A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study

Abstract

Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers.

Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest.

Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN).

Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.

Keywords: Aquaporin 4 (AQP4); Cerebrospinal fluid; LASSO; Neurofilament medium polypeptide (NEFM); Neuronal pentraxin 2 (NPTX2); Neurosecretory protein VGF (VGF); Random forest; Suspension bead array.

Fig. 1

Affected vs unaffected. Four proteins (NEFM, AQP4, NPTX2 and VGF) selected by both Random forest and LASSO when comparing affected and unaffected individuals. Yellow and circles = affected individuals (n = 39), blue and triangles = unaffected individuals (n = 174). A Violin plots for NEFM, AQP4, NPRX2 and VGF, with p-values from Wilcoxon rank sum test. B A PCA plot based on the four selected proteins. C A hierarchical clustering based on PC1 and PC2. NEFM, neurofilament medium polypeptide; AQP4, apolipoprotein E isoform 4; NPTX2, neuronal pentraxin 2; VGF, neurosecretory protein VGF; AU, arbitrary units; PCA, principal component analysis

Fig. 2

PMC vs NC. A PCA based on four proteins (GRN, KNG1, AQP4 and UPF0606 protein KIAA1549L) selected by either LASSO or Random forest when all PMC (n = 98, green triangles) and NC (n = 76, blue dots) were included. B PCA based on six proteins (GRN, TARDBP, KNG1, HBEGF, MBP and CLSTN1) selected by either LASSO or Random forest when the selection was based on age and pathology filtered individuals (NC n = 34 blue dots, PMC C9orf72 n = 13 red triangles, PMC GRN n = 22 orange squares). C One protein was selected by both LASSO and Random forest: GRN, presented with p-values from Wilcoxon rank sum test. Same number of individuals included as in B. NC, non-carriers; C9orf72, chromosome 9 open reading frame 72; GRN, progranulin; AU, arbitrary units