Kepe, V. et al. Serotonin 1A receptors in the living brain of Alzheimer's disease patients. Proc. Natl Acad. Sci. USA 103, 702-707

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2006; 103(3):702-7. DOI: 10.1073/pnas.0510237103
Source: PubMed


4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT(1A)) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT(1A) receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 +/- 0.07; ADs 1.18 +/- 0.26) and also in raphe nuclei (controls 0.63 +/- 0.09; ADs 0.37 +/- 0.20). When volume losses are included, 5-HT(1A) losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT(1A) receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT(1A) receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 +/- 0.04, ADs 0.72 +/- 0.04; posterior cingulate gyrus: controls 1.05 +/- 0.09, ADs 0.79 +/- 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.

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Available from: Kooresh Shoghi, Aug 12, 2014
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    • "The importance of 5-HT is further highlighted by the association between deregulation of serotonergic signalling and pathogenesis of various diseases ranging from psychiatric and neurological disorders, such as depression (Coppen 1967, Artigas et al. 1996) and Alzheimer's disease (AD) (Tohgi et al. 1992, Kepe et al. 2006), to functional and inflammatory disorders of the GI tract, such as irritable bowel syndrome (IBS) (Bearcroft et al. 1998, Coates et al. 2004, Spiller 2007) and inflammatory bowel disease (IBD) (Bishop et al. 1987, El-Salhy et al. 1997, Coates et al. 2004, Khan & Ghia 2010). Here, we review how 5-HT signalling modulates various biological functions, with a particular focus on its contribution in immune responses and inflam- mation. "
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    ABSTRACT: Serotonin or 5- hydoxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS), and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut; as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as “5-HT,” “EC cell,” “immune cells,” and “inflammation” in pubmed. gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation.This article is protected by copyright. All rights reserved.
    Acta Physiologica 11/2014; 213(3). DOI:10.1111/apha.12430 · 4.38 Impact Factor
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    • "In a former study by Kepe et al. (2006), researchers used FDG- PET combined with a selective 5-HT 1A receptor molecular imaging probe and indeed observed a significant decrease of 5-HT 1A receptor binding densities in the hippocampus of AD patients which strongly correlated with worsening of clinical symptoms (as measured by the MMSE scores) (R ¼ þ0.670, p ¼ 0.002, n ¼ 8). In this respect, pharmacotherapies enhancing the serotonergic neurotransmission, such as the administration of selective serotonin reuptake inhibitors and/or selective serotonin reuptake inhibitors combined with acetylcholinesterase inhibitors, demonstrated to effectively improve activities of daily living and global functioning in AD patients (Mowla et al., 2007; Taragano et al., 1997). "
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    ABSTRACT: Background: Depression and aggression in Alzheimer’s disease (AD) are two of the most severe and prominent neuropsychiatric symptoms (NPS). Altered monoaminergic neurotransmitter system functioning has been implicated in both NPS, although their neurochemical etiology remains to be elucidated. Methods: Left frozen hemispheres of 40 neuropathologically confirmed AD patients were regionally dissected. Dichotomization based on depression/aggression scores resulted in depressed/nondepressed (AD+D/-D) and aggressive/nonaggressive (AD+Agr/-Agr) groups. Concentrations of dopamine, serotonin (5-HT), (nor)epinephrine ((N)E) and respective metabolites were determined using RP-HPLC. Results: Significantly lower 3-methoxy-4-hydroxyphenylglycol (MHPG) and higher homovanillic acid levels were observed in Brodmann area (BA) 9 and 10 of AD+D compared to AD-D. In AD+Agr, 5-hydroxy-3-indoleacetic acid (5-HIAA) levels in BA9, 5-HIAA/5-HT ratios in BA11, and MHPG, NE, and 5-HIAA levels in hippocampus were significantly decreased compared to AD-Agr. Conclusions: These findings indicate that brain region-specific altered monoamines and metabolites may contribute to the occurrence of depression and aggression in AD.
    Neurobiology of Aging 05/2014; 35(12):2691-2700. DOI:10.1016/j.neurobiolaging.2014.05.031 · 5.01 Impact Factor
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    • "Numerous studies have confirmed that a reduced serotonergic neurotransmission impairs learning and memory function, whereas an increased serotonergic neurotransmission is associated with an improved cognitive and behavioral performance , not only in rodents, but also in humans with or without dementia [59]. Using FDG-PET combined with a selective 5-HT 1A receptor molecular imaging probe, Kepe et al. [60] indeed observed a significant decrease of 5-HT 1A receptor binding densities in the hippocampus of AD patients which strongly correlated with worsening of clinical symptoms (as measured by the MMSE scores) (R = +0.670; p = 0.002; n = 8). "
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    ABSTRACT: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are present during the disease course of nearly all AD patients and consist of psychosis, agitation/aggression, and depression, among others. Given their detrimental consequences regarding life expectancy, cognition, and socio-economic costs, it is essential to elucidate their neurochemical etiology to facilitate the development of novel and effective pharmacotherapeutics. This study attempted to identify brain region-specific monoaminergic correlates of NPS by measuring the levels of eight monoamines and metabolites in nine relevant postmortem brain regions of 40 behaviorally characterized AD patients, i.e., dopamine (DA), serotonin (5-HT), (nor)epinephrine and their respective metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid, 5-hydroxy-3-indoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), using RP-HPLC-ECD. Likewise, Mini-Mental State Examination (MMSE) score correlates of monoaminergic neurotransmitter alterations were calculated. As a result, MMSE scores, used as a measure of dementia severity, correlated positively with hippocampal 5-HIAA levels as well as with 5-HT levels of the superior temporal gyrus and cerebellar cortex. Furthermore, hippocampal 5-HIAA levels inversely correlated with agitation scores, whereas thalamic MHPG levels comparably did with the presence of hallucinations. Finally, in the cerebellar cortex, DOPAC/DA ratios, indicative of DA turnover, correlated with physically agitated behavior while MHPG levels correlated with affective disturbances. These findings support the assumption that specific NPS features in AD might be (in)directly related to brain region-specific monoaminergic neurotransmitter alterations. Additionally, the effect of AD pathology on neurochemical alterations in the cerebellum requires further examination due to its important but underestimated role in the neurochemical pathophysiology of NPS in AD.
    Journal of Alzheimer's disease: JAD 02/2014; 41(3):819-833. DOI:10.3233/JAD-140309 · 4.15 Impact Factor
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