Abstract
We investigated whether progranulin plasma levels are predictors of the presence of progranulin gene (GRN) null mutations or of the development of symptoms in asymptomatic at risk members participating in the Genetic Frontotemporal Dementia Initiative, including 19 patients, 64 asymptomatic carriers, and 77 noncarriers. In addition, we evaluated a possible role of TMEM106B rs1990622 as a genetic modifier and correlated progranulin plasma levels and gray-matter atrophy. Plasma progranulin mean ± SD plasma levels in patients and asymptomatic carriers were significantly decreased compared with noncarriers (30.5 ± 13.0 and 27.7 ± 7.5 versus 99.6 ± 24.8 ng/mL, p < 0.00001). Considering the threshold of >61.55 ng/mL, the test had a sensitivity of 98.8% and a specificity of 97.5% in predicting the presence of a mutation, independent of symptoms. No correlations were found between progranulin plasma levels and age, years from average age at onset in each family, or TMEM106B rs1990622 genotype (p > 0.05). Plasma progranulin levels did not correlate with brain atrophy. Plasma progranulin levels predict the presence of GRN null mutations independent of proximity to symptoms and brain atrophy.
Highlights
We investigated whether progranulin plasma levels are predictors of the presence of progranulin gene (GRN) null mutations or of the development of symptoms in asymptomatic at risk members participating in the Genetic Frontotemporal Dementia Initiative, including 19 patients, 64 asymptomatic carriers, and 77 noncarriers
Neither of the imaging analyses showed significant correlations of gray matter with progranulin levels. These data demonstrate that progranulin plasma levels represent an excellent predictor of the presence of a null GRN mutation independent of symptom proximity and brain atrophy
We acknowledge that progranulin levels are differently regulated in cerebrospinal fluid (CSF) and plasma, and it is likely that peripheral levels do not fully reflect the pathogenic cascade ongoing in the central nervous system (Nicholson et al, 2014; Wilke et al, 2016)
Summary
We investigated whether progranulin plasma levels are predictors of the presence of progranulin gene (GRN) null mutations or of the development of symptoms in asymptomatic at risk members participating in the Genetic Frontotemporal Dementia Initiative, including 19 patients, 64 asymptomatic carriers, and 77 noncarriers. Progranulin levels are differently regulated in plasma and CSF, peripheral levels may not adequately represent progranulin levels in the central nervous system (Nicholson et al, 2014; Wilke et al, 2016) It has been demonstrated in the Genetic Frontotemporal Dementia Initiative (GENFI) study that gray matter and cognitive changes can be identified 5e10 years before the expected onset of symptoms in adults at risk of genetic FTD, including a cohort carrying GRN mutations (Rohrer et al, 2015). Carriers of 2 copies of the minor allele of rs1990622 have a significantly reduced penetrance or the onset significantly delayed (Finch et al, 2011) Given these premises, the main aim of this study was to test the sensitivity and specificity of progranulin plasma levels as predictors of the presence of GRN null mutations in asymptomatic at risk members of families with known mutations enrolled in GENFI. Additional objectives include the analysis of (1) the TMEM106B rs1990622 genotype as a genetic modifier, and (2) the correlation between progranulin plasma levels and cortical gray-matter atrophy in both symptomatic and asymptomatic subjects
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