Effects of Apolipoprotein E ɛ4 and Risk Factors on Domains of Cognition in Mild Cognitive Impairment and Dementia.

BACKGROUND: The apolipoprotein E (APOE) gene is the most potent genetic risk factor for dementia. However, there are few studies on how the APOE gene affects cognitive domain functions. OBJECTIVE: This study aimed to investigate the effects of risk factors for dementia on cognitive function in patients with mild cognitive impairment and Alzheimer's disease (AD). METHODS: This study included subjects whose Clinical Dementia Rating scores ranged from 0.5 to 2 and who were older than 65 years. Risk factors for dementia included the APOE ɛ4 allele, age, education period, employment period, body mass index, and exercise. APOE genotyping was performed by polymerase chain reaction, and other factors were identified using medical charts or structured checklists. Cognitive function was measured using the Seoul Neuropsychological Screening Battery II. RESULTS: General cognitive function did not show a significant difference according to APOE ɛ4 status. However, the score for delayed verbal memory was lower in the APOE ɛ4-carrier group than in the non-carrier group (p < 0.05). In addition, age, education period, employment period, and exercise were correlated with different cognitive function domains in the non-carrier group (p < 0.05); however, the carrier group was showed a significant correlation between age, body mass index, and cognitive domains. CONCLUSION: Our findings suggest that APOE ɛ4 significantly decreases verbal memory in patients with AD. Moreover, the effects of risk factors on cognitive function were significantly different according to the APOE ɛ4 status.

Effects of contextual interference on feeding training in patients with stroke.

The contextual interference (CI) effect of motor skill has been demonstrated through numerous studies. However, few studies have reported on daily living tasks in patients with stroke. This study investigated the CI effect on spooning training in such patients. Fourteen right hemiparetic patients with stroke were assigned to one of two groups: a group with a random practice schedule or a group with a blocked practice schedule. The spooning task involved scooping go stones from a bowl 30 cm away in 3 different directions to a bowl in front of the patient. We evaluated the acquisition, retention, and transfer of motor learning for spooning. The transfer was evaluated while participants ate cereal in a bowl with a spoon. Upper extremity function, defined as far-transfer, was also evaluated using the box-and-block test. In the retention test, no significant difference between random and blocked practice groups was shown, although both groups showed differences between pre-test and post-test movement times. However, in the transfer test, the random practice group had a significantly shorter movement time than the blocked practice group and also revealed improvement between the pre- and follow-up tests. Additionally, in the far-transfer test, there were significant differences between the pre- and post-, and pre- and follow-up tests only in the random practice group. These findings show that the benefits of CI for transfer can be applied to the learning of feeding skills in patients with stroke and that although the blocked practice is also partially beneficial to long-lasting skill learning in a treatment setting, it may not be efficient under changed conditions. We also suggest the possibility that feeding training with the CI effect could apply to not only transfer but also to far-transfer.

Effects of resistive jaw opening exercise in stroke patients with dysphagia: A double- blind, randomized controlled study.

BACKGROUND: The resistive jaw opening exercise (RJOE) was suggested as a potential remedial treatment for patients with dysphagia. However, clinical evidence is insufficient. OBJECTIVE: To investigate the effect of RJOE on hyoid bone movement, aspiration, and oral intake level in stroke patients with dysphagia. METHODS: Forty stroke patients with dysphagia were randomly allocated into either the experimental group (n= 20) or placebo group (n= 20). The experimental group performed RJOE using a portable device, while the placebo group performed RJOE using a sham device with fewer loads. Intervention was conducted 5 times a week for 4 weeks. Hyoid bone movement was analyzed by two-dimensional analysis of anterior and superior motion based on a videofluoroscopic swallowing study. Aspiration was assessed using a penetration-aspiration scale (PAS), and oral intake level was assessed using the functional oral intake scale (FOIS). RESULTS: Both groups showed statistically significant differences in hyoid movement, PAS, and FOIS scale (p< 0.05). However, after the intervention, there was no significant difference between the two groups except for the liquid type of PAS. Effect sizes (Cohen's d) were 0.9 and 0.7, 0.6 and 0.6, and 1.1 for the anterior and superior movement of the hyoid bone, semisolid and liquid type of PAS, and FOIS scale respectively. CONCLUSIONS: This study suggests that RJOE helps in hyoid movement, aspiration reduction, and oral intake in patients with dysphagia after stroke.

Changes in the BDNF-immunopositive cell population of neocortical layers I and II/III after focal cerebral ischemia in rats.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is widely distributed in the central nervous system, including the cerebral cortex. BDNF plays an important role in normal neural development, survival of existing neurons, and activity-dependent neuroplasticity. BDNF can also be neuroprotective and evoke neurogenesis in certain pathological conditions, such as cerebral ischemia. Neocortical layer I is an important region that can integrate feedforward and feedback information from other cortical areas and subcortical regions. In addition, it has recently been proposed as a possible source of neuronal progenitor cells after ischemia. Therefore, we investigated changes in the BDNF-immunoreactive cell population of neocortical layers I and II/III after middle cerebral artery occlusion (MCAO)-induced cerebral ischemia in rats. In unaffected condition, the number of BDNF(+) cells in layer I was significantly less than in layer II/III in the cingulate cortex and in the motor and sensory areas. The increase in the number of BDNF(+) cells in layer I 8 days after MCAO was more remarkable than layer II/III, in all regions except the area of cingulate cortex farthest from the infarct core. Only BDNF(+)-Ox-42(+) cells showed a tendency to increase consistently toward the infarct core in both layers I and II/III, implying a major source of BDNF for response to ischemic injury. The present study suggests that some beneficial effects during recovery from ischemic injury, such as increased supportive microglia/macrophages, occur owing to a sensitive response of BDNF in layer I.

Administration of mesenchymal stem cells and ziprasidone enhanced amelioration of ischemic brain damage in rats.

Ziprasidone is a benzisothiazolyl piperazine derivative that was developed from the chemically related antipsychotic drug tiospirone, and it improves neurological functions of the ischemic brain and is effective in treatment of schizophrenia. Mesenchymal stem cells (MSCs) are considered as a leading candidate for neurological regenerative therapy because of their neural differentiation properties in damaged brain. We investigated whether the transplantation of neural progenitor cells (NPCs) derived from adipose mesenchymal stem cells combined with ziprasidone enhances neuroprotective effects in an animal model of focal cerebral ischemia. In combination therapy groups, significant reduction of infarct volume and improvement of neurological functions were observed at 3 days after middle cerebral artery occlusion (MCAO) compared with monotherapy. Co-administration of ziprasidone and NPCs enhanced the anti-apoptotic effect and reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells compared with the NPCs alone group at 7 days after MCAO. Ziprasidone or the combination of ziprasidone and NPCs induced the expression of endogenous neurotrophic factor gene brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF). The immunohistochemical investigation revealed that the ziprasidone and NPCs attenuated the increased intensity of microglial marker (Iba-1) in the infarcted cortical area. Moreover, the number of transplanted NPCs on day 7 with combination therapy was significantly higher than with NPCs alone. These effects might be responsible for improved functional behavior and increased survival of NPCs. Our finding indicates that combination therapy of ziprasidone and NPCs enhances neuroprotection against ischemic brain injury.

Ziprasidone attenuates brain injury after focal cerebral ischemia induced by middle cerebral artery occlusion in rats.

Ziprasidone is an atypical antipsychotic drug used for the treatment of schizophrenia. Recent studies have reported that atypical antipsychotics have neuroprotective effects against brain injury. In the present study, the effect of ziprasidone on ischemic brain injury was investigated. Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in rats. All the animals experienced ischemia for 1h and then underwent reperfusion. The infarct size induced by MCAO was significantly reduced in the animals that received acute treatment with 5mg/kg ziprasidone and subchronic treatment with 2.5mg/kg ziprasidone for 7 days compared with that in the vehicle-treated animals. The acute treatment with ziprasidone significantly improved neurological functions, as measured by the modified neurological severity score, in a dose-dependent manner. The subchronic treatment produced more rapid recovery from functional deficits than the vehicle treatment. The immunohistochemical investigation revealed that the subchronic treatment prevented severe loss of neuronal marker intensity and attenuated the increased in microglial marker intensity in the infarcted cortical area. These results suggest that ziprasidone has neuroprotective effects in a rat model of ischemic stroke and provide new insight for its clinical applications.

p-Hydroxybenzyl alcohol prevents brain injury and behavioral impairment by activating Nrf2, PDI, and neurotrophic factor genes in a rat model of brain ischemia.

The therapeutic goal in treating cerebral ischemia is to reduce the extent of brain injury and thus minimize neurological impairment. We examined the effects of p-hydroxybenzyl alcohol (HBA), an active component of Gastrodia elata Blume, on transient focal cerebral ischemia-induced brain injury with respect to the involvement of protein disulphide isomerase (PDI), nuclear factor-E2-related factor 2 (Nrf2), and neurotrophic factors. All animals were ovariectomized 14 days before ischemic injury. Ischemic injury was induced for 1 h by middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Three days before MCAO, the vehicle-treated and the HBA-treated groups received intramuscular sesame oil and HBA (25 mg/kg BW), respectively. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed decreased infarct volume in the ischemic lesion of HBA-treated animals. HBA pretreatment also promoted functional recovery, as measured by the modified neurological severity score (mNSS; p < 0.05). Moreover, expression of PDI, Nrf2, BDNF, GDNF, and MBP genes increased by HBA treatment. In vitro, H(2)O(2)-induced PC12 cell death was prevented by 24 h HBA treatment, but bacitracin, a PDI inhibitor, attenuated this cytoprotective effect in a dose-dependent manner. HBA treatment for 2 h also induced nuclear translocation of Nrf2, possibly activating the intracellular antioxidative system. These results suggest that HBA protects against brain damage by modulating cytoprotective genes, such as Nrf2 and PDI, and neurotrophic factors.

A composite element that binds basic helix loop helix and basic leucine zipper transcription factors is important for gonadotropin-releasing hormone regulation of the follicle-stimulating hormone beta gene.

Although FSH plays an essential role in controlling gametogenesis, the biology of FSHbeta transcription remains poorly understood, but is known to involve the complex interplay of multiple endocrine factors including GnRH. We have identified a GnRH-responsive element within the rat FSHbeta promoter containing an E-box and partial cAMP response element site that are bound by the basic helix loop helix transcription factor family members, upstream stimulating factor (USF)-1/USF-2, and the basic leucine zipper member, cAMP response element-binding protein (CREB), respectively. Expression studies with CREB, USF-1/USF-2, and activating protein-1 demonstrated that the USF transcription factors increased basal transcription, an effect not observed if the cognate binding site was mutated. Conversely, expression of a dominant negative CREB mutant or CREB knockdown attenuated induction by GnRH, whereas dominant negative Fos or USF had no effect on the GnRH response. GnRH stimulation specifically induced an increase in phosphorylated CREB occupation of the FSHbeta promoter, leading to the recruitment of CREB-binding protein to enhance gene transcription. In conclusion, a composite element bound by both USF and CREB serves to integrate signals for basal and GnRH-stimulated transcription of the rat FSHbeta gene.

Gonadotropin-releasing hormone pulse frequency-dependent activation of extracellular signal-regulated kinase pathways in perifused LbetaT2 cells.

The pattern of GnRH release is associated with differential synthesis and release of LH and FSH. Using a perifusion system, we previously reported that stimulation of the LbetaT2 cell line with varying GnRH pulse frequencies resulted in differential stimulation of LHbeta and FSHbeta gene transcription, analogous to previous observations in primary gonadotropes. In the present study, we investigated the patterns of MAPK activation by GnRH and the role of MAPK in mediating the frequency-dependent effects. In static culture, ERK activation in LbetaT2 cells stimulated with continuous GnRH (10 nM) was maximal by 10 min and persisted for up to 6 h, with a return to basal levels by 20 h. In contrast, stimulation with continuous GnRH (10 nM) in perifused cells resulted in a more sustained activation of ERK. To investigate the effects of GnRH pulse frequency on ERK activation, perifused LbetaT2 cells were stimulated with pulsatile GnRH at a frequency of one pulse every 30 min or one pulse every 2 h for 20 h (10 nM, 5 min/pulse). After the final GnRH pulse, cells were lysed at frequent intervals and levels of ERK phosphorylation were measured. Under high-frequency conditions, ERK activation was maximal 10 min after the GnRH pulse and returned to baseline levels by 20 min. In contrast, under lower GnRH pulse frequency conditions, ERK activation occurred more rapidly and activation was more sustained, with a slower rate of ERK dephosphorylation. These changes resulted in different levels of nuclear phosphorylated ERK. Blockade of ERK activation abolished GnRH-dependent activation of LHbeta and FSHbeta transcription at both high and low pulse frequencies. These results demonstrate that in perifused LbetaT2 cells, distinct patterns of ERK activation/inactivation are regulated by GnRH pulse frequency, and the difference in ERK activation may be important for GnRH pulse frequency-dependent differential stimulation of LHbeta and FSHbeta gene expression.

Oct-1 and nuclear factor Y bind to the SURG-1 element to direct basal and gonadotropin-releasing hormone (GnRH)-stimulated mouse GnRH receptor gene transcription.

The cis-regulatory element localized to position -292/-285 of the mouse GnRH receptor (mGnRHR) gene promoter, designated Sequence Underlying Responsiveness to GnRH 1 (SURG-1), has been shown previously to contribute to stimulation of mGnRHR gene expression by GnRH. We have identified three specific protein-DNA complexes on the SURG-1 element by EMSA using nuclear extracts from the gonadotrope-derived alphaT3-1 and LbetaT2 cell lines. Serial mutagenesis and supershift assays identified nuclear factor Y (NF-Y) binding to -288/-284 and Oct-1 binding to a TAAT sequence at -290/-287. Binding of these two transcription factors was confirmed in vivo by chromatin immunoprecipitation assay and increased in response to GnRH stimulation. To define the functional significance of these sequences in the regulation of mGnRHR gene transcription, transient transfection assays were performed in alphaT3-1 cells using a 1.2-kb mGnRHR (-1164/+62) gene promoter-luciferase reporter construct with selective mutations of the Oct-1, NF-Y, and/or the previously characterized activating protein 1 (AP-1) binding site (-274/-268). Individual mutations in the Oct-1, NF-Y, and AP-1 sites decreased both basal expression and stimulation by GnRH agonist, and the combined mutation of the Oct-1 and AP-1 binding sites further reduced basal transcriptional activity and abolished GnRH stimulation. Overexpression of NF-YA increased GnRHR promoter activity, whereas expression of a dominant negative NF-YA mutant decreased activity, further supporting a role of NF-Y in regulation of mGnRHR gene transcription. In addition, knockdown of Oct-1 by small interfering RNA confirmed that Oct-1 is important for mGnRHR gene expression. In conclusion, NF-Y and Oct-1 bind to the SURG-1 element to direct basal and GnRH-stimulated expression of the mGnRHR gene.

Influence of GnRH agonist and neural antagonists on stress-blockade of LH and prolactin surges induced by 17beta-estradiol in ovariectomized rats.

In our previous study, we demonstrated that immobilization stress blocked estrogen-induced luteinizing hormone (LH) surge possibly by inhibiting the synthesis and release of gonadotropin-releasing hormone (GnRH) at the hypothalamic level and by blocking estrogen-induced prolactin (PRL) surge by increasing the synthesis of dopamine receptor at the pituitary level in ovariectomized rats. The present study was performed to determine whether immobilization stress affects pituitary LH responsiveness to GnRH, and whether endogenous opioid peptide (EOP) and dopamine systems are involved in blocking LH and PRL surges during immobilization stress. Immobilization stress was found to inhibit basal LH release and to completely abolish LH surge. However, the intravenous application of GnRH agonist completely restored immobilization-blocked LH surge and basal LH release. Treatment with naloxone did not exert any effect on immobilization-blocked LH surge but increased basal LH release during immobilization stress. Pimozide did not affect immobilization-blocked LH surge or basal LH release. Naloxone also decreased immobilization-induced basal PRL release, but had no effect on immobilization-blocked PRL surge. Immobilization-increased basal PRL levels were augmented by pimozide treatment and immobilization-blocked PRL surge was dramatically restored by pimozide. We conclude that immobilization stress does not impair pituitary LH response to GnRH, and that the immobilization stress-induced blockage of LH surge is probably not mediated by either the opioidergic or the dopaminergic system. However, immobilization-blockade of PRL surge may be partly mediated by the dopaminergic system.