Serum and Cerebrospinal Fluid Levels of Transthyretin in Lewy Body Disorders with and without Dementia

Walter Maetzler,Benjamin Schmid,Daniela Berg,Christian Deuschle,Stephanie Maria Baur,Tina Gauger,Claudia Schulte,Anja Apel,Arthur Melms,Youyong Tian,Susanna Heck,Thomas Gasser,Bartholomäus Odoj

doi:10.1371/journal.pone.0048042

Abstract

Parkinson’s disease (PD) without (non-demented, PDND) and with dementia (PDD), and dementia with Lewy bodies (DLB) are subsumed under the umbrella term Lewy body disorders (LBD). The main component of the underlying pathologic substrate, i.e. Lewy bodies and Lewy neurites, is misfolded alpha-synuclein (Asyn), and - in particular in demented LBD patients - co-occurring misfolded amyloid-beta (Abeta). Lowered blood and cerebrospinal fluid (CSF) levels of transthyretin (TTR) - a clearance protein mainly produced in the liver and, autonomously, in the choroid plexus - are associated with Abeta accumulation in Alzheimer’s disease. In addition, a recent study suggests that TTR is involved in Asyn clearance. We measured TTR protein levels in serum and cerebrospinal fluid of 131 LBD patients (77 PDND, 26 PDD, and 28 DLB) and 72 controls, and compared TTR levels with demographic and clinical data as well as neurodegenerative markers in the CSF. Five single nucleotide polymorphisms of the TTR gene which are considered to influence the ability of the protein to carry its ligands were also analyzed. CSF TTR levels were significantly higher in LBD patients compared to controls. Post-hoc analysis demonstrated that this effect was driven by PDND patients. In addition, CSF TTR levels correlated negatively with CSF Abeta1–42, total tau and phospho-tau levels. Serum TTR levels did not significantly differ among the studied groups. There were no relevant associations between TTR levels and genetic, demographic and clinical data, respectively. These results suggest an involvement of the clearance protein TTR in LBD pathophysiology, and should motivate to elucidate TTR-related mechanisms in LBD in more detail.

Highlights

The term ‘‘Lewy body disorders (LBD)’’ subsumes the three entities Parkinson’s disease (PD) without dementia (PDND), PD with dementia (PDD), and dementia with Lewy bodies (DLB) [1]
In this study investigating TTR values in blood and cerebrospinal fluid (CSF) of LBD patients, CSF TTR levels were significantly higher in this cohort of patients compared to controls
The effect was mainly driven by non-demented LBD patients, explaining, as a diagnosis, approximately 7 percent of the variation in the CSF TTR levels

Summary

Introduction

The term ‘‘Lewy body disorders (LBD)’’ subsumes the three entities Parkinson’s disease (PD) without dementia (PDND), PD with dementia (PDD), and dementia with Lewy bodies (DLB) [1]. In LBD, alpha-synuclein (Asyn)-positive Lewy bodies (LB) and Lewy neurites occur together with neurodegeneration [2]. Co-occurrence of amyloid-beta (Abeta) deposits with Asyn pathology is common, in LBD patients with dementia [3,4]. It is widely accepted that an Abeta production higher than its removal results in an enhanced presence of Abeta monomers, oligomers, insoluble fibrils and plaques in the central nervous system [5]. Similar mechanisms may lead to Asyn accumulation, at least for late onset PD there is less evidence for this hypothesis [16]

Methods

Results

Conclusion