Cognitive decline in association with hyposmia in idiopathic rapid eye movement sleep behavior disorder: a prospective 2-year follow-up study.

BACKGROUND AND PURPOSE: The aim was to analyze the characteristics and progression of cognitive dysfunction in non-demented idiopathic rapid eye movement sleep behavior disorder (iRBD) patients with baseline olfactory function. METHODS: From a prospective polysomnography-confirmed iRBD cohort, 25 patients (16 patients in 2-year follow-up) and 13 normal controls were included. Initial and 2-year follow-up cognitive functions were analyzed with olfactory function and 18 F-fluorinated-N-3-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)-nortropane (18 F-FP-CIT) uptake in deep nuclei initially. RESULTS: Idiopathic RBD patients had impaired attention, memory and executive function compared to controls. Baseline cognitive tests were comparable between the iRBD subgroups with and without hyposmia. 18 F-FP-CIT uptake tended to be lower in the hyposmic group than in the normosmic group. The olfactory test score was positively correlated with amygdala uptake in iRBD patients (P = 0.027). After 2 years, visuospatial and verbal memory dysfunction worsened more in hyposmics than in normosmics. Lower initial olfactory test score was associated with more severe declines in verbal memory function. CONCLUSIONS: Hyposmia may be a predictive sign of cognitive decline in iRBD patients.

Altered serotonin transporter binding potential in patients with obsessive-compulsive disorder under escitalopram treatment: [11C]DASB PET study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic, relapsing mental illness. Selective serotonin reuptake inhibitors block serotonin transporters (SERTs) and are the mainstay of treatment for OCD. SERT abnormalities are reported in drug-free patients with OCD, but it is not known what happens to SERT levels during treatment. This is important as alterations in SERT levels in patients under treatment could underlie poor response, or relapse during or after treatment. The aim of the present study was first to validate a novel approach to measuring SERT levels in people taking treatment and then to investigate SERT binding potential (BP) using [11C]DASB PET in patients with OCD currently treated with escitalopram in comparison with healthy controls. METHOD: Twelve patients and age- and sex-matched healthy controls were enrolled. The patients and healthy controls underwent serial PET scans after administration of escitalopram and blood samples for drug concentrations were collected simultaneously with the scans. Drug-free BPs were obtained by using an inhibitory E max model we developed previously. RESULTS: The inhibitory E max model was able to accurately predict drug-free SERT BP in people taking drug treatment. The drug-free BP in patients with OCD currently treated with escitalopram was significantly different from those in healthy volunteers [Cohen's d = 0.03 (caudate), 1.16 (putamen), 1.46 (thalamus), -5.67 (dorsal raphe nucleus)]. CONCLUSIONS: This result extends previous findings showing SERT abnormalities in drug-free patients with OCD by indicating that altered SERT availability is seen in OCD despite treatment. This could account for poor response and the high risk of relapse in OCD.

Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[11C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy.

BACKGROUND AND PURPOSE: The development of resistance to antiepileptic drugs is explained well by the transporter hypothesis, which suggests that drug resistance is caused by inadequate penetration of drugs into the brain barrier as a result of increased levels of efflux transporter such as p-glycoprotein. To evaluate the brain expression of p-glycoprotein in patients with drug-resistant epilepsy, including neocortical epilepsy, we developed a noninvsive quantitative analysis including asymmetry indices based on (R)-[(11)C]-verapamil PET/MR imaging with cyclosporin A, a p-glycoprotein inhibitor. MATERIALS AND METHODS: Six patients with drug-resistant epilepsy, 5 patients with drug-sensitive epilepsy, and 8 healthy controls underwent dynamic (R)-[(11)C]-verapamil PET/MR imaging with an intravenous infusion of cyclosporin A. Asymmetry indices [(Right Region - Left Region)/(Right Region + Left Region) × 200%] of the standard uptake values in each of the paired lobes were calculated. RESULTS: All patients with drug-resistant epilepsy had significantly different asymmetry from the healthy controls, whereas all patients with drug-sensitive epilepsy had asymmetry similar to that in healthy controls. In the temporal lobe, the asymmetry indices of patients with left temporal lobe drug-resistant epilepsy were more positive than those of healthy controls (healthy controls: 4.0413 ± 1.7452; patients: 7.2184 ± 1.8237; P = .048), and those of patients with right temporal drug-resistant epilepsy were more negative (patients: -1.6496 ± 3.4136; P = .044). In addition, specific regions that had significant asymmetry were different between the lateral and medial temporal lobe epilepsy groups. In the frontal lobe, the asymmetry index of patients with right frontal lobe drug-resistant epilepsy was more negative than that in healthy controls. CONCLUSIONS: We confirmed that statistical parametric mapping analysis by using asymmetry indices of (R)-[(11)C]-verapamil PET/MR imaging with cyclosporin A could be used as a surrogate marker for drug-resistant epilepsy, and this approach might be helpful for localizing or lateralizing the epileptic zone.

Effect of probiotic-, bacteriophage-, or organic acid-supplemented feeds or fermented soybean meal on the growth performance, acute-phase response, and bacterial shedding of grower pigs challenged with Salmonella enterica serotype Typhimurium.

A 28-d experiment evaluated the growth performance, acute-phase response, and bacterial shedding patterns in pigs (n = 108; initially, 38.7 ± 6.7 kg) fed 6 treatment diets, including a control diet with no antimicrobial agents (CON), a positive control diet containing chlortetracycline, 100 mg/kg (CT), a diet containing anti-Salmonella Typhimurium bacteriophage, 3 × 10(9) plaque-forming units/kg of feed (ASB), Lactobacillus plantarum CJLP56, 6.5 × 10(8) cfu/kg of feed (LP), 0.2% microencapsulated organic acids (MOA), or 5% fermented soybean meal (FSM). Pigs were fed the diets for 2 wk before and 2 wk after challenging orally with Salmonella enterica serotype Typhimurium (SalT). Before bacterial challenge, ADFI was similar in all groups. After SalT challenge, ADFI of CON pigs was less (P < 0.05) than all other groups. Before challenge, pigs on MOA, FSM, and CT diets had greater (P < 0.05) ADG and G:F than CON pigs. After challenge (wk 3 to 4) and during the overall experimental period (wk 1 to 4), ADG of all treatment groups and G:F of all treatment groups except the LP group were greater (P < 0.05) than those of CON pigs. Relative to all other treatments, CON and LP pigs had greater (P < 0.05) bacterial shedding scores on d 7 after SalT challenge. At d 14 postchallenge, shedding scores declined (P < 0.05) in all treatment groups compared with CON pigs. Serum haptoglobin for all treatment groups increased from d 0 concentrations on d 6 postchallenge and declined to prechallenge concentrations on d 13 (P < 0.05). Circulating IGF-I concentrations declined from 2 to 6 d postchallenge and increased again by d 13 in ASB and LP groups, did not decline in FSM and CT groups, and continuously declined through d 13 in CON and LP groups (P < 0.05). However, in MOA group, IGF-I concentrations declined from preinfection concentrations on d 2, increased on d 4, and declined again until d 13 (P < 0.05). The serum concentrations of the cytokines IL-6 and IL-1ß were not generally affected by SalT challenge. In conclusion, acute infection of growing pigs with SalT was associated with short-term febrile responses in most pigs and reductions in ADFI and ADG of CON pigs. Compared with the CON diet, ASB, FSM, and MOA diets had a similar benefit to the antibiotic-supplemented diet in improving the performance of growing pigs, especially after bacterial challenge. However, further work needs to be done to better understand their mode of action in this class of pigs.

Protective effect of glutathione in HIV-1 lytic peptide 1-induced cell death in human neuronal cells.

To elucidate the pathogenic mechanisms involved in neurodegeneration in AIDS patients with cognitive deficits, we have examined the toxic effect of the lentivirus lytic peptide 1 (LLP-1) corresponding to the carboxyl terminus of HIV-1 transmembrane glycoprotein gp41 on human neuronal and glial cell lines. LLP-1 induced a significant lactate dehydrogenase (LDH, a marker of cell death) release from these cells in a concentration- and time-dependent manner, while the noncytolytic LLP-1 analog 2 had little effect. Application of LLP-1 to SH-SY5Y, a well-characterized human neuronal cell line, caused the decline of intracellular glutathione (GSH) content that appeared to occur before a significant LDH release. Furthermore, LLP-1 elicited a significant loss of mitochondrial function as measured by mitochondrial transmembrane potential (MTP). Among the reducing agents and antioxidants tested, GSH and a GSH prodrug N-acetylcysteine (NAC) provided protection against LLP-1-induced neuronal cell death, evidently by restoring the intracellular GSH levels and blocking the disruption of mitochondrial integrity. Thus, gp41-derived LLP-1 may be a potential neurotoxic agent capable of causing the intracellular GSH depletion and disturbing the mitochondrial function, possibly contributing to the neurodegenerative cascade as seen in HIV-1-associated dementia. Our data indicate that restoring both GSH concentration and mitochondrial function may hold promise as possible therapeutic strategies for slowing disease progression of dementia in AIDS patients.

Quantification of regional myocardial blood flow using dynamic H2(15)O PET and factor analysis.

UNLABELLED: Because the use of factor analysis has been proposed for extracting pure physiologic temporal or spatial information from dynamic nuclear medicine images, factor analysis should be capable of robustly estimating regional myocardial blood flow (rMBF) using H2(15)O PET without additional C15O PET, which is a cumbersome procedure for patients. Therefore, we measured rMBF using time-activity curves (TACs) obtained from factor analysis of dynamic myocardial H2(15)O PET images without the aid of C15O PET. METHODS: H2(15)O PET of six healthy dogs at rest and during stress was performed simultaneously with microsphere studies using 85Sr, 46Sc, and 113SN: We performed factor analysis in two steps after reorienting and masking the images to include only the cardiac region. The first step discriminated each factor in the spatial distribution and acquired the input functions, and the second step extracted regional-tissue TACS: Image-derived input functions obtained by factor analysis were compared with those obtained by the sampling method. rMBF calculated using a compartmental model with tissue TACs from the second step of the factor analysis was compared with rMBF measured by microsphere studies. RESULTS: Factor analysis was successful for all the dynamic H2(15)O PET images. The input functions obtained by factor analysis were nearly equal to those obtained by arterial blood sampling, except for the expected delay. The correlation between rMBF obtained by factor analysis and rMBF obtained by microsphere studies was good (r = 0.95). The correlation between rMBF obtained by the region-of-interest method and rMBF obtained by microsphere studies was also good (r = 0.93). CONCLUSION: rMBF can be measured robustly by factor analysis using dynamic myocardial H2(15)O PET images without additional C15O blood-pool PET.

Effects of the beta-amyloid and carboxyl-terminal fragment of Alzheimer's amyloid precursor protein on the production of the tumor necrosis factor-alpha and matrix metalloproteinase-9 by human monocytic THP-1.

To explore the direct role of beta-amyloid (Abeta) and carboxyl-terminal fragments of amyloid precursor protein in the inflammatory processes possibly linked to neurodegeneration associated with Alzheimer's disease, the effects of the 105-amino acid carboxyl-terminal fragment (CT(105)) of amyloid precursor protein on the production of tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinase-9 (MMP-9) were examined in a human monocytic THP-1 cell line and compared with that of Abeta. CT(105) elicited a marked increase in TNF-alpha and MMP-9 production in the presence of interferon-gamma in a dose- and time-dependent manner. Similar patterns were obtained with Abeta despite its low magnitude of induction. Autocrine TNF-alpha is likely to be a main mediator of the induction of MMP-9 because the neutralizing antibody to TNF-alpha inhibits MMP-9 production. Genistein, a specific inhibitor of tyrosine kinase, dramatically diminished both TNF-alpha secretion and subsequent MMP-9 release in response to CT(105) or Abeta. Furthermore, PD98059 and SB202190, specific inhibitors of ERK or p38 MAPK respectively, efficiently suppressed CT(105)-induced effects whereas only PD98059 was effective at reducing Abeta-induced effects. Our results suggest that CT(105) in combination with interferon-gamma might serve as a more potent activator than Abeta in triggering inflammatory processes and that both tyrosine kinase and MAPK signaling pathways may represent potential therapeutic targets for the control of Alzheimer's disease progression.