Abstract

Background: Decreased plasma progranulin levels are a specific marker in screening for Frontotemporal Lobar Degeneration (FTLD) caused by mutations in the GRN gene.
Objective: To describe the performance of this biomarker in clinical practice.
Methods: Using a commercial kit (AdipoGen Inc), we analysed progranulin plasma levels in 436 samples from 240 cases with FTLD phenotypes, 122 with Alzheimer type dementia, 20 with Lewy body type dementia, 15 with a psychiatric phenotype and frontotemporal atrophy, plus 39 cognitively-preserved elderly controls. The GRN gene was sequenced in cases with lower plasma levels. Clinical variables were correlated with plasma levels in cases with GRN mutations.
Results: Eight probands with FTLD phenotypes (3% of all FTLD cases, 12% of FTLD with autosomal dominant family history) and plasma levels below 70 ng/ml were found to carry seven different GRN mutations. The frequency of mutation-positive cases increased to 6% when considering only FTLD cases with asymmetric atrophy, though applying this criterion would have omitted two diagnosed cases. Few false positive cases (n=5) were due to technical errors, and no false negatives (70 to 90 ng/ml) were detected. In the 60 to 70 ng/ml interval, both carriers and non-carriers were found when pulling all procedures together, although they never overlapped in a single assay. None of the cases with non-FTLD
phenotypes had GRN mutations. Plasma levels did not correlate with mutation type, age of onset, or disease stage. Asymptomatic carriers had low levels even decades before the expected age at disease onset.
Conclusion: Progranulin plasma levels are a reliable biomarker to detect the small percentage of FTLD GRNmutation carriers in our cohort, though they are not useful for clinical follow-up.

Keywords: Biological markers; Frontotemporal dementia; Plasma; Progranulin levels; GRN mutations