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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 - EMBO Mol Med (2009)

Bottom Line: 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.These findings have important implications for preclinical AD diagnosis and treatment.

View Article: PubMed Central - PubMed

Affiliation: 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.

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Related in: MedlinePlus

Cortical amyloid as detected by PET PIB and its relationship to plasma Aβ42 and Aβ40 species in CDR 0 participants (n = 189)No relationship was observed between mean cortical PIB binding and plasmaAβ1–40 (r = −0.0724, p = 0.3234),Aβx–40 (r = 0.04583, p = 0.5323),Aβ1–42 (r = −0.1015, p = 0.1658) orAβx–42 (r = −0.03869, p = 0.5981). Five participants had levels of plasma Aβx–42 below the level of detection so they are represented as having 0 pg/ml. All Pearson correlation coefficients are corrected for age. n.s., not significant.
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fig03: Cortical amyloid as detected by PET PIB and its relationship to plasma Aβ42 and Aβ40 species in CDR 0 participants (n = 189)No relationship was observed between mean cortical PIB binding and plasmaAβ1–40 (r = −0.0724, p = 0.3234),Aβx–40 (r = 0.04583, p = 0.5323),Aβ1–42 (r = −0.1015, p = 0.1658) orAβx–42 (r = −0.03869, p = 0.5981). Five participants had levels of plasma Aβx–42 below the level of detection so they are represented as having 0 pg/ml. All Pearson correlation coefficients are corrected for age. n.s., not significant.

Mentions: Despite the strong relationship between PIB binding and CSF Aβ42, we observed no relationship between cortical amyloid load and plasma levels of Aβ42, Aβx–42, Aβ40 or Aβx–40 (Fig. 3). Our previous study reported the same results in a much smaller, clinically mixed cohort. Furthermore, for the present study we used the xMAP plasma kit (Inno-Bia Plasma Aβ Forms Multiplex Assay) which generates reliable values in the lower pg/ml range required for plasma measures (Blennow et al, 2009; Lachno et al, 2009). We obtained reliable values (with low coefficients of variability) for all but five samples; these five had very low levels of Aβx–42 that were below the level of detection so they were assigned a value of 0 pg/ml.


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 - EMBO Mol Med (2009)

Cortical amyloid as detected by PET PIB and its relationship to plasma Aβ42 and Aβ40 species in CDR 0 participants (n = 189)No relationship was observed between mean cortical PIB binding and plasmaAβ1–40 (r = −0.0724, p = 0.3234),Aβx–40 (r = 0.04583, p = 0.5323),Aβ1–42 (r = −0.1015, p = 0.1658) orAβx–42 (r = −0.03869, p = 0.5981). Five participants had levels of plasma Aβx–42 below the level of detection so they are represented as having 0 pg/ml. All Pearson correlation coefficients are corrected for age. n.s., not significant.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2806678&req=5

fig03: Cortical amyloid as detected by PET PIB and its relationship to plasma Aβ42 and Aβ40 species in CDR 0 participants (n = 189)No relationship was observed between mean cortical PIB binding and plasmaAβ1–40 (r = −0.0724, p = 0.3234),Aβx–40 (r = 0.04583, p = 0.5323),Aβ1–42 (r = −0.1015, p = 0.1658) orAβx–42 (r = −0.03869, p = 0.5981). Five participants had levels of plasma Aβx–42 below the level of detection so they are represented as having 0 pg/ml. All Pearson correlation coefficients are corrected for age. n.s., not significant.
Mentions: Despite the strong relationship between PIB binding and CSF Aβ42, we observed no relationship between cortical amyloid load and plasma levels of Aβ42, Aβx–42, Aβ40 or Aβx–40 (Fig. 3). Our previous study reported the same results in a much smaller, clinically mixed cohort. Furthermore, for the present study we used the xMAP plasma kit (Inno-Bia Plasma Aβ Forms Multiplex Assay) which generates reliable values in the lower pg/ml range required for plasma measures (Blennow et al, 2009; Lachno et al, 2009). We obtained reliable values (with low coefficients of variability) for all but five samples; these five had very low levels of Aβx–42 that were below the level of detection so they were assigned a value of 0 pg/ml.

Bottom Line: 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.These findings have important implications for preclinical AD diagnosis and treatment.

View Article: PubMed Central - PubMed

Affiliation: 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.

Show MeSH
Related in: MedlinePlus