Mark M Kushnir1,2, Wojciech Michno3, Alan L Rockwood4, Kaj Blennow3,5, Frederick G Strathmann6, Jörg Hanrieder3,7,8. 1. ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA. 2. Department of Pathology, University of Utah, Salt Lake City, UT, USA. 3. Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. 4. Rockwood Scientific Consulting, Salt Lake City, UT, USA. 5. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 6. NMS Labs, Willow Grove, PA, USA. 7. Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Gothenburg, Sweden. 8. Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, United Kingdom.
Abstract
BACKGROUND: Parathyroid hormone-related protein (PTHrP) is involved in intracellular calcium regulation, neural cell proliferation and synaptic transmission. To date, no studies have been performed to evaluate the potential of PTHrP concentrations in cerebrospinal fluid (CSF) as a biomarker of brain pathophysiology. In this study we evaluated the association between CSF concentrations of PTHrP with the core CSF biomarkers of Alzheimer's disease (AD). METHODS: PTHrP and calcium were analysed using validated mass spectrometry based methods in a set of CSF samples that tested positive (n = 45) and negative (n = 45) for the AD biomarkers, including total tau protein (T-tau), phosphorylated tau protein (P-tau) and amyloid-β 42 (Aβ42). The measured CSF concentrations of PTHrP and calcium (Ca) were evaluated for association with AD CSF biomarkers. RESULTS: PTHrP and Ca concentrations in CSF samples ranged between 25 and 137 pmol/L and 0.92-1.53 mmol/L, respectively. Higher concentrations of PTHrP were observed in association with increased concentrations of T-tau and P-tau in the AD and the control group; while a stronger correlation was observed in the control group (ρ = 0.6, p < 0.0001; and ρ = 0.72, p < 0.0001, for T-tau and P-tau, respectively). Negative correlation was observed between concentrations of PTHrP and Aβ42 in the AD group (ρ = 0.27, p = 0.015). A statistically significantly lower ratio Aβ42/PTHrP was observed in the AD group (p < 0.0001). CONCLUSION: In the current study, we observed an association of PTHrP concentrations with concentrations of clinically used CSF biomarkers of AD. Concentrations of PTHrP were positively correlated with concentrations of T-tau and P-tau, suggesting an association with neuronal secretion and function, which is reduced upon progression to AD pathology. Our data suggest potential utility of the Aβ42/PTHrP ratio in assessment of AD progression.
BACKGROUND: Parathyroid hormone-related protein (PTHrP) is involved in intracellular calcium regulation, neural cell proliferation and synaptic transmission. To date, no studies have been performed to evaluate the potential of PTHrP concentrations in cerebrospinal fluid (CSF) as a biomarker of brain pathophysiology. In this study we evaluated the association between CSF concentrations of PTHrP with the core CSF biomarkers of Alzheimer's disease (AD). METHODS: PTHrP and calcium were analysed using validated mass spectrometry based methods in a set of CSF samples that tested positive (n = 45) and negative (n = 45) for the AD biomarkers, including total tau protein (T-tau), phosphorylated tau protein (P-tau) and amyloid-β 42 (Aβ42). The measured CSF concentrations of PTHrP and calcium (Ca) were evaluated for association with AD CSF biomarkers. RESULTS: PTHrP and Ca concentrations in CSF samples ranged between 25 and 137 pmol/L and 0.92-1.53 mmol/L, respectively. Higher concentrations of PTHrP were observed in association with increased concentrations of T-tau and P-tau in the AD and the control group; while a stronger correlation was observed in the control group (ρ = 0.6, p < 0.0001; and ρ = 0.72, p < 0.0001, for T-tau and P-tau, respectively). Negative correlation was observed between concentrations of PTHrP and Aβ42 in the AD group (ρ = 0.27, p = 0.015). A statistically significantly lower ratio Aβ42/PTHrP was observed in the AD group (p < 0.0001). CONCLUSION: In the current study, we observed an association of PTHrP concentrations with concentrations of clinically used CSF biomarkers of AD. Concentrations of PTHrP were positively correlated with concentrations of T-tau and P-tau, suggesting an association with neuronal secretion and function, which is reduced upon progression to AD pathology. Our data suggest potential utility of the Aβ42/PTHrP ratio in assessment of AD progression.
Keywords:
15N PTHrP, parathyroid hormone related protein containing isotopically labelled nitrogen; AD, Alzheimer’s disease; Alzheimer’s disease; Aβ42, β-Amyloid; Beta-amyloid; CNS, central nervous system; CSF, cerebrospinal fluid; Ca, calcium; ICP-MS, inductively coupled plasma mass spectrometry; LC-MS/MS, liquid chromatography tandem mass spectrometry; LP, lumbar puncture; MS, mass spectrometry; Mass spectrometry; P-tau, phosphorylated tau protein; PTH, parathyroid hormone; PTHrP; PTHrP, parathyroid hormone-related protein; Parathyroid hormone-related protein; Phosphorylated tau protein; RIA, radioimmunoassay; T-tau, total tau protein; Tau protein
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