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Relationships between biomarkers in aging and dementia

From the Helen Wills Neuroscience Institute (W.J.J., S.M.L.), University of California Berkeley and Lawrence Berkeley National Laboratory, CA; Department of Pathology and Laboratory Medicine (L.M.S., J.Q.T.), Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA; Division of Nuclear Medicine (R.A.K.), Department of Radiology, University of Michigan, Ann Arbor, MI; Banner Alzheimer’s Institute and Banner Good Samaritan PET Center (E.M.R.), Phoenix, AZ; Center for Alzheimer’s Care, Imaging and Research and Department of Neurology (N.L.F.), University of Utah, Salt Lake City, UT; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Center for Imaging of Neurodegenerative Diseases (M.W.W.), Department of Veterans Affairs Medical Center, San Francisco, CA; and Department of Radiology (J.C.P., C.A.M.), University of Pittsburgh, PA.

Address correspondence and reprint requests to Dr. William Jagust, Helen Wills Neuroscience Institute, 132 Barker Hall, University of California, Berkeley, CA 94620 jagust{at}berkeley.edu

Background: PET imaging using [¹⁸F]fluorodeoxyglucose (FDG) and [¹¹C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid β-amyloid protein (Aβ_1-42) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood.

Methods: Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Aβ_1-42, t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts.

Results: Dichotomous categorization showed substantial agreement between PIB-PET and CSF Aβ_1-42 measures (91% agreement, = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, = 0.50), and minimal agreement for other comparisons ( <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Aβ_1-42. Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Aβ_1-42, t-tau, and p-tau_181p, whereas FDG-PET was correlated only with Aβ_1-42.

Conclusions: PET and CSF biomarkers of Aβ agree with one another but are not related to cognitive impairment. [¹⁸F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.

Abbreviations: Aβ_1-42 = 42 amino acid β-amyloid protein; AD = Alzheimer disease; ADNI = Alzheimer’s Disease Neuroimaging Initiative; CDR = Clinical Dementia Rating; CI = confidence interval; FDG = [¹⁸F]fluorodeoxyglucose; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; MR = magnetic resonance; PIB = [¹¹C]Pittsburgh compound B; p-tau = phosphorylated tau; ROC = receiver operating characteristic; ROI = region of interest; SUVR = standardized uptake value ratio; t-tau = total tau; WMS-R = Wechsler Memory Scale–Revised.

Supplemental data at www.neurology.org

*Data used in the preparation of this article were obtained in part from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis of writing of this report. ADNI investigators are listed at http://www.loni.ucla.edu/ADNI/Collaboration/ADNI_Authorship_list.pdf. Coinvestigators for this study are listed in appendix e-1 on the Neurology® Web site at www.neurology.org.

Supported by NIH grants AG024904 and AG027859.

Disclosure: Author disclosures are provided at the end of the article.

Received January 29, 2009. Accepted in final form July 20, 2009.