Elsevier

Neurobiology of Aging

Volume 24, Issue 4, July–August 2003, Pages 553-561
Neurobiology of Aging

Imaging of the 5-HT2A system: age-, gender-, and Alzheimer’s disease-related findings

https://doi.org/10.1016/S0197-4580(02)00137-9Get rights and content

Abstract

Serotonin (5-HT) and more specifically the 5-HT2A receptor is involved in cognitive and non-cognitive behavior and plays an important role in Alzheimer’s disease (AD). The objective was to assess the 5-HT2A binding potential (BP) in healthy volunteers and AD with SPECT and 123I-5-I-R91150, a selective radio-iodinated 5-HT2A receptor antagonist. Twenty-six controls and nine AD patients were included. A semiquantitive analysis with normalization on cerebellar uptake provided estimates of BP for 26 cortical regions of interest. An age-related decline of neocortical BP was found (11.6% per decade). Compared to age-matched controls, a generally decreased neocortical BP in AD was found with a significant regional reduction in the orbitofrontal, prefrontal, lateral frontal, cingulate, sensorimotor, parietal inferior, and occipital region. These results are in line with previous postmortem, in vitro, and PET findings. The age-related decline highlights the necessity for matched advanced age study samples. The fact that the 5-HT2A receptor is differentially affected in AD patients has implications for both the etiological basis and therapeutic management of AD.

Introduction

Approximately 90% of the total body amount of serotonin (5-HT) acts in the gastrointestinal system. Only 1–2% is present in the central nervous system where 5-HT receptors are generally involved in sleep, pain, behavior, learning, and memory [5], [10]. More specifically, serotonin type 2A (5-HT2A) receptors have been implicated in several brain functions, such as appetite control, sexuality, thermoregulation, and sustained attention and play an important role in the pathophysiology of mood, depressive, anxiety, and psychotic disorders, schizophrenia, aging and also Alzheimer’s disease (AD) [2], [5], [9], [18], [30], [31], [42].

AD, the most common form of dementia, is typically characterized by progressive impairment of recent memory. However, in the course of AD, other cognitive dysfunctions, behavioral and psychiatric symptoms emerge and become at least equally important [21]. The role of the 5-HT2A receptor in AD is manifold. Firstly, the 5-HT2A receptor has been suggested to play a role in the amyloid precursor protein secretion. Since this is linked to the β-amyloid fibrillogenesis, this could eventually lead to the subsequent formation of amyloid plaques, typically seen in AD [24], [25], [35], [36]. Second, several genetic associations between 5-HT2A receptor polymorphisms and the AD symptomatology, e.g. visual or auditory hallucinations have been reported [23], [34]. Third, 5-HT has a role in natural immunity in general, and more specifically in the superoxide production, phagocytosis, and the optimal accessory cell function of macrophages for natural killer and T-cells, which could eventually influence the removal of amyloid plaques [32]. Moreover, the cerebral availability of plasma tryptophan, the precursor of 5-HT, decreases with activation of the immune system, the latter believed to be upregulated in AD [1], [8]. Finally, a decrease in serotonergic cells in the central nervous system could eventually lead to a disturbance of functional interactions between the serotonergic on one hand and the cholinergic or dopaminergic system on the other hand [16], [19], [40], [44].

123I radiolabeled R91150 is a radio-iodinated 5-HT2A receptor antagonist with high affinity (KD=0.11±0.01 nM). The selectivity of this ligand for 5-HT2A receptors as compared to other neurotransmitter receptor binding sites such as 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C, 5-HT3, dopamine D2 receptors, α1 and α2 adrenoreceptors and histamine H1 receptors, is at least a factor of 50. 123I-5-I-R91150 binding is saturable and displaceable with the known 5-HT2A receptor antagonist ketanserin and proved suitable for the imaging of 5-HT2A receptors with single photon emission computed tomography (SPECT) in the human brain [11].

The objectives of the present study were, firstly, to study the age and gender effect of the 5-HT2A receptor binding potential (BP) in a large group of healthy subjects (n=26) with an age range of 22–85 years and, second, to determine whether there are abnormalities in the 5-HT2A receptor BP in AD patients compared to age-matched healthy controls, and if so, whether these abnormalities are correlated with cognitive defects or depressive symptomatology.

Section snippets

Patients

The study was approved by the medical ethics committee of the Ghent University Hospital and all patients gave informed (proxy-)consent. Nine AD patients (two males, mean age 81±6 years, range 73–88 years) according to the NINCDS-ADRDA criteria were included with the diagnosis made by a board-certified neurologist [27]. The diagnosis was supported by the fact that there was evidence of cerebral atrophy on computed tomography or magnetic resonance imaging in all AD patients and by the fact that

Results

Age, sex, GDS, MMSE-score, and cognitive deficits of the AD patients are presented in Table 1.

Discussion

The present findings concerning age dependency of 5-HT2A receptor density are in agreement with previous ex vivo distribution studies demonstrating a general decrease in cortical 5-HT and more specifically 5-HT2A receptor density [39]. This decline is also consistent with clinical observations of age-related changes in behaviors such as sleep or executive functioning, known to be linked to serotonergic function [15], [33]. Moreover, peak minus baseline prolactin responses to fenfluramine (a

Acknowledgements

This work was financially supported by the “Internationale stichting Alzheimer onderzoek.” The authors wish to thank Nuclear Diagnostics and SUN Microsystems for their technical support in the Division of Nuclear Medicine of the Ghent University Hospital.

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