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

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.

Keywords: Biomarker; Dementia; Neuropathology; Neurophysiology.

Fig. 1

Overview of neuropathological diagnoses in the FTD group. C9ORF72 chromosome 9 open reading frame 72, FTLD-U frontotemporal lobar degeneration with ubiquitin-positive inclusions, FTD frontotemporal dementia, GRN progranulin gene, TBK1 TANK-binding kinase 1, TDP-43 transactive response DNA-binding protein of 43 kDa, VCP valosin-containing protein

Fig. 2

Dopaminergic findings across diagnostic categories. Data are represented as box- and whisker plots with minimum–maximum ranges. Statistically significant differences after Mann–Whitney U tests with Benjamini–Hochberg post-hoc corrections are depicted by one, two or three asterisks if P ≤ 0.05, 0.001, or 0.0001, respectively. Sample sizes for CSF DOPAC are: CONTR: n = 26, FTD: n = 39, FTD-ALS: n = 4, ALS: n = 23, sample sizes for CSF DA and DOPAC/DA are CONTR: n = 21, FTD: n = 35, FTD-ALS: n = 2, ALS: n = 17. Sample sizes for serum DOPAC are: CONTR: n = 26, FTD: n = 39, FTD-ALS: n = 3, ALS: n = 20, sample sizes for serum DA and DOPAC/DA are: CONTR: n = 26, FTD: n = 35, FTD-ALS: n = 3, ALS: n = 20. The FTD-ALS group was not included in the statistical analysis. ALS amyotrophic lateral sclerosis, CONTR control, CSF cerebrospinal fluid, DA dopamine, DOPAC 3,4-dihydroxyphenylacetic acid, FTD frontotemporal dementia, FTD-ALS frontotemporal dementia—amyotrophic lateral sclerosis

Fig. 3

CSF HVA/DA ratios across diagnostic categories. Data are represented as box- and whisker plots with minimum–maximum ranges. Statistically significant differences after Mann–Whitney U analyses with Benjamini–Hochberg corrections are indicated by an asterisk (P < 0.05). Sample sizes for CSF HVA/DA are: CONTR: n = 21, FTD: n = 35, FTD-ALS: n = 2, ALS: n = 17. The FTD-ALS group was not included in the statistical analysis. ALS amyotrophic lateral sclerosis, CONTR control, CSF cerebrospinal fluid, DA dopamine, FTD frontotemporal dementia, FTD-ALS frontotemporal dementia-amyotrophic lateral sclerosis, HVA homovanillic acid

Fig. 4

CSF MHPG levels across diagnostic categories. Data are represented as box- and whisker plots with minimum–maximum ranges. Statistically significant differences after Mann–Whitney U analyses with Benjamini–Hochberg corrections are indicated by an asterisk (P < 0.05). Sample sizes for CSF MHPG are: CONTR: n = 26, FTD = 39, FTD-ALS: n = 4, ALS: n = 23. The FTD-ALS group was not included in the statistical analysis. ALS amyotrophic lateral sclerosis, CONTR control, CSF cerebrospinal fluid, FTD frontotemporal dementia, FTD-ALS frontotemporal dementia-amyotrophic lateral sclerosis, MHPG 3-methoxy-4-hydroxyphenylglycol

Fig. 5

The KP in CSF. Data are represented as box- and whisker plots with minimum–maximum ranges. Statistically significant differences after Mann–Whitney U analyses with Benjamini–Hochberg corrections are indicated by an asterisk (P < 0.05). Sample sizes for TRP are: CONTR: n = 23, FTD: n = 37, FTD-ALS: n = 4, ALS: n = 20, sample sizes for KYN are: CONTR: n = 21, FTD: n = 37, FTD-ALS: n = 4, ALS: n = 21, sample sizes for HK are: CONTR: n = 24, FTD: n = 36, FTD-ALS: n = 4, ALS: n = 21, sample sizes for KA are: CONTR: n = 25, FTD: n = 39, FTD-ALS: n = 4, ALS: n = 22, sample sizes for AA are: CONTR: n = 24, FTD: n = 39, FTD-ALS: n = 4, ALS: n = 22, sample sizes for XA are: CONTR: n = 17, FTD: n = 30, FTD-ALS: n = 3, ALS: n = 18, sample sizes for QA are: CONTR: n = 23, FTD: n = 37, FTD-ALS: n = 4, ALS: n = 21, sample sizes for PA are: CONTR: n = 24, FTD: n = 39, FTD-ALS: n = 4, ALS: n = 22, sample sizes for NA are: CONTR: n = 25, FTD: n = 39, FTD-ALS: n = 4, ALS: n = 22, sample sizes for KYN/TRP are: CONTR: n = 21, FTD: n = 35, FTD-ALS: n = 4, ALS: n = 20, sample sizes for HK/XA are: CONTR: n = 15, FTD: n = 30, FTD-ALS: n = 3, ALS: n = 18. AA anthranilic acid; ALS amyotrophic lateral sclerosis, CONTR control, CSF cerebrospinal fluid, FTD frontotemporal dementia, FTD-ALS frontotemporal dementia-amyotrophic lateral sclerosis, HK 3-hydroxykynurenine, KA kynurenic acid, KP kynurenine pathway, KYNl-kynurenine, NA nicotinic acid, PA picolinic acid, QA quinolinic acid, TRPl-tryptophan, XA xanthurenic acid

Fig. 6

The KP in serum. Data are represented as box- and whisker plots with minimum–maximum ranges. Statistically significant differences after Mann–Whitney U analyses with Benjamini–Hochberg corrections are indicated by an asterisk (P < 0.05). Sample sizes for TRP are: CONTR: n = 26, FTD: n = 39, FTD-ALS: n = 3, ALS: n = 20, sample sizes for KYN are: CONTR: n = 26, FTD: n = 39, FTD-ALS: n = 3, ALS: n = 20, sample sizes for HK are: CONTR: n = 24, FTD: n = 39, FTD-ALS: n = 3, ALS: n = 19, sample sizes for KA are: CONTR: n = 26, FTD: n = 39, FTD-ALS: n = 3, ALS: n = 20, sample sizes for AA are: CONTR: n = 26, FTD: n = 38, FTD-ALS: n = 3, ALS: n = 20, sample sizes for XA are: CONTR: n = 25, FTD: n = 39, FTD-ALS: n = 3, ALS: n = 20, sample sizes for QA are: CONTR: n = 25, FTD: n = 37, FTD-ALS: n = 3, ALS: n = 18, sample sizes for PA are: CONTR: n = 25, FTD: n = 39, FTD-ALS: n = 3, ALS: n = 20, sample sizes for NA are: CONTR: n = 24, FTD: n = 38, FTD-ALS: n = 3, ALS: n = 20, sample sizes for KYN/TRP are: CONTR: n = 26, FTD: n = 39, FTD-ALS: n = 3, ALS: n = 19, sample sizes for HK/XA are: CONTR: n = 22, FTD: n = 38, FTD-ALS: n = 3, ALS: n = 18