Monoaminergic and Kynurenergic Characterization of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Cerebrospinal Fluid and Serum

Jana Janssens,Ido P Kema,Martijn Van Faassen,Yannick Vermeiren,Peter P De Deyn,Claude Van Der Ley

doi:10.1007/s11064-020-03002-5

Abstract

Exploring the neurochemical continuum between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) with respect to monoamines and kynurenines in cerebrospinal fluid (CSF) and serum, may be useful to identify possible new research/therapeutic targets. Hence, we analysed monoamines and kynurenines in CSF and serum derived from patients with FTD (n = 39), ALS (n = 23), FTD-ALS (n = 4) and age-matched control subjects (n = 26), using reversed-phase ultra-high performance liquid chromatography (RP-UHPLC) with electrochemical detection (ECD) and liquid chromatography tandem mass spectrometry, respectively. We noted a shared dopaminergic disturbance in FTD and ALS when compared to CONTR, with significantly increased serum DA levels and decreased DOPAC concentrations, as well as decreased DOPAC/DA ratios in both disease groups. In CSF, significantly reduced DOPAC concentrations in FTD and ALS were observed as well. Here, a significant increase in DA levels and decrease in DOPAC/DA ratios was only found in FTD relative to CONTR. With respect to the kynurenine pathway (KP), we only found decreased HK/XA ratios, indicative for vitamin B6 status, in serum of ALS subjects compared to FTD. The dopaminergic commonalities observed in FTD and ALS might relate to a disturbance of dopaminergic nerve terminals in projection areas of the substantia nigra and/or ventral tegmental area, although these findings should first be confirmed in brain tissue. Lastly, based on the results of this work, the KP does not hold promise as a research/therapeutic target in FTD and ALS.

Highlights

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders demonstrating genetic and neuropathologic overlap
A general dopaminergic disturbance was noted in FTD and ALS compared to control subjects (CONTR) subjects, largely corresponding to previous reports
Reduced uptake of 11C-2βcarbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT), a cocaine analogue targeting DA transporters (DAT), in the putamen of FTD subjects was observed in another study [37]

Summary

Introduction

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders demonstrating genetic and neuropathologic overlap. The most common shared genetic mutation is a GGGGCCexpansion in C9ORF72, present in approximately 30–47% [1, 2] and 25–34% [1, 3] of familial ALS and FTD cases, respectively This hexanucleotide expansion is most often associated with the presence of cytoplasmic inclusions containing transactive response DNA-binding protein of 43 kDa (TDP-43) in both diseases [4, 5]. These inclusions are found in up to 97% of ALS and 45% of FTD cases [6]. Behavioural abnormalities and/or signs of cognitive impairment including executive dysfunction, are observed in 50% of patients with ALS, while 15% of these

Methods

Results

Conclusion