Structural network disruption of corticothalamic pathways in cerebral small vessel disease.

Generalized fractional anisotropy (GFA) can eliminate the crossing fiber effect, which may be more reflective of brain tissue changes in patients with cerebral small vessel disease (CSVD). This study aimed to explore the alterations of structural networks based on GFA and its relationship with cognitive performance in CSVD patients. We recruited 50 CSVD patients which were divided into two groups: cognitive impairment (CSVD-CI) and normal cognition (CSVD-NC), and 22 healthy controls (HCs). All participants underwent the Montreal Cognitive Assessment (MoCA) and MRI examinations. The structural topological properties were compared among the three groups. The correlation between these structural alterations and MoCA was analyzed. Compared with HCs, significantly decreased nodal efficiency and connectivity were detected in the corticothalamic pathways in both patient groups, of which some were significantly decreased in CSVD-CIs compared with CSVD-NCs. Moreover, both patient groups exhibited global network disruption including decreased global efficiency and increased characteristic path length compared with HCs. Furthermore, the nodal efficiency in the right pallidum positively correlated with MoCA in CSVD-NCs controlling for nuisance variables (r = 0.471, p = 0.031). The alterations in corticothalamic pathways indicated that the brain structural network underwent extensive disruption, providing evidence for the consideration of CSVD as a global brain disease.

Increased anterior insula connectivity associated with cognitive maintenance in amnestic mild cognitive impairment: a longitudinal study.

The insula, a crucial hub of the human brain network, can be divided into anterior and posterior regions. Previous studies have reported that different insula subregions play various roles in amnestic mild cognitive impairment (aMCI). However, the longitudinal changes in the functional connectivity (FC) of each insula subregion in aMCI patients over time remain unclear. Twenty aMCI patients and 20 healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI) scans and neuropsychological assessments at baseline and at the 15-month follow-up. FMRI data were preprocessed using SPM 12 and the CONN toolbox. Two-way analysis of covariance was used to compare longitudinal changes in the FC of each insula subregion with covariates including sex, age, education, follow-up interval, volume of gray matter, and global correlation (GCOR). Pearson's correlation was used to evaluate the relationship between insula subregional FC and neuropsychological performance in aMCI patients. In aMCI patients, the right anterior insula exhibited significantly increased FC with the left anterior cingulate cortex, whereas the left posterior insula exhibited decreased FC with the right precuneus compared with HCs. Furthermore, FC between the right anterior insula and left anterior cingulate cortex was significantly correlated with global cognition at follow-up. The current findings revealed different functional alterations in the insula subregions and provided new insights into the neurodegenerative process in aMCI patients.

The Association Between Serum Uric Acid and Cognitive Function Among Middle-Aged and Older Adults Without Hyperuricemia: The Mediating Role of Depressive Symptoms.

BACKGROUND: The association between serum uric acid (SUA) and cognitive function remains unclear, especially among individuals without hyperuricemia. We examined the cross-sectional and longitudinal bidirectional associations between SUA and cognition, as well as the mediating effect of depressive symptoms among Chinese adults. METHODS: Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS). SUA (continuous) and cognitive function (based on mental intactness and episodic memory) were measured at Wave 1 and Wave 3. Depressive symptoms (Center for Epidemiologic Studies Depression scale) were assessed at Wave 1. Bivariate latent change score models and mediation analysis were used to investigate these possible associations. RESULTS: A total of 6 236 participants free of hyperuricemia (aged 58.3 ±â€…8.5 years) were included. After controlling for potential confounders, the SUA level was associated with cognition at baseline (standardized r = 0.042; p = .001). Higher baseline SUA level was associated with slower subsequent cognitive decline (standardized ß = 0.026; p = .027), whereas baseline cognition was not significantly associated with subsequent change in SUA (standardized ß = 0.003; p = .817). In mediation analysis, baseline SUA was indirectly associated with subsequent cognition via baseline depressive symptoms (mediation effect 13.3%; p < .001). CONCLUSIONS: Higher baseline SUA level is associated with better baseline cognition and less subsequent cognitive decline among Chinese adults without hyperuricemia. Baseline depressive symptoms may partially mediate the association between baseline SUA and later cognition. Continued research is warranted to verify these findings and elucidate the causality and underlying mechanisms.

The longitudinal bidirectional association between sarcopenia and cognitive function in community-dwelling older adults: Findings from the China Health and Retirement Longitudinal Study.

Background: Although an association between sarcopenia and cognitive function has been demonstrated, the directional association remains unclear. The present study aimed to evaluate the longitudinal reciprocal relationship and identify the possible temporal sequence between sarcopenia and cognitive function in older Chinese adults. Methods: Data were collected from the China Health and Retirement Longitudinal Study (CHARLS) baseline survey in 2011 and the follow-up survey in 2015. Cognitive function was measured by episodic memory and executive function. Sarcopenia status (non-sarcopenia, possible sarcopenia and sarcopenia) was defined based on the Asian Working Group for Sarcopenia 2019 criteria. Linear regression analysis and ordinal logistic regression analysis were employed to investigate the relationship between baseline sarcopenia status and follow-up cognition, as well as the association of baseline cognition with follow-up sarcopenia status, respectively. A cross-lagged panel analysis was performed to simultaneously evaluate the bidirectional association and the strength of the temporal relationship. Results: Of 2689 participants, the median age was 65.0 years and 1249 (46.5%) were female. After adjusting for potential confounders and baseline measurements, baseline sarcopenia status was dose-dependently associated with subsequent cognitive scores (ß = -0.45; P for trend = 0.001), and baseline cognitive scores (in tertiles) were also dose-dependently associated with subsequent sarcopenia status (odds ratio (OR) = 0.86; P for trend = 0.017). The cross-lagged panel analysis indicated that the standardised effect size of sarcopenia status on cognitive function (ß = -0.09; P < 0.001) is larger relative to the effect of cognitive function on sarcopenia status (ß = -0.05; P = 0.019). Conclusions: There is a longitudinal, bidirectional relationship between sarcopenia status and cognitive function in older Chinese adults. Sarcopenia is likely the driving force in these dynamic associations. These findings imply that interventions in either sarcopenia or cognitive decline may have the ability to generate reciprocal benefits over time. More research is warranted to confirm these findings and to further elucidate underlying causal pathways.

Pericarotid adipose tissue computed tomography attenuation distinguishes different stages of carotid atherosclerotic disease: a cross-sectional study.

Background: Carotid atherosclerotic plaque inflammation plays a critical role in guiding the prevention of secondary stroke. Increased perivascular adipose tissue attenuation observed on computed tomography angiography (CTA) may indicate local inflammation. Our objective was to investigate whether pericarotid adipose tissue (PCAT), as a local inflammation biomarker, could distinguish between different stages of carotid atherosclerotic disease plaques. Methods: We prospectively enrolled 45 consecutive acute stroke patients with carotid artery stenosis from September 2019 to September 2021. We then matched them to non-stroke patients (n=67) and no carotid atherosclerotic disease controls (n=65) based on gender, age, and cardiovascular risk factors. We compared PCAT attenuation, carotid plaque features on CTA, clinical risk factors, and serum inflammatory factors across the different groups. To detect the association of PCAT attenuation with stage of carotid atherosclerotic disease, we used multivariable logistic regression analysis. Results: Patients with acute stroke had a higher PCAT attenuation (-78.80±11.62 HU) than patients with non-stroke (-89.01±10.81 HU, P<0.001) and no carotid atherosclerotic disease controls (-95.24±10.81 HU, P<0.001). PCAT attenuation was significantly increased in non-stroke patients compared to non-stroke patients over no carotid atherosclerotic disease controls (P=0.004). The association between PCAT attenuation and the stage of carotid atherosclerotic disease was independent of age, gender, cardiovascular risk factors, and CTA plaque characteristics. No interaction was observed between clinical features and CTA plaque characteristics on PCAT attenuation. Conclusions: PCAT attenuation, which is an imaging biomarker of local inflammation, independently distinguishes patients with different stages of carotid atherosclerotic disease. Quantitative evaluation of PCAT attenuation in carotid atherosclerotic disease is expected to guide targeted surgical treatment of carotid plaque.

Effect of corticosubcortical iron deposition on dysfunction in CADASIL is mediated by white matter microstructural damage.

Iron dysregulation may attenuate cognitive performance in patients with CADASIL. However, the underlying pathophysiological mechanisms remain incompletely understood. Whether white matter microstructural changes mediate these processes is largely unclear. In the present study, 30 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients were confirmed via genetic analysis and 30 sex- and age-matched healthy controls underwent multimodal MRI examinations and neuropsychological assessments. Quantitative susceptibility mapping and peak width of skeletonized mean diffusivity (PSMD) were analyzed. Mediation effect analysis was performed to explore the interrelationship between iron deposition, white matter microstructural changes and cognitive deficits in CADASIL. Cognitive deterioration was most affected in memory and executive function, followed by attention and working memory in CADASIL. Excessive iron in the temporal-precuneus pathway and deep gray matter specific to CADASIL were identified. Mediation analysis further revealed that PSMD mediated the relationship between iron concentration and cognitive profile in CADASIL. The present findings provide a new perspective on iron deposition in the corticosubcortical circuit and its contribution to disease-related selective cognitive decline, in which iron concentration may affect cognition by white matter microstructural changes in CADASIL.

Ferroptosis-Regulated Cell Death as a Therapeutic Strategy for Neurodegenerative Diseases: Current Status and Future Prospects.

Ferroptosis is increasingly being recognized as a key element in the pathogenesis of diverse diseases. Recent studies have highlighted the intricate links between iron metabolism and neurodegenerative disorders. Emerging evidence suggests that iron homeostasis, oxidative stress, and neuroinflammation all contribute to the regulation of both ferroptosis and neuronal health. However, the precise molecular mechanisms underlying the involvement of ferroptosis in the pathological processes of neurodegeneration and its impact on neuronal dysfunction remain incompletely understood. In our Review, we provide a comprehensive analysis and summary of the potential molecular mechanisms underlying ferroptosis in neurodegenerative diseases, aiming to elucidate the disease progression of neurodegeneration. Additionally, we discuss potential therapeutic agents that modulate ferroptosis with the goal of identifying novel drug molecules for the treatment of neurodegenerative disorders.

White Matter Microstructural Alterations over the Year after Acute Ischemic Stroke in Patients with Baseline Impaired Cognitive Functions.

Background: The disruption of white matter (WM) integrity is related to poststroke cognitive impairment (PSCI). The exploration of WM integrity alterations in the chronic stage of acute ischemic stroke (AIS) may help to improve the long-term outcomes of PSCI. Methods: Sixty patients showing impaired cognitive functions within 3 days after AIS (baseline) and 25 healthy controls underwent diffusion kurtosis imaging scan and cognitive assessment at baseline and 1 year. Based on the tract-based spatial statistics (TBSS), kurtosis fractional anisotropy (KFA) and mean kurtosis (MK) were compared in WM tracts between the groups. Results: One year after AIS, 25 patients were diagnosed with PSCI and 35 patients with non-cognitive impairment (NCI). Compared with baseline, cognitive performance improved in 54 patients and remained unchanged in 6 patients at 1 year. TBSS analysis showed that there were no significant differences in WM tract integrity between the AIS and control groups at baseline (P > 0.05). Compared with the control group, the KFA and MK in multiple WM tracts in the AIS group decreased significantly at 1 year (P < 0.05). Longitudinal analysis showed that the KFA and MK of multiple WM tracts recorded at 1 year were significantly lower than those recorded at baseline in the AIS, PSCI, and NCI groups (P < 0.05), and PSCI group had a faster degeneration than NCI group (P < 0.05). Conclusion: The finding suggests that the patients with baseline impaired cognitive functions still have WM microstructural damages at 1 year poststroke, even if their cognitive function has improved or returned to normal. Cautions should be taken against the possible negative impact of these changes on long-term cognition.

Sex Differences in Brain Structure in de novo Parkinson's Disease: A Cross-Sectional and Longitudinal Neuroimaging Study.

BACKGROUND: Parkinson's disease (PD) varies in occurrence, presentation, and severity between males and females. However, the sex effects on the patterns of brain structure, cross-sectionally and longitudinally, are still unclear. OBJECTIVE: We aimed to compare sex differences in brain features cross-sectionally and longitudinally using grey matter volume (GMV) and cortical thickness in a large sample of newly diagnosed drug-naive PD patients. METHODS: Cognitive assessments and structural MR images of 262 PD patients (171 males) and 113 healthy controls (68 males) were selected from the Parkinson's Progression Markers Initiative. Of these, 97 PD patients (66 males) completed 12- and 24-month follow-up examinations. After regressing out the expected effects of age and sex, brain maps of GMV and cortical thickness were compared using two-sample t tests cross-sectionally and were compared using repeated measurement analyses of variance longitudinally. RESULTS: At baseline, male PD patients exhibited a greater extent of brain atrophy and cortical thickness reduction than females, which mainly occurred in the cerebellum, frontal lobe, parietal lobe, and temporal lobe. At follow-up, female and male PD patients showed similar dynamics of disease progression, as both groups declined over time while the females maintained the advantage. The cortical thickness of the right precentral gyrus at baseline was negatively associated with the longitudinal changes of motor function in male PD patients. CONCLUSION: The current findings might demonstrate sex effect in neuroanatomy during the course of PD, provide new insights into the neurodegenerative process, and facilitate the development of more effective sex-specific therapeutic strategies.

Deep Learning Algorithm Enables Cerebral Venous Thrombosis Detection With Routine Brain Magnetic Resonance Imaging.

BACKGROUND: Cerebral venous thrombosis (CVT) is a rare cerebrovascular disease. Routine brain magnetic resonance imaging is commonly used to diagnose CVT. This study aimed to develop and evaluate a novel deep learning (DL) algorithm for detecting CVT using routine brain magnetic resonance imaging. METHODS: Routine brain magnetic resonance imaging, including T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images of patients suspected of CVT from April 2014 through December 2019 who were enrolled from a CVT registry, were collected. The images were divided into 2 data sets: a development set and a test set. Different DL algorithms were constructed in the development set using 5-fold cross-validation. Four radiologists with various levels of expertise independently read the images and performed diagnosis within the test set. The diagnostic performance on per-patient and per-segment diagnosis levels of the DL algorithms and radiologist's assessment were evaluated and compared. RESULTS: A total of 392 patients, including 294 patients with CVT (37±14 years, 151 women) and 98 patients without CVT (42±15 years, 65 women), were enrolled. Of these, 100 patients (50 CVT and 50 non-CVT) were randomly assigned to the test set, and the other 292 patients comprised the development set. In the test set, the optimal DL algorithm (multisequence multitask deep learning algorithm) achieved an area under the curve of 0.96, with a sensitivity of 96% (48/50) and a specificity of 88% (44/50) on per-patient diagnosis level, as well as a sensitivity of 88% (129/146) and a specificity of 80% (521/654) on per-segment diagnosis level. Compared with 4 radiologists, multisequence multitask deep learning algorithm showed higher sensitivity both on per-patient (all P<0.05) and per-segment diagnosis levels (all P<0.001). CONCLUSIONS: The CVT-detected DL algorithm herein improved diagnostic performance of routine brain magnetic resonance imaging, with high sensitivity and specificity, which provides a promising approach for detecting CVT.

The Bidirectional Association Between Cognitive Function and Gait Speed in Chinese Older Adults: Longitudinal Observational Study.

BACKGROUND: Cognitive and gait speed decline are common conditions in older adults and are often associated with future adverse consequences. Although an association between cognitive function and gait speed has been demonstrated, its temporal sequence remains unclear, especially in older Chinese adults. Clarifying this could help identify interventions to improve public health in older adults. OBJECTIVE: This study aims to examine the longitudinal reciprocal association between gait speed and cognitive function and the possible temporal sequence of changes in both factors in a national longitudinal cohort. METHODS: Data were derived from 2 waves (2011 baseline and 2015 follow-up) of the China Health and Retirement Longitudinal Study (CHARLS). Participants 60 years or older, without dementia or Parkinson disease at baseline, and with completed data on gait speed and cognition at both baseline and follow-up were included. Usual gait speed was measured over two 2.5-m walks. Mental intactness and episodic memory were used to assess global cognitive function. Cross-lagged panel models and linear mixed-effects models were used to examine the association between cognition and gait speed over time. Standardized coefficients were reported. RESULTS: A total of 3009 participants (mean age 66.4 years, SD 5.4 years; 1422/3009, 47.26%, female participants) were eligible for inclusion in our analyses. Cross-lagged panel analyses revealed that after accounting for baseline gait speed, cognition, and potential confounders, baseline global cognition (ß=.117, 95% CI 0.082-0.152; P<.001), mental intactness (ß=.082, 95% CI 0.047-0.118; P<.001), and episodic memory (ß=.102, 95% CI 0.067-0.137; P<.001) were associated with subsequent gait speed. Simultaneously, baseline gait speed was also associated with subsequent global cognition (ß=.056, 95% CI 0.024-0.087; P=.001), mental intactness (ß=.039, 95% CI 0.008-0.069; P=.01), and episodic memory (ß=.057, 95% CI 0.023-0.092; P=.001). The comparison of standardized cross-lagged coefficients suggested that the effect size of baseline global cognition on subsequent gait speed was significantly larger than the reverse effect (χ12=6.50, P for difference=.01). However, the effects of both mental intactness and episodic memory on subsequent gait speed were not significantly stronger than those of the reverse pathway (χ12=3.33, P for difference=.07 and χ12=3.21, P for difference=.07). Linear mixed-effects analyses further supported these bidirectional relationships, revealing that lower baseline cognitive scores predicted steeper declines in gait speed trajectory, and slower baseline gait speed predicted more declines in cognitive trajectory over time. CONCLUSIONS: There is a longitudinal bidirectional association between usual gait speed and both global cognitive function and specific domains of mental intactness and episodic memory among Chinese older adults. Baseline global cognition is likely to have a stronger association with subsequent gait speed than the reverse pathway. This interlinkage is noteworthy and may have implications for public health. Maintaining normal cognitive function may be an important interventional strategy for mitigating age-related gait speed reduction.

Morphological brain alterations in dialysis- and non-dialysis-dependent patients with chronic kidney disease.

To 1) investigate the morphological brain-tissue changes in patients with dialysis- and non-dialysis-dependent chronic kidney disease (CKD); 2) analyze the effects of CKD on whole-brain cortical thickness, cortical volume, surface area, and surface curvature; and 3) analyze the correlation of these changes with clinical and biochemical indices. This study included normal controls (NCs, n = 34) and patients with CKD who were divided into dialysis (dialysis-dependent chronic kidney disease [DD-CKD], n = 26) and non-dialysis (non-dialysis patients who underwent cranial magnetic resonance imaging scans [NDD-CKD], n = 26) groups. Cortical thickness, volume, surface area, and surface curvature in each group were calculated using FreeSurfer software. Brain morphological indicators with statistical differences were correlated with clinical and biochemical indicators. Patients with CKD exhibited a significant and widespread decrease in cortical thickness and volume compared with NCs. Among the brain regions associated with higher neural activity, patients with CKD exhibited more significant morphological changes in the paracentral gyrus, transverse temporal gyrus, and lateral occipital cortex than in other brain regions. Cortical thickness and volume in patients with CKD correlated with blood pressure, lipid, hemoglobin, creatinine, and urea nitrogen levels. The extent of brain atrophy was further increased in the DD-CKD group compared with that in the NDD-CKD group. Patients with CKD potentially exhibit a certain degree of structural brain-tissue imaging changes, with morphological changes more pronounced in patients with DD-CKD, suggesting that blood urea nitrogen and dialysis may be influential factors in brain morphological changes in patients with CKD.

Decreased water exchange rate across blood-brain barrier in hereditary cerebral small vessel disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation-related cerebral small vessel disease (CSVD) are the two types of dominant hereditary CSVD. Blood-brain barrier (BBB) failure has been hypothesized in the pathophysiology of CSVD. However, it is unclear whether there is BBB damage in the two types of hereditary CSVD, especially in heterozygous HTRA1 mutation-related CSVD. In this study, a case-control design was used with two disease groups including CADASIL (n = 24), heterozygous HTRA1 mutation-related CSVD (n = 9) and healthy controls (n = 24). All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labelling was used to estimate the water exchange rate across the BBB (kw). Correlation and multiple linear regression analyses were used to examine the association between kw and disease burden and neuropsychological performance, respectively. Compared with the healthy controls, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients (Bonferroni-corrected P < 0.007). In the CADASIL group, decreased kw in the whole brain (ß = -0.634, P = 0.001), normal-appearing white matter (ß = -0.599, P = 0.002) and temporal lobe (ß = -0.654, P = 0.001) was significantly associated with higher CSVD score after adjusting for age and sex. Reduced kw in the whole brain was significantly associated with poorer neuropsychological performance after adjusting for age, sex and education in both CADASIL and heterozygous HTRA1 mutation-related CSVD groups (ß = 0.458, P = 0.001; ß = 0.884, P = 0.008). This study showed that there was decreased water exchange rate across the BBB in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients, suggesting a common pathophysiological mechanism underlying the two types of hereditary CSVD. These results highlight the potential use of kw for monitoring the course of CADASIL and heterozygous HTRA1 mutation-related CSVD, a possibility which should be tested in future research.

Inflammation Disrupts the Brain Network of Executive Function after Cardiac Surgery.

OBJECTIVE: To investigate postoperative functional connectivity (FC) alterations across impaired cognitive domains and their causal relationships with systemic inflammation. BACKGROUND: Postoperative cognitive dysfunction commonly occurs after cardiac surgery, and both systemic and neuroinflammation may trigger its development. Whether FC alterations underlying deficits in specific cognitive domains after cardiac surgery are affected by inflammation remains unclear. METHODS: Seventeen patients, who underwent cardiac valve replacement, completed a neuropsychological test battery and brain MRI scan before surgery and on days 7 and 30 after surgery compared to age-matched healthy controls. Blood samples were taken for tumor necrosis factor-a and interleukin-6 measurements. Seed-to-voxel FC of the left dorsolateral prefrontal cortex (DLPFC) was examined. Bivariate correlation and linear regression models were used to determine the relationships among cognitive function, FC alterations, and cytokines. RESULTS: Executive function was significantly impaired after cardiac surgery. At day 7 follow-up, the surgical patients, compared to the controls, demonstrated significantly decreased DLPFC FC with the superior parietal lobe and attenuated negative connectivity in the default mode network, including the angular gyrus and posterior cingulate cortex. The left DLPFC enhanced the connectivity in the right DLPFC and posterior cingulate cortex, all of which were related to the increased tumor necrosis factor-a and decreased executive function up to day 7 after cardiac surgery. CONCLUSIONS: The decreased FC of executive control network and its anticorrelation with the default mode network may contribute to executive function deficits after cardiac surgery. Systemic inflammation may trigger these transient FC changes and executive function impairments.

Sex differences in frontotemporal atrophy in CADASIL revealed by 7-Tesla MRI.

Brain damage caused by small vessel disease (SVD) differs between males and females. We aimed to examine the pure sex-specific neuroanatomical mechanisms of SVD adjusted for voxel-based expected effects of age and sex on healthy brain volume. Thirty-one female and 32 male genetic SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL) patients and 55 sex- and age-matched healthy controls (HCs) underwent 7-Tesla MRI examinations. Voxel-based W-score maps were calculated from volumes and deformations of brain tissues, controlling for the expected effects of age and sex in HCs. Significant cognitive declines in working memory and executive function were identified in male CADASIL patients compared to female patients. Greater gray matter (GM) atrophy was found in the bilateral orbitofrontal cortex (OFC), left anterior cingulate cortex (ACC), left entorhinal cortex (EC), and right temporooccipital cortex in male CADASIL patients than in females. Working memory was associated with volumes in the right OFC specific to female CADASIL patients, whereas visuospatial ability was associated with the right hOcl (primary visual area, BA 17) volume specific to males. The current findings indicate that sex affects the pathogenesis of CADASIL, ranging from differences in neuroanatomy to those in behavioral performance, which may facilitate the development of more effective sex-specific therapeutic strategies for CADASIL and SVD.

Structural and functional alterations in cerebral small vessel disease: an ALE-based meta-analysis.

Cerebral small vessel disease (CSVD) is one of the most important causes of stroke and dementia. Although increasing studies have reported alterations of brain structural or neuronal functional activity exhibited in patients with CSVD, it is still unclear which alterations are reliable. Here, we performed a meta-analysis to establish which brain structural or neuronal functional activity changes in those studies were consistent. Activation likelihood estimation revealed that changes in neuronal functional activity in the left angular gyrus, bilateral anterior cingulate cortex/left medial prefrontal cortex, right rolandic operculum, and alterations of gray structure in the left insular cortex/superior temporal gyrus/claustrum were reliable in sporadic CSVD. Decreased neuronal functional activity in the caudate head, anterior cingulate cortex, and reduced gray matter volume in the insular cortex/superior temporal gyrus/claustrum were associated with CSVD-related cognitive impairment. Furthermore, unlike sporadic CSVD, the reliable alterations of neuronal functional activity in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were concentrated in the left parahippocampal gyrus. The current study presents stable brain structural and neuronal functional abnormalities within the brain, which can help further understand the pathogenesis of CSVD and CSVD-cognitive impairment and provide an index to evaluate the effectiveness of treatment protocols. HIGHLIGHTS: • Default mode network and salience network are reliable networks affected in sporadic CSVD in resting-state.• Altered corticostriatal circuitry is associated with cognitive decline.• Decreased gray matter volume in the insular cortex is stable "remote effects" of sporadic CSVD.• The parahippocampal gyrus may be a reliable affected brain region in CADASIL.

Comprehensive evaluation of plasma microbial cell-free DNA sequencing for predicting bloodstream and local infections in clinical practice: a multicenter retrospective study.

Background: Metagenomic next-generation sequencing (mNGS) of plasma cell-free DNA (cfDNA) shows promising application for complicated infections that cannot be resolved by conventional microbiological tests (CMTs). The criteria for cfDNA sequencing are currently in need of agreement and standardization. Methods: We performed a retrospective cohort observation of 653 patients who underwent plasma cfDNA mNGS, including 431 with suspected bloodstream infections (BSI) and 222 with other suspected systemic infections. Plasma mNGS and CMTs were performed simultaneously in clinical practice. The diagnostic efficacy of plasma mNGS and CMTs in the diagnosis of blood-borne and other systemic infections was evaluated using receiver operating characteristic (ROC) curves. The sensitivity and specificity of the two methods were analyzed based on the final clinical outcome as the gold standard. Results: The mNGS test showed an overall positive rate of 72.3% (472/653) for detecting microorganisms in plasma cfDNA, with a range of 2 to 6 different microorganisms detected in 171 patient specimens. Patients with positive mNGS results were more immunocompromised and had a higher incidence of severe disease (P<0·05). The sensitivity of mNGS was higher for BSI (93·5%) and other systemic infections (83·6%) compared to CMTs (37·7% and 14·3%, respectively). The mNGS detected DNA from a total of 735 microorganisms, with the number of microbial DNA reads ranging from 3 to 57,969, and a higher number of reads being associated with clinical infections (P<0·05). Of the 472 patients with positive mNGS results, clinical management was positively affected in 203 (43%) cases. Negative mNGS results led to a modified clinical management regimen in 92 patients (14.1%). The study also developed a bacterial and fungal library for plasma mNGS and obtained comparisons of turnaround times and detailed processing procedures for rare pathogens. Conclusion: Our study evaluates the clinical use and analytic approaches of mNGS in predicting bloodstream and local infections in clinical practice. Our results suggest that mNGS has higher positive predictive values (PPVs) for BSI and systemic infections compared to CMTs, and can positively affect clinical management in a significant number of patients. The standardized whole-process management procedure for plasma mNGS developed in this study will ensure improved pre-screening probabilities and yield clinically valuable data.

Application of metagenomic next-generation sequencing in the diagnosis of pulmonary invasive fungal disease.

Background: Metagenomic next-generation sequencing (mNGS) is increasingly being used to detect pathogens directly from clinical specimens. However, the optimal application of mNGS and subsequent result interpretation can be challenging. In addition, studies reporting the use of mNGS for the diagnosis of invasive fungal infections (IFIs) are rare. Objective: We critically evaluated the performance of mNGS in the diagnosis of pulmonary IFIs, by conducting a multicenter retrospective analysis. The methodological strengths of mNGS were recognized, and diagnostic cutoffs were determined. Methods: A total of 310 patients with suspected pulmonary IFIs were included in this study. Conventional microbiological tests (CMTs) and mNGS were performed in parallel on the same set of samples. Receiver operating characteristic (ROC) curves were used to evaluate the performance of the logarithm of reads per kilobase per million mapped reads [lg(RPKM)], and read counts were used to predict true-positive pathogens. Result: The majority of the selected patients (86.5%) were immunocompromised. Twenty species of fungi were detected by mNGS, which was more than was achieved with standard culture methods. Peripheral blood lymphocyte and monocyte counts, as well as serum albumin levels, were significantly negatively correlated with fungal infection. In contrast, C-reactive protein and procalcitonin levels showed a significant positive correlation with fungal infection. ROC curves showed that mNGS [and especially lg(RPKM)] was superior to CMTs in its diagnostic performance. The area under the ROC curve value obtained for lg(RPKM) in the bronchoalveolar lavage fluid of patients with suspected pulmonary IFIs, used to predict true-positive pathogens, was 0.967, and the cutoff value calculated from the Youden index was -5.44. Conclusions: In this study, we have evaluated the performance of mNGS-specific indicators that can identify pathogens in patients with IFIs more accurately and rapidly than CMTs, which will have important clinical implications.

Polyphyllin II induced apoptosis of NSCLC cells by inhibiting autophagy through the mTOR pathway.

CONTEXT: Polyphyllin II (PPII) is a steroidal saponin isolated from Rhizoma Paridis. It exhibits significant antitumor activity such as anti-proliferation and pro-apoptosis in lung cancer. OBJECTIVE: To explore whether PPII induce autophagy and the relationship between autophagy and apoptosis in non-small cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: The effects of PPII (0, 1, 5, and 10 µM) were elucidated by CCK8 assay, colony formation test, TUNEL staining, MDC method, and mRFP-GFP-LC3 lentivirus transfection in A549 and H1299 cells for 24 h. DMSO-treated cells were selected as control. The protein expression of autophagy (LC3-II, p62), apoptosis (Bcl-2, Bax, caspase-3) and p-mTOR was detected by Western blotting. We explored the relationship between autophagy and apoptosis by autophagy inhibitor CQ (10 µM) and 3-MA (5 mM). RESULTS: PPII (0, 1, 5, and 10 µM) inhibited the proliferation and induced apoptosis. The IC50 values of A549 and H1299 cells were 8.26 ± 0.03 and 2.86 ± 0.83 µM. We found that PPII could induce autophagy. PPII promoted the formation of autophagosome, increased the expression of LC3-II/LC3-I (p < 0.05), while decreased p62 and p-mTOR (p < 0.05). Additionally, the co-treatment with autophagy inhibitors promoted the protein expression of c-caspase-3 and rate of Bax/Bcl-2 (p < 0.05), compared with PPII-only treatment group. Therefore, our results indicated that PPII-induced autophagy may be a mechanism to promote cell survival, although it can also induce apoptosis. CONCLUSIONS: PPII-induced apoptosis exerts its anticancer activity by inhibiting autophagy, which will hopefully provide a prospective compound for NSCLC treatment.

Inhibition of autophagy potentiates the cytotoxicity of the irreversible FGFR1-4 inhibitor FIIN-2 on lung adenocarcinoma.

For patients with platinum-resistant lung adenocarcinoma (LUAD), the exploration of new effective drug candidates is urgently needed. Fibroblast growth factor receptors (FGFRs) have been identified as promising targets for LUAD therapy. The purpose of this study was to determine the exact role of the irreversible FGFR1-4 inhibitor FIIN-2 in LUAD and to clarify its underlying molecular mechanisms. Our results demonstrated that FIIN-2 significantly inhibited the proliferation, colony formation, and migration of A549 and A549/DDP cells but induced the mitochondria-mediated apoptosis of these cells. Meanwhile, FIIN-2 increased the autophagy flux of A549 and A549/DDP cells by inhibiting the mammalian target of rapamycin (mTOR) and further activating the class III PI3K complex pathway. More importantly, in vivo and in vitro experiments showed that autophagy inhibitors could enhance the cytotoxicity of FIIN-2 on A549 and A549/DDP cells, confirming that FIIN-2 induced protective autophagy. These findings indicated that FIIN-2 is a potential drug candidate for LUAD treatment, and its use in combination with autophagy inhibitors might be an efficient treatment strategy, especially for patients with cisplatin resistance.