Progranulin protein levels are differently regulated in plasma and CSF

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

doi:10.1212/wnl.0000000000000445

Cited by 72 publications

(101 citation statements)

References 29 publications

(32 reference statements)

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“…The observation that CSF levels, but not serum levels, of progranulin were reduced in FTD confirms and extends earlier findings from our group [8] and others [24,38,39] which demonstrated that progranulin levels in the CNS are regulated differently from those in the body periphery, both in healthy elderly subjects [24] and in various neurodegenerative diseases [8,38,39]. This differential regulation is in line with the notion that most CSF progranulin is either brain-derived or actively transported from the vascular compartment into the CSF, as suggested by the high intrathecal fraction of CSF progranulin (80-90%) [38].…”

Section: Discussionsupporting

confidence: 92%

“…Here, we investigated progranulin levels in the CSF of a carefully selected FTD cohort that was negative for mutations in GRN and other dementia genes, as demonstrated by WES. Our findings show that the CSF levels of progranulin are reduced, even in mutation-negative FTD, and that this reduction extends beyond the recognised modification of CSF progranulin levels by the SNP rs5848 [24]. This suggests that decreased central nervous progranulin levels not only contribute to FTD in the relatively rare cases of pathogenic GRN mutations [4,25], but could actually represent a more general mechanism in FTD neurodegeneration.…”

Section: Discussionmentioning

confidence: 63%

“…As age and gender have been shown to influence progranulin levels [24], we controlled for these 2 factors in our analysis. The difference between FTD and control subjects remained significant upon correction for age and gender as covariates (F 1, 68 = 11.44, p = 0.001, partial η 2 = 0.14, ANCOVA).…”

Section: Resultsmentioning

confidence: 99%

“…To preliminarily explore possible factors contributing to reduced progranulin levels in GRN -negative FTD patients, we genotyped the common, well-established single-nucleotide polymorphism (SNP) rs5848 [24]. It was genotyped in patients via WES (SNP coverage: 32-fold, IQR 24-38 and in controls by specific SNP genotyping.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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“…The effects of age and gender on blood and CSF PGRN levels have been recently studied, results are slightly discrepant showing no or minor effects. Blood and CSF PGRN levels were correlating with each other in these studies to a minor extent [15,31]. Inter-individual differences in serum PGRN concentrations are strongly determined by the rs5848 polymorphism related to FTD risk [32,33], which could have influenced group estimates of PGRN concentrations in studies that did not check for this genetic predisposition.…”

Section: Discussionmentioning

confidence: 79%

Stability of Progranulin Under Pre-Analytical Conditions in Serum and Cerebrospinal Fluid

Willemse

Durieux-Lu

Flier

et al. 2016

JAD

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Abstract. Progranulin (PGRN) levels in blood and cerebrospinal fluid (CSF) are increasingly studied as potential markers for neurodegenerative disorders. We aimed to 1) characterize two commercially available PGRN ELISAs on several assay validation parameters, 2) assess the stability of PGRN in serum and CSF under pre-analytical conditions, and 3) compare stability in the two assays. Intra-and inter-assay variation, inter-lot variation, linearity, lower limit of detection, and kit correlations were assessed for the Adipogen and R&D PGRN ELISA kits. Blood and serum samples were experimentally exposed to ≤9 freeze/thaw cycles, delayed processing for ≤24 h at room temperature and 4• C, and to temperature stability tests for ≤3 weeks at -20• C, 4• C, room temperature, and 37 • C. Both commercial PGRN ELISA kits showed acceptable ranges for intra-and inter-assay variation, where the R&D kit performed more accurate than the Adipogen kit, especially for inter-assay variation (intra-assay serum: 6.7 and 8.3%, respectively; inter-assay serum: 9.2 and 21.0%; intra-assay CSF: 3.6 and 12.0%; inter-assay CSF: 16.0 and 44.5%). Absolute serum PGRN concentrations were 1.9-fold higher in Adipogen than R&D (p < 0.001) and strongly correlated between both kits (ρ = 0.86, p < 0.0001) and CSF PGRN levels were on the borderline of detection in both kits. PGRN was typically stable under all pre-analytical conditions addressed, although two weeks at 37• C resulted in decreased PGRN concentrations in CSF, only when using the Adipogen kit. These results support further examination of PGRN as a potential marker in neurodegenerative diseases, since PGRN is stable in serum and CSF and can be measured using ELISA kits from several providers.

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A systematic review of progranulin concentrations in biofluids in over 7,000 people: Assessing the pathogenicity of GRN mutations and other influencing factors

Swift

Sogorb‐Esteve

Heller

et al. 2021

Alzheimer's & Dementia

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Background: Heterozygous mutations in the GRN gene are a major cause of genetic frontotemporal dementia (FTD), accounting for an estimated 5-10% of all people with FTD. GRN encodes for progranulin, with mutations causing haploinsufficiency, and being associated with significantly lower concentrations of progranulin in biofluids in mutation carriers compared to controls. Method:We performed a search of the literature (up to December 2019) looking for publications reporting progranulin concentrations within serum, plasma or CSF in any medical condition including FTD and other forms of dementia. We then contacted all authors and asked if they were able to share anonymised data from their study including progranulin concentrations and clinical data including specific mutation if present, clinical diagnosis, age at onset of dementia, sex, and GRN rs5848 polymorphism. Data from 7,071 people was collated and analysed.Result: Data on plasma progranulin concentrations measured using the Adipogen assay was available from 3,265 cases. Variability in levels across 109 different GRN mutations was seen and when split into mutation groups, missense variants outside the signal peptide had significantly higher levels compared to all other groups, suggesting that these variants are unlikely to be pathogenic. We established a plasma progranulin cut-off value of 74.8ng/µL between pathogenic GRN mutation carriers and noncarriers. We found that the GRN rs5848 polymorphism also affected plasma progranulin levels, with the TT genotype associated with significantly lower levels than CC. Sex differences were also seen, with significantly higher progranulin levels in females than males. Conclusion:Together these findings highlight the variable pathogenicity of different GRN mutations and the importance of considering other factors such as genetic risk factors and sex differences when looking at biofluid concentrations of progranulin. This is of particular relevance in upcoming clinical trials of progranulin-associated FTD where progranulin levels are being measured as outcome measures.

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Progranulin protein levels are differently regulated in plasma and CSF

Cited by 72 publications

References 29 publications

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in <b><i>GRN</i></b>-Negative Frontotemporal Dementia

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in <b><i>GRN</i></b>-Negative Frontotemporal Dementia

Stability of Progranulin Under Pre-Analytical Conditions in Serum and Cerebrospinal Fluid

A systematic review of progranulin concentrations in biofluids in over 7,000 people: Assessing the pathogenicity of GRN mutations and other influencing factors

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