Progranulin protein levels are differently regulated in plasma and CSF

Alexandra M. Nicholson, NiCole A. Finch, Colleen S. Thomas, Aleksandra Wojtas, Nicola J. Rutherford, Michelle M Mielke, Rosebud O Roberts, Bradley F Boeve, David S Knopman, Ronald Carl Petersen, Rosa V Rademakers

Research output: Contribution to journalArticle

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Abstract

Objective: We aimed to investigate the relationship between plasma and CSF progranulin (PGRN) levels. Methods: Plasma and CSF PGRN were measured in a cohort of 345 subjects from the Mayo Clinic Study of Aging by ELISA. Single nucleotide polymorphism genotyping was performed using Taq-Man assays. Associations between PGRN and sex, age at sample collection, diagnosis, single nucleotide polymorphism genotypes (GRN, SORT1, and APOE), and Pittsburgh compound B score were explored separately in CSF and plasma using single variable linear regression models. Pearson partial correlation coefficient was used to estimate the correlation of PGRN in CSF and plasma. Results: Plasma (p = 0.0031) and CSF (p = 0.0044) PGRN significantly increased with age, whereas plasma PGRN levels were 7% lower (p = 0.0025) and CSF PGRN levels 5% higher (p = 0.0024) in male compared with female participants. Correcting for age and sex, higher plasma PGRN was associated with higher CSF PGRN (partial r = 0.17, p = 0.004). In plasma, both rs5848 (GRN; p = 0.002) and rs646776 (SORT1; p = 3.56E-7) were associated with PGRN, while only rs5848 showed highly significant association in CSF (p = 5.59E-14). Age, sex, rs5848 genotype, and plasma PGRN together accounted for only 18% of the variability observed in CSF PGRN. Conclusions: While some correlation exists between plasma and CSF PGRN, age, sex, and genetic factors differently affect PGRN levels. Therefore, caution should be taken when using plasma PGRN to predict PGRN changes in the brain. These findings further highlight that plasma PGRN levels may not accurately predict clinical features or response to future frontotemporal lobar degeneration therapies.

Original languageEnglish (US)
Pages (from-to)1871-1878
Number of pages8
JournalNeurology
Volume82
Issue number21
DOIs
StatePublished - May 27 2014

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Proteins
Single Nucleotide Polymorphism
Plasma
Protein
Linear Models
Genotype
Frontotemporal Lobar Degeneration
Sex Factors
Enzyme-Linked Immunosorbent Assay
Brain
Polymorphism
Therapeutics

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Nicholson, A. M., Finch, N. A., Thomas, C. S., Wojtas, A., Rutherford, N. J., Mielke, M. M., ... Rademakers, R. V. (2014). Progranulin protein levels are differently regulated in plasma and CSF. Neurology, 82(21), 1871-1878. https://doi.org/10.1212/WNL.0000000000000445

Progranulin protein levels are differently regulated in plasma and CSF. / Nicholson, Alexandra M.; Finch, NiCole A.; Thomas, Colleen S.; Wojtas, Aleksandra; Rutherford, Nicola J.; Mielke, Michelle M; Roberts, Rosebud O; Boeve, Bradley F; Knopman, David S; Petersen, Ronald Carl; Rademakers, Rosa V.

In: Neurology, Vol. 82, No. 21, 27.05.2014, p. 1871-1878.

Research output: Contribution to journalArticle

Nicholson AM, Finch NA, Thomas CS, Wojtas A, Rutherford NJ, Mielke MM et al. Progranulin protein levels are differently regulated in plasma and CSF. Neurology. 2014 May 27;82(21):1871-1878. https://doi.org/10.1212/WNL.0000000000000445
Nicholson, Alexandra M. ; Finch, NiCole A. ; Thomas, Colleen S. ; Wojtas, Aleksandra ; Rutherford, Nicola J. ; Mielke, Michelle M ; Roberts, Rosebud O ; Boeve, Bradley F ; Knopman, David S ; Petersen, Ronald Carl ; Rademakers, Rosa V. / Progranulin protein levels are differently regulated in plasma and CSF. In: Neurology. 2014 ; Vol. 82, No. 21. pp. 1871-1878.
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abstract = "Objective: We aimed to investigate the relationship between plasma and CSF progranulin (PGRN) levels. Methods: Plasma and CSF PGRN were measured in a cohort of 345 subjects from the Mayo Clinic Study of Aging by ELISA. Single nucleotide polymorphism genotyping was performed using Taq-Man assays. Associations between PGRN and sex, age at sample collection, diagnosis, single nucleotide polymorphism genotypes (GRN, SORT1, and APOE), and Pittsburgh compound B score were explored separately in CSF and plasma using single variable linear regression models. Pearson partial correlation coefficient was used to estimate the correlation of PGRN in CSF and plasma. Results: Plasma (p = 0.0031) and CSF (p = 0.0044) PGRN significantly increased with age, whereas plasma PGRN levels were 7{\%} lower (p = 0.0025) and CSF PGRN levels 5{\%} higher (p = 0.0024) in male compared with female participants. Correcting for age and sex, higher plasma PGRN was associated with higher CSF PGRN (partial r = 0.17, p = 0.004). In plasma, both rs5848 (GRN; p = 0.002) and rs646776 (SORT1; p = 3.56E-7) were associated with PGRN, while only rs5848 showed highly significant association in CSF (p = 5.59E-14). Age, sex, rs5848 genotype, and plasma PGRN together accounted for only 18{\%} of the variability observed in CSF PGRN. Conclusions: While some correlation exists between plasma and CSF PGRN, age, sex, and genetic factors differently affect PGRN levels. Therefore, caution should be taken when using plasma PGRN to predict PGRN changes in the brain. These findings further highlight that plasma PGRN levels may not accurately predict clinical features or response to future frontotemporal lobar degeneration therapies.",
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AU - Nicholson, Alexandra M.

AU - Finch, NiCole A.

AU - Thomas, Colleen S.

AU - Wojtas, Aleksandra

AU - Rutherford, Nicola J.

AU - Mielke, Michelle M

AU - Roberts, Rosebud O

AU - Boeve, Bradley F

AU - Knopman, David S

AU - Petersen, Ronald Carl

AU - Rademakers, Rosa V

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N2 - Objective: We aimed to investigate the relationship between plasma and CSF progranulin (PGRN) levels. Methods: Plasma and CSF PGRN were measured in a cohort of 345 subjects from the Mayo Clinic Study of Aging by ELISA. Single nucleotide polymorphism genotyping was performed using Taq-Man assays. Associations between PGRN and sex, age at sample collection, diagnosis, single nucleotide polymorphism genotypes (GRN, SORT1, and APOE), and Pittsburgh compound B score were explored separately in CSF and plasma using single variable linear regression models. Pearson partial correlation coefficient was used to estimate the correlation of PGRN in CSF and plasma. Results: Plasma (p = 0.0031) and CSF (p = 0.0044) PGRN significantly increased with age, whereas plasma PGRN levels were 7% lower (p = 0.0025) and CSF PGRN levels 5% higher (p = 0.0024) in male compared with female participants. Correcting for age and sex, higher plasma PGRN was associated with higher CSF PGRN (partial r = 0.17, p = 0.004). In plasma, both rs5848 (GRN; p = 0.002) and rs646776 (SORT1; p = 3.56E-7) were associated with PGRN, while only rs5848 showed highly significant association in CSF (p = 5.59E-14). Age, sex, rs5848 genotype, and plasma PGRN together accounted for only 18% of the variability observed in CSF PGRN. Conclusions: While some correlation exists between plasma and CSF PGRN, age, sex, and genetic factors differently affect PGRN levels. Therefore, caution should be taken when using plasma PGRN to predict PGRN changes in the brain. These findings further highlight that plasma PGRN levels may not accurately predict clinical features or response to future frontotemporal lobar degeneration therapies.

AB - Objective: We aimed to investigate the relationship between plasma and CSF progranulin (PGRN) levels. Methods: Plasma and CSF PGRN were measured in a cohort of 345 subjects from the Mayo Clinic Study of Aging by ELISA. Single nucleotide polymorphism genotyping was performed using Taq-Man assays. Associations between PGRN and sex, age at sample collection, diagnosis, single nucleotide polymorphism genotypes (GRN, SORT1, and APOE), and Pittsburgh compound B score were explored separately in CSF and plasma using single variable linear regression models. Pearson partial correlation coefficient was used to estimate the correlation of PGRN in CSF and plasma. Results: Plasma (p = 0.0031) and CSF (p = 0.0044) PGRN significantly increased with age, whereas plasma PGRN levels were 7% lower (p = 0.0025) and CSF PGRN levels 5% higher (p = 0.0024) in male compared with female participants. Correcting for age and sex, higher plasma PGRN was associated with higher CSF PGRN (partial r = 0.17, p = 0.004). In plasma, both rs5848 (GRN; p = 0.002) and rs646776 (SORT1; p = 3.56E-7) were associated with PGRN, while only rs5848 showed highly significant association in CSF (p = 5.59E-14). Age, sex, rs5848 genotype, and plasma PGRN together accounted for only 18% of the variability observed in CSF PGRN. Conclusions: While some correlation exists between plasma and CSF PGRN, age, sex, and genetic factors differently affect PGRN levels. Therefore, caution should be taken when using plasma PGRN to predict PGRN changes in the brain. These findings further highlight that plasma PGRN levels may not accurately predict clinical features or response to future frontotemporal lobar degeneration therapies.

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