Serum MHPG Strongly Predicts Conversion to Alzheimer's Disease in Behaviorally Characterized Subjects with Down Syndrome

Article type: Research Article

Authors: Dekker, Alain D.^{a; b} | Coppus, Antonia M.W.^{c; d; e} | Vermeiren, Yannick^b | Aerts, Tony^b | van Duijn, Cornelia M.^d | Kremer, Berry P.^a | Naudé, Pieter J.W.^a | Van Dam, Debby^b | De Deyn, Peter P.^{a; b; *}

Affiliations: [a] Department of Neurology and Alzheimer Research Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands | [b] Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Wilrijk, Antwerp, Belgium | [c] Dichterbij, Center for the Intellectually Disabled, Gennep, The Netherlands | [d] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands | [e] Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, The Netherlands

Correspondence: [*] Correspondence to: Dr. Peter P. De Deyn, Department of Neurology and Alzheimer Research Center, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Tel.: +31 50 361 4650; E-mail: p.p.de.deyn@umcg.nl.

Abstract: Background:Down syndrome (DS) is the most prevalent genetic cause of intellectual disability. Early-onset Alzheimer's disease (AD) frequently develops in DS and is characterized by progressive memory loss and behavioral and psychological signs and symptoms of dementia (BPSD). Predicting and monitoring the progression of AD in DS is necessary to enable adaptive caretaking. Objective:Reliable blood biomarkers that aid the prediction of AD are necessary, since cerebrospinal fluid sampling is rather burdensome, particularly for people with DS. Here, we investigate serum levels of eight biogenic amines and their metabolites in relation to dementia staging and probable BPSD items. Methods:Using RP-HPLC with electrochemical detection, (nor)adrenergic (NA/A and MHPG), serotonergic (5-HT and 5-HIAA), and dopaminergic (DA, HVA, and DOPAC) compounds were quantified in the serum of DS subjects with established AD at baseline (n = 51), DS subjects without AD (n = 50), non-demented DS individuals that converted to AD over time (n = 50), and, finally, healthy non-DS controls (n = 22). Results:Serum MHPG levels were significantly lower in demented and converted DS subjects (p < 0.0001) compared to non-demented DS individuals and healthy controls. Those subjects with MHPG levels below median had a more than tenfold increased risk of developing dementia. Furthermore, significant correlations were observed between monoaminergic serum values and various probable BPSD items within each DS group. Conclusion:Decreased serum MHPG levels show great potential as biomarker to monitor and predict conversion to AD in DS. Moreover, significant monoaminergic alterations related to probable BPSD items, suggesting that monoaminergic dysregulation is an underlying biological mechanism, and demonstrating the need to develop a validated rating scale for BPSD in DS.

Keywords: Alzheimer's disease, behavioral and psychological signs and symptoms of dementia (BPSD), biogenic amines, biomarkers, Down syndrome, MHPG, RP-HPLC

DOI: 10.3233/JAD-140783

Journal: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 871-891, 2015