Distinct proteomic CSF profiles in genetic frontotemporal lobar degeneration.
Julie F H De Houwer1, Elise G Dopper1, Renee van Buuren1
1Department of Neurology and Alzheimer Centre, Erasmus MC University Medical Centre, Rotterdam 3015 GD, The Netherlands.
Brain : a Journal of Neurology
|December 4, 2025
Summary
Researchers identified specific protein changes in cerebrospinal fluid (CSF) to diagnose frontotemporal lobar degeneration (FTLD). Two diagnostic panels were developed, showing promise for early FTLD detection and distinguishing between FTLD subtypes.
Area of Science:
- Neuroscience
- Proteomics
- Biomarker Discovery
Background:
- Frontotemporal lobar degeneration (FTLD) lacks reliable fluid biomarkers for diagnosis.
- Understanding proteomic changes in cerebrospinal fluid (CSF) is crucial for identifying FTLD subtypes and progression.
- Genetic factors significantly influence FTLD pathogenesis, necessitating subgroup-specific investigations.
Purpose of the Study:
- To identify unique proteomic signatures in CSF associated with FTLD pathogenesis across different genetic groups.
- To discover proteins that can distinguish FTLD-spectrum disorders from healthy controls.
- To develop and validate protein-based diagnostic panels for FTLD and FTLD with TDP pathology.
Main Methods:
- Utilized proximity extension assay technology to measure over 2900 proteins in CSF from two FTLD cohorts.
- Employed linear regression and overrepresentation analysis to assess differentially abundant proteins and biological pathways.
- Applied LASSO regression to develop and validate diagnostic panels for FTLD and FTLD-TDP.
Main Results:
- Identified 23 dysregulated proteins in symptomatic FTLD carriers, with NEFL and TPM3 consistently significant across cohorts.
- Discovered distinct proteomic signatures in MAPT, C9orf72, and GRN genetic subgroups, linked to immune function, energy metabolism, and neuronal development, respectively.
- Developed and validated two diagnostic panels (FTLD panel: 6 proteins; TDP panel: 7 proteins) with high accuracy (AUC 0.94-0.96) in distinguishing FTLD patients from controls.
Conclusions:
- Distinct proteomic signatures exist across FTLD genetic subgroups and pathologies.
- Developed novel CSF-based proteomic panels offer a promising tool for improved clinical diagnosis of FTLD-spectrum disorders.
- This targeted proteomic approach advances the understanding of FTLD pathogenesis and biomarker discovery.
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