title: Progranulin as a candidate biomarker for therapeutic trial in patients with ALS and FTLD.
abstract: The loss-of-function mechanism in progranulin (PGRN) mutation carriers makes PGRN an interesting target for upregulation as a therapeutic approach in neurodegenerative diseases like frontotemporal lobar degeneration. This gives rise to several questions: (1) how stable are PGRN levels in blood and cerebrospinal fluid (CSF) in follow-up? (2) Is it necessary to measure PGRN levels in CSF to monitor a therapeutic effect? Therefore, concentrations of PGRN were measured in paired CSF and serum samples of 22 patients with behavioural variant frontotemporal dementia, including one GRN mutation carrier (c.349+1G>C), 16 patients with amyotrophic lateral sclerosis and 17 non-neurodegenerative patients, which included 22 follow-up levels. PGRN levels of 14 patients with isolated dysfunction of the blood-CSF barrier were measured and PGRN was correlated with albumin quotients as a marker for blood-CSF barrier function. The intrathecal fraction of PGRN was calculated on the basis of CSF-to-serum ratios and hydrodynamic properties. Follow-up measurements of CSF and serum PGRN levels did not show any significant change in diagnostic groups. Mean PGRN levels are 35 times higher in blood than in CSF. However, the CSF-to-serum PGRN ratio does not correlate with the albumin quotient even in patients with severe impairment of the blood-CSF barrier. The calculated intrathecal fraction of CSF PGRN levels ranged between 80 and 90 %. Assuming that CSF PGRN is either brain-derived or transported from the vascular compartment via receptor mediated mechanisms, we propose that monitoring CNS specific effects of PGRN modulating drugs should be done in CSF.
authors.affiliation: Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Emily
authors.initials: E
authors.lastname: Feneberg
authors.affiliation: Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Steinacker
authors.affiliation: Department of Human Genetics, University of Hamburg, Hamburg, Germany.
authors.forename: Alexander Erich
authors.initials: AE
authors.lastname: Volk
authors.affiliation: Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Jochen Hans
authors.initials: JH
authors.lastname: Weishaupt
authors.affiliation: Department of Gerontopsychiatry, Asklepios Klinik Nord, Hamburg, Germany.
authors.forename: Marc Axel
authors.initials: MA
authors.lastname: Wollmer
authors.affiliation: Department of Neurology, University of California San Francisco School of Medicine, San Francisco, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Boxer
authors.affiliation: Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Tumani
authors.affiliation: Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Albert Christian
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany. markus.otto@uni-ulm.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077153:Progranulins
chemical_list: D015415:Biomarkers; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
keywords: Amyotrophic lateral sclerosis; Biomarker; Cerebrospinal fluid; Frontotemporal dementia; Progranulin