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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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Cortical amyloid as detected by PET PIB and fluid biomarkers in CDR 0 participants (n = 189) as a function of ageLevels ofcortical amyloid are positively correlated with age in this CDR 0 cohort,The level of CSF Aβ38 is not correlated with age,nor is CSF Aβ40.CSF Aβ42 is negatively correlated with age.Positive correlations with age are observed for CSF tau,CSF ptau181 andplasma Aβ1–40.Plasma Aβ1–42 is not correlated with age in this cohort.
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fig01: Cortical amyloid as detected by PET PIB and fluid biomarkers in CDR 0 participants (n = 189) as a function of ageLevels ofcortical amyloid are positively correlated with age in this CDR 0 cohort,The level of CSF Aβ38 is not correlated with age,nor is CSF Aβ40.CSF Aβ42 is negatively correlated with age.Positive correlations with age are observed for CSF tau,CSF ptau181 andplasma Aβ1–40.Plasma Aβ1–42 is not correlated with age in this cohort.

Mentions: Given the wide range of ages in the present cohort, we first investigated whether any of the biomarker measures correlated with age at the time of LP. As shown in Fig. 1, positive correlations were observed between age and cortical amyloid (represented by mean cortical PIB binding potential (MCBP); Mintun et al, 2006), CSF tau and ptau181 and plasma Aβ1–40. An inverse correlation was observed between age and CSF Aβ42, and no relationships between age and CSF Aβ38 or Aβ40 were found. Due to these age effects, all subsequent analyses were corrected for age.


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 fluid biomarkers in CDR 0 participants (n = 189) as a function of ageLevels ofcortical amyloid are positively correlated with age in this CDR 0 cohort,The level of CSF Aβ38 is not correlated with age,nor is CSF Aβ40.CSF Aβ42 is negatively correlated with age.Positive correlations with age are observed for CSF tau,CSF ptau181 andplasma Aβ1–40.Plasma Aβ1–42 is not correlated with age in this cohort.
© Copyright Policy
Related In: Results  -  Collection

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

fig01: Cortical amyloid as detected by PET PIB and fluid biomarkers in CDR 0 participants (n = 189) as a function of ageLevels ofcortical amyloid are positively correlated with age in this CDR 0 cohort,The level of CSF Aβ38 is not correlated with age,nor is CSF Aβ40.CSF Aβ42 is negatively correlated with age.Positive correlations with age are observed for CSF tau,CSF ptau181 andplasma Aβ1–40.Plasma Aβ1–42 is not correlated with age in this cohort.
Mentions: Given the wide range of ages in the present cohort, we first investigated whether any of the biomarker measures correlated with age at the time of LP. As shown in Fig. 1, positive correlations were observed between age and cortical amyloid (represented by mean cortical PIB binding potential (MCBP); Mintun et al, 2006), CSF tau and ptau181 and plasma Aβ1–40. An inverse correlation was observed between age and CSF Aβ42, and no relationships between age and CSF Aβ38 or Aβ40 were found. Due to these age effects, all subsequent analyses were corrected for age.

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