Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer’s Disease

Article type: Research Article

Authors: Vermeiren, Yannick^{a; b; 1} | Janssens, Jana^{a; b; 1} | Aerts, Tony^a | Martin, Jean-Jacques^d | Sieben, Anne^{d; e} | Van Dam, Debby^{a; b} | De Deyn, Peter P.^{a; b; c; d; *}

Affiliations: [a] Department of Biomedical Sciences, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Wilrijk (Antwerp), Belgium | [b] Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen (UMCG), Groningen, The Netherlands | [c] Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium | [d] Biobank, Institute Born-Bunge, University of Antwerp, Wilrijk (Antwerp), Belgium | [e] Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium

Correspondence: [*] Correspondence to: Prof. Dr. Peter P. De Deyn, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, BE-2610 Wilrijk (Antwerp), Belgium. Tel.: +32 3 2652620; Fax: +32 3 2652618; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer’s disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) 6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α1/2/β1-blockers, seem to have a rationale and should be considered.

Keywords: Alzheimer’s disease, brain tissue, frontotemporal dementia, monoamines, neurochemistry, neuropsychiatric symptoms, noradrenaline, prefrontal cortex, RP-HPLC-ECD, serotonin

DOI: 10.3233/JAD-160320

Journal: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1079-1096, 2016