Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia

Carlo Wilke, Frank Gillardon, Christian Deuschle, Markus A. Hobert, Iris E. Jansen, Florian G. Metzger, Peter Heutink, Thomas Gasser, Walter Maetzler, Cornelis Blauwendraat, Matthis Synofzik

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background and Objective: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Methods: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Results: Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Conclusions: Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.

Original languageEnglish
Pages (from-to)83-88
Number of pages6
JournalNeurodegenerative Diseases
Volume17
Issue number2-3
DOIs
Publication statusPublished - 1 Feb 2017

Cite this

Wilke, Carlo ; Gillardon, Frank ; Deuschle, Christian ; Hobert, Markus A. ; Jansen, Iris E. ; Metzger, Florian G. ; Heutink, Peter ; Gasser, Thomas ; Maetzler, Walter ; Blauwendraat, Cornelis ; Synofzik, Matthis. / Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia. In: Neurodegenerative Diseases. 2017 ; Vol. 17, No. 2-3. pp. 83-88.
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title = "Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia",
abstract = "Background and Objective: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Methods: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Results: Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Conclusions: Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.",
keywords = "Cerebrospinal fluid, Frontotemporal dementia, Neurodegeneration, Progranulin, Serum levels, Tau, Whole-exome sequencing",
author = "Carlo Wilke and Frank Gillardon and Christian Deuschle and Hobert, {Markus A.} and Jansen, {Iris E.} and Metzger, {Florian G.} and Peter Heutink and Thomas Gasser and Walter Maetzler and Cornelis Blauwendraat and Matthis Synofzik",
year = "2017",
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language = "English",
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Wilke, C, Gillardon, F, Deuschle, C, Hobert, MA, Jansen, IE, Metzger, FG, Heutink, P, Gasser, T, Maetzler, W, Blauwendraat, C & Synofzik, M 2017, 'Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia' Neurodegenerative Diseases, vol. 17, no. 2-3, pp. 83-88. https://doi.org/10.1159/000448896

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia. / Wilke, Carlo; Gillardon, Frank; Deuschle, Christian; Hobert, Markus A.; Jansen, Iris E.; Metzger, Florian G.; Heutink, Peter; Gasser, Thomas; Maetzler, Walter; Blauwendraat, Cornelis; Synofzik, Matthis.

In: Neurodegenerative Diseases, Vol. 17, No. 2-3, 01.02.2017, p. 83-88.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia

AU - Wilke, Carlo

AU - Gillardon, Frank

AU - Deuschle, Christian

AU - Hobert, Markus A.

AU - Jansen, Iris E.

AU - Metzger, Florian G.

AU - Heutink, Peter

AU - Gasser, Thomas

AU - Maetzler, Walter

AU - Blauwendraat, Cornelis

AU - Synofzik, Matthis

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Background and Objective: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Methods: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Results: Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Conclusions: Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.

AB - Background and Objective: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Methods: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Results: Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Conclusions: Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.

KW - Cerebrospinal fluid

KW - Frontotemporal dementia

KW - Neurodegeneration

KW - Progranulin

KW - Serum levels

KW - Tau

KW - Whole-exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=84991822143&partnerID=8YFLogxK

U2 - 10.1159/000448896

DO - 10.1159/000448896

M3 - Article

VL - 17

SP - 83

EP - 88

JO - Neurodegenerative Diseases

JF - Neurodegenerative Diseases

SN - 1660-2854

IS - 2-3

ER -