Plasma proteome profiling identifies changes associated to AD but not to FTD
Acta Neuropathologica Communications, vol. 10, pp. 148
Abstract
BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.
Authors 16
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Alzheimer Center and Department of Neurology Amsterdam, Department of Neurology, Neuroscience Campus Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
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Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam · Wageningen University & Research
Affiliation as printed
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Mathematical and Statistical Methods Group (Biometris), Wageningen University and Research Wageningen, Wageningen, The Netherlands
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Affiliation as printed
Alzheimer Center Erasmus MC and Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands
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Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
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Affiliation as printed
Alzheimer Center Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
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H.A.M. Middelkoop Aachen Department of Neurology, Leiden University Medical Centre Institute of Psychology, Health Medical and Neuropsychology Unit
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden University, Leiden, the Netherlands
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University Medical Center Groningen · University of Antwerp · University of Groningen · Institute Born-Bunge
Affiliation as printed
Department of Neurology and Alzheimer Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Laboratory of Neurochemistry and Behavior, Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Geriatric Medicine, Radboud University Medical Center, Radboudumc Alzheimer Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
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Affiliation as printed
Alzheimer Center Erasmus MC and Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
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Amsterdam University Medical Centers · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Pathology, Amsterdam University Medical Centers Location VUmc, Amsterdam, The Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Alzheimer Center and Department of Neurology Amsterdam, Department of Neurology, Neuroscience Campus Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Alzheimer Center and Department of Neurology Amsterdam, Department of Neurology, Neuroscience Campus Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Alzheimer Center and Department of Neurology Amsterdam, Department of Neurology, Neuroscience Campus Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Charlotte Elisabeth Teunissen corresponding
Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. c.teunissen@amsterdamumc.nl
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Vrije Universiteit Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
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