Brain Volumetric Trajectories in Down Syndrome and Autosomal Dominant Alzheimer Disease

Abstract Background Alzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early‐mid 50s) and in those with autosomal dominant mutations (ADAD, 40‐50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD. Method Data for cognitively stable and declining participants was obtained from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS) and the Dominantly Inherited Alzheimer Network (DIAN). Stability/decline was identified based on cognitive testing and interview of individuals and caregivers by trained assessors. Cognitively stable family members without DS/ADAD mutations were recruited as controls from both studies. Participants underwent MRI and amyloid positron emission tomography (PET) scans from which brain volumes and amyloid (centiloids) were derived, respectively. Participants from DIAN had Pittsburgh Compound‐B (PIB) scans, ABC‐DS had PIB or florbetapir. Nonlinear cross‐sectional associations between regional brain volumes and estimated years to onset of cognitive decline (EYO, negative values before onset, positive after) and centiloid were evaluated using generalized additive models while controlling for sex and random effects of family. EYO was set to 52 for all participants with DS and based on parental decline/mutation type for participants with ADAD. EYO for controls was based on the EYO of their family member. Result Data from 239 participants with DS (47 declining), and 340 participants with ADAD (122 declining), and 263 familial controls were included. Higher EYO and centiloid values were associated with lower brain volumes in almost all regions. At earlier EYOs, individuals with DS typically had smaller regional volumes than ADAD or sibling controls, with volume declining linearly across the EYO range. By contrast, ADAD mutation carriers had similar volumes to non‐carriers at early EYOs, with volumes diverging as early as 10 years before decline. Brain volumes and centiloid values were inversely related in ADAD and DSAD. Volume in key cortical regions were similar by the expected year of onset in both groups. Conclusion ADAD and DSAD demonstrated different temporal patterns of regional neurodegeneration prior to cognitive change despite being similarly affected by early onset amyloid.

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Journal
Alzheimer s & Dementia
Published
2024-12-01
DOI
https://doi.org/10.1002/alz.089313
Citations
1
Primary Topic
Down syndrome and intellectual disability research
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article
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0.54
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article

Brain Volumetric Trajectories in Down Syndrome and Autosomal Dominant Alzheimer Disease

Tammie L.S. Benzinger, Stephen Salloway, Mithra Sathishkumar, Benjamin L. Handen et al.
1 citations
Alzheimer s & Dementia
Down syndrome and intellectual disability research
0.54
article

Brain Volumetric Trajectories in Down Syndrome and Autosomal Dominant Alzheimer Disease

Tammie L.S. Benzinger, Stephen Salloway, Mithra Sathishkumar, Benjamin L. Handen, Adam M. Brickman, Richard J. Perrin, Charles M. Laymon, Sharon J. Krinsky‐McHale, Joseph H. Lee, Randall John Bateman, Sarah Berman, Michael S. Rafii, Liv McMillan, Patrick J. Lao, Johannes Levin, William E. Klunk, Carlos C Cruchaga, Nicole Schupf, Julie K. Wisch, Raquel Sánchez‐Valle, Shahid Zaman, Chengjie Xiong, Sigan L. Hartley, Sid E. O’Bryant, Gregory Scott Day, Ralph N. Martins, Ricardo Allegri, Florence Lai, Eric McDade, Anna H. Boerwinkle, Elizabeth Head, Martin R. Farlow, Julie C. Price, Beau M. Ances, Mark E. Mapstone, Michael A. Yassa, Jasmeer P. Chhatwal, Ira T. Lott, Brian A. Gordon, Jae‐Hong Lee, Hiroshi Mori, Bradley T. Christian, Jason J. Hassenstab, Peter William Schofield, Helena C. Chui, H. Diana Rosas, James Tyler Kennedy
article en
1 citations

Abstract

Abstract Background Alzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early‐mid 50s) and in those with autosomal dominant mutations (ADAD, 40‐50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD. Method Data for cognitively stable and declining participants was obtained from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS) and the Dominantly Inherited Alzheimer Network (DIAN). Stability/decline was identified based on cognitive testing and interview of individuals and caregivers by trained assessors. Cognitively stable family members without DS/ADAD mutations were recruited as controls from both studies. Participants underwent MRI and amyloid positron emission tomography (PET) scans from which brain volumes and amyloid (centiloids) were derived, respectively. Participants from DIAN had Pittsburgh Compound‐B (PIB) scans, ABC‐DS had PIB or florbetapir. Nonlinear cross‐sectional associations between regional brain volumes and estimated years to onset of cognitive decline (EYO, negative values before onset, positive after) and centiloid were evaluated using generalized additive models while controlling for sex and random effects of family. EYO was set to 52 for all participants with DS and based on parental decline/mutation type for participants with ADAD. EYO for controls was based on the EYO of their family member. Result Data from 239 participants with DS (47 declining), and 340 participants with ADAD (122 declining), and 263 familial controls were included. Higher EYO and centiloid values were associated with lower brain volumes in almost all regions. At earlier EYOs, individuals with DS typically had smaller regional volumes than ADAD or sibling controls, with volume declining linearly across the EYO range. By contrast, ADAD mutation carriers had similar volumes to non‐carriers at early EYOs, with volumes diverging as early as 10 years before decline. Brain volumes and centiloid values were inversely related in ADAD and DSAD. Volume in key cortical regions were similar by the expected year of onset in both groups. Conclusion ADAD and DSAD demonstrated different temporal patterns of regional neurodegeneration prior to cognitive change despite being similarly affected by early onset amyloid.

Alzheimer s & DementiaVol. 20(S2)
Ulsan College (KR), University of Southern California (US), Edith Cowan University (AU), University of North Texas (US), Brigham and Women's Hospital (US), Autism Research Institute (US), University of Wisconsin–Madison (US), University of North Texas Health Science Center (US), University of Pittsburgh (US), University of California, Irvine (US), Washington University in St. Louis (US), University of Cambridge (GB), Brown University (US), Columbia University Irving Medical Center (US), New York State Office for People With Developmental Disabilities (US), German Center for Neurodegenerative Diseases (DE), Asan Medical Center (KR), WinnMed (US), Osaka City University (JP), University of Ulsan (KR), Massachusetts General Hospital (US), Hospital Clínic de Barcelona (ES), Mayo Clinic in Florida (US), Instituto de Neurología de Buenos Aires (AR), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Universitat de Barcelona (ES), Columbia University (US), University of Newcastle Australia (AU)
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Down syndrome and intellectual disability research
0.54
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