Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers

Julia Remnestål,Jennie Olofsson,Peter Nilsson,Sofia Bergström,Linn Öijerstedt,Mathias Uhlén,Martin Ingelsson,Abbe Ullgren,Caroline Graff,Kim Kultima,Anna Månberg,Lena Kilander

doi:10.1186/s40035-020-00198-y

Abstract

BackgroundThe clinical presentations of frontotemporal dementia (FTD) are diverse and overlap with other neurological disorders. There are, as of today, no biomarkers in clinical practice for diagnosing the disorders. Here, we aimed to find protein markers in cerebrospinal fluid (CSF) from patients with FTD, presymptomatic mutation carriers and non-carriers.MethodsAntibody suspension bead arrays were used to analyse 328 proteins in CSF from patients with behavioural variant FTD (bvFTD, n = 16) and progressive primary aphasia (PPA, n = 13), as well as presymptomatic mutation carriers (PMC, n = 16) and non-carriers (NC, n = 8). A total of 492 antibodies were used to measure protein levels by direct labelling of the CSF samples. The findings were further examined in an independent cohort including 13 FTD patients, 79 patients with Alzheimer’s disease and 18 healthy controls.ResultsWe found significantly altered protein levels in CSF from FTD patients compared to unaffected individuals (PMC and NC) for 26 proteins. The analysis show patterns of separation between unaffected individuals and FTD patients, especially for those with a clinical diagnosis of bvFTD. The most statistically significant differences in protein levels were found for VGF, TN-R, NPTXR, TMEM132D, PDYN and NF-M. Patients with FTD were found to have higher levels of TN-R and NF-M, and lower levels of VGF, NPTXR, TMEM132D and PDYN, compared to unaffected individuals. The main findings were reproduced in the independent cohort.ConclusionIn this pilot study, we show a separation of FTD patients from unaffected individuals based on protein levels in CSF. Further investigation is required to explore the CSF profiles in larger cohorts, but the results presented here has the potential to enable future clinical utilization of these potential biomarkers within FTD.

Highlights

The clinical presentations of frontotemporal dementia (FTD) are diverse and overlap with other neurological disorders
Participants The exploratory cohort 1 was recruited at the Memory clinic at Karolinska University Hospital and consisted of both patients diagnosed with FTD and unaffected subjects enrolled in the GENFI-study (GENetic Frontotemporal Dementia Initiative): 29 were diagnosed with FTD, between 1997 and 2016, according to the criteria by Rascovsky et al 2008 or Gorno-Tempini et al 2011 [1, 2] and 24 were clinically unaffected participants from the GENFI-study (Table 1) [22, 23]
When comparing the subgroups nonmutation carriers (NC), PMC, progressive aphasia (PPA) and behavioural variant FTD (bvFTD), the most statistically significant differences in protein levels were found for Neurosecretory protein VGF (VGF), TN-R, neuronal pentraxin receptor (NPTXR), TMEM132D, PDYN and neurofilament medium polypeptide (NF-M), none of which were affected by age

Summary

Introduction

The clinical presentations of frontotemporal dementia (FTD) are diverse and overlap with other neurological disorders. The clinical presentations are diverse and overlap with other psychiatric and neurological disorders [1]. The major phenotypes are behavioural variant FTD (bvFTD) and primary progressive aphasia (PPA). Approximately 15% of FTD patients develop amyotrophic lateral sclerosis (ALS) and other motoric symptoms [3]. This phenotypic heterogeneity and lack of objective diagnostic tests may result in misdiagnosis and incorrect care of patients and their families [4, 5]

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