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Original Investigation |

Cross-Sectional and Longitudinal Relationships Between Cerebrospinal Fluid Biomarkers and Cognitive Function in People Without Cognitive Impairment From Across the Adult Life Span

Ge Li, MD, PhD1; Steven P. Millard, PhD2; Elaine R. Peskind, MD1,2; Jing Zhang, MD, PhD3; Chang-En Yu, PhD4,5; James B. Leverenz, MD1,6; Cynthia Mayer, DO2; Jane S. Shofer, MS1; Murray A. Raskind, MD1,2; Joseph F. Quinn, MD7,8; Douglas R. Galasko, MD9; Thomas J. Montine, MD, PhD3
[+] Author Affiliations
1School of Medicine, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle
2Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
3Department of Pathology, School of Medicine, University of Washington, Seattle
4Department of Medicine, School of Medicine, University of Washington, Seattle
5Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
6Department of Neurology, School of Medicine, University of Washington, Seattle
7Department of Neurology, School of Medicine, Oregon Health and Science University, Portland
8VA Parkinson’s Disease Research, Education, and Clinical Centers, Portland, Oregon
9School of Medicine, Department of Neurosciences, University of California, San Diego, La Jolla
JAMA Neurol. 2014;71(6):742-751. doi:10.1001/jamaneurol.2014.445.
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Importance  Age-related cognitive decline among older individuals with normal cognition is a complex trait that potentially derives from processes of aging, inherited vulnerabilities, environmental factors, and common latent diseases that can progress to cause dementia, such as Alzheimer disease and vascular brain injury.

Objective  To use cerebrospinal fluid (CSF) biomarkers to gain insight into this complex trait.

Design, Setting, and Participants  Secondary analyses of an academic multicenter cross-sectional (n = 315) and longitudinal (n = 158) study of 5 neuropsychological tests (Immediate Recall, Delayed Recall, Trail Making Test Parts A and B, and Category Fluency) in cognitively normal individuals aged 21 to 100 years.

Main Outcomes and Measures  To investigate the association of these cognitive function test results with age, sex, educational level, inheritance of the ε4 allele of the apolipoprotein E gene, and CSF concentrations of β-amyloid 42 (Aβ42) and tau (biomarkers of Alzheimer disease) as well as F2-isoprostanes (measures of free radical injury).

Results  Age and educational level were broadly predictive of cross-sectional cognitive performance; of the genetic and CSF measures, only greater CSF F2-isoprostane concentration was significantly associated with poorer executive function (adjusted R2 ≤0.31). Longitudinal measures of cognitive abilities, except Category Fluency, also were associated broadly with age; of the genetic and CSF measures, only lower baseline CSF Aβ42 concentration was associated with longitudinal measures of immediate and delayed recall (marginal R2 ≤0.31).

Conclusions and Relevance  Our results suggest that age and educational level accounted for a substantial minority of variance in cross-sectional or longitudinal cognitive test performance in this large group of cognitively normal adults. Latent Alzheimer disease and other diseases that produce free radical injury, such as vascular brain injury, accounted for a small amount of variation in cognitive test performance across the adult human life span. Additional genetic and environmental factors likely contribute substantially to age-related cognitive decline.

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Figure 1.
Cross-Sectional Relationships Between Concentration of Cerebrospinal Fluid (CSF) β-Amyloid 42 (Aβ42), Tau, and F2-Isoprostanes (F2-IsoPs) vs Age at Baseline for 315 Cognitively Normal Participants

A, Aβ42 slope (95% CI), −0.3 (−1.2 to 0.6); r2 = 0.001; P = .54. B, Tau slope, 0.2 (0.1 to 0.3); R2 = 0.06; P < .001. C, F2-IsoPs slope, 0.1 (0.04 to 0.15); R2 = 0.04; P < .001. Solid line indicates the fitted least-squares line unadjusted for any covariates; dashed lines, 95% CIs. AD indicates Alzheimer disease; MCI, mild cognitive impairment.

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Figure 2.
Cross-Sectional Relationship Between Trail Making Test Part B Scores and Concentration of Cerebrospinal Fluid (CSF) F2-Isoprostanes at Baseline for 315 Cognitively Normal Participants

The solid line indicates the fitted least-squares line for the log10 score unadjusted for any covariates; dashed lines are 95% CIs for the line. Slope, 0.005; 95% CI, 0.003-0.007; R2 = 0.06; P < .001. AD indicates Alzheimer disease; MCI, mild cognitive impairment.

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