Independent replication of advanced brain age in mild cognitive impairment and dementia: detection of future cognitive dysfunction.

We previously developed a novel machine-learning-based brain age model that was sensitive to amyloid. We aimed to independently validate it and to demonstrate its utility using independent clinical data. We recruited 650 participants from South Korean memory clinics to undergo magnetic resonance imaging and clinical assessments. We employed a pretrained brain age model that used data from an independent set of largely Caucasian individuals (n = 757) who had no or relatively low levels of amyloid as confirmed by positron emission tomography (PET). We investigated the association between brain age residual and cognitive decline. We found that our pretrained brain age model was able to reliably estimate brain age (mean absolute error = 5.68 years, r(650) = 0.47, age range = 49-89 year) in the sample with 71 participants with subjective cognitive decline (SCD), 375 with mild cognitive impairment (MCI), and 204 with dementia. Greater brain age was associated with greater amyloid and worse cognitive function [Odds Ratio, (95% Confidence Interval {CI}): 1.28 (1.06-1.55), p = 0.030 for amyloid PET positivity; 2.52 (1.76-3.61), p < 0.001 for dementia]. Baseline brain age residual was predictive of future cognitive worsening even after adjusting for apolipoprotein E e4 and amyloid status [Hazard Ratio, (95% CI): 1.94 (1.33-2.81), p = 0.001 for total 336 follow-up sample; 2.31 (1.44-3.71), p = 0.001 for 284 subsample with baseline Clinical Dementia Rating ≤ 0.5; 2.40 (1.43-4.03), p = 0.001 for 240 subsample with baseline SCD or MCI]. In independent data set, these results replicate our previous findings using this model, which was able to delineate significant differences in brain age according to the diagnostic stages of dementia as well as amyloid deposition status. Brain age models may offer benefits in discriminating and tracking cognitive impairment in older adults.

Are All Anxieties Created Equal? Stress-related Networks and Anxiety Phenotypes in Old Age.

OBJECTIVE: The dysregulation of stress-related networks due to chronic symptoms such as severe worry and/or rumination is one of the putative pathways linking anxiety in late-life with cognitive decline and increased cardiovascular burden. Symptoms such as severe worry or rumination respond poorly to standard treatment and drive the morbidity associated with anxiety in older adults. We assessed if any of the neural networks anchored in the stress-related regions of interest (ROIs) are associated with distinct anxiety phenotypes (worry, rumination and global anxiety). METHODS: We recruited older participants (over 50 years of age) with varying levels of worry (N = 91) to undergo resting state fMRI. We computed seed-based connectivity for each ROI: the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus, habenula, and amygdala. We limited our connectivity analyses to extracted regions for each seeded ROI-based network based on their canonical networks in 1,000 participants (Neurosynth). Using connectivity and clinical factors, we fit cross-validated elastic net models to predict scores on Penn State Worry Questionnaire, Rumination Subscale Questionnaire, Hamilton Anxiety Rating Scale, and Perceived Stress Scale. RESULTS: We identified several distinct connectivity patterns that predict anxiety phenotypes' severity. Greater worry was associated with greater paraventricular nucleus of the hypothalamus -subgenual anterior cingulate cortex, parahippocampal, and olfactory and amygdala-PHC connectivity. Greater global anxiety was associated with lower amygdala-superior temporal gyrus connectivity. Greater perceived stress was associated with lower amygdala-inferior temporal gyrus and amygdala-fusiform gyrus connectivity. CONCLUSION: Our study suggests that various late-life anxiety phenotypes (worry, global anxiety, rumination) may be associated with varying functional connectivity related to stress and emotion regulation. This may aid in the development of future targeted interventions.

The roles of study setting, response bias, and personality in subjective memory complaints of cognitively normal older adults.

OBJECTIVES: This study investigated subjective memory complaints in older adults and the roles of setting, response bias, and personality. DESIGN: Cognitively normal older adults from two settings completed questionnaires measuring memory complaints, response bias, and personality. SETTINGS: (A) Neuroimaging study with community-based recruitment and (B) academic memory clinic. PARTICIPANTS: Cognitively normal older adults who (A) volunteer for research (N = 92) or (B) self-referred to a memory clinic (N = 20). MEASUREMENTS: Neuropsychological evaluation and adjudication of normal cognitive status were done by the neuroimaging study or memory clinic. This study administered self-reports of subjective memory complaints, response bias, five-factor personality, and depressive symptoms. Primary group differences were examined with secondary sensitivity analyses to control for sex, age, and education differences. RESULTS: There was no significant difference in over-reporting response bias between study settings. Under-reporting response bias was higher in volunteers. Cognitive complaints were associated with response bias for two cognitive complaint measures. Neuroticism was positively associated with over-reporting in evaluation-seekers and negatively associated with under-reporting in volunteers. The relationship was reversed for Extraversion. Under-reporting bias was positively correlated with Agreeableness and Conscientiousness in volunteers. CONCLUSION: Evaluation-seekers do not show bias toward over-reporting symptoms compared to volunteers. Under-reporting response bias may be important to consider when screening for memory impairment in non-help-seeking settings. The Memory Functioning Questionnaire was less sensitive to reporting biases. Over-reporting may be a facet of higher Neuroticism. Findings help elucidate psychological influences on self-perceived cognitive decline and help seeking in aging and may inform different strategies for assessment by setting.

Partitioning light spectra: Adaptive stratification of phytobenthic communities in Antarctic lakes.

Competition for light has an important influence for phototrophic community structures, especially, along the perpendicular axis. Here we develop a mathematical model for perpendicular community buildup of phototrophic species that differ in light absorption spectra and compete for incident light. Details of photon capture efficiencies and the roles of photoinhibition were taken into consideration to define species' fitness. Our theory showed that, if there is strong light irradiation due, for example, to the high transparency of the water in freshwater lakes in Antarctica, protective absorption of light should occur near the surface and photosynthetic absorption should gradually increase with depth. These results were then validated in comparison with observed vertical distributions of pigments in phytobenthic-mat communities from Antarctic lakes.

Voxel-wise hemispheric Amyloid Asymmetry and its association with cerebral metabolism and grey matter density in cognitively normal older adults.

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by changes in beta amyloid (Aß) and tau as well as changes in cerebral glucose metabolism and gray matter volume. This has been categorized as three distinct stages of amyloid, tau, and neurodegeneration. Past studies have shown asymmetric Aß accumulation and its association with asymmetric cerebral metabolism in preclinical AD. We analyzed data to replicate these findings and extend them to associations with gray matter volume and cognitive function. Methods: We recruited 93 (mean age = 76.4±6.1 years) cognitively normal adults who underwent magnetic resonance imaging (MRI) and positron emission tomography (PET) with Pittsburgh compound B (PiB) and Fluorodeoxyglucose (FDG) tracers (to estimate Aß and glucose metabolism, respectively). We conducted voxel-wise paired t-test on PiB (left vs. right hemispheres) to identify regions that differ in Aß between the left and right cortex. We identified whether these regions showed asymmetry in FDG and gray matter volume using paired t-tests on each region. We then conducted correlations between asymmetry indices for each region that had significant asymmetry in PiB, FDG, and gray matter volume. We ran a group regression analysis on cognitive functions. Results: We found 26 regions that had significant rightward asymmetry in PiB including prefrontal cortex, temporal cortex, insula, parahippocampus, caudate, and putamen. All these regions showed significant gray matter rightward asymmetry, and most of these regions showed significant FDG asymmetry except the caudate, orbital cortex, medial frontal gyrus, and superior temporal gyrus. Only in the superior frontal gyrus, we found that greater rightward asymmetry in PiB was associated with greater rightward asymmetry in FDG, r(82) =0.38, p<0.005 (FDR corrected) - no other regions showed significant Aß asymmetry correlation with either FDG or gray matter volume asymmetry. We found that greater rightward FDG asymmetry in the superior frontal gyrus was associated with greater visuospatial processing scores in our cognitive domain group regression analysis. Discussion: AD has previously been modeled in three-stages: however, our results indicate that cerebral glucose metabolism may be dynamic throughout the disease progression and may serve as a compensatory pathway for maintaining cognitive functioning.

History of major depressive disorder is associated with differences in implicit learning of emotional faces.

Major depressive disorder is often associated with worsened reward learning, with blunted reward response persisting after remission. In this study, we developed a probabilistic learning task with social rewards as a learning signal. We examined the impacts of depression on social rewards (facial affect displays) as an implicit learning signal. Fifty-seven participants without a history of depression and sixty-two participants with a history of depression (current or remitted) completed a structured clinical interview and an implicit learning task with social reward. Participants underwent an open-ended interview to evaluate whether they knew the rule consciously. Linear mixed effects models revealed that participants without a history of depression learned faster and showed a stronger preference towards the positive than the negative stimulus when compared to the participants with a history of depression. In contrast, those with a history depression learned slower on average and displayed greater variability in stimulus preference. We did not detect any differences in learning between those with current and remitted depression. The results indicate that on a probabilistic social reward task, people with a history of depression exhibit slower reward learning and greater variability in their learning behavior. Improving our understanding of alterations in social reward learning and their associations with depression and anhedonia may help to develop translatable psychotherapeutic approaches for modification of maladaptive emotion regulation.

Depressive symptoms anticipate behavioral and emotional factors among older adults: A prospective cross-lagged panel design.

This study examined the temporal relationship among depression, anxiety, insomnia, perceived stress, and physical activity in adults aged 60+ years with a history of major depressive disorder. We conducted a longitudinal study with 12 weeks of follow-up. Assessments consisted of phone or video interviews and included questionnaires evaluating depression, anxiety, insomnia, perceived stress, and physical activity. Our analytic approach consisted of a depression-focused cross-lagged panel model (CLPM) to examine week-to-week correlations among the five measures. The depression-focused CLPM identified statistically significant week-to-week self-predictive effects for each of the five measures. Higher depressive symptom burden was a strong predictor of increased stress, greater insomnia, and less physical activity the following week. No other cross-measure predictions were statistically significant. Our analytical approach clarifies the directional relationship among variables that typically co-occur with depression showing that higher depression symptom burden predisposes older adults to poor sleep, a reduced level of daytime activity, and a greater sense of stress. These findings support the need for longitudinal assessments and targeted interventions for reducing symptoms of depression in older adults.

Functional Asymmetry During Working Memory and Its Association with Markers of Alzheimer's Disease in Cognitively Normal Older Adults.

BACKGROUND: Amyloid-ß (Aß) deposits asymmetrically early in Alzheimer's disease (AD). This process is variable and has been associated with asymmetric hypometabolism. OBJECTIVE: We investigated whether neural asymmetry during working memory and executive function processing was associated with AD genetic risk and markers of AD as well as other brain neuropathology biomarkers, cognitive function, and cognitive reserve in cognitively normal older adults. METHODS: We analyzed data from 77 cognitively healthy, older adults who completed functional magnetic resonance imaging, positron emission tomography, and cognitive testing. We identified regions of significant activation and asymmetry during the Digital Symbol Substitution Task (DSST). We examined associations between regions with significant hemispheric asymmetry (directional and absolute) and global cerebral Aß, cerebral glucose metabolism, white matter hyperintensities, APOE ɛ4 allele status, DSST reaction time, age, sex, education, and cognitive function. RESULTS: Asymmetry was not associated with several factors including cognitive function, Aß, and white matter hyperintensities. The presence of at least one ɛ4 APOE allele in participants was associated with less asymmetric activation in the angular gyrus (right dominant activation). Greater education was associated with less asymmetric activation in mediodorsal thalamus (left dominant activation). CONCLUSIONS: Genetic risk of AD was associated with lower asymmetry in angular gyrus activation, while greater education was associated with lower asymmetry in mediodorsal thalamus activation. Changes in asymmetry may reflect components of compensation or cognitive reserve. Asymmetric neural recruitment during working memory may be related to maintenance of cognitive function in cognitively normal older adults.

Impact of symptomatic menopausal transition on the occurrence of depression, anxiety, and sleep disorders: A real-world multi-site study.

BACKGROUND: The menopause transition is a vulnerable period that can be associated with changes in mood and cognition. The present study aimed to investigate whether a symptomatic menopausal transition increases the risks of depression, anxiety, and sleep disorders. METHODS: This population-based, retrospective cohort study analysed data from five electronic health record databases in South Korea. Women aged 45-64 years with and without symptomatic menopausal transition were matched 1:1 using propensity-score matching. Subgroup analyses were conducted according to age and use of hormone replacement therapy (HRT). A primary analysis of 5-year follow-up data was conducted, and an intention-to-treat analysis was performed to identify different risk windows over 5 or 10 years. The primary outcome was first-time diagnosis of depression, anxiety, and sleep disorder. We used Cox proportional hazard models and a meta-analysis to calculate the summary hazard ratio (HR) estimates across the databases. RESULTS: Propensity-score matching resulted in a sample of 17,098 women. Summary HRs for depression (2.10; 95% confidence interval [CI] 1.63-2.71), anxiety (1.64; 95% CI 1.01-2.66), and sleep disorders (1.47; 95% CI 1.16-1.88) were higher in the symptomatic menopausal transition group. In the subgroup analysis, the use of HRT was associated with an increased risk of depression (2.21; 95% CI 1.07-4.55) and sleep disorders (2.51; 95% CI 1.25-5.04) when compared with non-use of HRT. CONCLUSIONS: Our findings suggest that women with symptomatic menopausal transition exhibit an increased risk of developing depression, anxiety, and sleep disorders. Therefore, women experiencing a symptomatic menopausal transition should be monitored closely so that interventions can be applied early.

Low thalamic activity during a digit-symbol substitution task is associated with symptoms of subjective cognitive decline.

Introduction: Subjective cognitive decline (SCD) may represent the earliest preclinical stage of Alzheimer's Disease (AD) for some older adults. However, the underlying neurobiology of SCD is not completely understood. Since executive function may be affected earlier than memory function in the progression of AD, we aimed to characterize SCD symptoms in terms of fMRI brain activity during the computerized digit-symbol substitution task (DSST), an executive function task. We also explored associations of DSST task performance with brain activation, SCD severity, and amyloid-ß (Aß) load. Methods: We analyzed data from 63 cognitively normal older individuals (mean age 73.6 ± 7.2) with varying degree of SCD symptoms. Participants completed a computerized version of DSST in the MR scanner and a Pittsburgh Compound-B (PiB)-PET scan to measure global cerebral Aß load. Results: A voxel-wise analysis revealed that greater SCD severity was associated with lower dorsomedial thalamus activation. While task performance was not associated with brain activation nor Aß load, slower reaction time was associated with greater SCD severity. Discussion: The observed lower dorsomedial thalamus activation may reflect declining familiarity-based working memory and the trans-thalamic executive function pathway in SCD. SCD symptoms may reflect altered neural function and subtle decline of executive function, while Aß load may have an indirect impact on neural function and performance. Self-perceived cognitive decline may serve as a psychological/subjective marker reflecting subtle brain changes.

The neural basis of deictic shifting in linguistic perspective-taking in high-functioning autism.

Personal pronouns, such as 'I' and 'you', require a speaker/listener to continuously re-map their reciprocal relation to their referent, depending on who is saying the pronoun. This process, called 'deictic shifting', may underlie the incorrect production of these pronouns, or 'pronoun reversals', such as referring to oneself with the pronoun 'you', which has been reported in children with autism. The underlying neural basis of deictic shifting, however, is not understood, nor has the processing of pronouns been studied in adults with autism. The present study compared the brain activation pattern and functional connectivity (synchronization of activation across brain areas) of adults with high-functioning autism and control participants using functional magnetic resonance imaging in a linguistic perspective-taking task that required deictic shifting. The results revealed significantly diminished frontal (right anterior insula) to posterior (precuneus) functional connectivity during deictic shifting in the autism group, as well as reliably slower and less accurate behavioural responses. A comparison of two types of deictic shifting revealed that the functional connectivity between the right anterior insula and precuneus was lower in autism while answering a question that contained the pronoun 'you', querying something about the participant's view, but not when answering a query about someone else's view. In addition to the functional connectivity between the right anterior insula and precuneus being lower in autism, activation in each region was atypical, suggesting over reliance on individual regions as a potential compensation for the lower level of collaborative interregional processing. These findings indicate that deictic shifting constitutes a challenge for adults with high-functioning autism, particularly when reference to one's self is involved, and that the functional collaboration of two critical nodes, right anterior insula and precuneus, may play a critical role for deictic shifting by supporting an attention shift between oneself and others.

Thinking of Me or Thinking of You? Behavioral Correlates of Self vs. Other Centered Worry and Reappraisal in Late-Life.

Psychotherapeutic approaches in late-life anxiety have limited effect on reducing worry severity. The self-referential processing of worry contents (self- vs. other-focused worry) and reappraisal styles (internal vs. external locus of control) are important elements in psychotherapy, but little is known about these processes in late-life. We aimed to characterize severe worry from a self-referential processing perspective. We recruited 104 older adults with various levels of worry and used a personalized task to induce and reappraise worry. We analyzed the association between (1) worry severity/frequency for worry content (self- or other-focused) and (2) for reappraisal style (internal vs. external locus of control) with clinical inventories measuring anxiety, worry, depression, rumination, neuroticism, emotion regulation strategies, perceived stress, and physical illness burden. Higher self-worry severity was associated with higher scores of clinical inventories of worry, depression, perceived stress, and neuroticism, whereas other-worry severity did not show any association. Greater self-worry frequency was associated with higher medical burden. External locus of control in reappraisal statements was associated with lower worry severity in men. Overall, more severe and frequent self-focused worry was associated with a greater psychological and physiological burden. These results are useful in tailoring psychotherapy for older adults with severe worry.

Network modeling of anxiety and psychological characteristics on suicidal behavior: Cross-sectional study.

BACKGROUND: Suicide is influenced by complex interactions among various psychopathological features. We aimed to examine the relationship between suicide risk and psychological risk factors such as defense mechanisms, personality, and anxiety. METHODS: We established a psychiatric database by utilizing the Observational Medical Outcomes Partnership Common Data Model. We conducted a 1:1 propensity score matching with age, sex, and depression severity, and identified a sample (n = 258) with two groups: those with suicidal behavior and those with non-suicidal behavior. Using principal component analysis, we extracted nine psychological scales and applied network analysis to compare relationships among psychological factors between the two groups. RESULTS: Patients with non-suicidal behaviors showed associations between trait anxiety and defense mechanisms, while those with suicidal behaviors did not. For patients with suicidal ideation there was an association between somatization and trait anxiety. Patients with suicide attempts showed associations between paranoia and dissociation connected to trait anxiety. LIMITATIONS: Longitudinal research is required to fully observe transitions from suicidal ideation to attempts and recurrent suicidal events. In addition, these networks may not generalize suicidal behaviors because the group participants are not homogeneous. Lastly, data from self-report questionnaires limits the reliability of responses. CONCLUSIONS: We presented important new insights on suicidal behavior by estimating psychological networks. Patients with non-suicidal behavior may exhibit discrete relationships between defense mechanisms and anxiety, compared to those with suicidal behavior. Patients with suicidal ideation and suicide attempts may show distinct associations between anxiety and psychopathological features.

An Effect of Education on Memory-Encoding Activation in Subjective Cognitive Decline.

BACKGROUND: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer's disease. Elevated amyloid-ß (Aß) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aß is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates. OBJECTIVE: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aß, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations. METHODS: We measured brain activation during the "face-name" memory-encoding fMRI task and Aß deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n = 63, mean age 73.1 ± 7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aß, and interactions with education. RESULTS: Activation was not directly associated with SCD symptoms or Aß. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education. CONCLUSION: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve.

Improving brain age prediction models: incorporation of amyloid status in Alzheimer's disease.

Brain age prediction is a machine learning method that estimates an individual's chronological age from their neuroimaging scans. Brain age indicates whether an individual's brain appears "older" than age-matched healthy peers, suggesting that they may have experienced a higher cumulative exposure to brain insults or were more impacted by those pathological insults. However, contemporary brain age models include older participants with amyloid pathology in their training sets and thus may be confounded when studying Alzheimer's disease (AD). We showed that amyloid status is a critical feature for brain age prediction models. We trained a model on T1-weighted MRI images participants without amyloid pathology. MRI data were processed to estimate gray matter density voxel-wise, which were then used to predict chronological age. Our model performed accurately comparable to previous models. Notably, we demonstrated more significant differences between AD diagnostic groups than other models. In addition, our model was able to delineate significant differences in brain age relative to chronological age between cognitively normal individuals with and without amyloid. Incorporation of amyloid status in brain age prediction models ultimately improves the utility of brain age as a biomarker for AD.

The effects of the evolution of stoichiometry-related traits on population dynamics in plankton communities.

Both ecological stoichiometry and the evolution of traits for energetic interactions such as prey protection and predatory efficiency are considered to be important aspects affecting population dynamics. However, no attempt has been made to examine the effect of the evolution of traits relating to stoichiometry. This study first examined the effects of the evolution of nutrient utilization traits (i.e., the minimum nutrient content of prey, the maximum nutrient uptake affinity of prey and the nutrient contents of predators) on population dynamics in a plankton community. When the evolution of these traits was assumed, the range of the nutrient loading conditions where the system became unstable was smaller than when the evolution was not assumed, but the range of the conditions for zooplankton extinction became larger. Furthermore, when the trade-offs (i.e. genetic correlation between the traits) were assumed, the system rarely became extinct and the range of the nutrient loading conditions where the system became stable became larger through evolution. Stable dynamics were caused by increasing uptake affinity through evolution, and zooplankton extinction was caused by decreasing the minimum content of limiting nutrients. Thus, our results suggest that the evolution of traits relating to stoichiometry can affect the dynamics of the systems, and the outcomes the dynamics change greatly depend on which traits can evolve.

[A case of Legionnaires' disease with abnormal neurological findings showing the corpus callosum abnormality on brain MRI].

A 47-year-old man was admitted to our hospital because of dysarthric speech and high fever. His brain magnetic resonance imaging (MRI) showed high intensity in the splenium of the corpus callosum (SCC) on diffusion-weighted and FLAIR imaging. His chest CT showed ground-glass attenuation in bilateral lung upper lobes, and consolidation in the right lower lobe. Because of his neurological findings and radiographic imaging, we started antibiotic therapy using quinolone, which is effective for Legionellosis. Later, Legionella species were identified by sputum culture. Pneumonia was relieved after antibiotic therapy and in parallel with clinical improvement, and the MRI findings also resolved. We report a patient who showed abnormal neurological findings and abnormality on brain MRI, both of which were reversible, in the setting of acute Legionnaires' disease.

Light quality determines primary production in nutrient-poor small lakes.

The availability of nutrients for primary producers has long been thought to be the main limiting factor for primary productivity in nutrient-poor lake ecosystems. However, recent studies have indicated that the availability of light energy is also important. On the other hand, the amount of phototroph was reported to decrease in summer in Antarctic lakes, furthermore, the light environment underwater was shown containing high amount of ultraviolet energy in small Antarctic lakes. Here, we hypothesized that primary productivity is limited by not only nutrients and simple light quantity but also light quality in nutrient-poor lakes. Then, we investigate factors influencing primary production by benthic phototrophic communities in shallow nutrient-poor lakes. We examine the relationships between primary production in 17 Antarctic freshwater lakes and nutrient concentrations in lake and benthic water, temperature and light energy. Primary production is decreased by ultraviolet energy reaching the lake bed, showing that production is determined by light quality. We also correlate ultraviolet energy in lake water with the catchment area of each lake. Our results show that the underwater light environment has an important influence on primary production as a key limitation factor and is sensitive to materials in runoff from the surrounding environment for pristine lakes.

[Management of difficult-to-treat asthma using a flow sheet for systematic evaluation and therapeutic intervention].

BACKGROUND: Although most patients of asthma can be controlled by inhaled corticosteroid (ICS), some patients remain uncontrolled even after the introduction of ICS treatment. In management of such difficult-to-treat asthma, systematic review including additional differential diagnosis and avoidance of exacerbating factors is very important. METHODS: Here we postulate a flow sheet presenting an algorithm which intends to achieve better asthma control following ATS refractory asthma guidance. For patients with poor controlled asthma even after using ICS more than moderate dose, we used the sheet in our daily outpatient management and investigated whether we could improve the control in such patients. The sheet was constructed by an algorithm which included (1) reevaluation of inhalation technique of ICS; (2) additional differential diagnosis of COPD and other similar diseases; and (3) reevaluation of presence of exacerbating factors. RESULTS: In our outpatient department, seven clinicians managed 22 difficult-to-treat asthma patients using this sheet. Additional factors which might worsen asthma control could be detected in 21 patients (95.5%). Firstly, smoking was disclosed in 8 patients (36.4%). Secondly, keeping pets was identified in 7 patients (31.8%). 5 patients (22.7%) were diagnosed as COPD rather than asthma and 4 patients (18.2%) were diagnosed as having rhinosinusitis. Some improvement of asthma control was achieved in 9 patients (40.9%). CONCLUSIONS: Reevaluation of refractory asthma patients using our newly developed flow sheet is essential and it may facilitate understanding of management of difficult-to-treat asthma.

A Homeostatic Model of Subjective Cognitive Decline.

Subjective Cognitive Decline (SCD) is possibly one of the earliest detectable signs of dementia, but we do not know which mental processes lead to elevated concern. In this narrative review, we will summarize the previous literature on the biomarkers and functional neuroanatomy of SCD. In order to extend upon the prevailing theory of SCD, compensatory hyperactivation, we will introduce a new model: the breakdown of homeostasis in the prediction error minimization system. A cognitive prediction error is a discrepancy between an implicit cognitive prediction and the corresponding outcome. Experiencing frequent prediction errors may be a primary source of elevated subjective concern. Our homeostasis breakdown model provides an explanation for the progression from both normal cognition to SCD and from SCD to advanced dementia stages.