Optimal Plasma Progranulin Cutoff Value for Predicting Null Progranulin Mutations in Neurodegenerative Diseases: A Multicenter Italian Study

Ghidoni, Roberta; Stoppani, Elena; Rossi, Giacomina; Piccoli, Elena; Albertini, Valentina; Paterlini, Anna; Glionna, Michela; Pegoiani, Eleonora; Agnati, Luigi F.; Fenoglio, Chiara; Scarpini, Elio; Galimberti, Daniela; Morbin, Michela; Tagliavini, Fabrizio; Binetti, Giuliano; Benussi, Luisa

doi:10.1159/000333132

Cited by 91 publications

(63 citation statements)

References 49 publications

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“…In this group of mutation carriers, no relation could be established between serum PGRN levels and age at onset of symptoms, as the 2 patients with the lowest levels (cases 1 and 3) exhibit the lowest (43 years) and highest age of onset (63 years). This result disagrees with a large multicenter study [54], where PGRN null mutation carriers with the lowest PGRN levels showed a slight anticipation of disease onset. Interestingly, patients carrying the same mutation had similar serum PGRN levels (g.2263_2264dupGT < g.2631delG < g.1932_1933dupCC < g.2271delC), however, as already reported by Schofield et al [52] in 2010, the position of the mutation did not seem to be related with the level of serum PGRN, as mutations in exon 9 resulted in the lowest and highest serum PGRN levels within our group of PGRN mutation carriers.…”

Section: Discussioncontrasting

confidence: 99%

“…We observed a good correlation between serum PGRN levels determined by both kits and the levels obtained with the AdiPogen kit are in line with the ones previously reported in the literature [52,55]. Moreover, the cut-off value for the discrimination between PGRN null mutation carriers and non-carriers obtained by the Adipogen kit was very similar to the one reported by others [52,54]. Despite the method used for establishing the cut-off levels for the R&D kit (ROC curve analysis to differentiate between PGRN null mutation carriers and non-carriers vs. -2 SD of the mean control level), the value was very similar: 23.6 vs. 24.4 ng/ml in serum and 20.5 ng/ml for both methods in plasma and a 100% accuracy in determining PGRN null mutations was achieved.…”

Section: Discussionsupporting

confidence: 90%

“…In a subgroup of serum samples (48 FTLD patients, 21 controls), PGRN levels were also assessed by the already reported ELISA kit from Adipogen, Inc. (Incheon, Korea) [51,52,54,57] and the results were compared with the ones obtained with the R&D kit. The technicians responsible for performing the PGRN ELISAs were unaware of the results of the mutation analysis.…”

Section: Methodsmentioning

confidence: 99%

“…In fact, a severe reduction of PGRN levels is observed in biological fluids such as cerebrospinal fluid (CSF), plasma and serum, of patients with PGRN mutations, even in unaffected mutation carriers [49,50,51]. Moreover, this assessment has been proposed as a useful screening method for the detection of PGRN mutations, with a good sensitivity and specificity [52,53,54,55]. …”

Section: Introductionmentioning

confidence: 99%

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Progranulin Peripheral Levels as a Screening Tool for the Identification of Subjects with Progranulin Mutations in a Portuguese Cohort

et al. 2013

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Background: Progranulin (PGRN) mutations are associated with different clinical phenotypes, including frontotemporal lobar degeneration (FTLD), corticobasal syndrome (CBS) and Alzheimer's disease (AD). As all pathogenic PGRN mutations identified so far cause disease through haploinsufficiency, determination of PGRN levels has been proposed as a reliable method to identify mutation carriers. Objective: To evaluate the accuracy of peripheral PGRN levels in the identification of the PGRN mutation carriers detected thus far in our Portuguese cohort. Methods: Serum PGRN levels were measured in 244 subjects (124 patients in the spectrum of FTLD, 2 asymptomatic descendants of a FTLD patient, 56 AD patients and 64 controls) by a novel commercial ELISA kit. Results: Low PGRN levels were detected in 7 individuals (5 behavioral variant frontotemporal dementia, 1 CBS, and 1 still clinically unaffected) that constituted the group of the null PGRN mutation carriers previously identified in our molecular diagnostic laboratory. The pathogenic mutations found consisted of 4 insertion-deletions, causing frameshifts resulting in premature stop codons, 3 of which were novel. In addition, a normal PGRN level was found in a patient harboring a novel missense variant. For this novel ELISA kit, we established a PGRN cut-off level that identified with 100% accuracy the pathogenic mutation carriers. Conclusion: This study supports the use of a novel assay for the determination of PGRN levels as a screening procedure to identify patients harboring null PGRN mutations. This approach would significantly decrease the required PGRN mutation analysis workload and should be extended to other clinical phenotypes than behavioral variant frontotemporal dementia and to apparently sporadic cases.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Progranulin Peripheral Levels as a Screening Tool for the Identification of Subjects with Progranulin Mutations in a Portuguese Cohort

et al. 2013

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“…While previous research mainly focused on the role of progranulin as a biomarker and predictor of GRN -mediated FTD [3,4,26,27], the contribution of progranulin to GRN -negative FTD remains to be elucidated. 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.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in <b><i>GRN</i></b>-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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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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Optimal Plasma Progranulin Cutoff Value for Predicting Null Progranulin Mutations in Neurodegenerative Diseases: A Multicenter Italian Study

Cited by 91 publications

References 49 publications

Progranulin Peripheral Levels as a Screening Tool for the Identification of Subjects with Progranulin Mutations in a Portuguese Cohort

Progranulin Peripheral Levels as a Screening Tool for the Identification of Subjects with Progranulin Mutations in a Portuguese Cohort

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

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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