Development of a stroke risk score with MRI asymptomatic brain lesions attributes to evaluate prognostic vascular events.

BACKGROUND: The use of a combination of stroke predictors, such as clinical factors and asymptomatic lesions on brain magnetic resonance imaging (MRI), may improve the accuracy of stroke risk prediction. Therefore, we attempted to develop a stroke risk score for healthy individuals. METHODS: We investigated the presence of cerebral stroke in 2365 healthy individuals who underwent brain dock screening at the Health Science Center in Shimane. We examined the factors that contributed to stroke and attempted to determine the risk of stroke by comparing background factors and MRI findings. RESULTS: The following items were found to be significant risk factors for stroke: age (≥60 years), hypertension, subclinical cerebral infarction, deep white matter lesion, and microbleeds. Each item was scored with 1 point, and the hazard ratios for the risk of developing stroke based on the group with 0 points were 17.2 (95% confidence interval [CI] 2.31-128) for 3 points, 18.1 (95% CI 2.03-162) for 4 points, and 102 (95% CI 12.6-836) for 5 points. CONCLUSIONS: A precise stroke prediction score biomarker can be obtained by combining MRI findings and clinical factors.

Altered Feedback-Related Negativity in Mild Cognitive Impairment.

INTRODUCTION: Feedback-related negativity (FRN) is electrical brain activity related to the function of monitoring behavior and its outcome. FRN is generated by negative feedback input, such as punishment or monetary loss, and its potential is distributed maximally over the frontal-central part of the skull. Our previous study demonstrated that FRN latency was delayed and that the amplitude was increased in patients with mild Alzheimer's disease (AD). As mild cognitive impairment (MCI) is considered to be a prodromal stage of AD, we speculated that FRN would also be altered in MCI, as in AD. The aim of this study is to examine whether MCI patients showed changes in FRN during a gambling task. METHODS: Thirteen MCI patients and thirteen age-matched healthy elderly individuals participated in a simple gambling task and underwent neuro-psychological assessments. The participants were asked to choose one out of two options and randomly received positive or negative feedback to their response. An EEG was recorded during the task, and FRN was obtained by subtracting the positive feedback-related activity from the negative feedback-related activity. RESULTS: The reaction time to probe stimuli was comparable in the two groups. The group comparisons revealed that the FRN amplitude was significantly larger for the MCI group than for the healthy elderly (F(1,24) = 6.4, ηp2 = 0.22, p = 0.019), but there was no group difference in the FRN latency. The FRN amplitude at the frontocentral electrode positively correlated with the mini-mental state examination score (Spearman's rhopartial = 0.41, p = 0.043). The finding of increased FRN amplitude in MCI was consistent with the previous finding in AD. CONCLUSION: Our findings indicate that monitoring dysfunction might also be involved in the prodromal stage of dementia.

Complex of global functional network as the core of consciousness.

Finding the neural basis of consciousness is challenging, and the distribution location of the core of consciousness remains inconclusive. Integrated information theory (IIT) argues that the posterior part of the brain is the hot zone of consciousness, especially phenological consciousness. The IIT has proposed a "main complex", a set of elements determined such that the information loss in a hierarchical partition approach is the largest among those of any other supersets and subsets, as the core of consciousness in a dynamic system. This approach may be applicable not only to phenomenal but also to access-consciousness. This study estimated the main complex of brain dynamics using functional magnetic resonance imaging in Human Connectome Project (HCP) and sleep datasets. The complex analyses revealed the common networks across various tasks and rest-state in HCP, composed of executive control, salience, and dorsal/ventral attention networks. The set of networks of the main complex was maintained during sleep. However, compared with the wakefulness stage, the amount of information of these networks and the default mode network, was reduced for the hypnagogic stage. The global interconnected structure composed of major functional networks can comprise the core of consciousness.

Effects of Obesity, Blood Pressure, and Blood Metabolic Biomarkers on Grey Matter Brain Healthcare Quotient: A Large Cohort Study of a Magnetic Resonance Imaging Brain Screening System in Japan.

This study investigated the relationship between grey matter (GM) volume and blood biomarkers, blood pressure, and obesity. We aimed to elucidate lifestyle factors that promote GM volume loss. A total of 1799 participants underwent the brain dock as a medical checkup. Data regarding blood pressure, obesity measurements, and standard blood biomarkers were obtained. Further, brain magnetic resonance imaging (MRI), including high-resolution T1-weighted imaging, was performed. We calculated the grey matter brain healthcare quotient (GM-BHQ), which represents GM volume as a deviation value. After adjusting for confounding variables, multiple regression analysis revealed that body mass index (BMI) (b = −0.28, p < 0.001), gamma-glutamyltransferase (γ-GTP) (b = −0.01, p = 0.16), and fasting blood glucose (b = −0.02, p = 0.049) were significantly correlated with GM-BHQ. Although the current cross-sectional study cannot determine a cause-and-effect relationship, elevated BMI, γ-GTP, and fasting blood glucose could promote GM volume loss.

Pulse pressure is associated with cognitive performance in Japanese non-demented population: a cross-sectional study.

BACKGROUND: Growing evidence suggests that vascular risk factors, especially hypertension, relate not only to cardiovascular disease but also to cognitive impairment. However, the impact of pulse pressure on cognitive function remains controversial. In this study, we evaluated the associations between pulse pressure and cognitive function in a Japanese health examination cohort using propensity matching analysis. METHODS: We examined 2,546 individuals with a mean age of 60.8 ± 10.3 years who voluntarily participated in health examination. Clinical variables included pulse pressure, and brain magnetic resonance imaging (MRI). We divided the participants into the high and low pulse pressure groups with a pre-defined cut-off value of 65 mmHg and evaluated their physical examination data, cognitive functions including Okabe's test, Kohs' test, and silent brain lesions using propensity matching. To clarify whether pulse pressure and blood pressure have different implications for cognitive function, a mediating analysis was also conducted. RESULTS: From the 2,546 subjects, 439 (17.2%) were in the high PP group. The propensity matching algorithm produced 433 pairs of patients with similar propensities. Higher pulse pressure corresponded to lower Okabe and Kohs' scores (44.3 ± 7.1 vs 42.7 ± 7.5; p = 0.002, 97.9 ± 18.0 vs 95.0 ± 18.1 p = 0.019, respectively). The relationship between pulse pressure and cognitive impairment was not significantly mediated by systolic blood pressure. We observed no significant associations between silent brain lesions and pulse pressure. CONCLUSION: High pulse pressure was associated with lower cognitive performance without systolic blood pressure mediation in Japanese subjects without dementia.

Altered resting-state functional connectivity of the frontal-striatal circuit in elderly with apathy.

Apathy is defined as reduction of goal-directed behaviors and a common nuisance syndrome of neurodegenerative and psychiatric disease. The underlying mechanism of apathy implicates changes of the front-striatal circuit, but its precise alteration is unclear for apathy in healthy aged people. The aim of our study is to investigate how the frontal-striatal circuit is changed in elderly with apathy using resting-state functional MRI. Eighteen subjects with apathy (7 female, 63.7 ± 3.0 years) and eighteen subjects without apathy (10 female, 64.8 ± 3.0 years) who underwent neuropsychological assessment and MRI measurement were recruited. We compared functional connectivity with/within the striatum between the apathy and non-apathy groups. The seed-to-voxel group analysis for functional connectivity between the striatum and other brain regions showed that the connectivity was decreased between the ventral rostral putamen and the right dorsal anterior cingulate cortex/supplementary motor area in the apathy group compared to the non-apathy group while the connectivity was increased between the dorsal caudate and the left sensorimotor area. Moreover, the ROI-to-ROI analysis within the striatum indicated reduction of functional connectivity between the ventral regions and dorsal regions of the striatum in the apathy group. Our findings suggest that the changes in functional connectivity balance among different frontal-striatum circuits contribute to apathy in elderly.

Multiscale Entropy of Resting-State Functional Magnetic Resonance Imaging Differentiates Progressive Supranuclear Palsy and Multiple System Atrophy.

Distinguishing progressive supranuclear palsy (PSP) from multiple system atrophy (MSA) in the early clinical stages is challenging; few sensitive and specific biomarkers are available for their differential diagnosis. Resting-state functional magnetic resonance imaging (rs-fMRI) is used to study the fluctuations in blood oxygen level-dependent (BOLD) signals at rest, which provides evidence for aberrant brain functional networks in neurodegenerative diseases. We aimed to examine whether rs-fMRI data could differentiate between PSP and MSA via a multiscale entropy (MSE) analysis of BOLD signals, which estimates the complexity of temporal fluctuations in brain activity. We recruited 14 and 18 patients with PSP and MSA, respectively, who underwent neuropsychological tests and rs-fMRI. PSP patients demonstrated greater cognitive function impairments, particularly in the frontal executive function. The bilateral prefrontal cortex revealed lower entropy BOLD signal values in multiple time scales for PSP, compared to the values observed in MSA patients; however, the functional connectivity of the representative brain networks was comparable between the diseases. The reduced complexity of BOLD signals in the prefrontal cortex was associated with frontal dysfunction. Thus, an MSE analysis of rs-fMRI could differentiate between PSP and MSA, and the reduced complexity of BOLD signals could be associated with cognitive impairment.

Grey-matter brain healthcare quotient and cognitive function: A large cohort study of an MRI brain screening system in Japan.

There is sometimes a divergence between brain atrophy and impairments in cognitive function. The present study aimed to assess the relationship between cognitive function and the grey-matter brain healthcare quotient (GM-BHQ), which represents brain volume as a deviation value. In addition, we aimed to investigate lifestyle factors that can help maintain cognitive function despite brain atrophy. A total of 1,757 adults included in a Japanese MRI brain screening cohort underwent MRI. We classified the participants into two age groups: under 65 years old (young adult/middle age group) and over 64 years old (elder group). The GM-BHQ was more strongly correlated with cognitive function in the young adult/middle age group than in the elder group (p < .01). Regression analysis revealed that years of education was associated with the maintenance of cognitive function despite brain atrophy (p < .05). In conclusion, our findings suggest that the relationship between brain volume and cognitive function becomes more obscure with age.

Environmental Factors Affecting Cognitive Function among Community-Dwelling Older Adults: A Longitudinal Study.

Although neighborhood environmental factors have been found to be associated with cognitive decline, few longitudinal studies have focused on their effect on older adults living in rural areas. This longitudinal study aimed to investigate the role of neighborhood environmental factors in cognitive decline among rural older adults. The data of 485 older adults aged ≥60 years who were living in Unnan City in Japan and had participated in two surveys conducted between 2014 and 2018 were analyzed. Cognitive function was assessed using the Cognitive Assessment for Dementia, iPad version 2. Elevation, hilliness, residential density, and proximity to a community center were determined using geographic information system. We applied a generalized estimating equation with odds ratios (OR) and 95% confidence intervals (CIs) of cognitive decline in the quartiles of neighborhood environmental factors. A total of 56 (11.6%) participants demonstrated a decrease in cognitive function at follow up. Elevation (adjusted OR 2.58, 95% CI (1.39, 4.77) for Q4 vs. Q1) and hilliness (adjusted OR 1.93, 95% CI (1.03, 3.63) for Q4 vs. Q1) were associated with a higher likelihood of cognitive decline. The second quartiles of residential density showed significantly lower likelihoods of cognitive decline compared with the first quartiles (adjusted OR 0.36, 95% CI (0.19, 0.71) for Q2 vs. Q1). Thus, an elevated hilly environment and residential density predicted cognitive decline among rural older adults.

Predicting intraocular pressure using systemic variables or fundus photography with deep learning in a health examination cohort.

The purpose of the current study was to predict intraocular pressure (IOP) using color fundus photography with a deep learning (DL) model, or, systemic variables with a multivariate linear regression model (MLM), along with least absolute shrinkage and selection operator regression (LASSO), support vector machine (SVM), and Random Forest: (RF). Training dataset included 3883 examinations from 3883 eyes of 1945 subjects and testing dataset 289 examinations from 289 eyes from 146 subjects. With the training dataset, MLM was constructed to predict IOP using 35 systemic variables and 25 blood measurements. A DL model was developed to predict IOP from color fundus photographs. The prediction accuracy of each model was evaluated through the absolute error and the marginal R-squared (mR2), using the testing dataset. The mean absolute error with MLM was 2.29 mmHg, which was significantly smaller than that with DL (2.70 dB). The mR2 with MLM was 0.15, whereas that with DL was 0.0066. The mean absolute error (between 2.24 and 2.30 mmHg) and mR2 (between 0.11 and 0.15) with LASSO, SVM and RF were similar to or poorer than MLM. A DL model to predict IOP using color fundus photography proved far less accurate than MLM using systemic variables.

Prevalence of Epiretinal Membrane among Subjects in a Health Examination Program in Japan.

The prevalence of an epiretinal membrane (ERM) was elucidated using a dataset from a health examination program database in Japan. From the cohort database, 5042 eyes of 2552 subjects were included. The presence of an ERM, cellophane macular reflex (CMR), or preretinal macular fibrosis (PMF) was detected using color fundus photographs, and crude and age-standardized prevalence were obtained. To further assess the possible risk factors of ERM, background parameters were compared between ERM+ and - groups, and multiple logistic regression analysis was performed. ERM was detected in fundus photographs of 275 eyes (eye-based prevalence of 5.5%) from 217 subjects (subject-based prevalence of 8.5%). CMR was detected in 169 eyes (3.4%) of 138 subjects (5.4%), and PMF was detected in 106 eyes (2.1%) of 97 subjects (3.8%). By univariate analyses, compared with ERM- eyes or subjects, higher Scheie's H grade (p < 0.0001), S grade (p < 0.0001), and glaucoma prevalence (p = 0.0440) were found in ERM+ eyes, and older age (p < 0.0001), more frequent histories of hypertension (p = 0.0033) and hyperlipidemia (p = 0.0441), and more frequent uses of medication for hypertension (p = 0.0034) and hyperlipidemia (p = 0.0074), shorter body height (p = 0.0122), and higher systolic blood pressure (p = 0.0078), and thicker intimal medial thickness (p = 0.0318) were found in ERM+ subjects. By multivariate analyses, older age (p < 0.0001, estimate = 0.05/year) was the only significant factor of ERM prevalence. Age-standardized prevalence of ERM was calculated to be 2.4%, 6.7%, and 13.3% for all ages, subjects older than 40 years, and subjects older than 65 years, respectively. We reported the prevalence of ERM and its subclasses in Japanese subjects. Since its prevalence is remarkably high in older subjects, an ERM can be seen as an important cause of visual impairment in Japan and in areas of the world where individuals live to an advanced age.

Distinct decrease in peripheral lymphocytes in EBER-positive cases of MTX-LPD.

OBJECTIVES: To determine the clinical characteristics of methotrexate-associated lymphoproliferative disorder (MTX-LPD). METHODS: In this study, 12 RA patients who developed MTX-LPD were assessed. The peripheral blood lymphocyte (PBL) count at the onset of MTX-LPD was compared to that 6 months before the onset, in Epstein-Barr virus-encoded RNA (EBER)-positive and -negative subgroups. We examined the change in the PBL count after MTX withdrawal. In patients with relapsed LPD, changes in the PBL count before relapse were also examined. RESULTS: Regression of LPD after MTX withdrawal was noted in eight patients. In these patients, the PBL count was decreased at the onset of MTX-LPD compared to 6 months before the onset; the decrease was significantly more prominent in EBER-positive patients. In cases of spontaneous regression of LPD, the PBL count recovered quickly after MTX withdrawal. Four of eight patients showed a recurrence of LPD after they improved following MTX withdrawal. These patients also exhibited a decreased PBL count at recurrence compared to 6 months before recurrence. CONCLUSION: A decrease in the PBL count might be involved in the pathogenesis of MTX-LPD, especially in EBER-positive cases and in patients with LPD relapse after MTX withdrawal following initial improvement.

The right hemisphere is important for driving-related cognitive function after stroke.

Considering quality of life (QOL) after stroke, car driving is one of the most important abilities for returning to the community. In this study, directed attention and sustained attention, which are thought to be crucial for driving, were examined. Identification of specific brain structure abnormalities associated with post-stroke cognitive dysfunction related to driving ability would help in determining fitness for car driving after stroke. Magnetic resonance imaging was performed in 57 post-stroke patients (51 men; mean age, 63 ± 11 years) who were assessed for attention deficit using a standardized test (the Clinical Assessment for Attention, CAT), which includes a Continuous Performance Test (CPT)-simple version (CPT-SRT), the Behavioral Inattention Test (BIT), and a driving simulator (handle task for dividing attention, and simple and selective reaction times for sustained attention). A statistical non-parametric map (SnPM) that displayed the association between lesion location and cognitive function for car driving was created. From the SnPM analysis, the overlay plots were localized to the right hemisphere during handling the hit task for bilateral sides (left hemisphere damage related to right-side neglect and right hemisphere damage related to left-side neglect) and during simple and selective reaction times (false recognition was related to damage of both hemispheres). A stepwise multiple linear regression analysis confirmed the importance of both hemispheres, especially the right hemisphere, for cognitive function and car driving ability. The present study demonstrated that the right hemisphere has a crucial role for maintaining directed attention and sustained attention, which maintain car driving ability, improving QOL for stroke survivors.

Prediction of conversion to Alzheimer's disease using deep survival analysis of MRI images.

The prediction of the conversion of healthy individuals and those with mild cognitive impairment to the status of active Alzheimer's disease is a challenging task. Recently, a survival analysis based upon deep learning was developed to enable predictions regarding the timing of an event in a dataset containing censored data. Here, we investigated whether a deep survival analysis could similarly predict the conversion to Alzheimer's disease. We selected individuals with mild cognitive impairment and cognitively normal subjects and used the grey matter volumes of brain regions in these subjects as predictive features. We then compared the prediction performances of the traditional standard Cox proportional-hazard model, the DeepHit model and our deep survival model based on a Weibull distribution. Our model achieved a maximum concordance index of 0.835, which was higher than that yielded by the Cox model and comparable to that of the DeepHit model. To our best knowledge, this is the first report to describe the application of a deep survival model to brain magnetic resonance imaging data. Our results demonstrate that this type of analysis could successfully predict the time of an individual's conversion to Alzheimer's disease.

The association of motivation with mind wandering in trait and state levels.

Mind wandering (MW) is a phenomenon in which attention drifts away from task-related thoughts toward task-unrelated thoughts. Recent studies have demonstrated that MW occurs during tasks in which participants are unmotivated. However, motivation ranges on a continuum from trait to state. We examined the association between trait-state motivation and trait-state MW. Participants (176 undergraduate students 18-24 years old; 68 male) completed three questionnaires for our trait level investigation. State level indices were measured using the experience sampling method with 104 students completing a sustained attention to response task. Through correlation analyses, we demonstrated an association between motivation and MW within the same dimension (trait and state, respectively) but found no association across dimensions in which the correlation coefficient was nearly zero. We show the significant association between motivation and MW whose novelty is especially evident in the trait level. Although the relationship between motivation and MW is substantial, trait-state dimensionality would be important for them. The state MW is a phasic phenomenon driven by a range of factors, one being state motivation. The causality and confounding factors remain to be further studied.

Systemic factors associated with intraocular pressure among subjects in a health examination program in Japan.

BACKGROUND: To elucidate the possible effect of various systemic factors on intraocular pressure (IOP) using a dataset from a health examination program database in Japan. METHODS: This cross-sectional study included 1569 subjects selected from the 2287 subjects who comprised the database. Various systemic parameters including age, sex, height, body weight, waist circumference, percent body fat, blood pressure (BP), pulse rate, body mass index, 28 blood examination values, intimal medial thicknesses of both carotid arteries, and intraocular pressure (IOP) values measured by non-contact tonometry in both eyes were collected. The possible correlation between the IOP and other parameters was assessed initially by univariate analyses followed by multivariate analyses. RESULTS: Stepwise multivariate analyses, which included all parameters extracted by the univariate analyses (p<0.1) and sex, identified the same six parameters as indicators of the IOP values for each right and left IOP model. Among the parameters, age (r = -0.05 and -0.04/year for right and left IOPs, respectively) was associated negatively and the percent body fat (r = 0.06 and 0.05/%), systolic BP (r = 0.02 and 0.03/mmHg), pulse rate (r = 0.03 and 0.03/counts/minutes), albumin (r = 1.12 and 1.00/g/dL), and hemoglobin A1c (r = 0.38 and 0.44/%) were associated positively with the IOP in each eye. CONCLUSIONS: Older age was associated with low IOP, while factors reflecting the metabolic syndrome were associated with high IOP in our study population.

iTRAQ-based proteomic analysis after mesenchymal stem cell line transplantation for ischemic stroke.

Transplantation with mesenchymal stem cells (MSCs) has been reported to promote functional recovery in animal models of ischemic stroke. However, the molecular mechanisms underlying the therapeutic effects of MSC transplantation have been only partially elucidated. The purpose of this study was to comprehensively identify changes in brain proteins in rats treated with MSCs for ischemic stroke, and to explore the multi-target mechanisms of MSCs using a proteomics-based strategy. Twenty-eight proteins were found to be differentially expressed following B10 MSC transplantation in adult male Wistar rats, as assessed using isobaric tagging for relative and absolute protein quantification (iTRAQ). Subsequent bioinformatic analysis revealed that these proteins were mainly associated with energy metabolism, glutamate excitotoxicity, oxidative stress, and brain structural and functional plasticity. Immunohistochemical staining revealed decreased expression of EAAT1 in the phosphate-buffered saline group as opposed to normal levels in the B10 transplantation group. Furthermore, ATP levels were also significantly higher in the B10 transplantation group, thus supporting the iTRAQ results. Our results suggest that the therapeutic effects of B10 transplantation might arise from the modulation of the acute ischemic cascade via multiple molecular pathways. Thus, our findings provide valuable clues to elucidate the mechanisms underlying the therapeutic effects of MSC transplantation in ischemic stroke.

Reduced Dynamic Complexity of BOLD Signals Differentiates Mild Cognitive Impairment From Normal Aging.

Mild cognitive impairment (MCI) is characterized as a transitional phase between cognitive decline associated with normal aging and Alzheimer's disease (AD). Resting-state functional magnetic resonance imaging (fMRI) measuring blood oxygenation level-dependent (BOLD) signals provides complementary information considered essential for understanding disease progression. Previous studies suggested that multi-scale entropy (MSE) analysis quantifying the complexity of BOLD signals is a novel and promising method for investigating neurodegeneration associated with cognitive decline in different stages of MCI. Therefore, the current study used MSE to explore the changes in the complexity of resting-state brain BOLD signals in patients with early MCI (EMCI) and late MCI (LMCI). We recruited 345 participants' data from the Alzheimer's Disease Neuroimaging Initiative database, including 176 normal control (NC) subjects, 87 patients with EMCI and 82 patients with LMCI. We observed a significant reduction of brain signal complexity toward regularity in the left fusiform gyrus region in the EMCI group and in the rostral anterior cingulate cortex in the LMCI group. Our results extend prior work by revealing that significant reductions of brain BOLD signal complexity can be detected in different stages of MCI independent of age, sex and regional atrophy. Notably, the reduction of BOLD signal complexity in the rostral anterior cingulate cortex was significantly associated with greater risk of progression to AD. The present study thus identified MSE as a potential imaging biomarker for the early diagnosis of pre-clinical Alzheimer's disease and provides further insights into the neuropathology of cognitive decline in prodromal AD.

Association between cystatin C gene polymorphism and the prevalence of white matter lesion in elderly healthy subjects.

Cystatin C (CST3) is a cysteine protease inhibitor abundant in the central nervous system, and demonstrated to have roles in several pathophysiological processes including vascular remodeling and inflammation. Previously, we showed a relation of CST3 gene polymorphisms with deep and subcortical white matter hyperintensity (DSWMH) in a small case-control study. In this study, we aimed to investigate the relation in a larger cross-sectional study. Participants of a brain health examination program were recruited (n = 1795) in the study, who underwent routine blood tests and cognitive function tests. Cerebral white matter changes were analyzed by MRI. Additionally, 7 single nucleotide polymorphisms (SNPs) (-82G/C, -78T/G, -5G/A, +4A/C, +87C/T, +148G/A and +213G/A) in the promoter and coding regions of CST3 gene were examined. Among them, carriers of the minor allele haplotype -82C/+4C/+148A were significantly associated with decreased CST3 concentration in the plasma. Unadjusted analysis did not show significant relation between carriers of the minor allele haplotype and periventricular hyperintensity (PVH), but DSWMH was marginally (p < 0.054) increased in this group. After adjusting the effects of other variables like age and kidney function, logistic regression analysis revealed that carriers of the minor allele haplotype were at a significantly increased risk of developing both PVH and DSWMH. Thus, our results suggest that carriers of the minor allele haplotype -82C/+4C/+148A of CST3 gene could be at an increased risk to develop cerebral white matter disturbance.