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To investigate the effect of exogenous nitric oxide (NO) on aluminum tolerance of Eucalyptus seedlings under aluminum stress. In this study, sodium nitroproside (SNP) was used as exogenous NO donor in four kinds of Eucalyptus seedlings (Eucalyptus grandis, E. urophylla, E. tereticornis, E. urophylla×E. grandis). The effects of different concentrations of NO (0, 50, 100, 200, 400, 800 μmol·L-1) on the physiological indices of ROS, antioxidant enzyme activities and the contents of organic osmotic regulatory substances of Eucalyptus seedlings under 120 mg·L-1 aluminum stress were studied, and the differences of aluminum tolerance of four Eucalyptus species under NO treatment were compared. The results were as follows: (1) The addition of exogenous NO (50 μmol·L-1≤NO≤200 μmol·L-1) under aluminum stress promoted the contents of soluble sugar and soluble protein, the activities of antioxidant enzymes (SOD, POD, CAT, APX), the removal of ROS in the body, the reduction of MDA accumulation, and the improvement of aluminum stress resistance. However, under high concentration of NO(≥800 μmol·L-1), the activities of antioxidant enzymes and the contents of osmotic regulatory substances decreased in Eucalyptus seedlings, showing stress response. (2) NO significantly improved the aluminum tolerance of sensitive Eucalyptus, but not significantly improved the aluminum tolerance of tolerant Eucalyptus. Finally, the aluminum resistance of four Eucalyptus species tended to be consistent under the action of NO. (3) SOD, MDA, CAT, O2-, soluble protein and soluble sugar could be used as key indicators to evaluate the aluminum tolerance of Eucalyptus. This study provides a scientific reference for the selection of aluminum tolerance germplasm resources of Eucalyptus, and laid a foundation for further understanding of the mechanism of NO regulating the difference of aluminum tolerance between Eucalyptus species.

IntroductionThe ε4 allele of the apolipoprotein E gene (APOE4) is expressed abundantly in both the brain and peripheral circulation as a genetic risk factor for Alzheimer’s disease (AD). Cerebral blood flow (CBF) dysfunction is an essential feature of AD, and the liver plays an important role in the pathogenesis of dementia. However, the associations of APOE4 with CBF and liver function markers in patients with cognitive impairment remains unclear. We aimed to evaluate the associations of APOE4 with CBF measured by arterial spin labeling (ASL) magnetic resonance imaging (MRI) and serum liver function markers in participants who were diagnosed with cognitive impairment.MethodsFourteen participants with AD and sixteen with amnestic mild cognitive impairment (MCI) were recruited. In addition to providing comprehensive clinical information, all patients underwent laboratory tests and MRI. All participants were divided into carriers and noncarriers of the ε4 allele, and T-tests and Mann–Whitney U tests were used to observe the differences between APOE4 carriers and noncarriers in CBF and liver function markers.ResultsRegarding regional cerebral blood flow (rCBF), APOE4 carriers showed hyperperfusion in the bilateral occipital cortex, bilateral thalamus, and left precuneus and hypoperfusion in the right lateral temporal cortex when compared with noncarriers. Regarding serum liver function markers, bilirubin levels (including total, direct, and indirect) were lower in APOE4 carriers than in noncarriers.ConclusionAPOE4 exerts a strong effect on CBF dysfunction by inheritance, representing a risk factor for AD. APOE4 may be related to bilirubin metabolism, potentially providing specific neural targets for the diagnosis and treatment of AD.

Summary: Background: Having more cognitive activities may prevent dementia, but its evidence of modulating the functional brain network is limited. This randomised controlled trial (RCT) investigated the effect of increased cognitive activity participation on the default mode network (DMN) in older adults who had already been having regular cognitive activity participation and experiencing subjective cognitive decline (SCD). Methods: Community-living Chinese individuals aged 55–75 years with regular practice of Chinese calligraphy and screened positive for SCD (but negative for mild cognitive impairment or dementia) were randomly allocated to either the intervention or control group. Over 6 months, the intervention group doubled their weekly calligraphy practice time, while the control group maintained their usual amount of practice. The primary outcome was functional connectivities (FCs) of DMN, with pre-specified regions of interest including medial prefrontal cortex (mPFC), inferior parietal lobe (IPL), hippocampal formation (HF), posterior cingulate cortex (PCC), and lateral temporal cortex (LTC). FC changes were compared using repeated measures multivariate analysis of variance (MANOVA). This study is registered at the Chinese Clinical Trial Registry, ChiCTR1900024433. Findings: Between 15 January 2020 and 31 December 2021, 112 individuals consented and completed the baseline assessment. The participants, who had a mean age of 66.3 (SD 4.3) years, with 83 (74%) being women, had been practising calligraphy for an average duration of 9.7 years before enrolment and, in the preceding six months, for an average of 3.1 hours per week. 96 (86%) completed the post-intervention fMRI scan. Significant between-group differences were observed in the FCs between mPFC and right LTC (group difference = 0.25 [95% CI = 0.06–0.44], p = 0.009), mPFC and right IPL (0.23 [0.06–0.39]; p = 0.007), left HF and right LTC (0.28 [0.002–0.57]; p = 0.04), and left HF and right IPL (0.34 [0.09–0.60]; p = 0.009). Interpretation: Our findings, which reveal positive neuromodulatory effects with increased calligraphy practice, highlight the importance of engaging more in cognitive activities in late life for better brain health. Funding: Research Grants Council, Hong Kong (grant number 24114519).

BackgroundAsymptomatic chronic cerebrovascular steno-occlusive disease is common, but the cognitive function and alterations in the brain’s structural and functional profiles have not been well studied. This study aimed to reveal whether and how patients with asymptomatic middle cerebral artery (MCA) steno-occlusive disease and normal-appearing white matter differ in brain structural and functional profiles from normal controls and their correlations with cognitive function.MethodsIn all, 26 patients with asymptomatic MCA steno-occlusive disease and 22 healthy controls were compared for neurobehavioral assessments, brain volume, cortical thickness, fiber connectivity density (FiCD) value, and resting-state functional connectivity (FC) using multimodal MRI. We also investigated the associations between abnormal cortical thicknesses, FiCD values, and functional connectivities with the neurobehavioral assessments.ResultsPatients performed worse on memory tasks (Auditory Verbal Learning Test-Huashan version) compared with healthy controls. Patients were divided into two groups: the right group (patients with right MCA steno-occlusive disease) and the left group (patients with left MCA steno-occlusive disease). The left group showed significant cortical thinning in the left superior parietal lobule, while the right group showed significant cortical thinning in the right superior parietal lobule and caudal portion of the right middle frontal gyrus. Increased FiCD values in the superior frontal region of the left hemisphere were observed in the left group. In addition, a set of interhemispheric and intrahemispheric FC showed a significant decrease or increase in both the left and right groups. Many functional connectivity profiles were positively correlated with cognitive scores. No correlation was found between cortical thickness, FiCD values, and cognitive scores.ConclusionEven if the patients with MCA steno-occlusive disease were asymptomatic and had normal-appearing white matter, their cognitive function and structural and functional profiles had changed, especially the FC. Alterations in FC may be an important mechanism underlying the neurodegenerative process in patients with asymptomatic MCA steno-occlusive disease before structural changes occur, so FC assessment may promote the detection of network alterations, which may be used as a biomarker of disease progression and therapeutic efficacy evaluation in these patients.

Abstract Aims/Introduction To examine the association between cholesterol efflux capacity (CEC) of serum high‐density lipoprotein (HDL) and cognitive function and brain structures in older people with diabetes mellitus. Materials and Methods Participants of a randomized placebo‐controlled trial of 27‐month vitamin B12 supplementation in older people with diabetes mellitus, which showed no effect on cognition, were further followed up at month 72. Cognitive tests included the Clinical Dementia Rating scale, Neuropsychological Test Battery in memory, executive function and psychomotor speed. Brain magnetic resonance imaging scans were carried out in a subset at baseline, month 27 and month 45. Fasting serum at baseline, month 9, month 27 and month 72 were analyzed for adenosine triphosphate‐binding cassette transporter A1‐mediated CEC of HDL and apolipoprotein A1 (ApoA1). Results Serum HDL cholesterol at baseline was associated with better executive and memory function at follow up. Serum ApoA1 was associated with a better memory Z‐score at month 18. Serum CEC and ApoA1 were not associated with Clinical Dementia Rating scale, Neuropsychological Test Battery, hippocampal volume and white matter disease on magnetic resonance imaging at baseline and whole brain atrophy rates. They were also not associated with cognitive function at month 27 and 72 on multilevel modeling. CEC and ApoA1 decreased significantly from baseline to month 27. Faster decliners in CEC had a greater increase in brain peak width of skeletonized mean diffusivity. Conclusions Higher serum HDL cholesterol was associated with more favorable changes in memory and executive function in older people with diabetes mellitus. However, this was not due to CEC or ApoA1. A decline in CEC was associated with small vessel disease in the brain.

Abstract Background Automated brain volumetry has been widely used to assess brain volumetric changes that may indicate clinical states and progression. Among the tools that implement automated brain volumetry, AccuBrain has been validated for its accuracy, reliability and clinical applications for the older version (IV1.2). Here, we aim to investigate the performance of an updated version (IV2.0) of AccuBrain for future use from several aspects. Methods Public datasets with 3D T1-weighted scans were included for version comparisons, each with Alzheimer’s disease (AD) patients and normal control (NC) subjects that were matched in age and gender. For the comparisons of the brain volumetric measures quantified from the same scans, we investigated the difference of hippocampal segmentation accuracy (using Dice similarity coefficient [DSC] as the major measurement). As AccuBrain generates a composite index (AD resemblance atrophy index, AD-RAI) that indicates similarity with AD-like brain atrophy pattern, we also compared the two versions for the diagnostic accuracy of AD versus NC with AD-RAI. Also, we examined the intra-scanner reproducibility of the two versions for the scans acquired with short-intervals using intraclass correlation coefficient. Results AccuBrain IV2.0 presented significantly higher accuracy of hippocampal segmentation (DSC: 0.91 vs. 0.89, p

Abstract There is evidence that the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is highly expressed at the apical pole of ciliated cells in human bronchial epithelium (HBE), however recent studies have detected little CFTR mRNA in those cells. To understand this discrepancy we immunostained well differentiated primary HBE cells using CFTR antibodies. We confirmed apical immunofluorescence in ciliated cells and quantified the covariance of the fluorescence signals and that of an antibody against the ciliary marker centrin-2 using image cross-correlation spectroscopy (ICCS). Super-resolution stimulated emission depletion (STED) imaging localized the immunofluorescence in distinct clusters at the bases of the cilia. However, similar apical fluorescence was observed when the monoclonal CFTR antibodies 596, 528 and 769 were used to immunostain ciliated cells expressing F508del-CFTR, or cells lacking CFTR due to a Class I mutation. A BLAST search using the CFTR epitope identified a similar amino acid sequence in the ciliary protein rootletin X1. Its expression level correlated with the intensity of immunostaining by CFTR antibodies and it was detected by 596 antibody after transfection into CFBE cells. These results may explain the high apparent expression of CFTR in ciliated cells and reports of anomalous apical immunofluorescence in well differentiated cells that express F508del-CFTR.

BackgroundAutomated tools for characterising dementia risk have the potential to aid in the diagnosis, prognosis, and treatment of Alzheimer’s disease (AD). Here, we examined a novel machine learning-based brain atrophy marker, the AD-resemblance atrophy index (AD-RAI), to assess its test-retest reliability and further validate its use in disease classification and prediction.MethodsAge- and sex-matched 44 probable AD (Age: 69.13 ± 7.13; MMSE: 27–30) and 22 non-demented control (Age: 69.38 ± 7.21; MMSE: 27–30) participants were obtained from the Minimal Interval Resonance Imaging in Alzheimer’s Disease (MIRIAD) dataset. Serial T1-weighted images (n = 678) from up to nine time points over a 2-year period, including 179 pairs of back-to-back scans acquired on same participants on the same day and 40 pairs of scans acquired at 2-week intervals were included. All images were automatically processed with AccuBrain® to calculate the AD-RAI. Its same-day repeatability and 2-week reproducibility were first assessed. The discriminative performance of AD-RAI was evaluated using the receiver operating characteristic curve, where DeLong’s test was used to evaluate its performance against quantitative medial temporal lobe atrophy (QMTA) and hippocampal volume adjusted by intracranial volume (ICV)-proportions and ICV-residuals methods, respectively (HVR and HRV). Linear mixed-effects modelling was used to investigate longitudinal trajectories of AD-RAI and baseline AD-RAI prediction of cognitive decline. Finally, the longitudinal associations between AD-RAI and MMSE scores were assessed.ResultsAD-RAI had excellent same-day repeatability and excellent 2-week reproducibility. AD-RAI’s AUC (99.8%; 95%CI = [99.3%, 100%]) was equivalent to that of QMTA (96.8%; 95%CI = [92.9%, 100%]), and better than that of HVR (86.8%; 95%CI = [78.2%, 95.4%]) or HRV (90.3%; 95%CI = [83.0%, 97.6%]). While baseline AD-RAI was significantly higher in the AD group, it did not show detectable changes over 2 years. Baseline AD-RAI was negatively associated with MMSE scores and the rate of the change in MMSE scores over time. A negative longitudinal association was also found between AD-RAI values and the MMSE scores among AD patients.ConclusionsThe AD-RAI represents a potential biomarker that may support AD diagnosis and be used to predict the rate of future cognitive decline in AD patients.

ObjectivesThis study aimed to primarily examine the association between memory deficit and increased fall risk, second, explore the underlying neuroanatomical linkage of this association in the elderly with aMCI and mild AD.MethodsIn this cross-sectional study, a total of 103 older adults were included (55 cognitively normal, CN; 48 cognitive impairment, CI, elderly with aMCI, and mild AD). Memory was assessed by the Auditory Verbal Learning Test (AVLT). Fall risk was evaluated by the Timed Up and Go (TUG) Test, heel strike angles, and stride speed, which were collected by an inertial-sensor-based wearable instrument (the JiBuEn™ gait analysis system). Brain volumes were full-automatic segmented and quantified using AccuBrain® v1.2 from three-dimensional T1-weighted (3D T1W) MR images. Multivariable regression analysis was used to examine the extent of the association between memory deficit and fall risk, the association of brain volumes with memory, and fall risk. Age, sex, education, BMI, and HAMD scores were adjusted. Sensitivity analysis was conducted.ResultsCompared to CN, participants with aMCI and mild AD had poorer cognitive performance (p < 0.001), longer TUG time (p = 0.018), and smaller hippocampus and medial temporal volumes (p = 0.037 and 0.029). In the CI group, compared to good short delayed memory (SDM) performance (AVLT > 5), the elderly with bad SDM performance (AVLT ≤ 3) had longer TUG time, smaller heel strike angles, and slower stride speed. Multivariable regression analysis showed that elderly with poor memory had higher fall risk than relative good memory performance among cognitive impairment elderly. The TUG time increased by 2.1 s, 95% CI, 0.54∼3.67; left heel strike angle reduced by 3.22°, 95% CI, −6.05 to −0.39; and stride speed reduced by 0.09 m/s, 95% CI, −0.19 to −0.00 for the poor memory elderly among the CI group, but not found the association in CN group. In addition, serious medial temporal atrophy (MTA), small volumes of the frontal lobe and occipital lobe were associated with long TUG time and small heel strike angles; small volumes of the temporal lobe, frontal lobe, and parietal lobe were associated with slow stride speed.ConclusionOur findings suggested that memory deficit was associated with increased fall risk in the elderly with aMCI and mild AD. The association might be mediated by the atrophy of medial temporal, frontal, and parietal lobes. Additionally, increased fall risk, tested by TUG time, heel stride angles, and stride speed, might be objective and convenient kinematics markers for dynamic monitoring of both memory function and fall risk.

BackgroundWhite matter hyperintensities (WMHs) and regional brain lobe atrophy coexist in the brain of patients with Alzheimer's disease (AD), but the association between them in patients with AD still lacks comprehensive investigation and solid imaging data support.ObjectiveWe explored whether WMHs can promote the pathological process of AD by aggravating atrophy in specific brain regions and tried to explain the regional specificity of these relationships.MethodsA sample of 240 adults including 180 normal controls (NCs) and 80 cases with AD were drawn from the ADNI database. T1-weighted magnetic resonance imaging (MRI) and T2-weighted fluid-attenuated MRI of the participants were downloaded and were analyzed using AccuBrain® to generate the quantitative ratio of WMHs (WMHr, WMH volumes corrected by intracranial volume) and regional brain atrophy. We also divided WMHr into periventricular WMHr (PVWMHr) and deep WMHr (DWMHr) for the purpose of this study. The Cholinergic Pathways Hyperintensities Scale (CHIPS) scores were conducted by two evaluators. Independent t-test, Mann–Whitney U test, or χ2 test were used to compare the demographic characteristics, and Spearman correlation coefficient values were used to determine the association between WMHs and different regions of brain atrophy.ResultsPositive association between WMHr and quantitative medial temporal lobe atrophy (QMTA) (rs = 0.281, p = 0.011), temporal lobe atrophy (rs = 0.285, p = 0.011), and insular atrophy (rs = 0.406, p < 0.001) was found in the AD group before Bonferroni correction. PVWMHr contributed to these correlations. By separately analyzing the relationship between PVWMHr and brain atrophy, we found that there were still positive correlations after correction in QMTA (rs = 0.325, p = 0.003), temporal lobe atrophy (rs = 0.298, p = 0.007), and insular atrophy (rs = 0.429, p < 0.001) in AD group.ConclusionWMH severity tends to be associated with regional brain atrophy in patients with AD, especially with medial temporal lobe, temporal lobe, and insular lobe atrophy. PVWMHs were devoted to these correlations.

Abstract Background The differential diagnosis of frontotemporal dementia (FTD) and Alzheimer’s disease (AD) is difficult due to the overlaps of clinical symptoms. Structural magnetic resonance imaging (sMRI) presents distinct brain atrophy and potentially helps in their differentiation. In this study, we aim at deriving a novel integrated index by leveraging the volumetric measures in brain regions with significant difference between AD and FTD and developing an MRI-based strategy for the differentiation of FTD and AD. Methods In this study, the data were acquired from three different databases, including 47 subjects with FTD, 47 subjects with AD, and 47 normal controls in the NACC database; 50 subjects with AD in the ADNI database; and 50 subjects with FTD in the FTLDNI database. The MR images of all subjects were automatically segmented, and the brain atrophy, including the AD resemblance atrophy index (AD-RAI), was quantified using AccuBrain®. A novel MRI index, named the frontotemporal dementia index (FTDI), was derived as the ratio between the weighted sum of the volumetric indexes in “FTD dominant” structures over that obtained from “AD dominant” structures. The weights and the identification of “FTD/AD dominant” structures were acquired from the statistical analysis of NACC data. The differentiation performance of FTDI was validated using independent data from ADNI and FTLDNI databases. Results AD-RAI is a proven imaging biomarker to identify AD and FTD from NC with significantly higher values (p

Background and ObjectiveEarly identification is important for timely Alzheimer’s disease (AD) treatment. Apolipoprotein E ε4 allele (APOE-ε4) is an important genetic risk factor for sporadic AD. The AD-Resemblance Atrophy Index (RAI)—a structural magnetic resonance imaging-derived composite index—was found to predict the risk of progression from mild cognitive impairment (MCI) to AD. Therefore, we investigated whether the AD-RAI can predict cognitive decline and progression to AD in patients with MCI carrying APOE ε4.MethodsWe included 733 participants with MCI from the Alzheimer’s Disease Neuroimaging Initiative Database (ADNI). Their APOE genotypes, cognitive performance, and levels of AD-RAI were assessed at baseline and follow-up. Linear regression models were used to test the correlations between the AD-RAI and baseline cognitive measures, and linear mixed models with random intercepts and slopes were applied to investigate whether AD-RAI and APOE-ε4 can predict the level of cognitive decline. Cox proportional risk regression models were used to test the association of AD-RAI and APOE status with the progression from MCI to AD.ResultsThe baseline AD-RAI was higher in the MCI converted to AD group than in the MCI stable group (P < 0.001). The AD-RAI was significantly correlated with cognition, and had a synergistic effect with APOE-ε4 to predict the rate of cognitive decline. The AD-RAI predicted the risk and timing of MCI progression to AD. Based on the MCI population carrying APOE-ε4, the median time to progression from MCI to AD was 24 months if the AD-RAI > 0.5, while the median time to progression from MCI to AD was 96 months for patients with an AD-RAI ≤ 0.5.ConclusionThe AD-RAI can predict the risk of progression to AD in people with MCI carrying APOE ε4, is strongly correlated with cognition, and can predict cognitive decline.

PurposeCombined the number, volume, and location of cerebral microbleeds (CMBs), this study aimed to explore the different features of CMBs and their correlation with cognitive ability in patients with type 2 diabetes mellitus (T2DM).MethodsThis study recruited 95 patients with T2DM and 80 healthy control (HC) individuals. AccuBrain®, an automated tool, was used to obtain the number and volume of CMBs. The scores on global cognition and five cognitive domains were derived from a battery of cognitive tests. The logistic regression and multivariate linear regression were conducted to determine the relationship between the CMBs (number, volume, and location) and cognitive ability in patients with T2DM.ResultsAfter adjusting for several variables, the total volume of CMBs (OR = 0.332, 95%CI: 0.133–0.825, and p = 0.018) was independent risk factor for cognitive impairment, whereas the total number of CMBs was not (OR = 0933, 95%CI: 0.794–1.097, and p = 0.400). Furthermore, the volume of CMBs in lobar regions was independently associated with working memory (β = −0.239, 95%CI: −0.565 to −0.035, and p = 0.027). However, no significant correlation between the number of CMBs (both lobar and deep/infratentorium) and any cognitive domains was observed.ConclusionsLobar CMBs was related with cognitive impairment in patients with T2DM and might be a potential early warning signal. Compared with the counting analysis, the quantitative method offered a more sensitive and objective measurement for studying imaging features of CMBs.

Abstract Background Hippocampal sclerosis (HS) is associated with post-surgery outcome in patients with temporal lobe epilepsy (TLE), and an automated method that quantifies HS severity is still lacking. Here, we aim to propose an MRI-based HS index (HSI) that integrates hippocampal volume and FLAIR signal to measure the severity of HS. Methods Forty-two pre-surgery TLE patients were included retrospectively, with T1-weighted (T1W) and FLAIR images acquired from each subject. Two experienced neurosurgeons (W.D. and C.S.) and one neurologist (Q.L.) rated HS severity with a four-class grading scale (normal, mild, moderate and severe) based on both hippocampal volume loss and increased FLAIR signal. A consensus of HS severity for each subject was made by voting among the three visual rating results. Regarding the automatic quantification, the hippocampal volume was quantified by AccuBrain on T1W image, and the FLAIR signal of hippocampus was calculated as the mean intensity of hippocampal region on the FLAIR image (normalized by the mean intensity of gray matter). To fit the HSI from visual rating, we applied ordinal regression with the voted visual rating as the dependent variable, and hippocampal volume and FLAIR signal as the independent variables. The HSI was calculated by weighting the predicted probabilities of the four-class grading scales from ordinal regression. Results The intra-class correlation coefficient (single measure) of the three raters was 0.806. The generated HSI was significantly correlated with the visual rating scales of the three raters (W.D.: 0.823, Q.L.: 0.817, C.S.: 0.717). HSI scores well differentiated the different HS categories as defined by the agreed HS visual rating (normal vs. mild: p

Background: Increasing evidence has shown that amyotrophic lateral sclerosis (ALS) can result in abnormal energy metabolism and sleep disorders, even before motor dysfunction. Although the hypothalamus and thalamus are important structures in these processes, few ALS studies have reported abnormal MRI structural findings in the hypothalamus and thalamus.Purpose: We aimed to investigate volumetric changes in the thalamus and hypothalamus by using the automatic brain structure volumetry tool AccuBrain®.Methods: 3D T1-weighted magnetization-prepared gradient echo imaging (MPRAGE) scans were acquired from 16 patients with ALS with normal cognitive scores and 16 age-, sex- and education-matched healthy controls. Brain tissue and structure volumes were automatically calculated using AccuBrain®.Results: There were no significant differences in bilateral thalamic (F = 1.31, p = 0.287) or hypothalamic volumes (F = 1.65, p = 0.213) between the ALS and control groups by multivariate analysis of covariance (MANCOVA). Left and right hypothalamic volumes were correlated with whole-brain volume in patients with ALS (t = 3.19, p = 0.036; t = 3.03, p = 0.044), while the correlation between age and bilateral thalamic volumes tended to be significant after Bonferroni correction (t = 2.76, p = 0.068; t = 2.83, p = 0.06). In the control group, left and right thalamic volumes were correlated with whole-brain volume (t = 4.26, p = 0.004; t = 4.52, p = 0.004).Conclusion: Thalamic and hypothalamic volumes did not show differences between patients with normal frontotemporal function ALS and healthy controls, but further studies are still needed.

PurposeThis study aimed to determine if people living with HIV (PLWH) in preclinical human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), with no clinical symptoms and without decreased daily functioning, suffer from brain volumetric alterations and its patterns.MethodFifty-nine male PLWH at the HAND preclinical stage were evaluated, including 19 subjects with asymptomatic neurocognitive impairment (ANI), 17 subjects with cognitive abnormality that does not reach ANI (Not reach ANI), and 23 subjects with cognitive integrity. Moreover, 23 healthy volunteers were set as the seronegative normal controls (NCs). These individuals underwent sagittal three-dimensional T1-weighted imaging (3D T1WI). Quantified data and volumetric measures of brain structures were automatically segmented and extracted using AccuBrain®. In addition, the multiple linear regression analysis was performed to analyze the relationship of volumes of brain structures and clinical variables in preclinical HAND, and the correlations of the brain volume parameters with different cognitive function states were assessed by Pearson’s correlation analysis.ResultsThe significant difference was shown in the relative volumes of the ventricular system, bilateral lateral ventricle, thalamus, caudate, and left parietal lobe gray matter between the preclinical HAND and NCs. Furthermore, the relative volumes of the bilateral thalamus in preclinical HAND were negatively correlated with attention/working memory (left: r = −0.271, p = 0.042; right: r = −0.273, p = 0.040). Higher age was associated with increased relative volumes of the bilateral lateral ventricle and ventricular system and reduced relative volumes of the left thalamus and parietal lobe gray matter. The lower CD4+/CD8+ ratio was associated with increased relative volumes of the left lateral ventricle and ventricular system. Longer disease course was associated with increased relative volumes of the bilateral thalamus. No significant difference was found among preclinical HAND subgroups in all indices, and the difference between the individual groups (Not reach ANI and Cognitive integrity groups) and NCs was also insignificant. However, there was a significant difference between ANI and NCs in the relative volumes of the bilateral caudate and lateral ventricle.ConclusionMale PLWH at the HAND preclinical stage suffer from brain volumetric alterations. AccuBrain® provides potential value in evaluating HIV-related neurocognitive dysfunction.

BackgroundMagnetic resonance imaging (MRI) has a wide range of applications in medical imaging. Recently, studies based on deep learning algorithms have demonstrated powerful processing capabilities for medical imaging data. Previous studies have mostly focused on common diseases that usually have large scales of datasets and centralized the lesions in the brain. In this paper, we used deep learning models to process MRI images to differentiate the rare neuromyelitis optical spectrum disorder (NMOSD) from multiple sclerosis (MS) automatically, which are characterized by scattered and overlapping lesions.MethodsWe proposed a novel model structure to capture 3D MRI images’ essential information and converted them into lower dimensions. To empirically prove the efficiency of our model, firstly, we used a conventional 3-dimensional (3D) model to classify the T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) images and proved that the traditional 3D convolutional neural network (CNN) models lack the learning capacity to distinguish between NMOSD and MS. Then, we compressed the 3D T2-FLAIR images by a two-view compression block to apply two different depths (18 and 34 layers) of 2D models for disease diagnosis and also applied transfer learning by pre-training our model on ImageNet dataset.ResultsWe found that our models possess superior performance when our models were pre-trained on ImageNet dataset, in which the models’ average accuracies of 34 layers model and 18 layers model were 0.75 and 0.725, sensitivities were 0.707 and 0.708, and specificities were 0.759 and 0.719, respectively. Meanwhile, the traditional 3D CNN models lacked the learning capacity to distinguish between NMOSD and MS.ConclusionThe novel CNN model we proposed could automatically differentiate the rare NMOSD from MS, especially, our model showed better performance than traditional3D CNN models. It indicated that our 3D compressed CNN models are applicable in handling diseases with small-scale datasets and possess overlapping and scattered lesions.

Objectives Alzheimer’s disease (AD), impaired fasting glucose (IFG), and Type 2 diabetes mellitus (T2DM) were reported associated with smaller brain volumes. Nevertheless, the association of hyperglycemia with brain volume changes in AD patients remains unclear. To investigate this issue, structural magnetic resonance imaging was used to compare brain volumes among AD patients with different fasting glucose levels. Methods Eighty-five AD patients were divided into three groups based on their fasting glucose level as suggested by the American Diabetes Association: normal fasting glucose group (AD_NFG, n = 45), AD_IFG group (n = 15), and AD_T2DM group (n = 25). Sagittal 3D T1-weighted images were obtained to calculate the brain volume. Brain parenchyma and 33 brain structures were automatically segmented. Each regional volume was analyzed among groups. For regions with statistical significance, partial correlation analysis was used to evaluate their relationships with fasting glucose level, corrected for Mini-Mental State Examination score, age, education level, cholesterol, triglyceride, and blood pressure. Results Compared with the AD_IFG and AD_NFG groups, the volume of pons in AD_T2DM group was significantly smaller. Fasting glucose was negatively correlated with pontine volume. Conclusions T2DM may exacerbate pontine atrophy in AD patients, and fasting glucose level is associated with pontine volume.

Objectives: To evaluate white matter hyperintensities (WMH) quantification reproducibility from multiple aspects of view and examine the effects of scan–rescan procedure, types of scanner, imaging protocols, scanner software upgrade, and automatic segmentation tools on WMH quantification results using magnetic resonance imaging (MRI).Methods: Six post-stroke subjects (4 males; mean age = 62.8, range = 58–72 years) were scanned and rescanned with both 3D T1-weighted, 2D and 3D T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) MRI across four different MRI scanners within 12 h. Two automated WMH segmentation and quantification tools were used to measure WMH volume based on each MR scan. Robustness was assessed using the coefficient of variation (CV), Dice similarity coefficient (DSC), and intra-class correlation (ICC).Results: Experimental results show that the best reproducibility was achieved by using 3D T2-FLAIR MRI under intra-scanner setting with CV ranging from 2.69 to 2.97%, while the largest variability resulted from comparing WMH volumes measured based on 2D T2-FLAIR MRI with those of 3D T2-FLAIR MRI, with CV values in the range of 15.62%–29.33%. The WMH quantification variability based on 2D MRIs is larger than 3D MRIs due to their large slice thickness. The DSC of WMH segmentation labels between intra-scanner MRIs ranges from 0.63 to 0.77, while that for inter-scanner MRIs is in the range of 0.63–0.65. In addition to image acquisition, the choice of automatic WMH segmentation tool also has a large impact on WMH quantification.Conclusion: WMH reproducibility is one of the primary issues to be considered in multicenter and longitudinal studies. The study provides solid guidance in assisting multicenter and longitudinal study design to achieve meaningful results with enough power.

A network-level investigation of the volumetric changes of subcortical stroke patients is still lacking. Here, we explored the alterations of structural covariance caused by subcortical stroke with automated brain volumetry. T1-weighed brain MRI scans were obtained from 63 normal controls (NC), 46 stroke patients with infarct in left internal capsule (CI_L), 33 stroke patients with infarct in right internal capsule (CI_R). We performed automatic anatomical segmentation of the T1-weighted brain images with AccuBrain. Volumetric structural covariance analyses were first performed within the basal ganglia structures that were both identified by voxel-based morphometry with AAL atlas and AccuBrain. Subsequently, we additionally included the infratentorial regions that were particularly quantified by AccuBrain for the structural covariance analyses and investigated the alterations of anatomical connections within these subcortical regions in CI_L and CI_R compared with NC. The association between the regional brain volumetry and motor function was also evaluated in stroke groups. There were significant and extensive volumetric differences in stroke patients. These significant regions were generally symmetric for CI_L and CI_R group depending on the side of stroke, involving both regions close to lesions and remote regions. The structural covariance analyses revealed the synergy volume alteration in subcortical regions both in CI_L and CI_R group. In addition, the alterations of volumetric structural covariance were more extensive in CI_L group than CI_R group. Moreover, we found that the subcortical regions with atrophy contributed to the deficits of motor function in CI_R group but not CI_L group, indicating a lesion-side effect of brain volumetric changes after stroke. These findings indicated that the chronic subcortical stroke patients have extensive disordered anatomical connections involving the whole-brain level network, and the connections patterns depend on the lesion-side. Keywords: Brain segmentation, Brain volumetric changes, MRI imaging, Stroke, Structural covariance, Lesion-side effect

White matter hyperintensities (WMH) are common in acute ischemic stroke patients. Although WMH volume has been reported to influence post-stroke cognition, it is still not clear whether WMH location, independent of acute ischemic lesion (AIL) volume and location, contributes to cognitive impairment after stroke. Here, we proposed a multiple-lesion symptom mapping model that considers both the presence of WMH and AIL to measure the additional contribution of WMH locations to post-stroke cognitive impairment. Seventy-six first-ever stroke patients with AILs in the left hemisphere were examined by Montreal Cognitive Assessment (MoCA) at baseline and 1 year after stroke. The association between the location of AIL and WMH and global cognition was investigated by a multiple-lesion symptom mapping (MLSM) model based on support vector regression (SVR). To explore the relative merits of MLSM over the existing lesion-symptom mapping approaches with only AIL considered (mass-univariate VLSM and SVR-LSM), we measured the contribution of the significant AIL and/or WMH clusters from these models to post-stroke cognitive impairment. In addition, we compared the significant WMH locations identified by the optimal SVR-MLSM model for cognitive impairment at baseline and 1 year post stroke. The identified strategic locations of WMH significantly contributed to the prediction of MoCA at baseline (short-term) and 1 year (long-term) after stroke independent of the strategic locations of AIL. The significant clusters of WMH for short-term and long-term post-stroke cognitive impairment were mainly in the corpus callosum, corona radiata, and posterior thalamic radiation. We noted that in some regions, the AIL clusters that were significant for short-term outcome were no longer significant for long-term outcome, and interestingly more WMH clusters in these regions became significant for long-term outcome compared to short-term outcome. This indicated that there are some regions where local WMH burden has larger impact than AIL burden on the long-term post-stroke cognitive impairment. In consequence, SVR-MLSM was effective in identifying the WMH locations that have additional impact on post-stroke cognition on top of AIL locations. Such a method can also be applied to other lesion-behavior studies where multiple types of lesions may have potential contributions to a specific behavior.

Given that the morphology of Chinese brains statistically differs from that of Caucasian, there is an urgent need to develop a Chinese brain template for neuroimaging studies in Chinese populations. Based on a multi-center dataset, we developed a statistical Chinese brain template, named as Chinese2020 (Liang et al., 2015). This new Chinese brain atlas has been validated in brain normalization and segmentation for anatomical Magnetic Resonance Imaging (MRI) studies, and is publicly available at http://www.chinese-brain-atlases.org/. In our previous study, we have demonstrated this Chinese atlas showed higher accuracy in segmentation and relatively smaller shape deformations during registration. Because the spatial normalization of functional images is mainly based on the segmentation and normalization of anatomical image, the population-specific brain atlas should also be more appropriate for functional studies involving Chinese populations. The aim of this technology report is to validate the performance of Chinsese2020 template in functional neuroimaging studies, and demonstrated that for Chinese population studies, the use of the Chinese2010 template produces more valid results. The steps of how to use the Chinese2020 template in SPM software were given in details in this technology report, and based on an example of finger tapping fMRI study, this technology report demonstrated the Chinese2020 template could improve the performance of the neuroimaging analysis of Chinese populations.

In epithelia, Cl- channels play a prominent role in fluid and electrolyte transport. Of particular importance is the cAMP-dependent cystic fibrosis transmembrane conductance regulator Cl- channel (CFTR) with mutations of the CFTR encoding gene causing cystic fibrosis. The bulk transepithelial transport of Cl- ions and electrolytes needs however to be coupled to an increase in K+ conductance in order to recycle K+ and maintain an electrical driving force for anion exit across the apical membrane. In several epithelia, this K+ efflux is ensured by K+ channels, including KCa3.1, which is expressed at both the apical and basolateral membranes. We show here for the first time that CFTR and KCa3.1 can physically interact. We first performed a two-hybrid screen to identify which KCa3.1 cytosolic domains might mediate an interaction with CFTR. Our results showed that both the N-terminal fragment M1-M40 of KCa3.1 and part of the KCa3.1 calmodulin binding domain (residues L345-A400) interact with the NBD2 segment (G1237-Y1420) and C- region of CFTR (residues T1387-L1480), respectively. An association of CFTR and F508del-CFTR with KCa3.1 was further confirmed in co-immunoprecipitation experiments demonstrating the formation of immunoprecipitable CFTR/KCa3.1 complexes in CFBE cells. Co-expression of KCa3.1 and CFTR in HEK cells did not impact CFTR expression at the cell surface, and KCa3.1 trafficking appeared independent of CFTR stimulation. Finally, evidence is presented through cross-correlation spectroscopy measurements that KCa3.1 and CFTR colocalize at the plasma membrane and that KCa3.1 channels tend to aggregate consequent to an enhanced interaction with CFTR channels at the plasma membrane following an increase in intracellular Ca2+ concentration. Altogether, these results suggest 1) that the physical interaction KCa3.1/CFTR can occur early during the biogenesis of both proteins and 2) that KCa3.1 and CFTR form a dynamic complex, the formation of which depends on internal Ca2+.

Neuroimage registration is crucial for brain morphometric analysis and treatment efficacy evaluation. However, existing advanced registration algorithms such as FLIRT and ANTs are not efficient enough for clinical use. In this paper, a GPU implementation of FLIRT with the correlation ratio (CR) as the similarity metric and a GPU accelerated correlation coefficient (CC) calculation for the symmetric diffeomorphic registration of ANTs have been developed. The comparison with their corresponding original tools shows that our accelerated algorithms can greatly outperform the original algorithm in terms of computational efficiency. This paper demonstrates the great potential of applying these registration tools in clinical applications.

Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA) are major respiratory pathogens and can concurrently colonize the airways of patients with chronic obstructive diseases, such as cystic fibrosis (CF). Airway epithelial cell signalling is critical to the activation of innate immune responses. In the setting of polymicrobial colonization or infection of the respiratory tract, how epithelial cells integrate different bacterial stimuli remains unknown. Our study examined the inflammatory responses to PA and SA co-stimulations. Immortalised airway epithelial cells (Beas-2B) exposed to bacteria-free filtrates from PA (PAF) induced a robust production of the neutrophil chemoattractant IL-8 while bacteria-free filtrates from SA (SAF) had a minimal effect. Surprisingly, co-stimulation with PAF+SAF demonstrated that SAF strongly inhibited the PAF-driven IL-8 production, showing that SAF has potent anti-inflammatory effects. Similarly SAF decreased IL-8 production induced by the TLR1/TLR2 ligand Pam3CysSK4 but not the TLR4 ligand LPS nor TLR5 ligand flagellin in Beas-2B cells. Moreover, SAF greatly dampened TLR1/TLR2-mediated activation of the NF-κB pathway, but not the p38 MAPK pathway. We observed this SAF-dependent anti-inflammatory activity in several SA clinical strains, as well as in the CF epithelial cell line CFBE41o-. These findings show a novel direct anti-inflammatory effect of SA on airway epithelial cells, highlighting its potential to modulate inflammatory responses in the setting of polymicrobial infections.

Membrane proteins often cluster in nanoscale membrane domains (lipid rafts) that coalesce into ceramide-rich platforms during cell stress, however the clustering mechanisms remain uncertain. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in cystic fibrosis (CF), forms clusters that are cholesterol dependent and become incorporated into long-lived platforms during hormonal stimulation. We report here that clustering does not involve known tethering interactions of CFTR with PDZ domain proteins, filamin A or the actin cytoskeleton. It also does not require CFTR palmitoylation but is critically dependent on membrane lipid order and is induced by detergents that increase the phase separation of membrane lipids. Clustering and integration of CFTR into ceramide-rich platforms are abolished by the disease mutations F508del and S13F and rescued by the CFTR modulators elexacaftor plus tezacaftor. These results indicate CF therapeutics that correct mutant protein folding restore both trafficking and normal lipid interactions in the plasma membrane. This article has an associated First Person interview with the first author of the paper. [ABSTRACT FROM AUTHOR]