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

ABSTRACT: BACKGROUND:The 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. METHODS:Antibody 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. RESULTS:We 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. CONCLUSION:In 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.

SUBMITTER: Remnestal J

PROVIDER: S-EPMC7310563 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Remnestål Julia J Öijerstedt Linn L Ullgren Abbe A Olofsson Jennie J Bergström Sofia S Kultima Kim K Ingelsson Martin M Kilander Lena L Uhlén Mathias M Månberg Anna A Graff Caroline C Nilsson Peter P

Translational neurodegeneration 20200623 1

<h4>Background</h4>The 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.<h4>Methods</h4>Antibody suspension bead arrays were used to analyse 328 proteins in CSF from patients with behavioural variant FTD ...[more]

PMID: 32576262

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Project description:BackgroundA 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.MethodsA 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.ResultsWhen 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).ConclusionIn 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.

Dataset Information

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

Publications

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

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