Clinical features and alterations in the inferior horn sizes in lateral ventricle in Alzheimer's patients with different ApoE genotype in Japanese population

E4 allele of Apolipoprotein E (ApoE) is considered to be not only a risk factor for Alzheimer's disease (AD) but also a determinant of clinical features in AD. However, it is still controversial whether ApoE e4 allele is related to age at onset, severity of memory impairment or brain morphological changes in AD patients. The present study examined the issue in Japanese population: 1) ApoE genotype on in 38 normal controls and 32 AD patients; 2) association between e4 allele of ApoE and clinical features including Wechsler Memory Scale-Revised in 32 AD patients; and 3) association between e4 allele of ApoE and change in size of inferior horn in lateral ventricle (LV) in 13 out of 32 AD patients. The e4 allele of ApoE frequency was higher in AD patients than in normal controls. There was no significant difference in age at onset or neuropsychological results between AD with and without e4 allele of ApoE. Alteration per month of the inferior horn sizes in LV measured by MRI was similar in the AD patients with and without e4 allele of ApoE. These results suggest that e4 allele of ApoE is a risk factor but not a determinant of clinical features for AD in Japanese population.     

Methamphetamine-induced locomotor activity and sensitization in dopamine transporter and vesicular monoamine transporter 2 double mutant mice

Rationale The dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) play pivotal roles in the action of methamphetamine (MAP), including acute locomotor effects and behavioral sensitization. However, the relative impact of heterozygous DAT and VMAT2 knockouts (KOs) on the behavioral effects of MAP remains unknown. Objectives To evaluate the roles of DAT and VMAT2 in MAP-induced locomotor behavior, we examined locomotor activity and sensitization in heterozygous DAT KO (DAT+/−), heterozygous VMAT2 KO (VMAT2+/−), double heterozygous DAT/VMAT2 KO (DAT+/−VMAT2+/−), and wild-type (WT) mice. Results Acute 1 mg/kg MAP injection induced significant locomotor increases in WT and VMAT2+/− mice but not in DAT+/− and DAT+/−VMAT2+/− mice. Acute 2 mg/kg MAP significantly increased locomotor activity in all genotypes. Repeated 1 mg/kg MAP injections revealed a delayed and attenuated development of sensitization in DAT+/− and DAT+/−VMAT2+/− mice compared to WT mice and delayed development in VMAT2+/− mice. In repeated 2 mg/kg MAP injections, DAT+/− and DAT+/−VMAT2+/− mice showed delayed but not attenuated development of sensitization, while there was no difference in the onset of sensitization between VMAT2+/− and WT mice. In DAT+/−VMAT2+/− mice, all of MAP-induced behavioral responses were similar to those in DAT+/− but not VMAT2+/− mice. Conclusions Heterozygous deletion of DAT attenuates the locomotor effects of MAP and may play larger role in behavioral responses to MAP compared to heterozygous deletion of VMAT2.     

Efficacy and safety of erenumab in Japanese migraine patients with prior preventive treatment failure or concomitant preventive treatment: subgroup analyses of a phase 3, randomized trial

BackgroundThese subgroup analyses of a Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of erenumab 70 mg in Japanese migraine patients with/without prior preventive treatment failure(s) (“failed-yes” and “failed-no” subgroups) and with/without concomitant preventive treatment (“concomitant preventive-yes” and “concomitant preventive-no” subgroups).MethodsOverall, 261 patients were randomized; 130 and 131 patients to erenumab 70 mg and placebo, respectively. Subgroup analyses evaluated the change from baseline to Months 4–6 in mean monthly migraine days (MMD) (primary endpoint), achievement of a ≥50% reduction in mean MMD, and change from baseline in mean monthly acute migraine-specific medication (MSM) treatment days. Treatment-emergent adverse events were also evaluated.ResultsOf the 261 patients randomized, 117 (44.8%) and 92 (35.3%) patients were in the failed-yes and concomitant preventive-yes subgroups, respectively. Erenumab 70 mg demonstrated consistent efficacy across all subgroups, with greater reductions from baseline in mean MMD versus placebo at Months 4–6 (treatment difference versus placebo [95% CI], failed-yes: − 1.9 [− 3.3, − 0.4]; failed-no: − 1.4 [− 2.6, − 0.3]; concomitant preventive-yes: − 1.7 [− 3.3, 0.0]; concomitant preventive-no: − 1.6 [− 2.6, − 0.5]). Similar results were seen for achievement of ≥50% reduction in mean MMD and change from baseline in mean monthly acute MSM treatment days. The safety profile of erenumab 70 mg was similar across subgroups, and similar to placebo in each subgroup.ConclusionErenumab was associated with clinically relevant improvements in all efficacy endpoints and was well tolerated across all subgroups of Japanese migraine patients with/without prior preventive treatment failure(s) and with/without concomitant preventive treatment.Trial registrationClinicaltrials.gov. {"type":"clinical-trial","attrs":{"text":"NCT03812224","term_id":"NCT03812224"}}NCT03812224. Registered January 23, 2019.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01313-8.     

Methamphetamine alters expression of DNA methyltransferase 1 mRNA in rat brain

Methamphetamine, a potent and indirect dopaminergic agonist, also increases glucocorticoid hormone secretion. Glucocorticoid hormones facilitate behavioral effects of methamphetamine in rodents. Several reports suggest that glucocorticoid hormones modulate expression of DNA (cytosine-5-)-methyltransferase 1 (Dnmt1). Dnmt1 was originally recognized as being involved in DNA replication, but a recent study found high levels of Dnmt1 in rodent brains, suggesting a neuron-specific unknown function of Dnmt1. In the present study, we found subchronic methamphetamine treatment (4 mg/kg, i.p., once daily for 21 days) to induce different patterns of Dnmt1 mRNA expression in the nucleus caudatus and nucleus accumbens of two inbred rat strains, Fischer 344/N (increased Dnmt1) and Lewis/N (decreased Dnmt1). These patterns paralleled methamphetamine-induced striatal glucocorticoid receptor mRNA in these two rat strains in our previous study. Because Fischer rats have a hyperresponsive negative feedback in their hypothalamic-pituitary-adrenocortical (HPA) axis and thus a shorter duration corticosterone response to subchronic methamphetamine treatment, they were resistant to sensitizing effects of methamphetamine and their glucocorticoid receptor mRNA levels were upregulated. Lewis rats which have a hyporesponsive feedback in their HPA axis and a longer duration of corticosterone secretion with subchronic methamphetamine were prone to methamphetamine sensitization and their striatal glucocorticoid receptor mRNA levels were downregulated. Our present data suggest that methamphetamine results in differential DNA methylation as well as gene expression in the nucleus caudatus and nucleus accumbens of F344 and Lewis rats. Methamphetamine-induced differences in gene expression might be related to the contrasting susceptibilities of these rats to behavioral and neurochemical effects of methamphetamine.     

Unilateral exophthalmos caused by a prolactin producing ectopic pituitary adenoma: case report

OBJECTIVE: We report a case of a patient with a prolactin (PRL) producing ectopic pituitary adenoma presenting a unilateral exophthalmos. CASE: This 70-year-old woman presented an ophthalmologist with progressive left-sided exophthalmos over the previous 2 months. Bone window CT scan revealed extensive bony destructions of the skull base including the clivus, sphenoid sinus and medial aspect of the middle cranial fossa. Gd-DTPA MRI revealed an abnormal enhancement lesion in the sphenoid sinus, but no abnormal enhancement was seen in the sella turcica. Since these findings suggested malignant tumors of the cranial base, several biopsies through the transnasal route were carried out to confirm the diagnosis. This procedure caused the complication of cerebrospinal fluid (CSF) leakage. Because the biopsy specimen revealed a PRL producing adenoma (serum PRL-level 645.7 ng/ml), the patient was admitted to our department. On admission neurological examination showed an exophthalmos with external ocular movement disorders and disturbance of visual acuity on the left side. She underwent transsphenoidal surgery to remove the tumor and to reconstruct the sphenoid sinus and the sellar floor. Surgical exploration revealed a yellowish and soft tumor underneath the normal mucous membrane in the sphenoid sinus. The sellar floor was destructed extensively, but the dura mater of the pituitary fossa was intact except for a small pin-hole which was thought to be produced during the several biopsy procedures. No surgical procedure was applied to the intrasellar region. The sphenoid sinus was packed with a piece of fascia and fat applied with the aid of fibrin glue to prevent CSF leakage. RESULT: The patient followed a satisfactory postoperative course. Her visual acuity disturbance and exophthalmos disappeared one year after surgery. Postoperative serum PRL level remained high (66.9 ng/ml), but, subsequently, was normalized (9.5 ng/ml) with a bromocriptine therapy (15 mg daily). CONCLUSION: As far as we are aware, this is the first case report of an ectopic pituitary adenoma causing unilateral exophthalmos. Although it is extremely rare, pituitary adenomas should be kept in mind in a differential diagnosis of exophthalmos.     

Frontal and right temporal activations correlate negatively with depression severity during verbal fluency task: a multi-channel near-infrared spectroscopy study

Multi-channel near-infrared spectroscopy (NIRS) is a noninvasive, on-the-spot, functional neuroimaging technique allowing detection of the spatiotemporal characteristics of brain activity. Previous NIRS studies indicated the oxy-hemoglobin (oxy-Hb) increase during a verbal fluency task (VFT) is attenuated in patients with major depressive disorder (MDD) as compared with healthy controls. However, the possible relationship between depression symptom severity and oxy-Hb change on NIRS has not yet been elucidated. To examine this relationship, we recruited 30 patients with MDD and 30 age-, gender- and intelligence quotient-matched controls. All underwent NIRS during VFT. As expected, the oxy-Hb increase during the task was significantly smaller in patients than in controls. After false discovery rate correction using 31 channels, the mean increase in oxy-Hb during the task showed a significant negative correlation with the total score of the Hamilton Rating Scale for Depression 21-item version (ch25: rho = ?.56; FDR-corrected p: .001). When each item of the HAM-D21 was examined individually, insomnia early in 9 channels (rho = ?.63 to ?.46; FDR corrected p: .000–.014), work and activity in 2 channels (rho = ?.61 to ?.57; FDR corrected p: .001 to .003) and psychomotor retardation in 12 channels (rho = ?.70 to ?.44; FDR corrected p: .000–.018) showed significant negative correlations with the mean oxy-Hb increase in the right frontal temporal region. Although it is possible that our results were affected by medication, these data suggest reduced right frontal temporal activation on NIRS during VFT is related to the symptom severity of MDD.     

The absence of impairment of cliff avoidance reaction induced by subchronic methamphetamine treatment in inbred strains of mice

Cliff avoidance reaction (CAR), an index of behavioral teratology in rodents, can be impaired by motor, arousal, or cognitive dysfunction. We formerly reported subchronic administration of methamphetamine (MAP) induced the CAR impairment, which might reflect MAP-induced cognitive dysfunction, in three strains of rats. In this study, the effects of subchronic MAP treatment on the behavioral sensitization in stereotypy (stereotypy sensitization) and CAR were examined in two inbred strains of male mice; C57BL/6J(C57) and DBA/2J(DBA). The animals received 4 mg/kg/day MAP intraperitoneally for 28 days. There were apparent strain differences in the development of stereotypy sensitization induced by chronic MAP; DBA mice developed stereotypy sensitization quickly, but C57 did not. Unlike rats, neither strains of mice showed the CAR impairment. These results suggest that chronic MAP (4 mg/kg) administration did not introduce any cognitive dysfunction measured by CAR in the two inbred mice, DBA and C57. The discrepancy between rats and mice is still unclear. It might relate to the species-selective effect of MAP on the CAR impairment. Further studies should to be required.