Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity

Willem Huijbers, Aaron P Schultz, Kathryn V Papp, Molly R LaPoint, Bernard Hanseeuw, Jasmeer P Chhatwal, Trey Hedden, Keith A Johnson, Reisa A Sperling

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-β proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-β accumulation, apolipoprotein ε4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-β and tau accumulation) before clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-β accumulation with PiB-positron emission tomography imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions before clinical impairment. SIGNIFICANCE STATEMENT The circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in vivo characterization of amyloid-β and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, before the clinical manifestations of Alzheimer's disease.

Original languageEnglish
Pages (from-to)548-556
Number of pages9
JournalJournal of Neuroscience
Volume39
Issue number3
Early online date27 Nov 2018
DOIs
Publication statusPublished - 16 Jan 2019

Fingerprint

Alzheimer Disease
Pathology
tau Proteins
Entorhinal Cortex
Neocortex
Neuroimaging
Neurons

Keywords

  • ALZHEIMERS-DISEASE
  • AMYLOID DEPOSITION
  • AUTOSOMAL-DOMINANT
  • Alzheimer's disease
  • BASE-LINE
  • BETA DEPOSITION
  • BRAIN ACTIVATION
  • EPILEPTIFORM ACTIVITY
  • MILD COGNITIVE IMPAIRMENT
  • MOUSE MODELS
  • NEURONAL-ACTIVITY
  • PiB
  • excitotoxicity
  • fMRI
  • flortaucipir
  • memory

Cite this

Huijbers, W., Schultz, A. P., Papp, K. V., LaPoint, M. R., Hanseeuw, B., Chhatwal, J. P., ... Sperling, R. A. (2019). Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity. Journal of Neuroscience, 39(3), 548-556. https://doi.org/10.1523/JNEUROSCI.1397-18.2018
Huijbers, Willem ; Schultz, Aaron P ; Papp, Kathryn V ; LaPoint, Molly R ; Hanseeuw, Bernard ; Chhatwal, Jasmeer P ; Hedden, Trey ; Johnson, Keith A ; Sperling, Reisa A. / Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity. In: Journal of Neuroscience. 2019 ; Vol. 39, No. 3. pp. 548-556.
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Huijbers, W, Schultz, AP, Papp, KV, LaPoint, MR, Hanseeuw, B, Chhatwal, JP, Hedden, T, Johnson, KA & Sperling, RA 2019, 'Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity', Journal of Neuroscience, vol. 39, no. 3, pp. 548-556. https://doi.org/10.1523/JNEUROSCI.1397-18.2018

Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity. / Huijbers, Willem; Schultz, Aaron P; Papp, Kathryn V; LaPoint, Molly R; Hanseeuw, Bernard; Chhatwal, Jasmeer P; Hedden, Trey; Johnson, Keith A; Sperling, Reisa A.

In: Journal of Neuroscience, Vol. 39, No. 3, 16.01.2019, p. 548-556.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity

AU - Huijbers, Willem

AU - Schultz, Aaron P

AU - Papp, Kathryn V

AU - LaPoint, Molly R

AU - Hanseeuw, Bernard

AU - Chhatwal, Jasmeer P

AU - Hedden, Trey

AU - Johnson, Keith A

AU - Sperling, Reisa A

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N2 - Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-β proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-β accumulation, apolipoprotein ε4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-β and tau accumulation) before clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-β accumulation with PiB-positron emission tomography imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions before clinical impairment. SIGNIFICANCE STATEMENT The circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in vivo characterization of amyloid-β and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, before the clinical manifestations of Alzheimer's disease.

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KW - ALZHEIMERS-DISEASE

KW - AMYLOID DEPOSITION

KW - AUTOSOMAL-DOMINANT

KW - Alzheimer's disease

KW - BASE-LINE

KW - BETA DEPOSITION

KW - BRAIN ACTIVATION

KW - EPILEPTIFORM ACTIVITY

KW - MILD COGNITIVE IMPAIRMENT

KW - MOUSE MODELS

KW - NEURONAL-ACTIVITY

KW - PiB

KW - excitotoxicity

KW - fMRI

KW - flortaucipir

KW - memory

U2 - 10.1523/JNEUROSCI.1397-18.2018

DO - 10.1523/JNEUROSCI.1397-18.2018

M3 - Article

VL - 39

SP - 548

EP - 556

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 3

ER -