Progranulin protein levels are differently regulated in plasma and CSF.
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 TaqMan 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.
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
Alexandra M
AM
Nicholson
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
NiCole A
NA
Finch
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
Colleen S
CS
Thomas
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
Aleksandra
A
Wojtas
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
Nicola J
NJ
Rutherford
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
Michelle M
MM
Mielke
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
Rosebud O
RO
Roberts
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
Bradley F
BF
Boeve
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
David S
DS
Knopman
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN.
Ronald C
RC
Petersen
From the Department of Neuroscience (A.M.N., N.A.F., A.W., N.J.R., R.R.) and Division of Biomedical Statistics and Informatics (C.S.T.), Mayo Clinic, Jacksonville, FL; and Division of Epidemiology, Department of Health Sciences Research (M.M.M., R.O.R.) and Department of Neurology (R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN. rademakers.rosa@mayo.edu.
Rosa
R
Rademakers
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis* / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D012737:Sex Factors
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins