Journal
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
Volume 6, Issue 4, Pages 698-707Publisher
WILEY
DOI: 10.1002/acn3.745
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Funding
- Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development) [733050813, 733050103]
- Memorabel grants from Deltaplan Dementie (Alzheimer Nederland) [733050813, 733050103]
- Bluefield Project to Cure Frontotemporal Dementia
- Dioraphte foundation [1402 1300]
- European Joint Programme - Neurodegenerative Disease Research [PreFrontALS: 733051042, RiMod-FTD: 733051024]
- Netherlands Organisation for Health Research and Development [PreFrontALS: 733051042, RiMod-FTD: 733051024]
- Spanish National Institute of Health Carlos III (ISCIII) under the aegis of the EU Joint Programme - Neurodegenerative Disease Research (JPND) [AC14/00013]
- Fundacio Marato de TV3 [20143810]
- Swedish Alzheimer foundation
- Stockholm County Council
- Karolinska Institutet
- Strategic Research Program in Neuroscience at Karolinska Institutet
- Karolinska Institutet Doctoral Funding
- Swedish Medical Research Council
- Swedish Brain Foundation
- Old Servants foundation
- Gun and Bertil Stohne's foundation
- Schorling Foundation Swedish FTD Initiative
- Italian Ministry of Health
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Objective To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by >= 4 peptides and if fold change was <= 0.5 or >= 2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.
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