title: Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression.
abstract: Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity--consistent with findings in genetic at-risk populations--and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model, amyloid-β status, hippocampal activation, and hippocampal volume independently predicted clinical progression. These results indicate that amyloid-β positive patients with mild cognitive impairment are more likely on a path towards Alzheimer's disease dementia than amyloid-β negative patients. Increased hippocampal activity is discussed in relation to neuronal compensation and/or amyloid-β induced excitoxicity.
authors: 1 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA w.huijbers@gmail.com.
authors: Willem
authors: W
authors: Huijbers
authors: 1 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 3 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors: Elizabeth C
authors: EC
authors: Mormino
authors: 3 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors: Aaron P
authors: AP
authors: Schultz
authors: 1 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors: Sarah
authors: S
authors: Wigman
authors: 1 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA 4 Helen Willis Neuroscience Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
authors: Andrew M
authors: AM
authors: Ward
authors: 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA 3 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors: Mykol
authors: M
authors: Larvie
authors: 1 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors: Rebecca E
authors: RE
authors: Amariglio
authors: 1 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors: Gad A
authors: GA
authors: Marshall
authors: 1 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors: Dorene M
authors: DM
authors: Rentz
authors: 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA 3 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors: Keith A
authors: KA
authors: Johnson
authors: 1 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA 3 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors: Reisa A
authors: RA
authors: Sperling
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D001284:Atrophy / Q000175:diagnosis / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000175:diagnosis* / Q000378:metabolism*; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male
chemical_list: D016229:Amyloid beta-Peptides
keywords: MCI; amyloid deposition; clinical progression; functional MRI; hippocampal activation