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Original Contributions |

Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System

Yafei Huang, PhD; Rachel Potter, BA; Wendy Sigurdson, MSN; Anna Santacruz, BSN; Shirley Shih, BA; Yo-El Ju, MD; Tom Kasten, PhD; John C. Morris, MD; Mark Mintun, MD; Stephen Duntley, MD; Randall J. Bateman, MD
Arch Neurol. 2012;69(1):51-58. doi:10.1001/archneurol.2011.235.
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Background The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD).

Objective To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD.

Design Repeated-measures case-control study.

Setting Washington University School of Medicine in St Louis, Missouri.

Participants Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants.

Main Outcome Measures In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data.

Results Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake.

Conclusions A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.

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Figures

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Figure 1. Diagram of a participant during the monitoring of Aβ levels in cerebrospinal fluid (CSF) samples. These samples were collected from a lumbar intrathecal catheter approximately every hour for 36 hours from each participant, and electroencephalograms (EEGs) and video recordings were obtained continuously from a subset of study patients. The concentrations of CSF Aβ40 and Aβ42 were measured using an enzyme-linked immunosorbent assay and were analyzed over time for Aβ dynamics.

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Figure 2. Mean-adjusted Aβ42 levels over time in 20 participants younger than 60 years of age from the younger normal control (YNC) group. A linear increase and a circadian pattern in Aβ42 levels over the duration of our study were observed (A), and the Aβ42 circadian patterns remained after the linear trend was removed (P < .05) (B).

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Figure 3. Mean percent change with respect to the linear increase in Aβ42 level per 24 hours, by mean cortical binding potential (MCBP) of carbon 11–labeled Pittsburgh Compound B. In general, individuals without amyloid deposition (young normal controls [YNCs] and older cognitively normal controls who tested negative for amyloid plaque [amyloid]) had significant increases in Aβ42 level, independent of age, whereas participants with amyloid deposition (older cognitively normal controls who tested positive for amyloid plaque [amyloid+]) had lower increases in Aβ42 level (P < .05).

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Figure 5. Cosinor fit for group-averaged Aβ42 (A) and Aβ40 (B) levels over time showing that the cerebrospinal fluid Aβ circadian amplitude decreases with age. The Aβ42 circadian amplitude decreased with age and amyloidosis. The Aβ40 circadian amplitude was lower in the older groups. Amyloid indicates participants who tested negative for amyloid plaque; amyloid+, participants who tested positive for amyloid plaque; YNC, younger normal controls.

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Figure 6. Circadian rhythms of mean total sleep times (minutes of sleep per hour) and Aβ circadian patterns in a subset of 12 younger normal control participants. The cerebrospinal fluid Aβ circadian pattern follows sleep after a 6-hour delay. A delay of 6 hours was observed between the maximum sleep times and the minimum Aβ levels.

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Figure 4. Decreased Aβ42 circadian amplitude with increasing age. An Aβ42 circadian amplitude was calculated for each participant and correlated with the participant's age. Age and Aβ42 circadian amplitude were negatively correlated (P < .01). Young normal control (YNC) participants had the highest circadian amplitudes, older participants who tested negative for amyloid plaque (amyloid) had decreased circadian amplitudes, and older participants who tested positive for amyloid plaque (amyloid+) had the lowest circadian amplitudes.

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