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1. High content, multi-parameter analyses in buccal cells to identify Alzheimer's disease

Author

François, M., Fenech, M., Thomas, P., Hor, M., Rembach, A., Martins, R.N., Rainey-Smith, S.R., Masters, C.L., Ames, D., Rowe, C.C., Macaulay, S.L., Hill, A.F., Leifert, W.R., Appannah, A., Barnes, M., Barnham, K., Bedo, J., Bellingham, S., Bon, L., Bourgeat, P., Brown, B., Buckley, R., Burnham, S., Bush, A., Chandler, G., Chen, K., Clarnette, R., Collins, S., Cooke, I., Cowie, T., Cox, K., Cuningham, E., Cyarto, E., Dang, P.A.V., Darby, D., Desmond, P., Doecke, J., Dore, V., Downing, H., Dridan, B., Duesing, K., Fahey, M., Farrow, M., Faux, N., Fernandez, S., Fernando, B., Fowler, C., Fripp, J., Frost, S., Gardener, S., Gibson, S., Graham, P., Gupta, V., Hansen, D., Harrington, K., Hone, E., Horne, M., Huckstepp, B., Jones, A., Jones, G., Kamer, A., Kanagasingam, Y., Keam, L., Kowalczyk, A., Krivdic, B., Lam, C.P., Lamb, F., Lautenschlager, N., Laws, S., Lenzo, N., Leroux, H., Lftikhar, F., Li, Q-X, Lim, F., Lim, L., Lockett, L., Lucas, K., Mano, M., Marczak, C., Martins, G., Matsumoto, Y., Bird, S., McBride, S., McKay, R., Mulligan, R., Nash, T., Nigro, J., O'Keefe, G., Ong, K., Parker, B., Pedrini, S., Peiffer, J., Pejoska, S., Penny, L., Perez, K., Pertile, K., Phal, P., Porter, T., Raniga, P., Restrepo, C., Riley, M., Roberts, B., Robertson, J., Rodrigues, M., Rooney, A., Rumble, R., Ryan, T., Salvado, O., Samuel, M., Saunders, I., Savage, G., Silbert, B., Sohrabi, H.R., Syrette, J., Szoeke, C., Taddei, K., Taddei, T., Tan, S., Tegg, M., Trivedi, D., Trounson, B., Veljanovski, R., Verdile, G., Villemagne, V., Volitakis, I., Vockler, C., Vovos, M., Vrantsidis, F., Walker, S., Watt, A., Weinborn, M., Wilson, B., Woodward, M., Yastrubetskaya, O., Yates, P., Zhang, P., Chatterjee, P., Creegan, R., De Ruyck, K., Ding, H., Groth, D., Head, R., Krause, D., Lachovitzki, R., Lim, Y.Y., Lintern, T., Mondal, A., Nuttall, S., O'Callaghan, N., Osborne, L., Pang, C., Patten, G., Tuckfield, A., Varghese, J., Wilson, A., Zhang, Q., François, M., Fenech, M., Thomas, P., Hor, M., Rembach, A., Martins, R.N., Rainey-Smith, S.R., Masters, C.L., Ames, D., Rowe, C.C., Macaulay, S.L., Hill, A.F., Leifert, W.R., Appannah, A., Barnes, M., Barnham, K., Bedo, J., Bellingham, S., Bon, L., Bourgeat, P., Brown, B., Buckley, R., Burnham, S., Bush, A., Chandler, G., Chen, K., Clarnette, R., Collins, S., Cooke, I., Cowie, T., Cox, K., Cuningham, E., Cyarto, E., Dang, P.A.V., Darby, D., Desmond, P., Doecke, J., Dore, V., Downing, H., Dridan, B., Duesing, K., Fahey, M., Farrow, M., Faux, N., Fernandez, S., Fernando, B., Fowler, C., Fripp, J., Frost, S., Gardener, S., Gibson, S., Graham, P., Gupta, V., Hansen, D., Harrington, K., Hone, E., Horne, M., Huckstepp, B., Jones, A., Jones, G., Kamer, A., Kanagasingam, Y., Keam, L., Kowalczyk, A., Krivdic, B., Lam, C.P., Lamb, F., Lautenschlager, N., Laws, S., Lenzo, N., Leroux, H., Lftikhar, F., Li, Q-X, Lim, F., Lim, L., Lockett, L., Lucas, K., Mano, M., Marczak, C., Martins, G., Matsumoto, Y., Bird, S., McBride, S., McKay, R., Mulligan, R., Nash, T., Nigro, J., O'Keefe, G., Ong, K., Parker, B., Pedrini, S., Peiffer, J., Pejoska, S., Penny, L., Perez, K., Pertile, K., Phal, P., Porter, T., Raniga, P., Restrepo, C., Riley, M., Roberts, B., Robertson, J., Rodrigues, M., Rooney, A., Rumble, R., Ryan, T., Salvado, O., Samuel, M., Saunders, I., Savage, G., Silbert, B., Sohrabi, H.R., Syrette, J., Szoeke, C., Taddei, K., Taddei, T., Tan, S., Tegg, M., Trivedi, D., Trounson, B., Veljanovski, R., Verdile, G., Villemagne, V., Volitakis, I., Vockler, C., Vovos, M., Vrantsidis, F., Walker, S., Watt, A., Weinborn, M., Wilson, B., Woodward, M., Yastrubetskaya, O., Yates, P., Zhang, P., Chatterjee, P., Creegan, R., De Ruyck, K., Ding, H., Groth, D., Head, R., Krause, D., Lachovitzki, R., Lim, Y.Y., Lintern, T., Mondal, A., Nuttall, S., O'Callaghan, N., Osborne, L., Pang, C., Patten, G., Tuckfield, A., Varghese, J., Wilson, A., and Zhang, Q.

Abstract

Alzheimer’s disease (AD) is a degenerative brain disorder and is the most common form of dementia. Minimally invasive approaches are required that combine biomarkers to identify individuals who are at risk of developing mild cognitive impairment (MCI) and AD, to appropriately target clinical trials for therapeutic discovery as well as lifestyle strategies aimed at prevention. Buccal mucosa cells from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing cohort (n=60) were investigated for cytological markers that could be used to identify both MCI and AD individuals. Visual scoring of the buccal cytome demonstrated a significantly lower frequency of basal and karyorrhectic cells in the MCI group compared with controls. A high content, automated assay was developed using laser scanning cytometry to simultaneously measure cell types, nuclear DNA content and aneuploidy, neutral lipid content, putative Tau and amyloid-β (Aβ) in buccal cells. DNA content, aneuploidy, neutral lipids and Tau were similar in all groups. However, there was significantly lower Tau protein in both basal and karyolytic buccal cell types compared with differentiated buccal cells. Aβ, as measured by frequency of cells containing Aβ signal, as well as area and integral of Aβ signal, was significantly higher in the AD group compared with the control group. Buccal cell Aβ was correlated with mini-mental state examination (MMSE) scores (r = -0.436, P=0.001) and several blood-based biomarkers. Combining newly identified biomarkers from buccal cells with those already established may offer a potential route for more specific biomarker panels which may substantially increase the likelihood of better predictive markers for earlier diagnosis of AD.

Published
2016

2. Non-invasive assessment of Alzheimer's disease neurofibrillary pathology using 18F-THK5105 PET

Author

Okamura, N, Furumoto, S, Fodero-Tavoletti, MT, Mulligan, RS, Harada, R, Yates, P, Pejoska, S, Kudo, Y, Masters, CL, Yanai, K, Rowe, CC, Villemagne, VL, Okamura, N, Furumoto, S, Fodero-Tavoletti, MT, Mulligan, RS, Harada, R, Yates, P, Pejoska, S, Kudo, Y, Masters, CL, Yanai, K, Rowe, CC, and Villemagne, VL

Abstract

Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer's disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimer's disease (three male and five females, 66-82 years) and eight healthy elderly controls (three male and five females, 63-76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90-100 min and 40-70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer's disease compared with healthy control subjects. In patients with Alzheimer's disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer's disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer's disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer's disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neo

Published
2014

3. The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer’s disease

Author

Ellis, K., Bush, A., Darby, D., de Fazio, D., Foster, Jonathan, Hudson, P., Lautenschlager, N., Lenzo, N., Martins, R., Maruff, P., Masters, C., Milner, A., Pike, K., Rowe, C., Savage, G., Szoeke, C., Taddei, K., Villemagne, V., Woodward, M., Ames, D., Acosta, O., Ames, J., Agarwal, M., Bahar-Fuchs, A., Baxendale, D., Bechta-Metti, K., Bevage, C., Bevege, L., Bourgeat, P., Brown, B., Clarnette, R., Cowie, T., Crowley, K., Currie, A., El- Sheikh, D., Dickinson, K., Farrow, M., Faux, N., Fripp, J., Fowler, C., Gupta, V., Jones, G., Khoo, J., Killedar, A., Killeen, N., Kim, T.W., Kotsopoulos, E., Lachovitzki, R., Li, Q., Liang, X., Lucas, K., Lui, J., Martins, G., Montague, C., Moore, L., Muir, A., O’Halloran, C., O’Keefe, G., Panayiotou, A., Paton, A., Paton, J., Peiffer, J., Pejoska, S., Pertile, K., Porter, L., Price, R., Raniga, P., Rees, G., Rembach, A., Rimajova, M., Robins, P., Ronsisvalle, E., Rumble, R., Rodrigues, M., Salvado, O., Sach, J., Samuel, M., Sittironnarit, G., Taddei, T., Trivedi, D., Trounson, B., Tsikkos, M., Walker, S., Ward, V., Yastrubetskaya, O., Ellis, K., Bush, A., Darby, D., de Fazio, D., Foster, Jonathan, Hudson, P., Lautenschlager, N., Lenzo, N., Martins, R., Maruff, P., Masters, C., Milner, A., Pike, K., Rowe, C., Savage, G., Szoeke, C., Taddei, K., Villemagne, V., Woodward, M., Ames, D., Acosta, O., Ames, J., Agarwal, M., Bahar-Fuchs, A., Baxendale, D., Bechta-Metti, K., Bevage, C., Bevege, L., Bourgeat, P., Brown, B., Clarnette, R., Cowie, T., Crowley, K., Currie, A., El- Sheikh, D., Dickinson, K., Farrow, M., Faux, N., Fripp, J., Fowler, C., Gupta, V., Jones, G., Khoo, J., Killedar, A., Killeen, N., Kim, T.W., Kotsopoulos, E., Lachovitzki, R., Li, Q., Liang, X., Lucas, K., Lui, J., Martins, G., Montague, C., Moore, L., Muir, A., O’Halloran, C., O’Keefe, G., Panayiotou, A., Paton, A., Paton, J., Peiffer, J., Pejoska, S., Pertile, K., Porter, L., Price, R., Raniga, P., Rees, G., Rembach, A., Rimajova, M., Robins, P., Ronsisvalle, E., Rumble, R., Rodrigues, M., Salvado, O., Sach, J., Samuel, M., Sittironnarit, G., Taddei, T., Trivedi, D., Trounson, B., Tsikkos, M., Walker, S., Ward, V., and Yastrubetskaya, O.

Abstract

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging aimed to recruit 1000 individuals aged over 60 to assist with prospective research into Alzheimer's disease (AD). This paper describes the recruitment of the cohort and gives information about the study methodology, baseline demography, diagnoses, medical comorbidities, medication use, and cognitive function of the participants. Methods: Volunteers underwent a screening interview, had comprehensive cognitive testing, gave 80 ml of blood, and completed health and lifestyle questionnaires. One quarter of the sample also underwent amyloid PET brain imaging with Pittsburgh compound B (PiB PET) and MRI brain imaging, and a subgroup of 10% had ActiGraph activity monitoring and body composition scanning. Results: A total of 1166 volunteers were recruited, 54 of whom were excluded from further study due to comorbid disorders which could affect cognition or because of withdrawal of consent. Participants with AD (211) had neuropsychological profiles which were consistent with AD, and were more impaired than participants with mild cognitive impairment (133) or healthy controls (768), who performed within expected norms for age on neuropsychological testing. PiB PET scans were performed on 287 participants, 100 had DEXA scans and 91 participated in ActiGraph monitoring. Conclusion: The participants comprising the AIBL cohort represent a group of highly motivated and well-characterized individuals who represent a unique resource for the study of AD. They will be reassessed at 18-month intervals in order to determine the predictive utility of various biomarkers, cognitive parameters and lifestyle factors as indicators of AD, and as predictors of future cognitive decline.

Published
2009

4. 11C-PiB PET ABri imaging in Worster-Drought syndrome (familial British dementia): a case report.

Author

Villemagne VL, Pike K, Pejoska S, Boyd A, Power M, Jones G, Masters CL, Rowe CC, Villemagne, Victor L, Pike, Kerryn, Pejoska, Svetlana, Boyd, Alison, Power, Margaret, Jones, Gareth, Masters, Colin L, and Rowe, Christopher C

Abstract

Brain amyloid imaging is becoming an essential tool for the pre-mortem evaluation of Alzheimer's disease (AD). This study explores the pattern of 11C-PiB retention in a subject with Worster-Drought syndrome (WDS). A 55 year-old male carrier of the WDS gene mutation with mild signs of ataxia and subtle cognitive impairment underwent MRI and 11C-PiB-PET studies.Brain PiB regional distribution was compared to those from cohorts of healthy controls and AD patients. While no significant cortical 11C-PiB retention was present, a high degree of cerebellar 11C-PiB retention was observed in a genetically confirmed carrier of the WDS gene. We speculate that the sparsity of ABri plaques in the neocortex together with its high deposition in the cerebellum, might explain the observed pattern of 11C-PiB retention. [ABSTRACT FROM AUTHOR]

Published
2010
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6. High content, multi-parameter analyses in buccal cells to identify alzheimer’s disease

Author

François, M., Fenech, M. F., Thomas, P., Hor, M., Rembach, A., Martins, R. N., Rainey-Smith, S. R., Masters, C. L., Ames, D., Rowe, C. C., Lance Macaulay, S., Hill, A. F., Leifert, W. R., Appannah, A., Barnes, M., Barnham, K., Bedo, J., Bellingham, S., Bon, L., Bourgeat, P., Brown, B., Buckley, R., Burnham, S., Bush, A., Chandler, G., Chen, K., Clarnette, R., Collins, S., Cooke, I., Cowie, T., Cox, K., Cuningham, E., Cyarto, E., Dang, P. A. V., Darby, D., Desmond, P., Doecke, J., Dore, V., Downing, H., Dridan, B., Duesing, K., Fahey, M., Farrow, M., Faux, N., Fenech, M., Fernandez, S., Fernando, B., Fowler, C., Francois, M., Fripp, J., Frost, S., Gardener, S., Gibson, S., Graham, P., Gupta, V., Hansen, D., Harrington, K., Hill, A., Hone, E., Horne, M., Huckstepp, B., Jones, A., Jones, G., Kamer, A., Kanagasingam, Y., Keam, L., Kowalczyk, A., Krivdic, B., Lam, C. P., Lamb, F., Lautenschlager, N., Laws, S., Leifert, W., Lenzo, N., Leroux, H., Lftikhar, F., Li, Q. -X, Lim, F., Lim, L., Lockett, L., Lucas, K., Mano, M., Marczak, C., Martins, G., Maruff, P., Matsumoto, Y., Bird, S., Mcbride, S., Mckay, R., Mulligan, R., Nash, T., Nigro, J., O Keefe, G., Ong, K., Parker, B., Pedrini, S., Peiffer, J., Pejoska, S., Penny, L., Perez, K., Pertile, K., Phal, P., Porter, T., Rainey-Smith, S., Raniga, P., Restrepo, C., Riley, M., Roberts, B., Robertson, J., Rodrigues, M., Rooney, A., Rumble, R., Ryan, T., Salvado, O., Samuel, M., Saunders, I., Savage, G., Silbert, B., Sohrabi, H., Syrette, J., Cassandra Szoeke, Taddei, K., Taddei, T., Tan, S., Tegg, M., Trivedi, D., Trounson, B., Veljanovski, R., Verdile, G., Villemagne, V., Volitakis, I., Vockler, C., Vovos, M., Vrantsidis, F., Walker, S., Watt, A., Weinborn, M., Wilson, B., Woodward, M., Yastrubetskaya, O., Yates, P., Zhang, P., Chatterjee, P., Creegan, R., Ruyck, K., Ding, H., Groth, D., Head, R., Krause, D., Lachovitzki, R., Lim, Y. Y., Lintern, T., Mondal, A., Nuttall, S., O Callaghan, N., Osborne, L., Pang, C., Patten, G., Tuckfield, A., Varghese, J., Wilson, A., and Zhang, Q.

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

Author

Rowe CC, Jones G, Doré V, Pejoska S, Margison L, Mulligan RS, Chan JG, Young K, and Villemagne VL

Subjects
Adult, Aniline Compounds, Brain diagnostic imaging, Female, Fluorine Radioisotopes pharmacokinetics, Humans, Male, Molecular Imaging standards, Positron-Emission Tomography methods, Practice Guidelines as Topic, Protein Interaction Mapping standards, Radiopharmaceuticals pharmacokinetics, Reproducibility of Results, Sensitivity and Specificity, Thiazoles, Tissue Distribution, Amyloid beta-Peptides metabolism, Benzofurans pharmacokinetics, Benzothiazoles pharmacokinetics, Brain metabolism, Hydrocarbons, Fluorinated pharmacokinetics, Image Interpretation, Computer-Assisted standards, Positron-Emission Tomography standards
Abstract

Unlabelled: 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-(18)F-fluoro-6-(methylamino)-3-pyridinyl]-1-benzofuran-5-ol ((18)F-NAV4694) and (11)C-Pittsburgh compound B ((11)C-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 (11)C-PiB and (18)F-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 ((18)F-NAV4694 SUVR = 1.09 × (11)C-PiB SUVR - 0.08, R(2) = 0.99). The equation to convert (18)F-NAV4694 to centiloids [100 × ((18)F-NAV4694 SUVR - 1.028)/1.174] was similar to a published equation for (11)C-PiB [100 × ((11)C-PiB SUVR - 1.009)/1.067]. In the young controls, the variance ratio ((18)F-NAV4694 centiloid SD divided by (11)C-PiB centiloid SD) was 0.85., Conclusion: The results for both (11)C-PiB and (18)F-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 (18)F-NAV4694 has slightly higher Aβ binding and lower variance than (11)C-PiB, important properties for detecting early Aβ deposition and change over time., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Published
2016
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9. Non-invasive assessment of Alzheimer's disease neurofibrillary pathology using 18F-THK5105 PET.

Author

Okamura N, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Harada R, Yates P, Pejoska S, Kudo Y, Masters CL, Yanai K, Rowe CC, and Villemagne VL

Subjects
Aged, Aged, 80 and over, Alzheimer Disease diagnostic imaging, Amyloid beta-Peptides metabolism, Brain Mapping methods, Carbon Radioisotopes, Female, Humans, Male, Neurofibrillary Tangles diagnostic imaging, Radiopharmaceuticals, Thiazoles, Alzheimer Disease pathology, Aniline Compounds, Neurofibrillary Tangles pathology, Plaque, Amyloid pathology, Positron-Emission Tomography methods, Quinolines
Abstract

Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer's disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimer's disease (three male and five females, 66-82 years) and eight healthy elderly controls (three male and five females, 63-76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90-100 min and 40-70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer's disease compared with healthy control subjects. In patients with Alzheimer's disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer's disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer's disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer's disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neocortex. Notably, unlike 11C-Pittsburgh compound B, 18F-THK5105 retention was significantly correlated with cognitive parameters, hippocampal and whole brain grey matter volumes, which was consistent with findings from previous post-mortem studies showing significant correlations of neurofibrillary tangle density with dementia severity or neuronal loss. From these results, 18F-THK5105 positron emission tomography is considered to be useful for the non-invasive assessment of tau pathology in the living brain. This technique would be applicable to the longitudinal evaluation of tau deposition and allow a better understanding of the pathophysiology of Alzheimer's disease., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2014
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10. In vivo evaluation of a novel tau imaging tracer for Alzheimer's disease.

Author

Villemagne VL, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Hodges J, Harada R, Yates P, Piguet O, Pejoska S, Doré V, Yanai K, Masters CL, Kudo Y, Rowe CC, and Okamura N

Subjects
Aged, Aged, 80 and over, Amyloid beta-Peptides metabolism, Brain diagnostic imaging, Case-Control Studies, Female, Frontotemporal Dementia diagnostic imaging, Humans, Male, Middle Aged, Positron-Emission Tomography, Protein Binding, Thiazoles pharmacokinetics, Tissue Distribution, Alzheimer Disease diagnostic imaging, Aniline Compounds pharmacokinetics, Quinolines pharmacokinetics, Radiopharmaceuticals pharmacokinetics, tau Proteins metabolism
Abstract

Purpose: Diagnosis of tauopathies such as Alzheimer's disease (AD) still relies on post-mortem examination of the human brain. A non-invasive method of determining brain tau burden in vivo would allow a better understanding of the pathophysiology of tauopathies. The purpose of the study was to evaluate (18)F-THK523 as a potential tau imaging tracer., Methods: Ten healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as (18)F-THK523 and (11)C-Pittsburgh compound B (PIB) positron emission tomography (PET) scans. Composite memory and non-memory scores, global and hippocampal brain volume, and partial volume-corrected tissue ratios for (18)F-THK523 and (11)C-PIB were estimated for all participants. Correlational analyses were performed between global and regional (18)F-THK523, (11)C-PIB, cognition and brain volumetrics., Results: (18)F-THK523 presented with fast reversible kinetics. Significantly higher (18)F-THK523 retention was observed in the temporal, parietal, orbitofrontal and hippocampi of AD patients when compared to healthy controls and SD patients. White matter retention was significantly higher than grey matter retention in all participants. The pattern of cortical (18)F-THK523 retention did not correlate with Aβ distribution as assessed by (11)C-PIB and followed the known distribution of tau in the AD brain, being higher in temporal and parietal areas than in the frontal region. Unlike (11)C-PIB, hippocampal (18)F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy., Conclusion: (18)F-THK523 does not bind to Aβ in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical (18)F-THK523 retention in AD patients as well as the association of hippocampal (18)F-THK523 retention with cognitive parameters and hippocampal volume suggests (18)F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high (18)F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings.

Published
2014
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11. Head-to-head comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for β-amyloid imaging in aging and dementia.

Author

Rowe CC, Pejoska S, Mulligan RS, Jones G, Chan JG, Svensson S, Cselényi Z, Masters CL, and Villemagne VL

Subjects
Aged, Aniline Compounds, Brain diagnostic imaging, Brain metabolism, Dementia diagnostic imaging, Female, Humans, Male, Positron-Emission Tomography, Thiazoles, Aging metabolism, Amyloid beta-Peptides metabolism, Benzofurans metabolism, Benzothiazoles metabolism, Dementia metabolism, Hydrocarbons, Fluorinated metabolism, Molecular Imaging methods
Abstract

Unlabelled: (11)C-Pittsburgh compound-B ((11)C-PiB) is the benchmark radiotracer for imaging of β-amyloid (Aβ) plaque in Alzheimer disease (AD). (18)F-labeled Aβ tracers subsequently developed for clinical use show higher nonspecific white matter binding and, in some cases, lower cortical binding in AD that could lead to less accurate interpretation of scans. We compared the cortical and white matter binding of a new (18)F-labeled Aβ tracer, (18)F-AZD4694 (recently renamed NAV4694), with (11)C-PiB in the same subjects., Methods: Forty-five participants underwent PET imaging with (11)C-PiB and (18)F-AZD4694 (25 healthy elderly controls [HCs], 10 subjects with mild cognitive impairment, 7 subjects with probable AD, and 3 subjects with probable frontotemporal dementia). Images were coregistered so that region-of-interest placement was identical on both scans, and standardized uptake value ratios (SUVRs) using the cerebellar cortex as a reference region were calculated between 40 and 70 min after injection for both tracers., Results: (18)F-AZD4694 showed reversible binding kinetics similar to (11)C-PiB, reaching an apparent steady state at 50 min after injection. Both radiotracers showed a similar dynamic range of neocortical SUVR (1.1-3.3 and 1.0-3.2 SUVR for (11)C-PiB and (18)F-AZD4694, respectively) and identical low nonspecific white matter binding, with frontal cortex-to-white matter ratios of 0.7 ± 0.2 and 1.3 ± 0.2 for both radiotracers in HCs and AD subjects, respectively. There was an excellent linear correlation between (11)C-PiB and (18)F-AZD4694 neocortical SUVR (slope of 0.95, r = 0.99, P < 0.0001)., Conclusion: (18)F-AZD4694 displays imaging characteristics nearly identical to those of (11)C-PiB. The low white matter and high cortical binding in AD indicate that this tracer is well suited to both clinical and research use.

Published
2013
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12. Comparison of 11C-PiB and 18F-florbetaben for Aβ imaging in ageing and Alzheimer's disease.

Author

Villemagne VL, Mulligan RS, Pejoska S, Ong K, Jones G, O'Keefe G, Chan JG, Young K, Tochon-Danguy H, Masters CL, and Rowe CC

Subjects
Aged, Brain diagnostic imaging, Brain metabolism, Female, Humans, Male, Middle Aged, Thiazoles, Aging metabolism, Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Aniline Compounds metabolism, Benzothiazoles metabolism, Positron-Emission Tomography methods, Stilbenes metabolism
Abstract

Purpose: Amyloid imaging with (18)F-labelled radiotracers will allow widespread use of this technique, facilitating research, diagnosis and therapeutic development for Alzheimer's disease (AD). The purpose of this analysis was to compare data on cortical Aβ deposition in subjects who had undergone both (11)C-PiB (PiB) and (18)F-florbetaben (FBB) PET imaging., Methods: We identified ten healthy elderly controls (HC) and ten patients with AD who had undergone PET imaging after intravenous injection of 370 MBq of PiB and 300 MBq of FBB under separate research protocols. PiB and FBB images were coregistered so that placement of regions of interest was identical on both scans and standard uptake value ratios (SUVR) using the cerebellar cortex as reference region were calculated between 40 and 70 min and between 90 and 110 min after injection for PiB and FBB, respectively., Results: Significantly higher SUVR values (p < 0.0001) in most cortical areas were observed in AD patients when compared with HC with both radiotracers. Global SUVR values in AD patients were on average 75% higher than in HC with PiB and 56% higher with FBB. There was an excellent linear correlation between PiB and FBB global SUVR values (r = 0.97, p < 0.0001) with similar effect sizes for distinguishing AD from HC subjects for both radiotracers (Cohen's d 3.3 for PiB and 3.0 for FBB)., Conclusion: FBB, while having a narrower dynamic range than PiB, clearly distinguished HC from AD patients, with a comparable effect size. FBB seems a suitable (18)F radiotracer for imaging AD pathology in vivo.

Published
2012
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13. Differential diagnosis in Alzheimer's disease and dementia with Lewy bodies via VMAT2 and amyloid imaging.

Author

Villemagne VL, Okamura N, Pejoska S, Drago J, Mulligan RS, Chételat G, O'Keefe G, Jones G, Kung HF, Pontecorvo M, Masters CL, Skovronsky DM, and Rowe CC

Subjects
Aged, Aged, 80 and over, Aniline Compounds, Brain Mapping, Carbon Radioisotopes, Case-Control Studies, Corpus Striatum diagnostic imaging, Corpus Striatum pathology, Diagnosis, Differential, Female, Fluorine Radioisotopes, Humans, Male, Middle Aged, Positron-Emission Tomography methods, Tetrabenazine analogs & derivatives, Thiazoles, Alzheimer Disease diagnostic imaging, Amygdala diagnostic imaging, Amygdala pathology, Lewy Body Disease diagnostic imaging, Vesicular Monoamine Transport Proteins metabolism
Abstract

Background: The noninvasive evaluation of nigrostriatal dopaminergic integrity by PET can provide useful information for the differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD)., Objectives: To evaluate the diagnostic potential of imaging striatal monoaminergic terminal integrity with the novel vesicular monoamine transporter type 2 (VMAT2) radioligand [(18)F]AV-133 and PET to distinguish DLB from AD., Methods: Fifty participants [9 DLB, 11 AD, 20 Parkinson's disease (PD) and 10 healthy age-matched control subjects (HC)] underwent [(18)F]AV-133 PET studies. Additionally, 20 participants underwent amyloid imaging PET scans with either [(11)C]PiB or (18)F-florbetaben. VMAT2 density was calculated through normalized tissue uptake value ratios (R(T)) at 120-140 min after injection using the primary visual or the cerebellar cortex as reference region. Comparison of the R(T) for [(18)F]AV-133 was done between the different clinical diagnostic groups., Results: Significantly lower striatal VMAT2 densities were observed in DLB and PD when compared to AD and HC, especially in the posterior putamen. In contrast to PD and DLB, no reductions were observed in AD patients when compared to HC., Conclusions: [(18)F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. In contrast to amyloid imaging, VMAT2 imaging with [(18)F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in DLB patients, assisting in the differential diagnosis from AD., (Copyright © 2012 S. Karger AG, Basel.)

Published
2012
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14. Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias.

Author

Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska S, Jones G, O'Keefe G, Ackerman U, Tochon-Danguy H, Chan JG, Reininger CB, Fels L, Putz B, Rohde B, Masters CL, and Rowe CC

Subjects
Aged, Aged, 80 and over, Case-Control Studies, Cerebellum diagnostic imaging, Female, Frontotemporal Dementia diagnostic imaging, Humans, Image Processing, Computer-Assisted, Lewy Bodies diagnostic imaging, Male, Middle Aged, Neurodegenerative Diseases diagnostic imaging, Positron-Emission Tomography methods, Radioisotopes pharmacology, Treatment Outcome, Alzheimer Disease diagnostic imaging, Amyloid beta-Peptides metabolism, Aniline Compounds pharmacology, Dementia diagnostic imaging, Fluorine Radioisotopes pharmacology, Stilbenes pharmacology
Abstract

Unlabelled: Amyloid imaging with (18)F-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 (18)F-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 (18)F-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 (18)F-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: (18)F-florbetaben had high sensitivity for AD, clearly distinguished patients with FTLD from AD, and provided results comparable to those reported with (11)C-Pittsburgh Compound B in a variety of neurodegenerative diseases.

Published
2011
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15. In vivo assessment of vesicular monoamine transporter type 2 in dementia with lewy bodies and Alzheimer disease.

Author

Villemagne VL, Okamura N, Pejoska S, Drago J, Mulligan RS, Chételat G, Ackermann U, O'Keefe G, Jones G, Gong S, Tochon-Danguy H, Kung HF, Masters CL, Skovronsky DM, and Rowe CC

Subjects
Aged, Aged, 80 and over, Area Under Curve, Brain Mapping, Female, Fluorine Radioisotopes, Humans, Male, Middle Aged, Positron-Emission Tomography methods, ROC Curve, Alzheimer Disease diagnostic imaging, Lewy Body Disease diagnostic imaging, Tetrabenazine analogs & derivatives, Vesicular Monoamine Transport Proteins metabolism
Abstract

Objective: To assess the diagnostic potential of imaging striatal monoaminergic terminal integrity with the vesicular monoamine transporter type 2 (VMAT2) radioligand (18)F 9-fluropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) and positron emission tomography to distinguish dementia with Lewy bodies (DLB) from Alzheimer disease (AD)., Design, Setting, and Participants: Nine patients with DLB, 10 patients with AD, 20 patients with Parkinson disease (PD), and 10 healthy age-matched control subjects underwent [(18)F]AV-133 positron emission tomography studies. VMAT2 density was calculated through normalized tissue uptake value ratios at 120 to 140 minutes postinjection using the primary visual cortex as the reference region., Main Outcome Measure: Comparison of the tissue ratio for [(18)F]AV-133 between the different clinical diagnostic groups., Results: Lower VMAT2 densities were observed in patients with DLB when compared with patients with AD especially in the posterior putamen (caudate: mean [SD], 1.24 [0.6] vs 2.83 [0.9]; P < .001; effect size = 2.1; anterior putamen: mean [SD], 0.90 [0.5] vs 3.01 [0.9]; P < .001; effect size = 2.9; posterior putamen: mean [SD], 0.62 [0.5] vs 2.87 [0.8]; P < .001; effect size = 3.4). Compared with healthy controls, [(18)F]AV-133 tissue ratios were significantly lower by 88% and 74% in the posterior putamen, 74% and 65% in the anterior putamen, and 53% and 51% in the caudate nucleus of patients with PD and DLB, respectively. In contrast to patients with PD and DLB, no reductions were observed in patients with AD., Conclusions: [(18)F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. [(18)F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in patients with DLB and assist in the differential diagnosis from AD.

Published
2011
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16. In vivo measurement of vesicular monoamine transporter type 2 density in Parkinson disease with (18)F-AV-133.

Author

Okamura N, Villemagne VL, Drago J, Pejoska S, Dhamija RK, Mulligan RS, Ellis JR, Ackermann U, O'Keefe G, Jones G, Kung HF, Pontecorvo MJ, Skovronsky D, and Rowe CC

Subjects
Aged, Case-Control Studies, Caudate Nucleus diagnostic imaging, Caudate Nucleus metabolism, Corpus Striatum diagnostic imaging, Corpus Striatum metabolism, Dopamine Plasma Membrane Transport Proteins metabolism, Female, Fluorine Radioisotopes, Humans, Male, Middle Aged, Parkinson Disease physiopathology, Positron-Emission Tomography, Putamen diagnostic imaging, Putamen metabolism, Radiopharmaceuticals, Tetrabenazine analogs & derivatives, Tissue Distribution, Brain diagnostic imaging, Brain metabolism, Parkinson Disease diagnostic imaging, Parkinson Disease metabolism, Vesicular Monoamine Transport Proteins metabolism
Abstract

Unlabelled: PET provides a noninvasive means to evaluate the functional integrity of the presynaptic monoaminergic system in the living human brain., Methods: In this study, a novel (18)F-labeled tetrabenazine derivative, (18)F-(+)fluoropropyldihydrotetrabenazine ((18)F-AV-133), was used for the noninvasive assessment of the vesicular monoamine transporters type 2 (VMAT2) in 17 Parkinson disease (PD) patients and 6 healthy controls. The binding potential (BP) of (18)F-AV-133 was calculated using Logan graphical analysis. Voxel-based and volume-of-interest-based analyses of BP images were performed to examine brain regional reductions in VMAT2 density in PD., Results: VMAT2 BP was decreased by 81% in the posterior putamen, 70% in the anterior putamen, and 48% in the caudate nucleus of PD patients. Voxel-based analysis demonstrated VMAT2 reductions in the striatum and mid brain of PD patients. Furthermore, VMAT2 BPs in the caudate nuclei significantly correlated with the clinical severity of PD., Conclusion: These findings indicate that the novel (18)F-labeled ligand (18)F-AV-133 can sensitively detect monoaminergic terminal reductions in PD patients. Studies with (18)F-AV-133 may allow the presymptomatic identification of individuals with disorders characterized by degeneration of dopaminergic nigrostriatal afferents.

Published
2010
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