title: Acceleration of hippocampal atrophy rates in asymptomatic amyloidosis.
abstract: Increased rates of brain atrophy measured from serial magnetic resonance imaging precede symptom onset in Alzheimer's disease and may be useful outcome measures for prodromal clinical trials. Appropriate trial design requires a detailed understanding of the relationships between β-amyloid load and accumulation, and rate of brain change at this stage of the disease. Fifty-two healthy individuals (72.3 ± 6.9 years) from Australian Imaging, Biomarkers and Lifestyle Study of Aging had serial (0, 18 m, 36 m) magnetic resonance imaging, (0, 18 m) Pittsburgh compound B positron emission tomography, and clinical assessments. We calculated rates of whole brain and hippocampal atrophy, ventricular enlargement, amyloid accumulation, and cognitive decline. Over 3 years, rates of whole brain atrophy (p < 0.001), left and right hippocampal atrophy (p = 0.001, p = 0.023), and ventricular expansion (p < 0.001) were associated with baseline β-amyloid load. Whole brain atrophy rates were also independently associated with β-amyloid accumulation over the first 18 months (p = 0.003). Acceleration of left hippocampal atrophy rate was associated with baseline β-amyloid load across the cohort (p < 0.02). We provide evidence that rates of atrophy are associated with both baseline β-amyloid load and accumulation, and that there is presymptomatic, amyloid-mediated acceleration of hippocampal atrophy. Clinical trials using rate of hippocampal atrophy as an outcome measure should not assume linear decline in the presymptomatic phase.
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Centre for Medical Image Computing, UCL, London, UK.
authors.forename: K Abigail
authors.initials: KA
authors.lastname: Andrews
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Frost
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Centre for Medical Image Computing, UCL, London, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Modat
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Centre for Medical Image Computing, UCL, London, UK.
authors.forename: M Jorge
authors.initials: MJ
authors.lastname: Cardoso
authors.affiliation: Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Chris C
authors.initials: CC
authors.lastname: Rowe
authors.affiliation: Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Victor
authors.initials: V
authors.lastname: Villemagne
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Centre for Medical Image Computing, UCL, London, UK.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Ourselin
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. Electronic address: j.schott@ucl.ac.uk.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001284:Atrophy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000175:diagnosis / Q000473:pathology*; D002552:Cerebral Ventricles / Q000473:pathology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides
keywords: Acceleration; Asymptomatic amyloidosis; Atrophy; Hippocampus; MRI; PET