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November 12, 2013; 81 (20) Article

CSF biomarker changes precede symptom onset of mild cognitive impairment

Abhay Moghekar, Shanshan Li, Yi Lu, Ming Li, Mei-Cheng Wang, Marilyn Albert, Richard O’Brien, For the BIOCARD Research Team
First published October 16, 2013, DOI: https://doi.org/10.1212/01.wnl.0000435558.98447.17
Abhay Moghekar
From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Shanshan Li
From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Yi Lu
From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Ming Li
From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Mei-Cheng Wang
From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Marilyn Albert
From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Richard O’Brien
From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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CSF biomarker changes precede symptom onset of mild cognitive impairment
Abhay Moghekar, Shanshan Li, Yi Lu, Ming Li, Mei-Cheng Wang, Marilyn Albert, Richard O’Brien, For the BIOCARD Research Team
Neurology Nov 2013, 81 (20) 1753-1758; DOI: 10.1212/01.wnl.0000435558.98447.17

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Abstract

Objective: This study evaluated longitudinal CSF biomarker measures collected when participants were cognitively normal to determine the magnitude and time course of biomarker changes before the onset of clinical symptoms in subjects with mild cognitive impairment (MCI).

Methods: Longitudinal CSF collection and cognitive assessments were performed on a cohort of 265 participants who were cognitively normal at their baseline assessment and subsequently developed MCI or dementia. CSF β-amyloid 1–42 (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) were determined longitudinally. Consensus diagnoses were completed annually. Cox regression analyses were performed, with baseline CSF values and time-dependent rate of change in CSF values as covariates (adjusted by baseline age, race, and education), in relation to time to onset of mild cognitive symptoms.

Results: The mean time from baseline to onset of mild cognitive symptoms was 5.41 years. Increased risk of progressing from normal cognition to onset of clinical symptoms was associated with baseline values of Aβ1–42, p-tau, and the ratios of p-tau/Aβ1–42 and t-tau/Aβ1–42 (p < 0.002). Additionally, the rate of change in the ratios of t-tau/Aβ1–42 (p < 0.004) and p-tau/Aβ1–42 (p < 0.02) was greater among participants who were subsequently diagnosed with MCI.

Conclusions: Baseline differences in CSF values were predictive of clinical symptoms that were a harbinger of a diagnosis of MCI more than 5 years before symptom onset, and continue to show longitudinal changes as cognitive symptoms develop, demonstrating that baseline and longitudinal changes in CSF biomarkers are evident during the preclinical phase of Alzheimer disease.

GLOSSARY

Aβ1–42=
β-amyloid 1–42;
AD=
Alzheimer disease;
BIOCARD=
Biomarkers for Older Controls at Risk for Dementia;
DIAN=
Dominantly Inherited Alzheimer Network;
MCI=
mild cognitive impairment;
p-tau=
phosphorylated tau;
t-tau=
total tau

Footnotes

  • BIOCARD Research Team coinvestigators are listed on the Neurology® Web site at www.neurology.org.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at www.neurology.org

  • Received March 31, 2013.
  • Accepted in final form August 14, 2013.
  • © 2013 American Academy of Neurology
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