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Original Contributions |

Longitudinal Change of Biomarkers in Cognitive Decline

Raymond Y. Lo, MD, MS; Alan E. Hubbard, PhD; Leslie M. Shaw, PhD; John Q. Trojanowski, MD, PhD; Ronald C. Petersen, MD, PhD; Paul S. Aisen, MD; Michael W. Weiner, MD; William J. Jagust, MD; for the Alzheimer's Disease Neuroimaging Initiative
Arch Neurol. 2011;68(10):1257-1266. doi:10.1001/archneurol.2011.123.
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Objective To delineate the trajectories of Aβ42 level in cerebrospinal fluid (CSF), fludeoxyglucose F18 (FDG) uptake using positron emission tomography, and hippocampal volume using magnetic resonance imaging and their relative associations with cognitive change at different stages in aging and Alzheimer disease (AD).

Design Cohort study.

Setting The 59 study sites for the Alzheimer's Disease Neuroimaging Initiative.

Participants A total of 819 participants 55 to 90 years of age with normal cognition, mild cognitive impairment, and AD who were followed up during the period from 2005 to 2007.

Main Outcome Measures Rates of change in level of Aβ42 in CSF, FDG uptake, hippocampal volume, and the Alzheimer Disease's Assessment Scale–cognitive subscale score during up to 36 months of follow-up by diagnostic group as well as prediction of cognitive change by each biomarker.

Results Reductions in the level of Aβ42 in CSF were numerically greater in participants with normal cognition than in participants with mild cognitive impairment or AD; whereas both glucose metabolic decline and hippocampal atrophy were significantly slower in participants with normal cognition than in participants with mild cognitive impairment or AD. Positive APOE4 status accelerated hippocampal atrophic changes in participants with mild cognitive impairment or AD, but did not modify rates of change in level of Aβ42 in CSF or FDG uptake. The Alzheimer Disease's Assessment Scale–cognitive subscale scores were related only to the baseline level of Aβ42 in CSF and the baseline FDG uptake in participants with normal cognition, which were about equally associated with change in FDG uptake and hippocampal volume in participants with mild cognitive impairment and best modeled by change in FDG uptake in participants with AD.

Conclusion Trajectories of Aβ42 level in CSF, FDG uptake, and hippocampal volume vary across different cognitive stages. The longitudinal patterns support a hypothetical sequence of AD pathology in which amyloid deposition is an early event before hypometabolism or hippocampal atrophy, suggesting that biomarker prediction for cognitive change is stage dependent.

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Figure. Hypothetical longitudinal changes in the Aβ42 level in cerebrospinal fluid (CSF), fludeoxyglucose F18 (FDG) uptake using positron emission tomography, hippocampal volume using magnetic resonance imaging, and Alzheimer Disease's Assessment Scale–cognitive subscale (ADAS-cog) score for a 75-year-old person at different cognitive states. AD indicates Alzheimer disease; MCI, mild cognitive impairment; and NC, normal cognition.

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