- Email: [email protected]
Regional patterns of 11C-PiB uptake and cortical atrophy distinguishes dementia with Lewy bodies from Alzheimer's disease
P140
Oral O3-06: Multimodal Dementia Research: Combining Neuroimaging, Neurogenetics and Biomarkers
Graeme O’Keefe1, Ralph Martins5, David Ames6, Colin L. Masters7, Christopher Rowe1, 1Austin Hospital, Melbourne, Australia; 2The Mental Health Research Institute, Melbourne, Australia; 3Department. of Psychiatry, University of Melbourne, Melbourne, Australia; 4Department. of Pathology, University of Melbourne, Melbourne, Australia; 5Edith Cowan University, Perth, Australia; 6National Ageing Research Institute, Melbourne, Australia; 7The Mental Health Research Institute, The University of Melbourne, Melbourne, Australia. Contact e-mail: [email protected]. au Background: Ongoing large longitudinal studies including both structural and amyloid neuroimaging studies as well as cognitive, genetic and biochemical biomarkers are allowing a better understanding of the role and relevance of brain Ab deposition in elderly controls and MCI subjects. These studies enable researchers to more clearly define the role of different biomarkers in the prediction of cognitive decline that might lead to dementia. The purpose of this study was to compare the accuracy of different biomarkers to predict cognitive decline and conversion to Alzheimer’s disease (AD). Methods: Clinical follow-up was obtained at 20 6 3 months after initial biochemical (plasma Ab42/Ab40), genetic (ApoE), cognitive (memory and non-memory scores) and neuroimaging (3D MRI, FDG and PiB-PET) evaluation in 188 subjects, 34 with AD, 57 with mild cognitive impairment (MCI) (79% amnestic) and 97 age-matched healthy controls (HC) (73 6 7 years of age). To date, three-year follow-up has been obtained in 35 subjects. Results: At 20 month follow-up progression to AD occurred in 47% of MCI, while 4% were re-classified as HC. Comparison of 20-month converters to non-converters showed a significant difference in episodic memory scores, prevalence of ApoE e4 allele, PiB retention, hippocampal volume (HV) and posterior cingulate glucose metabolism while there were no significant differences in plasma Ab42/Ab40 and non-memory scores. The accuracy in predicting conversion from MCI to AD at 20 months was 81% for PiB, 78% for episodic memory, 77% for ApoE, 72% for HV, 68% for FDG, and 61% for plasma Ab. Combining PiB, episodic memory and HV, the predictive accuracy increased to 86%. Of the high PiB HC, 14% developed MCI or AD by 20 months and at least 21% by 3 years. One (2%) low PiB HC developed MCI. Conclusions: The ability to correctly identify subjects at high risk of cognitive decline is critical for early intervention studies as well as for subject selection in therapeutic trials. Despite recent advances in molecular neurosciences, it is unlikely that a single biomarker will be able to provide the diagnostic certainty required for the identification of at-risk individuals before the development of the typical AD phenotype.
O3-06-06
REGIONAL PATTERNS OF 11C-PIB UPTAKE AND CORTICAL ATROPHY DISTINGUISHES DEMENTIA WITH LEWY BODIES FROM ALZHEIMER’S DISEASE
Kejal Kantarci1, Val J. Lowe1, Bradley F. Boeve1, Matthew L. Senjem1, Scott A. Przybelski1, Stephen D. Weigand1, Bradley J. Kemp1, Tanis J. Ferman2, David S. Knopman1, Ronald C. Petersen1, Clifford R. Jack, Jr,1, 1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: The two most common neurodegenerative disorders associated with dementia in the elderly are Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Patients who meet clinical criteria for DLB often have some degree of AD pathology at autopsy. 11C -Pittsburgh Compound-B (PiB) retention on PET is a surrogate marker for amyloidpathology and cortical atrophy on MRI is associated with neurodegeneration and the neurofibrillary pathology of AD. Our goal was to determine the differences in the regional distributions of PiB uptake and cortical atrophy which reflect distinct pathological mechanisms of AD in patients with DLB. Methods: We studied clinically diagnosed patients with DLB (n ¼ 11), AD (n ¼ 11), and cognitively normal subjects (CN) (n ¼ 22) with similar age, gender and years of education. DLB and AD subjects had similar Clinical Dementia Rating scores. Subjects underwent
clinical evaluation, MRI and PiB-PET. A global cortical PiB retention summary measure was formed by combining frontal, temporal and parietal PiB retention to cerebellar cortical retention. Voxel-based analysis (VBM) was performed to determine differences in cortical atrophy and PiB retention among the clinical groups. Results: Global PiB retention in DLB patients was lower than AD (p ¼ 0.004), but higher than CN (p ¼ 0.011). On VBM, PiB retention in DLB patients was higher in the frontal lobes compared to CN, but significantly lower in the temporoparietal cortex compared to AD. Similarly, AD patients had significantly greater cortical atrophy in the temporoparietal and occipital cortex compared to DLB patients. Plotting temporoparietal gray matter (GM) volume against temporoparietal PiB retention separated DLB and AD subjects better than either measurement alone (Figure). Conclusions: Although DLB patients have frontal PiB retention, temporoparietal PiB retention is significantly less in DLB than in AD. This difference in the pattern of PiB retention may be related to a fundamental difference in the topography of amyloid-b pathology between the two diseases. The differences in cortical atrophy follow a similar ‘‘posterior’’ pattern characterized by greater temporoparietal and occipital atrophy in AD than in DLB. Although similar in pattern, both MRI and PiB-PET appear to contribute to characterizing distinct neurodegenerative mechanisms of AD in these disorders.
O3-06-07
ADJUSTING FOR BASELINE CHARACTERISTICS REDUCES SAMPLE SIZES IN AD TREATMENT TRIALS
Josephine Barnes1, Jonathan W. Bartlett2, Kelvin K. Leung3, Sebastien Ourselin3, Nick C. Fox1, Jonathan M. Schott1, ADNI Investigators,1Institute of Neurology, University College London, London, United Kingdom; 2London School of Hygiene and Tropical Medicine, London, United Kingdom; 3Centre for Medical Image Computing, University College London, London, United Kingdom. Contact e-mail: j.barnes@ dementia.ion.ucl.ac.uk Background: Clinical trials of putative disease-modifying treatments in Alzheimer’s disease (AD) are both ongoing and planned. Cerebral atrophy rate is increasingly used as an outcome measure for such trials. We used the ADNI data-set to assess if adjusting for baseline information can reduce sample sizes for trials. Methods: We utilised data from the Alzheimer’s disease neuroimaging initiative (ADNI). We used baseline and one-year repeat MRI scans of controls (n ¼ 199), patients with MCI (n ¼ 334) and AD (n ¼ 144). Whole brain (KN-BSI) and hippocampal (HMAPSHBSI) atrophy rate, and ventricular expansion (VBSI) were calculated for each group. For each measure of atrophy in each group we estimated sample sizes for a placebo controlled randomized trial, and the percentage reduction in sample size obtained by adjusting for each (and all) of eleven a priori baseline measures: age, baseline brain volume, ventricle volume, hippocampal volume, MMSE, CDR-Sum of boxes, ADAS-Cog, CSF tau, CSF Aß1-42, CSF p-tau, or ApoE4 dose (0, 1 or 2). Sample sizes were calculated with and without adjusting for normal aging. Results: Atrophy rates by method and group are shown in the table. Estimated sample
Oral O3-06: Multimodal Dementia Research: Combining Neuroimaging, Neurogenetics and Biomarkers
Graeme O’Keefe1, Ralph Martins5, David Ames6, Colin L. Masters7, Christopher Rowe1, 1Austin Hospital, Melbourne, Australia; 2The Mental Health Research Institute, Melbourne, Australia; 3Department. of Psychiatry, University of Melbourne, Melbourne, Australia; 4Department. of Pathology, University of Melbourne, Melbourne, Australia; 5Edith Cowan University, Perth, Australia; 6National Ageing Research Institute, Melbourne, Australia; 7The Mental Health Research Institute, The University of Melbourne, Melbourne, Australia. Contact e-mail: [email protected]. au Background: Ongoing large longitudinal studies including both structural and amyloid neuroimaging studies as well as cognitive, genetic and biochemical biomarkers are allowing a better understanding of the role and relevance of brain Ab deposition in elderly controls and MCI subjects. These studies enable researchers to more clearly define the role of different biomarkers in the prediction of cognitive decline that might lead to dementia. The purpose of this study was to compare the accuracy of different biomarkers to predict cognitive decline and conversion to Alzheimer’s disease (AD). Methods: Clinical follow-up was obtained at 20 6 3 months after initial biochemical (plasma Ab42/Ab40), genetic (ApoE), cognitive (memory and non-memory scores) and neuroimaging (3D MRI, FDG and PiB-PET) evaluation in 188 subjects, 34 with AD, 57 with mild cognitive impairment (MCI) (79% amnestic) and 97 age-matched healthy controls (HC) (73 6 7 years of age). To date, three-year follow-up has been obtained in 35 subjects. Results: At 20 month follow-up progression to AD occurred in 47% of MCI, while 4% were re-classified as HC. Comparison of 20-month converters to non-converters showed a significant difference in episodic memory scores, prevalence of ApoE e4 allele, PiB retention, hippocampal volume (HV) and posterior cingulate glucose metabolism while there were no significant differences in plasma Ab42/Ab40 and non-memory scores. The accuracy in predicting conversion from MCI to AD at 20 months was 81% for PiB, 78% for episodic memory, 77% for ApoE, 72% for HV, 68% for FDG, and 61% for plasma Ab. Combining PiB, episodic memory and HV, the predictive accuracy increased to 86%. Of the high PiB HC, 14% developed MCI or AD by 20 months and at least 21% by 3 years. One (2%) low PiB HC developed MCI. Conclusions: The ability to correctly identify subjects at high risk of cognitive decline is critical for early intervention studies as well as for subject selection in therapeutic trials. Despite recent advances in molecular neurosciences, it is unlikely that a single biomarker will be able to provide the diagnostic certainty required for the identification of at-risk individuals before the development of the typical AD phenotype.
O3-06-06
REGIONAL PATTERNS OF 11C-PIB UPTAKE AND CORTICAL ATROPHY DISTINGUISHES DEMENTIA WITH LEWY BODIES FROM ALZHEIMER’S DISEASE
Kejal Kantarci1, Val J. Lowe1, Bradley F. Boeve1, Matthew L. Senjem1, Scott A. Przybelski1, Stephen D. Weigand1, Bradley J. Kemp1, Tanis J. Ferman2, David S. Knopman1, Ronald C. Petersen1, Clifford R. Jack, Jr,1, 1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: The two most common neurodegenerative disorders associated with dementia in the elderly are Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Patients who meet clinical criteria for DLB often have some degree of AD pathology at autopsy. 11C -Pittsburgh Compound-B (PiB) retention on PET is a surrogate marker for amyloidpathology and cortical atrophy on MRI is associated with neurodegeneration and the neurofibrillary pathology of AD. Our goal was to determine the differences in the regional distributions of PiB uptake and cortical atrophy which reflect distinct pathological mechanisms of AD in patients with DLB. Methods: We studied clinically diagnosed patients with DLB (n ¼ 11), AD (n ¼ 11), and cognitively normal subjects (CN) (n ¼ 22) with similar age, gender and years of education. DLB and AD subjects had similar Clinical Dementia Rating scores. Subjects underwent
clinical evaluation, MRI and PiB-PET. A global cortical PiB retention summary measure was formed by combining frontal, temporal and parietal PiB retention to cerebellar cortical retention. Voxel-based analysis (VBM) was performed to determine differences in cortical atrophy and PiB retention among the clinical groups. Results: Global PiB retention in DLB patients was lower than AD (p ¼ 0.004), but higher than CN (p ¼ 0.011). On VBM, PiB retention in DLB patients was higher in the frontal lobes compared to CN, but significantly lower in the temporoparietal cortex compared to AD. Similarly, AD patients had significantly greater cortical atrophy in the temporoparietal and occipital cortex compared to DLB patients. Plotting temporoparietal gray matter (GM) volume against temporoparietal PiB retention separated DLB and AD subjects better than either measurement alone (Figure). Conclusions: Although DLB patients have frontal PiB retention, temporoparietal PiB retention is significantly less in DLB than in AD. This difference in the pattern of PiB retention may be related to a fundamental difference in the topography of amyloid-b pathology between the two diseases. The differences in cortical atrophy follow a similar ‘‘posterior’’ pattern characterized by greater temporoparietal and occipital atrophy in AD than in DLB. Although similar in pattern, both MRI and PiB-PET appear to contribute to characterizing distinct neurodegenerative mechanisms of AD in these disorders.
O3-06-07
ADJUSTING FOR BASELINE CHARACTERISTICS REDUCES SAMPLE SIZES IN AD TREATMENT TRIALS
Josephine Barnes1, Jonathan W. Bartlett2, Kelvin K. Leung3, Sebastien Ourselin3, Nick C. Fox1, Jonathan M. Schott1, ADNI Investigators,1Institute of Neurology, University College London, London, United Kingdom; 2London School of Hygiene and Tropical Medicine, London, United Kingdom; 3Centre for Medical Image Computing, University College London, London, United Kingdom. Contact e-mail: j.barnes@ dementia.ion.ucl.ac.uk Background: Clinical trials of putative disease-modifying treatments in Alzheimer’s disease (AD) are both ongoing and planned. Cerebral atrophy rate is increasingly used as an outcome measure for such trials. We used the ADNI data-set to assess if adjusting for baseline information can reduce sample sizes for trials. Methods: We utilised data from the Alzheimer’s disease neuroimaging initiative (ADNI). We used baseline and one-year repeat MRI scans of controls (n ¼ 199), patients with MCI (n ¼ 334) and AD (n ¼ 144). Whole brain (KN-BSI) and hippocampal (HMAPSHBSI) atrophy rate, and ventricular expansion (VBSI) were calculated for each group. For each measure of atrophy in each group we estimated sample sizes for a placebo controlled randomized trial, and the percentage reduction in sample size obtained by adjusting for each (and all) of eleven a priori baseline measures: age, baseline brain volume, ventricle volume, hippocampal volume, MMSE, CDR-Sum of boxes, ADAS-Cog, CSF tau, CSF Aß1-42, CSF p-tau, or ApoE4 dose (0, 1 or 2). Sample sizes were calculated with and without adjusting for normal aging. Results: Atrophy rates by method and group are shown in the table. Estimated sample