Trait-anxiety and glial-related neuroinflammation of the amygdala and its associated regions in Alzheimer's disease: A significant correlation.

Background: Positron emission tomography, which assesses the binding of translocator protein radiotracers, 11C-DPA-713, may be a sensitive method for determining glial-mediated neuroinflammation levels. This study investigated the relationship between regional 11C-DPA713 binding potential (BPND) and anxiety in patients with Alzheimer's disease (AD) continuum. Methods: Nineteen patients with AD continuum determined to be amyloid-/p-tau 181-positive via cerebrospinal fluid analysis were included in this cross-sectional study (mild cognitive impairment [MCI, n = 5] and AD [n = 14]). Anxiety was evaluated using the State-Trait Anxiety Inventory (STAI). A whole-brain voxel-based analysis was performed to examine the relationship between 11C-DPA-713-BPND values at each voxel and the STAI score. Stepwise multiple regression analysis was performed to determine the predictors of STAI scores using independent variables, including 11C-DPA-713-BPND values within significant clusters. 11C-DPA-713-BPND values were compared between patients with AD continuum with low-to-moderate and high STAI scores. Results: Voxel-based analysis revealed a positive correlation between trait anxiety severity and 11C-DPA713-BPND values in the centromedial amygdala and the left inferior occipital area [P < 0.001 (uncorrected) at the voxel-level]. 11C-DPA713-BPND values in these regions were a strong predictor of the STAI trait anxiety score. Specifically, patients with AD continuum and high trait anxiety had increased 11C-DPA713-BPND values in these regions. Conclusions: The amygdala-occipital lobe circuit influences the control of emotional generation, and disruption of this network by AD pathology-induced inflammation may contribute to the expression of anxiety. Our findings suggest that suppression of inflammation can help effectively treat anxiety by attenuating damage to the amygdala and its associated areas.

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

Neuroimaging biomarkers of glial activation for predicting the annual cognitive function decline in patients with Alzheimer's disease.

BACKGROUND: Glial activation is central to the pathogenesis of Alzheimer's disease (AD). However, researchers have not demonstrated its relationship to longitudinal cognitive deterioration. We aimed to compare the prognostic effects of baseline positron emission tomography (PET) imaging of glial activation and amyloid/tau pathology on the successive annual cognitive decline in patients with AD. METHODS: We selected 17 patients diagnosed with mild cognitive impairment or AD. We assessed the annual changes in global cognition and memory. Furthermore, we assessed the predictive effects of baseline amyloid and tau pathology indicated by cerebrospinal fluid (CSF) concentrations and PET imaging of glial activation (11C-DPA-713-binding potential in the area of Braak 1-3 [11C-DPA-713-BPND]) on global cognition and memory using a stepwise regression analysis. RESULTS: The final multiple regression model of annual changes in global cognition and memory scores included 11C-DPA-713-BPND as the predictor. The CSF Aß42/40 ratios and p-tau concentrations were removed from the final model. In stepwise Bayesian regression analysis, the Bayes factor-based model comparison suggested that the best model included 11C-DPA-713-BPND as the predictor of decline in global cognition and memory. CONCLUSIONS: Translocator protein-PET imaging of glial activation is a stronger predictor of AD clinical progression than the amount of amyloid/tau pathology measured using CSF concentrations. Glial activation is the primary cause of tau-induced neuronal toxicity and cognitive deterioration, thereby highlighting the potential of blocking maladaptive microglial responses as a therapeutic strategy for AD treatment.

Association of adverse childhood experience-related increase in neurite density with sensory over-responsivity in autism spectrum disorder: A neurite orientation dispersion and density imaging study.

Sensory over-responsivity (SOR) causes social and daily distress in individuals with autism spectrum disorder (ASD). Compared to typically developed (TD) individuals, ASD individuals are at higher risk of adverse childhood experiences (ACEs), which induce abnormal neuronal development. However, whether or how ACEs are associated with abnormal neural development and SOR in ASD remains to be determined. Forty-five individuals with ASD and 43 TD individuals underwent T1-weighted and neurite orientation dispersion and density imaging; the axonal and dendritic densities were defined as the neurite density index (NDI). Voxel-based analyses were performed to explore the brain regions associated with SOR. The relationships between severity of ACEs and SOR, and NDI in the brain regions were examined. ASD individuals showed a significantly positive association between SOR severity and NDI in the right superior temporal gyrus (STG), which was not found in TD individuals. Severity of ACEs correlated significantly with that of SOR and NDI in the right STG in ASD; ASD individuals having severe SOR showed significantly higher NDI in the right STG than those with mild SOR and TD individuals. In individuals with ASD, NDI in the right STG, but not ACEs, could predict the severity of SOR, which was not shown in TD subjects. Our findings suggest that severe ACEs are involved in excessive neurite density in the right STG in ASD. ACE-associated excessive neurite density in the right STG is critical for SOR in ASD, which may be a therapeutic target in the future.

Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an in vivo positron emission tomography study.

BACKGROUND: The evaluation of 11 C-DPA-713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional 11 C-DPA713-binding potential (BPND ) and neuropsychiatric symptoms (NPS) in amyloid-positive Alzheimer's disease (AD) patients. METHODS: Fifteen AD patients were enrolled in this study. Correlations were evaluated between the 11 C-DPA713-BPND and Neuropsychiatric Inventory Questionnaire (NPI-Q) scores, including scores in its four domains: agitation, psychosis, affective, and apathy. 11 C-DPA713-BPND values were compared between groups with and without the neuropsychiatric symptoms for which a relationship was observed in the abovementioned correlation analysis. RESULTS: A positive correlation was found between the severity of agitation and 11 C-DPA713-BPND in the Braak 1-3 area, including the amygdala, hippocampal and parahippocampal regions, and lingual and fusiform areas. An increase in the 11 C-DPA713-BPND was observed in AD patients with agitation. We did not find any significant effects of possible confounding factors, such as age, duration of illness, education, gender, Mini-Mental State Examination score, cerebrospinal fluid amyloid ß 42/40 ratio, and apolipoprotein E4 positivity, on either the 11 C-DPA713-BPND or agitation score. CONCLUSIONS: Neuroinflammation in the medial temporal region and its neighbouring area was shown to be associated with the development of agitation symptoms in AD patients. Our findings extend those of previous studies showing an association between some NPS and inflammation, suggesting that immunologically based interventions for agitation can serve as an alternative treatment for dementia.

A multidimensional physical scale is a useful screening test for mild depression associated with childcare in Japanese child-rearing women.

Introduction: Maternal depression is one of the important problems of postpartum women. For its early detection and appropriate treatment, it is necessary to identify women at high risk for depression quickly and easily. Materials and methods: A simple screening scale for depression from physical aspects, the multidimensional physical scale (MDPS), which is a 17-item, self-report, three-step scale (0, 1, 2) according to the theory of Kampo medicine, was developed. The aim of the present study was to develop (n = 785) and validate (n = 350) the MDPS that was designed to rate the risk of depression. The Beck Depression Inventory-Second Edition was used for determination of depression. In the development cohort, the final model was determined using multi-regression logistic analysis. Results: The components of the MDPS for mothers (MDPS-M) were developed, containing the total score of MDPS (0-34 points) and resumption of menstruation or not (-3, 0 points). Receiver-operating characteristic curve analysis of the MDPS-M (-3 to 34) for identifying a high risk of depression showed moderately good discrimination [area under the curve (AUC) = 0.74, 95% confidence interval (CI): 0.70-0.78]. At the cutoff value of MDPS-M (9/10), its sensitivity, specificity, positive predictive value, and negative predictive value were 84.9, 45.7, 36.7, and 89.2%, respectively. External validation of the MDPS-M showed moderately good discrimination (AUC = 0.74, 95% CI: 0.68-0.79) using the same analysis as the development cohort. Conclusion: These results indicate that the MDPS-M is a useful, simple, clinical scale for early identification of mothers at high risk of depression in primary care.

Estimation of blood-based biomarkers of glial activation related to neuroinflammation.

Background: Neuroinflammation is a well-known feature of Alzheimer's disease (AD), and a blood-based test for estimating the levels of neuroinflammation would be expected. In this study, we examined and validated a model using blood-based biomarkers to predict the level of glial activation due to neuroinflammation, as estimated by 11C-DPA-713 positron emission tomography (PET) imaging. Methods: We included 15 patients with AD and 10 cognitively normal (CN) subjects. Stepwise backward deletion multiple regression analysis was used to determine the predictors of the TSPO-binding potential (BPND) estimated by PET imaging. The independent variables were age, sex, diagnosis, apolipoprotein E4 positivity, body mass index and the serum concentration of blood-based biomarkers, including monocyte chemotactic protein 1 (MCP-1), fractalkine, chitinase 3-like protein-1 (CHI3L1), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and clusterin. Results: Sex, diagnosis, and serum concentrations of MCP1 and sTREM2 were determined as predictors of TSPO-BPND in the Braak1-3 area. The serum concentrations of MCP1 and sTREM2 correlated positively with TSPO-BPND. In a leave one out (LOO) cross-validation (CV) analysis, the model gave a LOO CV R2 of 0.424, which indicated that this model can account for approximately 42.4% of the variance of brain TSPO-BPND. Conclusions: We found that the model including serum MCP-1 and sTREM2 concentration and covariates of sex and diagnosis was the best for predicting brain TSPO-BPND. The detection of neuroinflammation in AD patients by blood-based biomarkers should be a sensitive and useful tool for making an early diagnosis and monitoring disease progression and treatment effectiveness.

Season of birth and vulnerability to the pathology of Alzheimer's disease: an in vivo positron emission tomography study.

BACKGROUND: This study used positron emission tomography to examine whether the seasonal birth effect as an exogenic indicator of early life environmental factors influenced vulnerability to Alzheimer's disease (AD) pathology in the elderly. METHODS: We analysed datasets from the Alzheimer's Disease Neuroimaging Initiative, which included the data for 234 cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) (n = 114) and AD dementia (n = 38). As an index of amyloid ß (Aß)/tau accumulation, the 18 F-AV-45- and 18 F-AV-1451-standardized uptake value ratios (SUVRs) were compared between groups of spring-to-summer births and fall-to-winter births by analysis of covariance. In addition, a multiple linear regression analysis was performed to determine whether the season of birth was a predictor of 18 F-AV-45 and/or 18 F-AV-1451 SUVRs, for which a difference was observed. RESULTS: Seasonal birth difference was a good predictor of 18 F-AV-1451 SUVR. We found that participants with a fall-to-winter birth showed lower 18 F-AV-1451 SUVRs than those with a spring-to-summer birth in both the CN and MCI/AD groups, after correcting for the effect of age, sex, years of education, and Alzheimer's Disease Assessment Scale cognitive subscale score, that could possibly affect tau accumulation. CONCLUSIONS: Participants with a fall-to-winter birth showed less tau accumulation than those with a spring-to-summer birth after accounting for the factors that could affect tau accumulation. Our findings showed a vulnerability to tau pathology in participants with a fall-to-winter birth, which may be caused by perinatal or postnatal brain damage due to the risk factors associated with the cold season.

Kinetic modeling and non-invasive approach for translocator protein quantification with 11C-DPA-713.

INTRODUCTION: 11C-DPA-713 is a positron emission tomography (PET) radiotracer developed for imaging the expression of the translocator protein (TSPO) in glial cells, which is considered to be a marker of the neuroinflammatory burden. This study investigated the pharmacokinetic profile of 11C-DPA-713 and evaluated kinetic modeling and non-invasive TSPO quantification using dynamic PET imaging data in the Alzheimer's disease (AD) and cognitive normal (CN) participants. METHODS: Eleven patients with AD and 6 CN participants were examined using dynamic 11C-DPA-713 PET imaging for 60 min with arterial blood sampling. Time-activity curves were calculated from the cerebellum and three composite regions of interest (ROIs), according to the anatomical definitions of Braak's stages 1 to 3, stage 4, stage 5, and stage 6 that correspond to the pathological stages of tangle deposition. The total distribution volume (VT) was evaluated using compartmental modeling and graphical analysis. Reference region-based methods were implemented using an optimal area that was assumed to be void of the radiotracer target as reference tissue. RESULTS: The concentration of radioactivity in plasma demonstrated rapid clearance. 11C-DPA-713 peaked rapidly in the gray matter. Compartmental modeling resulted in a good fit, and the one-tissue model with estimated blood volume correction (1Tv) showed the best performance. The estimated VT obtained from the graphical plasma methods was highly correlated with that obtained from 1Tv. Reference region-based analysis was conducted using the Braak 6 area as the reference region, and the estimated non-displaceable binding potential was highly correlated with that obtained from 1Tv. CONCLUSION: 11C-DPA-713 possesses properties suitable for TSPO quantification with PET imaging. The Braak 6 area was shown to be a useful reference region in the patients with AD and the CN participants, and non-invasive reference tissue models using the Braak 6 area as a reference region can be employed for TSPO quantification with 11C-DPA-713-PET imaging as an alternative to the invasive compartmental model.

Apathy after subarachnoid haemorrhage: A systematic review.

BACKGROUND: Apathy is a common and debilitating symptom accompanying many neurological disorders including non-traumatic subarachnoid hemorrhage (SAH). OBJECTIVES: The aim of this systematic review was to identify and critically appraise all published studies that have reported the prevalence, severity, and time course of apathy after SAH, the factors associated with its development, and the impact of apathy on patients' quality of life after SAH. METHODS: The PubMed, EMBASE, PsycINFO, and Ovid Nursing databases were searched for studies published in English that recruited at least 10 patients (>18 years old) after SAH who were also diagnosed with apathy. RESULTS: Altogether 10 studies covering 595 patients met the study's inclusion criteria. The prevalence of apathy ranged from 15 to 68%, with a weighted proportion of 38%. The time course of apathy was unknown. Comorbid cognitive impairment increases the risk of apathy. Blood in lateral ventricles and hydrocephalus may also be related to apathy. Apathy reduces participation in leisure and sexual activities. There were several methodological shortcomings in the included studies, namely, heterogeneity in study design and timing of apathy assessment, hospitalized /clinic-based and biased sampling, small sample sizes and some had high attrition rates, and uncertain validity of the measures of apathy. CONCLUSIONS: Apathy is common after SAH. Further research is needed to clarify its time course and identify the neurochemical factors and brain circuits associated with the development of post-SAH apathy. Randomized controlled treatment trials targeting SAH-related apathy are warranted.

Association of adverse childhood experiences and precuneus volume with intrusive reexperiencing in autism spectrum disorder.

Compared to typically developing (TD) children, people with autism spectrum disorder (ASD) have an increased risk of adverse childhood experiences (ACEs). Exposure to ACEs is associated with adult ASD psychological comorbidities, such as posttraumatic stress disorder (PTSD). Occurrence of intrusive event reexperiencing, characteristic of PTSD, often causes social dysfunction in adults with ASD, but its pathological basis is unclear. This study examined brain regions related to the severity of intrusive reexperiencing and explored whether ACE severity was associated with that of intrusive reexperiencing and/or extracted regional gray matter volume. Forty-six individuals with ASD and 41 TD subjects underwent T1-weighted magnetic resonance imaging and evaluation of ACEs and intrusive reexperiencing. Brain regions related to the severity of intrusive reexperiencing in both groups were identified by voxel-based whole brain analyses. Associations among the severity of intrusive reexperiencing, that of ACEs, and gray matter volume were examined in both groups. The severities of intrusive reexperiencing and ACEs were significantly associated with reduced gray matter volume in the right precuneus in individuals with ASD but not in TD subjects. Although the right precuneus gray matter volume was smaller in individuals with ASD and severe ACEs than in those with mild ACEs or TD subjects, it was similar in the latter two groups. However, ACE-dependent gray matter volume reduction in the right precuneus led to intrusive reexperiencing in individuals with ASD. This suggests that exposure to ACEs is associated with right precuneus gray matter reduction, which is critical for intrusive reexperiencing in adults with ASD. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) are at increased risk of adverse childhood experiences (ACEs) and of subsequent manifestation of intrusive reexperiencing of stressful life events. The present study found that reduced gray matter volume in the right precuneus of the brain was associated with more severe intrusive reexperiencing of ACEs by individuals with ASD. These results suggest that ACEs affect neural development in the precuneus, which is the pathological basis of intrusive event reexperiencing in ASD.

Significant effects of cholinesterase inhibitors on tau pathology in the Alzheimer's disease continuum: An in vivo positron emission tomography study.

OBJECTIVES: No prior study has assessed the effects of cholinesterase inhibitors (ChEIs) on tau pathology in the brains of patients with Alzheimer's disease (AD). Using positron emission tomography, this study aimed to investigate whether ChEIs reduce tau aggregation in amyloid-positive participants. METHODS: We analyzed datasets from the Alzheimer's Disease Neuroimaging Initiative and included amyloid-positive participants who had undergone baseline and 1- or 2-year follow-up AV-1451 positron emission tomography scans. We included participants treated with and without ChEIs (ChEIs group: n = 15, No-ChEIs group, n = 45). The annual change in tau aggregation was calculated as the difference in AV-1451- standardized uptake value ratio (SUVR) between the two scans divided by the time between scans. Group differences in annual AV-1451-SUVR change were examined. RESULTS: We found a significantly lower annual change in AV-1451-SUVR in the Braak 1/2 regions (entorhinal cortex and hippocampus) of participants taking ChEIs. Increased AV-1451-SUVR between the first and second examinations were observed in 22 of 45 participants not taking ChEIs and 2 of 15 participants taking ChEIs. Fisher's exact test showed a significant difference in the ratio of participants with increased AV-1451-SUVR between the groups. CONCLUSIONS: The findings of this positron emission tomography study suggest that the administration of ChEIs has some neuroprotective effects in patients of the AD continuum, at least in the early stage of the disease progression. This in vivo effect may be mediated via tau, preventing amyloid ß-induced neurotoxicity.

A retrospective study of factors associated with persistent delirium.

BACKGROUND: It has been reported that delirium causes various problems. Many researchers have reported the risk factors associated with the onset of delirium; however, there are few reports focused on persistent delirium. This study aimed to identify the risk factors associated with persistent delirium. METHODS: A total of 573 patients hospitalised in Nara Prefecture General Medical Centre from October 2014 through September 2017 who were referred to the psychiatry consultation service were included in this study. Persistent delirium was defined as delirium lasting for 14 days or more. A retrospective study was carried out based on the patients' records. The relationship between various background factors and persistent delirium was statistically analysed. RESULTS: Of the 573 hospitalised patients, 295 were diagnosed as having delirium. Forty-six patients with persistent delirium and 181 patients with nonpersistent delirium were included in this study. Multivariable logistic regression analyses revealed that male gender, opioid analgesics use, non-opioid analgesics use, and low serum sodium were significantly and independently associated with persistent delirium. Ramelteon or trazodone was used significantly more in persistent delirium, although each use was not significant. CONCLUSION: This is the first study to reveal that male gender and use of analgesics were associated with persistent delirium in general hospital. However, as this is a case-control study and may contain bias, future cohort studies and intervention studies are needed. It is also necessary to investigate the relevance of the 'degree of pain' behind the use of analgesics.

Relationship between neuropsychiatric symptoms and Alzheimer's disease pathology: An in vivo positron emission tomography study.

OBJECTIVES: To investigate the relationship between amyloid-ß- and tau-based Alzheimer's disease (AD) pathologies assessed using positron emission tomography imaging and neuropsychiatric symptoms (NPS) in a sample of AD continuum including clinically normal subjects and patients with mild cognitive impairment or AD. METHODS: We analyzed datasets of the Alzheimer's disease Neuroimaging Initiative and included amyloid-positive subjects who underwent an AV-45 scan within 1 year of an AV-1451 scan (n = 99). Correlation between standardized uptake value ratio (SUVR) of AV-45 and AV-1451 and the Neuropsychiatric Inventory (NPI) score (and its four domain subscores for hyperactivity, psychosis, affective, and apathy) was evaluated. Stepwise logistic regression analysis was used to examine the influence of SUVRs on the presence of NPS. SUVRs were also tested for their ability to discriminate the group with NPS using receiver operating characteristic (ROC) curve analyses. RESULTS: Significant positive relationships were found between the total NPI score and affective symptoms and Braak 1&2 (transentorhinal region) AV-1451 SUVR. Stepwise logistic regression analysis identified tau accumulation in the area of Braak 1&2 as a significant covariate discriminating the presence of affective symptoms. The area under the ROC curve analysis showed that subjects with affective symptoms were discriminated by AV-1451 SUVR with an accuracy of 77.7%. CONCLUSIONS: Tau aggregation in the transentorhinal region, where neurodegeneration affected by tau pathology was seen in the early stage of AD, correlated with more severe NPS, especially affective symptoms. Therefore, tau pathology in the transentorhinal cortex might be associated with affective symptoms in the early stage of AD.

An evaluation of the amyloid cascade model using in vivo positron emission tomographic imaging.

AIM: The amyloid cascade hypothesis posits that the accumulation of amyloid ß (Aß) is the triggering factor for Alzheimer's disease, which consecutively induces aggregation of tau, synaptic loss, and cell death. Most experimental and clinical evidence supports this model, but the available data are largely qualitative. Here, we tested the amyloid cascade hypothesis by using in vivo evaluation of positron emission tomography and magnetic resonance imaging. METHODS: Path analysis was used to estimate the relationships among Aß accumulation (PiB standardized uptake value ratio (SUVR)), tau aggregation and its related neuroinflammation (THK5351 SUVR), grey matter atrophy in the medial temporal region, and memory function in Aß-positive subjects. We also performed additional regression analyses to evaluate the effect of Aß on the toxicity of tau aggregation/neuroinflammation. RESULTS: Path analysis supported our hypothesized model: Aß accumulation affected tau aggregation/neuroinflammation in the medial temporal region, and these pathological changes caused of the grey matter atrophy and memory dysfunction. In separate regression analyses, THK5351 SUVR had a significant effect on grey matter atrophy only in PiB-positive subjects. The analysis of the interaction effect showed that the effects of THK5351 SUVR on grey matter atrophy were significantly different between PiB-positive and PiB-negative groups. When we included the effect of being an apolipoprotein E ε4 carrier as a covariate, the interaction effect remained significant. CONCLUSION: Our in vivo evaluation of positron emission tomographic and magnetic resonance imaging data supported the amyloid cascade hypothesis. In addition, it indicated that Aß not only accelerates tau aggregation/neuroinflammation but promotes its toxicity. Our findings showed the importance of understanding the role and therapeutic potential of the interaction between amyloid and tau aggregation/neuroinflammation in Alzheimer's disease.

Adverse Childhood Experience Is Associated With Disrupted White Matter Integrity in Autism Spectrum Disorder: A Diffusion Tensor Imaging Study.

Individuals with autism spectrum disorder (ASD) have an increased risk of adverse childhood experiences (ACEs) than typically developed (TD) children. Since multiple lines of studies have suggested that ACEs are related to myelination in the frontal lobe, an exposure to ACEs can be associated with white matter microstructural disruption in the frontal lobe, which may be implicated in subsequential psychological deficits after the adulthood. In this study, we investigated the relationship between ACEs and microstructural integrity on frontal lobe-related white matter tracts using diffusion tensor imaging in 63 individuals with ASD and 38 TD participants. Using a tractography-based analysis, we delineated the uncinate fasciculus (UF), dorsal cingulum (Ci), and anterior thalamic radiation (ATR), which are involved in the neural pathology of ASD, and estimated each diffusion parameter. Compared to the TD participants, individuals with ASD displayed significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the left ATR. Then, ASD individuals exposed to severe ACEs displayed higher RD than those exposed to mild ACEs and TD participants in the left ATR. Moreover, the severity of ACEs, particularly neglect, correlated with lower FA and higher RD in the left UF and ATR in individuals with ASD, which was not observed in TD participants. These results suggest that an exposure to ACEs is associated with abnormality in the frontal lobe-related white matter in ASD.

Microstructural white matter changes following gait training with Hybrid Assistive Limb initiated within 1 week of stroke onset.

The early initiation of robot-assisted gait training in patients with acute stroke could promote neuroplasticity. The aim of this study was to clarify the microstructural changes of white matter associated with gait training using Hybrid Assistive Limb (HAL) by diffusion tensor imaging (DTI). Patients with first-ever stroke and requiring a walking aid started gait training within 1 week of stroke onset. The patients were quasi-randomly assigned either to the conventional physical therapy (CPT) group or gait training using HAL (HAL) group. Motor function and DTI were examined at baseline and after 3-5 months. Voxel-based statistical analyses of fractional anisotropy (FA) images were performed using diffusion metric voxel-wise analyses. Volume of interest (VOI)-based analyses were used to assess changes in FA (ΔFA). Twenty-seven patients (17 in the CPT group and 10 in the HAL group) completed the study. There were improvements in motor function and independency in the CPT and HAL groups (p < .001). Compared to baseline, there were decreases in FA in the ipsi-lesional cerebral peduncle in the CPT group (p < .001) and increases in the contra-lesional rostrum of the corpus callosum in the HAL group (p < .001) at the second assessment, consistent with the mean ΔFA in each group from VOI analysis (CPT/HAL: cerebral peduncle, -0.066/-0.027, p = .027; corpus callosum, 0.002/0.042, p < .001). Gait training using HAL initiated within 1 week after stroke onset facilitated the recovery of inter-hemispheric communication and prevented the progression of Wallerian degeneration of the affected pyramidal tract.

Increased Dendritic Orientation Dispersion in the Left Occipital Gyrus is Associated with Atypical Visual Processing in Adults with Autism Spectrum Disorder.

In autism spectrum disorder (ASD), the complexity-specific hypothesis explains that atypical visual processing is attributable to selective functional changes in visual pathways. We investigated dendritic microstructures and their associations with functional connectivity (FC). Participants included 28 individuals with ASD and 29 typically developed persons. We explored changes in neurite orientation dispersion and density imaging (NODDI) and brain areas whose FC was significantly correlated with NODDI parameters in the explored regions of interests. Individuals with ASD showed significantly higher orientation dispersion index (ODI) values in the left occipital gyrus (OG) corresponding to the secondary visual cortex (V2). FC values between the left OG and the left middle temporal gyrus (MTG) were significantly negatively correlated with mean ODI values. The mean ODI values in the left OG were significantly positively associated with low registration of the visual quadrants of the Adolescent/Adult Sensory Profile (AASP), resulting in a significant positive correlation with passive behavioral responses of the AASP visual quadrants; additionally, the FC values between the left OG and the left MTG were significantly negatively associated with reciprocal social interaction. Our results suggest that abnormal V2 dendritic arborization is associated with atypical visual processing by altered intermediation in the ventral visual pathway.

Interaction effect of Alzheimer's disease pathology and education, occupation, and socioeconomic status as a proxy for cognitive reserve on cognitive performance: in vivo positron emission tomography study.

AIM: Educational attainment, occupation, and socioeconomic status have been regarded as major factors influencing cognitive reserve (CR). This study aimed to investigate the interaction effect of amyloid-ß/tau burden and education/occupation/socioeconomic status as a proxy for CR on cognitive performance. METHODS: We analyzed the datasets of the Alzheimer's Disease Neuroimaging Initiative. We included clinically normal subjects and patients with mild cognitive impairment or Alzheimer's disease who had undergone a florbetapir scan within 1 year of a flortaucipir (AV-1451) scan (n = 127). Partial correlation analysis between the standardized uptake value ratio of florbetapir/AV-1451 and the proxy for CR was performed with the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) score as a covariate. Stepwise multiple linear regression analysis was performed to determine the predictors of ADAS-cog performance based on the interaction between the imaging biomarkers and the proxy for CR. RESULTS: We found a significant positive partial correlation between educational level and tau pathology in Braak stage 1/2 areas, and we observed significantly higher tau accumulation among participants with higher education when ADAS-cog score was used as a covariate. The interaction between tau and education was a good predictor of cognitive function, with higher tau accumulation showing a greater association with higher ADAS-cog score among participants with less education than among those with more education. CONCLUSION: Our findings indicate the protective effect of education against cognitive dysfunction in early-stage Alzheimer's disease pathology and suggest that education may exert a beneficial effect by reducing the adverse cognitive consequences of tau aggregation.

Microstructural Anomalies Evaluated by Neurite Orientation Dispersion and Density Imaging Are Related to Deficits in Facial Emotional Recognition via Perceptual-Binding Difficulties in Autism Spectrum Disorder.

The integration of visual features is important for recognizing objects as a coherent whole, a key domain of difficulty in autism spectrum disorder (ASD). We tested the hypothesis that ASD patients exhibit difficulties in facial emotional recognition via perceptual binding difficulties due to weak coherence. We assessed 18 ASD and 27 typically developing individuals for their ability to identify emotional expressions from faces in pictures moving behind a narrow vertical and horizontal slit. In this task, only a single local piece of facial information was provided at any one time through the slit. Using a voxel-based analysis of neurite-orientation dispersion and density imaging (NODDI), we examined the relationship between NODDI index values at each voxel and the behavioral performance of ASD patients in the slit-viewing paradigm. ASD patients demonstrated impaired recognition of facial emotional expression only in horizontal slit-viewing. This deficit was associated with deficits in communication ability. Voxel-based analysis revealed significant negative correlations between behavioral deficits in horizontal slit-viewing and NODDI index values in clusters including the ventral occipital complex region, superior temporal/parietal association areas, and forceps major of the corpus callosum. Our results indicated deficits for the first time in perceptual integration of facial expression across hemispheres in ASD patients due to microstructural disturbances in the corpus callosum and areas related to viewing of the human face. This may underscore the difficulties faced by ASD patients in understanding the emotions of other people, contributing to impairments in communication ability in ASD patients. Autism Res 2020, 13: 729-740. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We assessed ASD and typically developing individuals for their ability to identify emotional expressions from faces in pictures moving behind a narrow vertical and horizontal slit. ASD patients demonstrated impaired recognition of facial emotional expression only in horizontal slit-viewing. Voxel-based analysis revealed significant negative correlations between behavioral deficits and NODDI index values in clusters including the corpus callosum. Our results indicated deficits in perceptual integration of facial expression across hemispheres in ASD patients potentially resulting from microstructural disturbances.