Cascade process mediated by left hippocampus and left superior frontal gyrus affects relationship between aging and cognitive dysfunction.

BACKGROUND: Cognitive function declines with age and has been shown to be associated with atrophy in some brain regions, including the prefrontal cortex. However, the details of the relationship between aging and cognitive dysfunction are not well understood. METHODS: Across a wide range of ages (24- to 85-years-old), this research measured the gray matter volume of structural magnetic resonance imaging data in 39 participants, while some brain regions were set as mediator variables to assess the cascade process between aging and cognitive dysfunction in a path analysis. RESULTS: Path analysis showed that age affected the left hippocampus, thereby directly affecting the left superior frontal gyrus. Furthermore, the gyrus directly affected higher order flexibility and maintenance abilities calculated as in the Wisconsin card sorting test, and the two abilities affected the assessment of general cognitive function. CONCLUSION: Our finding suggests that a cascade process mediated by the left hippocampus and left superior frontal gyrus is involved in the relationship between aging and cognitive dysfunction.

Mammalian target of rapamycin inhibitors permit regulatory T cell reconstitution and inhibit experimental chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into C3H model and CD4(+) T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell-derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with CSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4(+) T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT.

Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.

Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-ß expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD.

Slow breathing and emotions associated with odor-induced autobiographical memories.

An important feature of olfactory perception is its dependence on respiratory activity. By inspiration, olfactory information ascends directly to olfactory-related limbic structures. Therefore, every breath with odor molecules activates these limbic areas associated with emotional experience and memory retrieval. We tested whether odors associated with autobiographical memories can trigger pleasant emotional experiences and whether respiration changes during stimulation with these odors. During presentation of odors related to autobiographical memories and control odors, we measured minute ventilation, tidal volume, respiratory frequency, O2 consumption, and end tidal CO2 concentration. Findings showed that autobiographical memory retrieval was associated with increasing tidal volume and decreasing respiratory frequency more than during presentation of control odors. Subjective feelings such as emotional arousal during retrieval of the memory, arousal level of the memory itself, or pleasantness and familiarity toward the odor evoked by autobiographical memory were more specific emotional responses compared with those related to control odors. In addition, high trait anxiety subjects responded with a stronger feeling of being taken back in time and had high arousal levels with tidal volume increases. We discussed assumptions regarding how deep and slow breathing is related to pleasantness and comfortableness of an autobiographical memory.

Influences of age-related positivity effect on characteristics of odor-evoked autobiographical memories in older Japanese adults.

Older adults tend to remember past life events more positively than younger adults. This tendency is the age-related positivity effect. The present study examined whether this effect occurred for odor-evoked autobiographical memories. In total, 317 young and 181 older Japanese participants were asked to recall autobiographical events evoked by odors. Participants then completed the odor-evoked autobiographical memory questionnaire (OEAMQ) to measure the characteristics of the recalled memories. In the results, older participants recalled more positive memories than younger participants. Older participants also rated the OEAMQ subscales higher than the younger participants. Furthermore, there were significant positive correlations between the ratings of odor emotional characteristics and OEAMQ subscales. The age-related positivity effect was observed for odor-evoked autobiographical memories. The emotion aroused by odor played a significant role in some attributes of odor-evoked autobiographical memory. The age-related positivity effect in odor-evoked autobiographical memories has important implications for understanding the cognitive mechanisms of aging in autobiographical memory and olfaction and for applications in well-being and dementia in older adults.

Odors Associated With Autobiographical Memory Induce Visual Imagination of Emotional Scenes as Well as Orbitofrontal-Fusiform Activation.

Specific odors can induce memories of the past, especially those associated with autobiographical and episodic memory. Odors associated with autobiographical memories have been found to elicit stronger activation in the orbitofrontal cortex, hippocampus, and parahippocampus compared with odors not linked to personal memories. Here, we examined whether continuous odor stimuli associated with autobiographical memories could activate the above olfactory areas in older adults and speculated regarding whether this odor stimulation could have a protective effect against age-related cognitive decline. Specifically, we used functional magnetic resonance imaging to investigate the relationship between blood oxygen levels in olfactory regions and odor-induced subjective memory retrieval and emotions associated with autobiographical memory in older adults. In our group of healthy older adults, the tested odors induced autobiographical memories that were accompanied by increasing levels of retrieval and the feeling of being "brought back in time." The strength of the subjective feelings, including vividness of the memory and degree of comfort, impacted activation of the left fusiform gyrus and left posterior orbitofrontal cortex. Further, our path model suggested that the strength of memory retrieval and of the emotions induced by odor-evoked autobiographical memories directly influenced neural changes in the left fusiform gyrus, and impacted left posterior orbitofrontal cortex activation through the left fusiform response.

Volume of the right supramarginal gyrus is associated with a maintenance of emotion recognition ability.

Emotion recognition is known to change with age, but associations between the change and brain atrophy are not well understood. In the current study atrophied brain regions associated with emotion recognition were investigated in elderly and younger participants. Group comparison showed no difference in emotion recognition score, while the score was associated with years of education, not age. We measured the gray matter volume of 18 regions of interest including the bilateral precuneus, supramarginal gyrus, orbital gyrus, straight gyrus, superior temporal sulcus, inferior frontal gyrus, insular cortex, amygdala, and hippocampus, which have been associated with social function and emotion recognition. Brain reductions were observed in elderly group except left inferior frontal gyrus, left straight gyrus, right orbital gyrus, right inferior frontal gyrus, and right supramarginal gyrus. Path analysis was performed using the following variables: age, years of education, emotion recognition score, and the 5 regions that were not different between the groups. The analysis revealed that years of education were associated with volumes of the right orbital gyrus, right inferior frontal gyrus, and right supramarginal gyrus. Furthermore, the right supramarginal gyrus volume was associated with the emotion recognition score. These results suggest that the amount of education received contributes to maintain the right supramarginal gyrus volume, and indirectly affects emotion recognition ability.

Entorhinal cortex and parahippocampus volume reductions impact olfactory decline in aged subjects.

INTRODUCTION: Pathological abnormalities first appear in the medial temporal regions including entorhinal cortex and parahippocampus in patients with Alzheimer's disease. Previous studies showed that olfactory decline in elderly subjects was associated with volume reductions in the left hippocampus and left parahippocampus without cognitive impairment. The aim of this study is to investigate the link between olfaction and volume reductions in the medial temporal regions including the parahippocampus, entorhinal cortex, and hippocampal subfields. METHOD: 27 elderly subjects and 27 young controls were measured olfaction acuity, cognitive function, and structural magnetic resonance imaging. Image processing and gray matter volumetric segmentation were performed with FreeSurfer. Volume data were analyzed with SPSS Statistics software. RESULTS: Interesting results of this study were that volume reduction in the entorhinal cortex was not directly linked with declining olfactory ability. Volume reduction in the left entorhinal cortex was correlated with volume reduction in the left parahippocampus and dentate gyrus. However, left parahippocampus volume reduction had the greatest impact on olfactory decline, and the entorhinal cortex and dentate gyrus might additionally contribute to olfactory decline. CONCLUSION: Our results indicate that olfactory decline may be directly reflected in the medial temporal regions as reduced parahippocampus volumes, rather than as morphological changes in the entorhinal cortex and hippocampus. The parahippocampus may play an important role in the association between memory retrieval and olfactory identification.

Hippocampus and Parahippocampus Volume Reduction Associated With Impaired Olfactory Abilities in Subjects Without Evidence of Cognitive Decline.

The aim of this study was to investigate the relationship between olfactory recognition and morphological changes in olfactory brain regions including the amygdala, hippocampus, rectus, parahippocampus, orbitofrontal cortex, and medial frontal cortex in 27 elderly subjects and 27 younger healthy controls. The specific aim of the study was to determine which brain areas are associated with the initial decline of olfaction in elderly subjects, which occurs before the onset of dementia. All subjects underwent magnetic resonance imaging to measure anatomical brain volume and cortical thickness, and subjects were assessed using tests of olfactory acuity and cognitive function measured with the Montreal Cognitive Assessment. Overall brain volume reductions were observed in elderly subjects compared with young healthy controls, but only reduction in the volume of the left hippocampus was associated with decreased olfactory ability. The parahippocampus of elderly subjects was not different from that of controls; the extent of the reduction of parahippocampus volume varied among individuals, and reduction in this region was associated with olfactory decline. Similarly, parahippocampus thinning was associated with decreased olfactory function. The path analysis showed direct and indirect effects of hippocampus and parahippocampus volume on olfactory ability and that volume reductions in these areas were not associated with cognitive function. Parahippocampus volume reduction and thinning exhibited individual variation; this may be the first appearance of pathological changes and may lead to dysfunction in the connection of olfactory memory to the neocortex. Parahippocampus change may reflect the first sign of olfactory impairment prior to pathological changes in the hippocampus, amygdala and orbitofrontal cortex.

Clinical outcomes of unrelated donor umbilical cord blood transplantation for 30 adults with hematological malignancies.

BACKGROUND: Umbilical cord blood transplantation (CBT) has increasingly been used as a therapeutic option for adult patients for whom allogeneic stem-cell transplantation is not indicated, due to the availability of cord blood. However, myeloablative conditioning regimens are associated with significant mortality, and high relapse rates in reduced-intensity regimens may result in a poor rate of disease-free survival for those with advanced stages of hematological malignancies. Therefore, it remains unknown whether CBT is a truly effective option for such adults with high-risk disease, as well as for those with standard-risk disease. PATIENTS AND METHODS: Thirty adult patients with a median age of 45 years (range: 16-67) with standard or high-risk disease underwent CBT from unrelated donors at Okayama University Hospital between October 2002 and May 2007. Twenty-one patients had diseases classified as high-risk for transplantation. The median number of nucleated cells in infused cord blood was 2.65 x 10(7)/kg (range: 1.73-4.87). RESULTS: Twenty-three patients achieved neutrophil engraftment at a median time of 22 days (range: 13-42) after CBT. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 53.6% . Out of the 30 patients, 11 were alive and disease-free at a median time of 446 days (range: 124-1153) after CBT. The cumulative 1-year overall survival in patients with standard-risk or high-risk disease was 63.5% and 15.4%, respectively (p=0.01). CONCLUSION: Although from a retrospective study, these results suggest that unrelated donor CBT could be safe and effective for adult patients with standard-risk disease who cannot find a suitable HLA-matched volunteer marrow or peripheral blood donor.

Remembering the past with slow breathing associated with activity in the parahippocampus and amygdala.

Breathing plays an important role in perception of odors and the experience of emotions. We used the dipole tracing method to analyze brain areas related to odor-induced autobiographical memory and emotions estimated from averaged electroencephalograms triggered by inspiration onset during odor presentation. Odor stimuli were perfumes subjects named that elicited a specific, pleasant and personal memory as well as two pleasant odors for controls. The perfumes induced specific emotional responses during memory retrieval, arousal level of the memory, feelings of pleasantness and a sense of familiarity with the odor. Respiration measurement indicated that tidal volume increased and respiratory frequency decreased during presentation of perfume stimuli, showing a deep and slow breathing pattern. Throughout the olfactory stimulation, electroencephalograms and respiration were simultaneously recorded. In the averaged potentials, low frequency oscillation was phase-locked to inspiration. Dipole analysis showed that perfumes activated more widespread areas of the right parahippocampal cortex and converged in the right amygdala compared to control odors. Slow breathing synchronized with odor-induced autobiographical memory and emotions may be subconsciously stored in the parahippocampal cortex and amygdala.

Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice.

Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-presenting cells of hematopoietic origin, and it is not well understood how alloantigen expression on non-hematopoietic cells affects GVL activity. Here we show, in mouse models of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation, that alloantigen expression on host epithelium drives donor T cells into apoptosis and dysfunction during GVHD, resulting in a loss of GVL activity. During GVHD, programmed death-1 (PD-1) and PD ligand-1 (PD-L1), molecules implicated in inducing T cell exhaustion, were upregulated on activated T cells and the target tissue, respectively, suggesting that the T cell defects driven by host epithelial alloantigen expression might be mediated by the PD-1/PD-L1 pathway. Consistent with this, blockade of PD-1/PD-L1 interactions partially restored T cell effector functions and improved GVL. These results elucidate a previously unrecognized significance of alloantigen expression on non-hematopoietic cells in GVL and suggest that separation of GVL from GVHD for more effective HSCT may be possible in human patients.

The effect of adding rituximab to CHOP-based therapy on clinical outcomes for Japanese patients with diffuse large B-cell lymphoma: a propensity score matching analysis.

We conducted a retrospective analysis to evaluate the impact on clinical outcomes of adding rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for diffuse large B-cell lymphoma (DLBCL) patients in Japan. A propensity score method was used to compensate for the non-randomized study design. From January 2000 to December 2004, 378 patients who were newly diagnosed with DLBCL at 13 institutes were enrolled: 123 in the rituximab plus CHOP-based chemotherapy (R+) group, and 255 in the CHOP-based chemotherapy only (R-) group. The complete response rate was significantly higher in the R+ group than in the R- group (77.7 vs. 69.4%, P < 0.001). The progression-free survival (PFS) at 2 years was 62.4% in the R+ group and 57.0% in the R- group. The 2-year overall survival (OS) was 76.9% for the R+ group and 70.5% for the R- group. A multivariate analysis revealed that the addition of rituximab was a strong independent prognostic factor for PFS (hazard ratio 0.64, 95% CI 0.43-0.96, P = 0.031). A subgroup analysis revealed that R+ particularly benefited younger patients (hazard ratio 0.25, 95% CI 0.08-0.75, P = 0.013). IPI also showed significant impact for PFS (hazard ratio 1.82, 95% CI 1.55-2.14 for one score increase, P < 0.001) as well as OS (hazard ratio 2.10, 95% CI 1.71-2.57, P < 0.001). In summary, the addition of rituximab to CHOP-based chemotherapy results in better outcomes for Japanese DLBCL patients, particularly younger patients.

Are olfactory images sensory in nature?

We investigated the features of olfactory mental images by comparing odour images with perceptual and semantic representations. Participants who were assigned to three groups made similarity judgments about 17 common odours by smelling odours, imagining odours, or on the basis of the meaning of odour source names. In the smelling group, every pair of odours was compared. In the imagining group, imagined odours were compared twice, both before and after associative learning of the odour/name combinations. In the meaning group, the odour source names were compared in terms of general word meanings. Nonmetric multidimensional scaling analysis was applied to each group of similarity data and three-dimensional sensory, mental, and semantic spaces were composed. 17 elements in the mental and semantic spaces were superimposed onto the sensory space by Procrustes rotation. We found that the averaged distances of the 17 elements between the sensory and the mental spaces (either before or after learning) were smaller than those between the sensory and semantic spaces. We suggest that odour images have sensory features, especially after associative learning between perceived odours and their names.