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

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., ... 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
Huijbers, Willem ; Mormino, Elizabeth C. ; Schultz, Aaron P. ; Wigman, Sarah ; Ward, Andrew M. ; Larvie, Mykol ; Amariglio, Rebecca E. ; Marshall, Gad A. ; Rentz, Dorene M. ; Johnson, Keith A. ; Sperling, Reisa A. / Amyloid-beta deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. In: Brain. 2015 ; Vol. 138. pp. 1023-1035.
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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.",
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author = "Willem Huijbers and Mormino, {Elizabeth C.} and Schultz, {Aaron P.} and Sarah Wigman and Ward, {Andrew M.} and Mykol Larvie and Amariglio, {Rebecca E.} and Marshall, {Gad A.} and Rentz, {Dorene M.} and Johnson, {Keith A.} and Sperling, {Reisa A.}",
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Huijbers, W, Mormino, EC, Schultz, AP, Wigman, S, Ward, AM, Larvie, M, Amariglio, RE, Marshall, GA, Rentz, DM, Johnson, KA & Sperling, RA 2015, 'Amyloid-beta deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression', Brain, vol. 138, pp. 1023-1035. https://doi.org/10.1093/brain/awv007

Amyloid-beta deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. / Huijbers, Willem; Mormino, Elizabeth C.; Schultz, Aaron P.; Wigman, Sarah; Ward, Andrew M.; Larvie, Mykol; Amariglio, Rebecca E.; Marshall, Gad A.; Rentz, Dorene M.; Johnson, Keith A.; Sperling, Reisa A.

In: Brain, Vol. 138, 01.04.2015, p. 1023-1035.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Amyloid-beta deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

AU - Huijbers, Willem

AU - Mormino, Elizabeth C.

AU - Schultz, Aaron P.

AU - Wigman, Sarah

AU - Ward, Andrew M.

AU - Larvie, Mykol

AU - Amariglio, Rebecca E.

AU - Marshall, Gad A.

AU - Rentz, Dorene M.

AU - Johnson, Keith A.

AU - Sperling, Reisa A.

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N2 - 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.

AB - 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.

KW - amyloid deposition

KW - MCI

KW - hippocampal activation

KW - functional MRI

KW - clinical progression

KW - PITTSBURGH COMPOUND-B

KW - ALZHEIMERS-DISEASE

KW - OLDER-ADULTS

KW - LIFE-SPAN

KW - DIAGNOSTIC GUIDELINES

KW - NATIONAL INSTITUTE

KW - BRAIN ACTIVATION

KW - FMRI ACTIVATION

KW - FUNCTIONAL MRI

KW - GENETIC RISK

U2 - 10.1093/brain/awv007

DO - 10.1093/brain/awv007

M3 - Article

VL - 138

SP - 1023

EP - 1035

JO - Brain

JF - Brain

SN - 0006-8950

ER -