PiB, important properties for detecting early Aβ deposition and change over time.

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

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.

Comparison of biomarkers for the prediction of cognitive decline

diffusion magnetic resonance imaging (MRI) at 3Tesla. The MRI data was analysed using Freesurfer (v4.4.0) to segment cortical and subcortical brain region volumes, which were then registered to the diffusion data. Linear regression models were used to assess differences in the volume and diffusion indices of subcortical brain regions between PSEN1 MCs and controls. Results: After adjusting for gender, age and total intracranial volume, MCs demonstrated significantly smaller volumes of the left caudate by 0.67ml (95%CI 0.29,1.06 p 1⁄4 0.002) adjacent left accumbens area by 0.13ml (95%CI 0.05,0.21 p 1⁄4 0.003) and right caudate by 0.51ml (95%CI 0.12,0.89 p 1⁄4 0.015). There was weaker evidence for a reduction in the volume of the left putamen by 0.45ml (95%CI -0.08,0.97 p 1⁄4 0.092), right putamen by 0.41ml (95%CI -0.05,0.87, p 1⁄4 0.075), left thalamus by 0.54ml (95%CI -0.04,1.11, p 1⁄4 0.065), right thalamus by 0.38ml (95%CI -0.17,0.94, p 1⁄4 0.160) and right accumbens area by 0.10ml (95%CI -0.01,0.20, p 1⁄4 0.061). The only subcortical region demonstrating evidence of a difference in diffusivity between MCs and controls was the right thalamus, where MCs showed a reduction in axial diffusivity of 55.0mm2/s (95%CI -2,112 p 1⁄4 0.059), radial diffusivity of 41.0mm2/s (95%CI -5,87 p 1⁄4 0.077) and mean diffusivity (MD) of 45.7mm2/s (95%CI -3,94 p 1⁄4 0.062). Within the group of PSEN1 MCs, increasing thalamic MD correlated with decreasing mini-mental state examination (MMSE) score. Conclusions: The early striatal and thalamic amyloid deposition witnessed in PSEN1 MCs is accompanied by reduced volumes of these brain regions. In the right thalamus, increased diffusivity indices suggest loss of tissue microstructural integrity and this appears to be associated with deteriorating cognitive function. O3-06-04 BASELINE AND FOLLOW-UP NEUROIMAGING RESULTS FROM THE AUSTRALIAN IMAGING, BIOMARKER, AND LIFESTYLE FLAGSHIP STUDY OF AGING (AIBL) Christopher C. Rowe, Kathryn Ellis, Gael Chetelat, Kerryn Pike, Miroslava Rimajova, Cassandra Szoeke, Pierrick Bourgeat, Olivier Salvado, Ralph Martins, Colin L. Masters, David Ames, Victor L. Villemagne, AIBL Research Group,Austin Hospital, Melbourne, Australia; Department of Psychiatry, University of Melbourne, Melbourne, Australia; Edith Cowan University, Perth, Australia; CSIRO ICT Centre, Brisbane, Australia; The Mental Health Research Institute, Melbourne, Australia; National Ageing Research Institute, Melbourne, Australia. Contact e-mail: Christopher.ROWE@austin.org.au

18F-AV-133 VMAT2 imaging in the differential diagnosis of dementia with Lewy Bodies from Alzheimer's disease

Neurology, JR Tokyo General Hospital, Tokyo, Japan; Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima, Japan; Department of Psychiatry, Ichihara Hospital, Teikyo University School of Medicine, Chiba, Japan; Department of Neurosurgery, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan; Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan; Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan; Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Department of Rehabilitation Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan. Contact e-mail: shim@ alpha.ocn.ne.jp

Test-retest variability studies in Alzheimer's disease and normal ageing of the new amyloid imaging agent [18F]BAY 94-9172

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(n1⁄410), DM(n1⁄413), DM+SH(n1⁄412), PD(n1⁄4 9), PD+SH(n1⁄410), and healthy controls (HC)(n1⁄410). 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.

IC-P3-208: In vivo characterization of 18F-BAY94-9172: A novel β-amyloid PET ligand for the diagnosis of Alzheimer's disease

were used to estimate the number of mild pAD and aMCI patients needed per group to detect disease-modifying treatment effects in sixor twelve-month multi-center RCTs with 80% power and P 0.001 uncorrected for multiple comparisons. Results: The pAD patients had twelve-month CMRgl declines in posterior cingulate, precuneus, parietal, temporal and frontal regions and the aMCI patients had twelvemonth CMRgl declines in the posterior cingulate, precuneus, parietal and temporal regions. To detect a 20% treatment effect on posterior cingulate CMRgl declines, we estimate the need for 153 mild pAD patients per group and 728 aMCI patients per group in twelve-month RCTs. Conclusions: This study provides preliminary information about twelve-month CMRgl declines in mild pAD and aMCI patients and the number of patients needed to detect disease-modifying treatment effects in a twelve-month multi-center RCT. Future analyses will extend our findings to the entire ADNI cohort, provide power estimates for 6, 12, 18 and 24-month multi-center RCTs using specified search regions versus ROIs, and compare these power estimates to those using clinical ratings, other imaging modalities and other image-analysis techniques.

O1-04-02: Initial results from human studies of a novel F-18 PET ligand for brain beta-amyloid imaging

with best practice methods to deliver care primarily via small group homes and that dementia care takes up a disproportionate amount of staff time in small care settings. Conclusions: To address early stage dementia related services in the most effective manner, a concerted effort needs to be in place to aid local service entities adapt services to dementia-related presentations among ID clientele, set up coordinated training for staff, secure funds for adapting group homes for community “dementia-capable” care, and construction of clinical support services and augmentation of family support services for parents and other kin carers.