EMBO Mol Med. 2009 Nov;1(8-9):371-80. doi: 10.1002/emmm.200900048.

Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease.

Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM.

Source

Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. fagana@neuro.wustl.edu

Abstract

Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-beta(42) (Abeta(42)) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau(181) (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Abeta(42) but not for plasma Abeta species. Some individuals have low CSF Abeta(42) but no cortical PIB binding. Together, these data suggest that changes in brain Abeta(42) metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Abeta(42) initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.

PMID:: 20049742; [PubMed - indexed for MEDLINE]
PMCID:: PMC2806678

Free PMC Article

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Figure 2

Cortical amyloid as detected by PET PIB and its relationship to CSF Aβ in CDR 0 participants (n = 189)

A. A high percentage (84%) of participants with low PIB values (MCBP < 0.18) had high CSF Aβ₄₂ levels (mean (SD) = 705 pg/ml (211)) whereas the vast majority of participants (86%) in the cohort who had high PIB binding (MCBP ≥ 0.18) had low CSF Aβ₄₂ (mean (SD) = 362 pg/ml (115)). Horizontal lines represent the group means, and these means are statistically different from each other (asterisk, p < 0.0001).
B. Relationship between CSF Aβ₄₂ levels and cortical amyloid. Most participants had low MCBP values. The vast majority (86%) of participants with MCBPs ≥ 0.18 had low CSF Aβ₄₂ levels. These CDR 0 participants are hypothesized to have preclinical AD. The box outlined by dashed lines identifies the 28 individuals who have low cortical PIB binding (MCBP < 0.18) with low CSF Aβ₄₂. There is a linear relationship between CSF Aβ₄₂ and the amount of cortical amyloid although CSF Aβ₄₂ appears to drop and then stay low as the amyloid load increases.
C. MRI (left) and PET PIB (right) images of a representative low PIB (MCBP = 0.0270) CDR 0 participant (top panel), a high PIB (MCBP = 0.7790) CDR 0 participant (middle panel), and a high PIB (MCBP = 0.7812) CDR > 0 participant (bottom panel). The amount of cortical PIB binding (yellow-red corresponds to high binding) in the high PIB CDR 0 participant and the high PIB CDR > 0 participant is comparable, whereas there is only background PIB binding (green) in white matter tracks in the low PIB CDR 0 participant.
D,E. No relationship between CSF Aβ₄₀ (D) and CSF Aβ₃₈ (E) levels and cortical amyloid was observed in this cognitively normal cohort (r = −0.0287, p = 0.6963; r = 0.06851, p = 0.3515, respectively).
F. A negative correlation was found between cortical amyloid and the CSF Aβ₃₈/Aβ₄₂ ratio. All Pearson correlation coefficients are corrected for age. n.s., not significant.

Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease

EMBO Mol Med. 2009 November;1(8-9):371-380.