Longitudinal changes in 18 F-THK5351 positron emission tomography in corticobasal syndrome.

BACKGROUND AND PURPOSE: Corticobasal syndrome (CBS) is pathologically characterized by tau deposits in neuronal and glial cells and by reactive astrogliosis. In several neurodegenerative disorders, 18 F-THK5351 has been observed to bind to reactive astrocytes expressing monoamine oxidase B. In this study, the aim was to investigate the progression of disease-related pathology in the brains of patients with CBS using positron emission tomography with 18 F-THK5351. METHODS: Baseline and 1-year follow-up imaging were acquired using magnetic resonance imaging and positron emission tomography with 18 F-THK5351 in 10 subjects: five patients with CBS and five age-matched normal controls (NCs). RESULTS: The 1-year follow-up scan images revealed that 18 F-THK5351 retention had significantly increased in the superior parietal gyrus of the patients with CBS compared with the NCs. The median increases in 18 F-THK5351 accumulation in the patients with CBS were 6.53% in the superior parietal gyrus, 4.34% in the precentral gyrus and 4.33% in the postcentral gyrus. In contrast, there was no significant increase in the regional 18 F-THK5351 retention in the NCs. CONCLUSIONS: Longitudinal increases in 18 F-THK5351 binding can be detected over a short interval in the cortical sites of patients with CBS. A monoamine oxidase B binding radiotracer could be useful in monitoring the progression of astrogliosis in CBS.

Tau imaging with [18 F]THK-5351 in progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Visualization of pathogenic protein aggregates is crucial to elucidate pathomechanisms and to make an accurate diagnosis in many neurodegenerative conditions. Aggregates of the microtubule-binding protein, tau, are one of the most important pathogenic molecules in neurodegenerative disorders. Progressive supranuclear palsy (PSP) is characterized by the deposition of tau proteins in some specific area such as the basal ganglia and brainstem. We tried to detect tau lesions in the brains of living patients with PSP with a novel positron emission tomography (PET) tracer, [18 F]THK-5351, which we have recently developed. METHODS: Paraffin-embedded brain sections of the patients with PSP were used for autoradiography with [3 H]THK-5351 and immunohistochemistry. Nine healthy controls, 13 patients with Alzheimer's disease and three patients with PSP participated in this PET study with [18 F]THK-5351. To detect amyloid-ß deposition, PET imaging with Pittsburgh compound B was also performed. RESULTS: Autoradiography in the brain sections of patients with PSP demonstrated [3 H]THK-5351 binding to tau deposits with a high selectivity. Although patients with PSP exhibited no remarkable [18 F]THK-5351 retention in the temporal cortex, significantly higher tracer retention was observed in the globus pallidus and midbrain. In contrast, amyloid imaging with Pittsburgh compound B showed no remarkable accumulation in the cerebral cortex of PSP. CONCLUSIONS: We conclude that [18 F]THK-5351 PET can potentially be used to detect the regional brain distribution of tau lesions in PSP, thereby facilitating the differential diagnosis of neurodegenerative disorders associated with tau protein.

Performance evaluation of the small-animal PET scanner ClairvivoPET using NEMA NU 4-2008 Standards.

The aim of this study was to evaluate the performance of ClairvivoPET using NEMA NU4 standards. The ClairvivoPET incorporates a LYSO dual depth-of-interaction detector system with 151 mm axial field of view (FOV). Spatial resolution, sensitivity, counting rate capabilities, and image quality were evaluated using NEMA NU4-2008 standards. Normal mouse imaging was also performed for 10 min after intravenous injection of (18)F(-)-NaF. Data were compared with 19 other preclinical PET scanners. Spatial resolution measured using full width at half maximum on FBP-ramp reconstructed images was 2.16 mm at radial offset 5 mm of the axial centre FOV. The maximum absolute sensitivity for a point source at the FOV centre was 8.72%. Peak noise equivalent counting rate (NECR) was 415 kcps at 14.6 MBq ml(-1). The uniformity with the image-quality phantom was 4.62%. Spillover ratios in the images of air and water filled chambers were 0.19 and 0.06, respectively. Our results were comparable with the 19 other preclinical PET scanners based on NEMA NU4 standards, with excellent sensitivity because of the large FOV. The ClairvivoPET with iterative reconstruction algorithm also provided sufficient visualization of the mouse spine. The high sensitivity and resolution of the ClairvivoPET scanner provided high quality images for preclinical studies.

Néel-type skyrmion lattice with confined orientation in the polar magnetic semiconductor GaV4S8.

Following the early prediction of the skyrmion lattice (SkL)--a periodic array of spin vortices--it has been observed recently in various magnetic crystals mostly with chiral structure. Although non-chiral but polar crystals with Cnv symmetry were identified as ideal SkL hosts in pioneering theoretical studies, this archetype of SkL has remained experimentally unexplored. Here, we report the discovery of a SkL in the polar magnetic semiconductor GaV4S8 with rhombohedral (C3v) symmetry and easy axis anisotropy. The SkL exists over an unusually broad temperature range compared with other bulk crystals and the orientation of the vortices is not controlled by the external magnetic field, but instead confined to the magnetic easy axis. Supporting theory attributes these unique features to a new Néel-type of SkL describable as a superposition of spin cycloids in contrast to the Bloch-type SkL in chiral magnets described in terms of spin helices.

The expression and function of histamine H3 receptors in pancreatic beta cells.

BACKGROUND AND PURPOSE: Histamine and its receptors in the CNS play important roles in energy homeostasis. Here, we have investigated the expression and role of histamine receptors in pancreatic beta cells, which secrete insulin. EXPERIMENTAL APPROACH: The expression of histamine receptors in pancreatic beta cells was examined by RT-PCR, Western blotting and immunostaining. Insulin secretion assay, ATP measurement and calcium imaging studies were performed to determine the function and signalling pathway of histamine H3 receptors in glucose-induced insulin secretion (GIIS) from MIN6 cells, a mouse pancreatic beta cell line. The function and signalling pathway of H3 receptors in MIN6 cell proliferation were examined using pharmacological assay and Western blotting. KEY RESULTS: Histamine H3 receptors were expressed in pancreatic beta cells. A selective H3 receptor agonist, imetit, and a selective inverse H3 receptor agonist, JNJ-5207852, had inhibitory and facilitatory effects, respectively, on GIIS in MIN6 cells. Neither imetit nor JNJ-5207852 altered intracellular ATP concentration, or intracellular calcium concentration stimulated by glucose and KCl, indicating that GIIS signalling was affected by H3 receptor signalling downstream of the increase in intracellular calcium concentration. Moreover, imetit attenuated bromodeoxyuridine incorporation in MIN6 cells. The phosphorylation of cAMP response element-binding protein (CREB), which facilitated beta cell proliferation, was inhibited, though not significantly, by imetit, indicating that activated H3 receptors inhibited MIN6 cell proliferation, possibly by decreasing CREB phosphorylation. CONCLUSIONS AND IMPLICATIONS: Histamine H3 receptors were expressed in mouse beta cells and could play a role in insulin secretion and, possibly, beta cell proliferation.

Safety considerations in the management of allergic diseases: focus on antihistamines.

OBJECTIVE: To conduct a systematic review of evidence supporting the safety profiles of frequently used oral H(1)-antihistamines (AHs) for the treatment of patients with histamine-release related allergic diseases, e.g. allergic rhinitis and urticaria, and to compare them to the safety profiles of other medications, mostly topical corticosteroids and leukotriene antagonists (LTRA). RESEARCH DESIGN AND METHODS: Systematic search of the published literature (PubMed) and of the regulatory authorities databases (EMA and FDA) for oral AHs. RESULTS: Similarly to histamine, antihistamines (AHs) have organ-specific efficacy and adverse effects. The peripheral H(1)-receptor (PrH1R) stimulation leads to allergic symptoms while the brain H(1)-receptor (BrH1R) blockade leads to somnolence, fatigue, increased appetite, decreased cognitive functions (impaired memory and learning), seizures, aggressive behaviour, etc. First-generation oral AHs (FGAHs) inhibit the effects of histamine not only peripherally but also in the brain, and additionally have potent antimuscarinic, anti-α-adrenergic and antiserotonin effects leading to symptoms such as visual disturbances (mydriasis, photophobia, and diplopia), dry mouth, tachycardia, constipation, urinary retention, agitation, and confusion. The somnolence caused by FGAHs interferes with the natural circadian sleep-wake cycle and therefore FGAHs are not suitable to be used as sleeping pills. Second-generation oral AHs (SGAHs) have proven better safety and tolerability profiles, much lower proportional impairment ratios, with at least similar if not better efficacy, than their predecessors. Only SGAHs, and especially those with a proven long-term (e.g., ≥12 months) clinical safety, should be prescribed for young children. Evidence exist that intranasally applied medications, like intranasal antihistamines, have the potential to reach the brain and cause somnolence. CONCLUSIONS: Second-generation oral antihistamines are the preferred first-line treatment option for allergic rhinitis and urticaria. Patients taking SGAHs report relatively little and mild adverse events even after long-term continuous treatments. An antihistamine should ideally possess high selectivity for the H(1)-receptor, high PrH1R occupancy and low to no BrH1R occupancy.

Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.

BACKGROUND AND AIMS: Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. METHODS: We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. RESULTS: Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). CONCLUSION: These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.

Prevalence of Bartonella infection in cats and dogs in a metropolitan area, Thailand.

The prevalence of Bartonella infection was studied in 312 cats and 350 dogs in the Bangkok metropolitan areas, Thailand, between June 2001 and February 2003. Bartonella was isolated from 47 (16.3%) of 288 stray cats, but from none of the 24 pet cats studied. Of the 47 Bartonella-positive cats, 45 animals were infected with only B. henselae, one was infected with only B. clarridgeiae, and one with both B. henselae and B. clarridgeiae. 16S rRNA typing showed that 40 cats were infected with B. henselae type I, four with B. henselae type II, and one with both B. henselae types I and II. These results indicated that B. henselae, especially type I, was prevalent in stray cats that constituted a large Bartonella reservoir in Bangkok. B. clarridgeiae was isolated for the first time in Asia from one of 350 dogs.

Search for type 2 diabetes susceptibility genes on chromosomes 1q, 3q and 12q.

To systematically evaluate genetic susceptibility to type 2 diabetes (T2D) in "candidate" regions on chromosomes 1q, 3q and 12q, we examined disease association by using a total of 2,083 SNPs in two-step screening; a screening panel comprised 473 cases and 285 controls and an extended (or combined) panel involved 658 cases and 474 controls. For the total interval screened (40.9 Mb), suggestive evidence of association was provided for several annotated gene loci. For example, in the MCF2L2 gene on 3q, a significant association (a nominal P value of 0.00009) was observed when logistic regression analysis was performed for three associated SNPs (rs684846, rs35069869 and rs35368790) that belonged to different LD groups. Also, in the SLC15A4 gene on 12q, rs3765108 showed a marginally significant association with an overall estimated odds ratio of 0.79 (P=0.001). No significant association was found for known candidate gene loci on 3q, such as ADIPOQ and IGF2BP2. Using the available samples, we have observed disease associations of SNPs derived from two novel gene loci in the Japanese population through high-density searches of diabetes susceptibility in three chromosomal regions. Independent replication will clarify the etiological relevance of these genomic loci to T2D.

Search of type 2 diabetes susceptibility gene on chromosome 20q.

Significant evidence of linkage to type 2 diabetes (T2D) has been shown in a relatively broad region on chromosome 20q, where the hepatocyte nuclear factor-4alpha (HNF4A) has been noted as a positional candidate. To systematically evaluate genetic susceptibility to T2D in the relevant region, we examined the disease association by using 1145 SNPs in two-step screening in the Japanese population. The marker screening enabled us to identify significant disease association in the lipopolysaccharide binding protein (LBP) but not in the HNF4A locus. In a 17.7-Mb interval screened, the strongest association was identified for a SNP, rs2232592, located in the intron of LBP, with an estimated odds ratio of 1.73 (95% CI 1.30-2.31) (P=0.0002) in the whole study panel involving 675 case and 474 control subjects. Our data suggest that the LBP gene may confer genetic susceptibility to T2D and this warrants further replication study.

Evidence for the presence of histamine uptake into the synaptosomes of rat brain.

Histamine has many physiological roles in the brain and periphery. Neuronal histamine is metabolized almost exclusively by histamine N-methyltransferase. Although several neurotransmitter systems such as dopamine and 5-hydroxytryptamine have their specific reuptake system in their neurons and glial cells, a specific histamine reuptake system into the corresponding nerve terminals or glial cells has not yet been clearly elucidated. We characterized the uptake of histamine into the P2 fractions of rat brain homogenized in 0.32 mol/l sucrose using in vitro uptake techniques. [3H]histamine uptake increased with the increment of added protein amount and elapsed time. [3H]histamine uptake was also temperature-dependent. The uptake of [3H]histamine into the P2 fractions occurs by two saturable processes, a high-affinity and a low-affinity, characterized by K(m) values of 0.16 and 1.2 micromol/l, respectively. Na(+), Cl(-) and HCO(3)(-) ions were essential for the uptake of histamine in P2 fractions. [3H]histamine uptake was inhibited in the presence of several tricyclic antidepressants. In accordance with this, the endogenous release of histamine from brain slices evoked by 100 mmol/l K(+) was augmented in the presence of 20 micromol/l imipramine. These results further support the existence of a specific histamine uptake system in the brain, although the precise molecular entities have not been identified until now.

Brain activity during distention of the descending colon in humans.

Brain-gut interaction is considered to be a major factor in the pathophysiology of irritable bowel syndrome. However, only limited information has been provided on the influence of gastrointestinal tract stimulation on the brain. Our aim in this study was to determine the specific regions of the brain that are responsible for visceral perception and emotion provoked by distention of the descending colon in humans. Fifteen healthy males aged 22 +/- 1 participated in this study. Using a colonoscope, a balloon was inserted into the descending colon of each subject. After sham stimulation, the colon was randomly stimulated with bag pressures of 20 and 40 mmHg, and regional cerebral blood flow was measured by [(15)O] positron emission tomography. The subjects were asked to report visceral perception and emotion using an ordinate scale of 0-10. Colonic distention pressure dependently induced visceral perception and emotion, which significantly correlated with activation of specific regions of the brain including the prefrontal, anterior cingulate, parietal cortices, insula, pons, and the cerebellum. In conclusion, distention of the descending colon induces visceral perception and emotion. These changes significantly correlate with activation of specific regions in the brain including the limbic system and the association cortex, especially the prefrontal cortex.

Measurement of hypocretin/orexin content in the mouse brain using an enzyme immunoassay: the effect of circadian time, age and genetic background.

The hypocretins (1 and 2) have emerged as key regulators of sleep and wakefulness. We developed a high-throughput enzyme immunoassay (EIA) to measure total brain hypocretin levels from large numbers of mice. Hypocretin levels were not altered by circadian time or age. However, significant differences in one or both hypocretin peptides were observed between different mouse strains. We studied hypocretin levels in knockout and transgenic mouse models with obesity, circadian gene mutations or monoaminergic defects. Compared to controls, only histamine receptor knockouts had lower hypocretin levels. This was most pronounced in H1 receptor knockouts suggesting the existence of a positive feedback loop between hypocretin and histaminergic neurons.

Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): a comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.

AIMS: Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET. METHODS: Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions. RESULTS: Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine (10 mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.

Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptic dogs.

A growing amount of evidence suggests that a deficiency in hypocretin/orexin neurotransmission is critically involved in animal and human forms of narcolepsy. Since hypocretin-containing neurons innervate and excite histaminergic tuberomammillary neurons, altered histaminergic neurotransmission may also be involved in narcolepsy. We found a significant decrease in histamine content in the cortex and thalamus, two structures important for histamine-mediated cortical arousal, in Hcrtr-2 mutated narcoleptic Dobermans. In contrast, dopamine and norepinephrine contents in these structures were elevated in narcoleptic animals, a finding consistent with our hypothesis of altered catecholaminergic transmission in these animals. Considering the fact that histamine promotes wakefulness, decreases in histaminergic neurotransmission may also account for the sleep abnormalities in hypocretin-deficient narcolepsy.

Histamine H1 receptor-mediated inhibition of potassium-evoked release of 5-hydroxytryptamine from mouse forebrains.

The release of endogenous serotonin and dopamine from slices of mouse forebrains induced by high extracellular K(+) was examined in histamine H1 receptor knockout mice. The release of 5-hydroxytryptamine (5-HT) evoked by 30 mM K(+) significantly decreased in the presence of 10-50 microM histamine in wild-type mice, but was not inhibited in the mutant mice. Histamine H1 receptor-mediated inhibition of serotonin release in wild-type mice was also observed in the presence of thioperamide, an H3 antagonist. From these data, we postulate that endogenous histamine indirectly inhibits the release of 5-HT through H1 receptors in addition to H3 receptors. The treatment of 2 microM tetrodotoxin could partly abolish the effects of histamine on K(+)-evoked 5-HT release. Bicuculline, a GABA(A) antagonist, could reverse the histamine-induced inhibition of 5-HT release in wild-type mice, suggesting that H1 receptors facilitate the release of GABA, which in turn inhibits 5-HT release through GABA(A) receptors. The difference in the effects of d- and l-chlorpheniramine on K(+)-evoked 5-HT release in wild-type mice further supports the evidence of the function of H1 receptor modulating 5-HT release.