Meredith L Phillips1, Eddie C Stage2,3, Kathleen A Lane3,4, Sujuan Gao3,4, Shannon L Risacher3,5, Naira Goukasian6, Andrew J Saykin3,5,7,8, Maria C Carrillo9, Bradford C Dickerson10, Gil D Rabinovici11, Liana G Apostolova2,3,5,7,8. 1. Department of Epidemiology and Biostatistics, Indiana University School of Public Health, Bloomington, Indiana, USA, merphill@iu.edu. 2. Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA. 3. Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. 4. Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana, USA. 5. Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, Indiana, USA. 6. Larner College of Medicine, Burlington, Vermont, USA. 7. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA. 8. Indiana University Network Science Institute, Indianapolis, Indiana, USA. 9. Alzheimer's Association, Chicago, Illinois, USA. 10. Harvard Medical School, Boston, Massachusetts, USA. 11. University of California San Francisco, San Francisco, California, USA.
Abstract
BACKGROUND/AIMS: Alzheimer's disease (AD) with onset before 65 (early-onset AD [EOAD]) occurs in approximately 6% of cases and can affect nonmemory domains. Here, we analyze patterns of impairment in amnestic EOAD individuals using data-driven statistical analyses. METHODS: Cognitive data of 146 EOAD subjects were Z-normalized to 395 cognitively normal (CN) individuals. Domain-averaged Z-scores were adjusted for age, sex, and education followed by Wald cluster analysis of residuals. Magnetic resonance imaging and positron emission tomography comparisons of EOAD clusters to age-matched CN were done using Statistic Parametric Mapping 8. Cluster-level-family-wise error (p < 0.05) correction was applied. Mixed-effect models were used to compute longitudinal change across clusters. RESULTS: Scree plot using the pseudo-T-squared suggested a 4-cluster solution. Cluster 1 (memory-predominant impairment) showed atrophy/hypometabolism in medial/lateral temporal, lateral parietal, and posterior cingulate regions. Cluster 2 (memory/visuospatial-predominant) showed atrophy/hypometabolism of medial temporal, temporoparietal, and frontal cortices. Cluster 3 (memory, language, and executive function) and Cluster 4 (globally impaired) manifested atrophy and hypometabolism throughout the brain. Longitudinally between-cluster differences in the visuospatial and language/executive domains were significant, suggesting phenotypic variation. CONCLUSION: We observed significant heterogeneity in cognitive presentation among amnestic EOAD subjects and patterns of atrophy/hypometabolism in each cluster in agreement with the observed cognitive phenotype.
BACKGROUND/AIMS: Alzheimer's disease (AD) with onset before 65 (early-onset AD [EOAD]) occurs in approximately 6% of cases and can affect nonmemory domains. Here, we analyze patterns of impairment in amnestic EOAD individuals using data-driven statistical analyses. METHODS:Cognitive data of 146 EOAD subjects were Z-normalized to 395 cognitively normal (CN) individuals. Domain-averaged Z-scores were adjusted for age, sex, and education followed by Wald cluster analysis of residuals. Magnetic resonance imaging and positron emission tomography comparisons of EOAD clusters to age-matched CN were done using Statistic Parametric Mapping 8. Cluster-level-family-wise error (p < 0.05) correction was applied. Mixed-effect models were used to compute longitudinal change across clusters. RESULTS: Scree plot using the pseudo-T-squared suggested a 4-cluster solution. Cluster 1 (memory-predominant impairment) showed atrophy/hypometabolism in medial/lateral temporal, lateral parietal, and posterior cingulate regions. Cluster 2 (memory/visuospatial-predominant) showed atrophy/hypometabolism of medial temporal, temporoparietal, and frontal cortices. Cluster 3 (memory, language, and executive function) and Cluster 4 (globally impaired) manifested atrophy and hypometabolism throughout the brain. Longitudinally between-cluster differences in the visuospatial and language/executive domains were significant, suggesting phenotypic variation. CONCLUSION: We observed significant heterogeneity in cognitive presentation among amnestic EOAD subjects and patterns of atrophy/hypometabolism in each cluster in agreement with the observed cognitive phenotype.
Authors: Raffaella Migliaccio; Federica Agosta; Katherine L Possin; Elisa Canu; Massimo Filippi; Gil D Rabinovici; Howard J Rosen; Bruce L Miller; Maria Luisa Gorno-Tempini Journal: J Alzheimers Dis Date: 2015 Impact factor: 4.472
Authors: William J Jagust; Susan M Landau; Robert A Koeppe; Eric M Reiman; Kewei Chen; Chester A Mathis; Julie C Price; Norman L Foster; Angela Y Wang Journal: Alzheimers Dement Date: 2015-07 Impact factor: 21.566
Authors: Manja Lehmann; Pia M Ghosh; Cindee Madison; Robert Laforce; Chiara Corbetta-Rastelli; Michael W Weiner; Michael D Greicius; William W Seeley; Maria L Gorno-Tempini; Howard J Rosen; Bruce L Miller; William J Jagust; Gil D Rabinovici Journal: Brain Date: 2013-01-28 Impact factor: 13.501
Authors: Shannon L Risacher; Sungeun Kim; Li Shen; Kwangsik Nho; Tatiana Foroud; Robert C Green; Ronald C Petersen; Clifford R Jack; Paul S Aisen; Robert A Koeppe; William J Jagust; Leslie M Shaw; John Q Trojanowski; Michael W Weiner; Andrew J Saykin Journal: Front Aging Neurosci Date: 2013-04-01 Impact factor: 5.750