Altered Brain Serotonin Transporter and Associated Glucose Metabolism in Alzheimer Disease

Abstract

Whether preclinical depression is one of the pathophysiologic features of Alzheimer disease (AD) has been under debate. In vivo molecular imaging helps clarify this kind of issue. Here, we examined in vivo changes in the brain serotoninergic system and glucose metabolism by scanning early-to moderate-stage AD patients with and without depression using PET with a radiotracer for the serotonin transporter, 11 C-3-amino-4-(2-dimethylaminomethylphenylsulfanyl) benzonitrile (DASB), and a metabolic marker, 18 F-FDG. Methods: Fifteen AD patients (8 nondepressed and 7 depressed) and 10 healthy subjects participated. All participants underwent 3-dimensional MRI and quantitative 11 C-DASB PET measurements, followed by 18 F-FDG PET scans in the AD group. Region-of-interest analysis was used to examine changes in 11 C-DASB binding potential estimated quantitatively by the Logan plot method in the serotonergic projection region. In addition, statistical parametric mapping was used to examine whether glucose metabolism in any brain region correlated with levels of 11 C-DASB binding in the dense serotonergic projection region (striatum) in AD. Results: Psychologic evaluation showed that general cognitive function (Mini-Mental State Examination) was similar between the 2 AD subgroups. Striatal 11 C-DASB binding was significantly lower in AD patients, irrespective of depression, than in healthy controls (P , 0.05, corrected), and 11 C-DASB binding in other dense projection areas decreased significantly in the depressive group, compared with the control group. The 11 C-DASB binding potential levels in the subcortical serotonergic projection region correlated negatively with depression score (Spearman correlation, P , 0.01) but not with dementia score. Statistical parametric mapping correlation analysis showed that glucose metabolism in the right dorsolateral prefrontal cortex was positively associated with the level of striatal 11 C-DASB binding in AD. Conclusion: The significant reduction in 11 C-DASB binding in nondepressed AD patients suggests that presynaptic serotonergic function is altered before the development of psychiatric problems such as depression in AD. The depressive AD group showed greater and broader reductions in binding, suggesting that a greater loss of serotonergic function relates to more severe psychiatric symptoms in the disease. This serotonergic dysfunction may affect the activity of the right dorsolateral prefrontal cortex, a higher center of cognition and emotion in AD. Al zheimer disease (AD) is a neurodegenerative disorder with progressive memory and cognitive deterioration followed by or concomitant with psychologic problems such as depression and hallucination, which have a strong negative impact on the course of the disease. The occurrence of these psychologic disturbances has been reported to closely relate to disruption of the serotonergic system (1). Loss of neurons in the serotonergic raphe nuclei (2) and dysfunction of its nerve terminals in the neocortex (3) have been reported in AD. Many li...

Indole compounds in fruiting bodies of some edible Basidiomycota species

“…However, the high level of serotonin is notable. Although the therapeutic value of serotonin is well known, and recently extended by its antioxidant actions and by its ability to prevent the progress of Alzheimer's disease (Ouchi et al, 2009;Baran, Jellinger, & Deecke, 1999), the high contents of this compound, observed in the present study, suggest that the continuation of the research on the accumulation of indole compounds in edible mushroom species is justified. In vitro cultures of interesting species can be helpful for evaluating the accumulation of these compounds in mushrooms, which we demonstrated in some preliminary studies on Tricholoma equestre and Xerocomus badius cultures (Muszyń ska et al, 2009).…”

Normative database of the serotonergic system in healthy subjects using multi-tracer PET

“…This system works in concert with various environmental and endogenous signals such as day light intensity and length and several hormones as cortisol , progesterone and dehydroepiandrosterone sulfate . Furthermore, it has shown an integral role in the pathophysiology of common neuropsychiatric disorders including major depression (Mann, 1999;Staley et al, 1998), bipolar disorder (Chee et al, 2001), obsessive compulsive disorder (Adams et al, 2005), anxiety disorders (Akimova et al, 2009;Lanzenberger et al, 2007;van der Wee et al, 2008), post-traumatic stress disorder (Davis et al, 1997;Murrough et al, 2011aMurrough et al, , 2011b, eating disorders (Bailer et al, 2005;Mayer and Walsh, 1998), sleep disturbance (Portas et al, 1998), attention deficit hyperactivity disorder (Quist et al, 2003), drug addiction (Carey et al, 2005;Muller et al, 2007), suicidal behavior (Mann, 1999), schizophrenia (Abi-Dargham, 2007;Aghajanian and Marek, 2000;Hurlemann et al, 2005;Hurlemann et al, 2008), Alzheimer (Ouchi et al, 2009), migraine (Panconesi, 2008) and epilepsy (Assem-Hilger et al, 2010).…”

Effects of Brain Amyloid Deposition and Reduced Glucose Metabolism on the Default Mode of Brain Function in Normal Aging

“…Nine 1 min PET scans for rCBF were performed under various conditions, as shown in Figure 1 B O-PET images from each participant were individually adjusted for mean image (normalized rCBF) (Ouchi et al, 2001). To evaluate glucose metabolism, a semiquantitative ratio index of [ 18 F]FDG was calculated as standardized uptake value ratio (SUVR) (Ouchi et al, 2009 (Nelissen et al, 2007), and smoothed with a 8 ϫ 8 ϫ 8 mm Gaussian kernel using SPM8 (Wellcome Department of Cognitive Neurology, http://www.fil.ion.ucl. ac.uk/spm/software/spm8/).…”