Affiliations: [a] Department of Neurology and Memory Clinic, Middelheim and Hoge Beuken General Hospitals (ZNA), Antwerpen, Belgium | [b] Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium | [c] Neurodegenerative Brain Diseases Group, Department of Molecular Genetics/, VIB, Antwerpen, Belgium | [d] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium | [e] Department of Health Care Sciences, Artesis University College, Antwerpen, Belgium | [f] Faculty of Medicine and Health Sciences, Department of Nursing and Midwifery Sciences, University of Antwerp, Antwerpen, Belgium
Correspondence:
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Correspondence to: Prof. Dr. P.P. De Deyn, Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerp, Belgium. Tel.: +32 3 265 26 20; Fax: +32 3 265 26 18; E-mail: [email protected].
Abstract: A prospective, longitudinal study was set up to investigate possible genetic associations of behavioral and psychological signs and symptoms of dementia (BPSD) in Alzheimer's disease (AD) with two candidate genes in the serotonergic neurotransmitter pathway: serotonin transporter (SLC6A4) and brain-specific tryptophan hydroxylase (TPH2). Patients with probable AD (n = 249) were diagnosed according to NINCDS/ADRDA criteria. During follow-up, autopsy-confirmation of clinical diagnosis was obtained in 32 AD patients. Taking into account follow-up behavioral assessments by means of validated behavioral assessment scales (Middelheim Frontality Score and Behave-AD), behavioral ratings reflecting the highest scores on any behavioral item ever observed since dementia onset were calculated and applied for statistical analyses. A functional insertion/deletion polymorphism in the promoter region of SLC6A4 (5-HTTLPR) and 10 selected SNPs within TPH2 were genotyped. Single-marker allelic association analyses (TPH2, 5-HTTLPR) were performed. TPH2 allelic analyses revealed significant associations with frontal lobe symptoms, as well as with diurnal rhythm disturbances. 5-HTTLPR S allele carriers had an increased risk to display loss of insight and judgment, another frontal lobe symptom. The present prospective, longitudinal study showed that mainly frontal lobe symptoms were significantly associated with TPH2 and 5-HTTLPR polymorphisms, pointing toward a role of the serotonergic neurotransmitter system in the pathophysiology of frontal lobe symptoms in AD.
Keywords: Alzheimer's disease, behavior, behavioral and psychological signs and symptoms of dementia (BPSD), dementia, serotonin, TPH2
