Amyloid-beta deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

Willem Huijbers*, Elizabeth C. Mormino, Aaron P. Schultz, Sarah Wigman, Andrew M. Ward, Mykol Larvie, Rebecca E. Amariglio, Gad A. Marshall, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

90 Citations (Scopus)

Abstract

In a 3-year longitudinal study, Huijbers et al. observe increased hippocampal activation, faster rates of hippocampal atrophy, and clinical progression in patients with mild cognitive impairment with elevated levels of amyloid-beta. Amyloid-beta accumulation likely contributes to abnormal neuronal activity on the trajectory towards Alzheimer's disease dementia.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-beta, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloid-beta 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-beta 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-beta 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-beta negative patients with mild cognitive impairment. Longitudinally, amyloid-beta 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-beta status, hippocampal activation, and hippocampal volume independently predicted clinical progression. These results indicate that amyloid-beta positive patients with mild cognitive impairment are more likely on a path towards Alzheimer's disease dementia than amyloid-beta negative patients. Increased hippocampal activity is discussed in relation to neuronal compensation and/or amyloid-beta induced excitoxicity.

Original languageEnglish
Pages (from-to)1023-1035
Number of pages13
JournalBrain
Volume138
DOIs
Publication statusPublished - 1 Apr 2015
Externally publishedYes

Keywords

  • amyloid deposition
  • MCI
  • hippocampal activation
  • functional MRI
  • clinical progression
  • PITTSBURGH COMPOUND-B
  • ALZHEIMERS-DISEASE
  • OLDER-ADULTS
  • LIFE-SPAN
  • DIAGNOSTIC GUIDELINES
  • NATIONAL INSTITUTE
  • BRAIN ACTIVATION
  • FMRI ACTIVATION
  • FUNCTIONAL MRI
  • GENETIC RISK

Cite this

Huijbers, W., Mormino, E. C., Schultz, A. P., Wigman, S., Ward, A. M., Larvie, M., Amariglio, R. E., Marshall, G. A., Rentz, D. M., Johnson, K. A., & Sperling, R. A. (2015). Amyloid-beta deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. Brain, 138, 1023-1035. https://doi.org/10.1093/brain/awv007