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.

Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia

“…Recent proteomic studies have shown decreased levels of NPTXR in symptomatic genetic FTD, in all three genetic groups [ 45 ], and in sporadic bvFTD and PPA [ 46 ]. Two further studies additionally showed that NPTX2 was decreased in symptomatic mutation carriers in all three groups compared with controls using antibody-based approaches [ 47 , 48 ], and one of these studies showed that NPTX1 was decreased in C9orf72 and MAPT mutation carriers [ 48 ]. In our study, NPTX1 and NPTX2 were significantly decreased in all symptomatic groups, but NPTXR was only decreased in C9orf72 and GRN mutation carriers.…”

Synaptic loss in behavioural variant frontotemporal dementia revealed by [11C]UCB-J PET

“…In addition, it is possible that tau and TDP-43 mediated bvFTD have distinct spatiotemporal profiles of synaptic loss. This could be tested with studies using [ 11 C]UCB-J PET in preclinical models and people with genetically determined familial frontotemporal dementia (Van Der Ende et al ., 2020; Bergström et al ., 2021), or in due course by post mortem examination of those who have undergone PET. However, we suggest that synaptic loss is a mechanistic convergence point, present across diverse molecular pathologies.…”

“…Previous evidence for synaptic loss in frontotemporal dementia has been indirect, including reduced synaptic density in carriers of mutations associated with frontotemporal dementia (Malpetti et al ., 2021), abnormal synaptic markers in cerebrospinal fluid (Goetzl et al ., 2016; Van Der Ende et al ., 2020; Bergström et al ., 2021), and progressive frontotemporal hypometabolism that is disproportionate to atrophy, indicated by [ 18 F]FDG PET (Diehl-Schmid et al ., 2007; Malpetti et al ., 2019; Bejanin et al ., 2020; see Chételat et al ., 2020 for review). Recently, new tools to quantify synaptic density in vivo have been developed, including radioligands that bind selectively to synaptic vesicle protein 2A (SV2A) as an assay of synaptic density (Finnema et al ., 2016; Heurling et al ., 2019).…”

Multi-Omics Interdisciplinary Research Integration to Accelerate Dementia Biomarker Development (MIRIADE)

“…The panel of proteins was further developed and narrowed in succeeding studies on various neurodegenerative disorders to investigate disease specificity. These studies focused on AD ( 15 , 16 ), PD ( 17 ), and FTD ( 18 , 19 ) amyotrophic lateral sclerosis (ALS) ( 20 )) and corticobasal degeneration (CBD) ( 21 ). In addition, one study investigated the associations of the selected panel proteins with the conventional CSF biomarkers for AD pathology on an asymptomatic cohort of asymptomatic 70-year-old individuals ( 22 ).…”