The relationship between inflammation, impaired glymphatic system, and neurodegenerative disorders: A vicious cycle.

The term "glymphatic" emerged roughly a decade ago, marking a pivotal point in neuroscience research. The glymphatic system, a glial-dependent perivascular network distributed throughout the brain, has since become a focal point of investigation. There is increasing evidence suggesting that impairment of the glymphatic system appears to be a common feature of neurodegenerative disorders, and this impairment exacerbates as disease progression. Nevertheless, the common factors contributing to glymphatic system dysfunction across most neurodegenerative disorders remain unclear. Inflammation, however, is suspected to play a pivotal role. Dysfunction of the glymphatic system can lead to a significant accumulation of protein and waste products, which can trigger inflammation. The interaction between the glymphatic system and inflammation appears to be cyclical and potentially synergistic. Yet, current research is limited, and there is a lack of comprehensive models explaining this association. In this perspective review, we propose a novel model suggesting that inflammation, impaired glymphatic function, and neurodegenerative disorders interconnected in a vicious cycle. By presenting experimental evidence from the existing literature, we aim to demonstrate that: (1) inflammation aggravates glymphatic system dysfunction, (2) the impaired glymphatic system exacerbated neurodegenerative disorders progression, (3) neurodegenerative disorders progression promotes inflammation. Finally, the implication of proposed model is discussed.

Diffusion magnetic resonance imaging of cerebrospinal fluid dynamics: Current techniques and future advancements.

Cerebrospinal fluid (CSF) plays a critical role in metabolic waste clearance from the brain, requiring its circulation throughout various brain pathways, including the ventricular system, subarachnoid spaces, para-arterial spaces, interstitial spaces, and para-venous spaces. The complexity of CSF circulation has posed a challenge in obtaining noninvasive measurements of CSF dynamics. The assessment of CSF dynamics throughout its various circulatory pathways is possible using diffusion magnetic resonance imaging (MRI) with optimized sensitivity to incoherent water movement across the brain. This review presents an overview of both established and emerging diffusion MRI techniques designed to measure CSF dynamics and their potential clinical applications. The discussion offers insights into the optimization of diffusion MRI acquisition parameters to enhance the sensitivity and specificity of diffusion metrics on underlying CSF dynamics. Lastly, we emphasize the importance of cautious interpretations of diffusion-based imaging, especially when differentiating between tissue- and fluid-related changes or elucidating structural versus functional alterations.

Paravascular fluid dynamics reveal arterial stiffness assessed using dynamic diffusion-weighted imaging.

Paravascular cerebrospinal fluid (pCSF) surrounding the cerebral arteries within the glymphatic system is pulsatile and moves in synchrony with the pressure waves of the vessel wall. Whether such pulsatile pCSF can infer pulse wave propagation-a property tightly related to arterial stiffness-is unknown and has never been explored. Our recently developed imaging technique, dynamic diffusion-weighted imaging (dynDWI), captures the pulsatile pCSF dynamics in vivo and can explore this question. In this work, we evaluated the time shifts between pCSF waves and finger pulse waves, where pCSF waves were measured by dynDWI and finger pulse waves were measured by the scanner's built-in finger pulse oximeter. We hypothesized that the time shifts reflect brain-finger pulse wave travel time and are sensitive to arterial stiffness. We applied the framework to 36 participants aged 18-82 years to study the age effect of travel time, as well as its associations with cognitive function within the older participants (N = 15, age > 60 years). Our results revealed a strong and consistent correlation between pCSF pulse and finger pulse (mean CorrCoeff = 0.66), supporting arterial pulsation as a major driver for pCSF dynamics. The time delay between pCSF and finger pulses (TimeDelay) was significantly lower (i.e., faster pulse propagation) with advanced age (Pearson's r = -0.44, p = 0.007). Shorter TimeDelay was further associated with worse cognitive function in the older participants. Overall, our study demonstrated pCSF as a viable pathway for measuring intracranial pulses and encouraged future studies to investigate its relevance with cerebrovascular functions.

Exploring Radial Asymmetry in MR Diffusion Tensor Imaging and Its Impact on the Interpretation of Glymphatic Mechanisms.

BACKGROUND: Diffusion imaging holds great potential for the non-invasive assessment of the glymphatic system in humans. One technique, diffusion tensor imaging along the perivascular space (DTI-ALPS), has introduced the ALPS-index, a novel metric for evaluating diffusivity within the perivascular space. However, it still needs to be established whether the observed reduction in the ALPS-index reflects axonal changes, a common occurrence in neurodegenerative diseases. PURPOSE: To determine whether axonal alterations can influence change in the ALPS-index. STUDY TYPE: Retrospective. POPULATION: 100 participants (78 cognitively normal and 22 with mild cognitive impairments) aged 50-90 years old. FIELD STRENGTH/SEQUENCE: 3T; diffusion-weighted single-shot spin-echo echo-planar imaging sequence, T1-weighted images (MP-RAGE). ASSESSMENT: The ratio of two radial diffusivities of the diffusion tensor (i.e., λ2/λ3) across major white matter tracts with distinct venous/perivenous anatomy that fulfill (ALPS-tracts) and do not fulfill (control tracts) ALPS-index anatomical assumptions were analyzed. STATISTICAL TESTS: To investigate the correlation between λ2/λ3 and age/cognitive function (RAVLT) while accounting for the effect of age, linear regression was implemented to remove the age effect from each variable. Pearson correlation analysis was conducted on the residuals obtained from the linear regression. Statistical significance was set at p < 0.05. RESULTS: λ2 was ~50% higher than λ3 and demonstrated a consistent pattern across both ALPS and control tracts. Additionally, in both ALPS and control tracts a reduction in the λ2/λ3 ratio was observed with advancing age (r = -0.39, r = -0.29, association and forceps tract, respectively) and decreased memory function (r = 0.24, r = 0.27, association and forceps tract, respectively). DATA CONCLUSIONS: The results unveil a widespread radial asymmetry of white matter tracts that changes with aging and neurodegeration. These findings highlight that the ALPS-index may not solely reflect changes in the diffusivity of the perivascular space but may also incorporate axonal contributions. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Hippocampal-subfield microstructures and their relation to plasma biomarkers in Alzheimer's disease.

Hippocampal subfields exhibit differential vulnerabilities to Alzheimer's disease-associated pathology including abnormal accumulation of amyloid-ß deposition and neurofibrillary tangles. These pathological processes extensively impact on the structural and functional interconnectivities of the subfields and may explain the association between hippocampal dysfunction and cognitive deficits. In this study, we investigated the degree of alterations in the microstructure of hippocampal subfields across the clinical continuum of Alzheimer's disease. We applied a grey matter-specific multi-compartment diffusion model (Cortical-Neurite orientation dispersion and density imaging) to understand the differential effects of Alzheimer's disease pathology on the hippocampal subfield microstructure. A total of 119 participants were included in this cross-sectional study. Participants were stratified into three categories, cognitively normal (n = 47), mild cognitive impairment (n = 52), and Alzheimer's disease (n = 19). Diffusion MRI, plasma biomarkers and neuropsychological test scores were used to determine the association between the microstructural integrity and Alzheimer's disease-associated molecular indicators and cognition. For Alzheimer's disease-related plasma biomarkers, we studied amyloid-ß, total tau and neurofilament light; for Alzheimer's disease-related neuropsychological tests, we included the Trail Making Test, Rey Auditory Verbal Learning Test, Digit Span and Montreal Cognitive Assessment. Comparisons between cognitively normal subjects and those with mild cognitive impairment showed significant microstructural alterations in the hippocampal cornu ammonis (CA) 4 and dentate gyrus region, whereas CA 1-3 was the most sensitive region for the later stages in the Alzheimer's disease clinical continuum. Among imaging metrics for microstructures, the volume fraction of isotropic diffusion for interstitial free water demonstrated the largest effect size in between-group comparisons. Regarding the plasma biomarkers, neurofilament light appeared to be the most sensitive biomarker for associations with microstructural imaging findings in CA4-dentate gyrus. CA 1-3 was the subfield which had stronger correlations between cognitive performance and microstructural metrics. Particularly, poor performance on the Rey Auditory Verbal Learning Test and Montreal Cognitive Assessment was associated with decreased intracellular volume fraction. Overall, our findings support the value of tissue-specific microstructural imaging for providing pathologically relevant information manifesting in the plasma biomarkers and neuropsychological outcomes across various stages of Alzheimer's disease.

Assessing pulsatile waveforms of paravascular cerebrospinal fluid dynamics within the glymphatic pathways using dynamic diffusion-weighted imaging (dDWI)

Cerebrospinal fluid (CSF) in the paravascular spaces of the surface arteries (sPVS) is a vital pathway in brain waste clearance. Arterial pulsations may be the driving force of the paravascular flow, but its pulsatile pattern remains poorly characterized, and no clinically practical method for measuring its dynamics in the human brain is available. In this work, we introduce an imaging and quantification framework for in-vivo non-invasive assessment of pulsatile fluid dynamics in the sPVS. It used dynamic Diffusion-Weighted Imaging (dDWI) at a lower b-values of 150s/mm2 and retrospective gating to detect the slow flow of CSF while suppressing the fast flow of adjacent arterial blood. The waveform of CSF flow over a cardiac cycle was revealed by synchronizing the measurements with the heartbeat. A data-driven approach was developed to identify sPVS and allow automatic quantification of the whole-brain fluid waveforms. We applied dDWI to twenty-five participants aged 18-82 y/o. Results demonstrated that the fluid waveforms across the brain showed an explicit cardiac-cycle dependency, in good agreement with the vascular pumping hypothesis. Furthermore, the shape of the CSF waveforms closely resembled the pressure waveforms of the artery wall, suggesting that CSF dynamics is tightly related to artery wall mechanics. Finally, the CSF waveforms in aging participants revealed a strong age effect, with a significantly wider systolic peak observed in the older relative to younger participants. The peak widening may be associated with compromised vascular compliance and vessel wall stiffening in the older brain. Overall, the results demonstrate the feasibility, reproducibility, and sensitivity of dDWI for detecting sPVS fluid dynamics of the human brain. Our preliminary data suggest age-related alterations of the paravascular pumping. With an acquisition time of under six minutes, dDWI can be readily applied to study fluid dynamics in normal physiological conditions and cerebrovascular/neurodegenerative diseases.

Tau-related white-matter alterations along spatially selective pathways.

Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model - neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-ß PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.

Decreased serum exosomal miR-29a expression and its clinical significance in papillary thyroid carcinoma.

BACKGROUND: Aberrant levels of circulating microRNAs (miRNAs) are potential biomarkers in papillary thyroid carcinoma (PTC) diagnosis and therapy. The aim of this study was to evaluate serum exosomal miR-29a expression as a non-invasive biomarker for PTC diagnosis and prognosis. METHODS: Quantitative reverse transcription polymerase chain reaction was applied to measure serum exosomal miR-29a expression levels in blood samples of 119 patients with PTC and 100 control subjects. RESULTS: Serum exosomal miR-29a expression levels were significantly decreased in PTC cases. In addition, receiver operating characteristic (ROC) analysis revealed serum exosomal miR-29a could well differentiate PTC from normal controls. Moreover, serum exosomal miR-29a levels increased progressively and significantly 30 days and 90 days after surgery. Furthermore, PTC patients with lower serum exosomal miR-29a expression had higher risk of recurrence. Decreased serum exosomal miR-29a expression was significantly associated with worse clinical variables including tumor size, extrathyroidal extension, and TNM stage, as well as shorter survival. Finally, both univariate and multivariate identified serum exosomal miR-29a as an independent prognostic indicator for overall survival. CONCLUSION: These results demonstrated that serum exosomal miR-29a might serve as a potential biomarker for PTC diagnosis and prognosis.

Rapid golden-angle diffusion-weighted propeller MRI for simultaneous assessment of ADC and IVIM.

PURPOSE: Golden-angle single-shot PROPLLER (GA-SS-PROP) is proposed to accelerate the PROPELLER acquisition for distortion-free diffusion-weighted (DW) imaging. Acceleration is achieved by acquiring one-shot per b-value and several b-values can be acquired along a diffusion direction, where the DW signal follows a bi-exponential decay (i.e. IVIM). Sparse reconstruction is used to reconstruct full resolution DW images. Consequently, apparent diffusion coefficient (ADC) map and IVIM maps (i.e., perfusion fraction (f) and the perfusion-free diffusion coefficient (D)) are obtained simultaneously. The performance of GA-SS-PROP was demonstrated with simulation and human experiments. METHODS: A realistic numerical phantom of high-quality diffusion images of the brain was developed. The error of the reconstructed DW images and quantitative maps were compared to the ground truth. The pulse sequence was developed to acquire human brain data. For comparison, fully sampled PROPELLER and conventional single-shot echo planar imaging (SS-EPI) acquisitions were performed. RESULTS: GA-SS-PROP was 5 times faster than conventional PROPELLER acquisition with comparable image quality. The simulation demonstrated that sparse reconstruction is effective in restoring contrast and resolution. The human experiments demonstrated that GA-SS-PROP achieved superior image fidelity compared to SS-EPI for the same acquisition time and same in-plane resolution (1 × 1 mm2). CONCLUSION: GA-SS-PROP offers fast, high-resolution and distortion-free DW images. The generated quantitative maps (f, D and ADC) can provide valuable information on tissue perfusion and diffusion properties simultaneously, which are desirable in many applications, especially in oncology. As a turbo spin-echo based technique, it can be applied in most challenging regions where SS-EPI is problematic.

GRASP-Pro: imProving GRASP DCE-MRI through self-calibrating subspace-modeling and contrast phase automation.

PURPOSE: To propose a highly accelerated, high-resolution dynamic contrast-enhanced MRI (DCE-MRI) technique called GRASP-Pro (golden-angle radial sparse parallel imaging with imProved performance) through a joint sparsity and self-calibrating subspace constraint with automated selection of contrast phases. METHODS: GRASP-Pro reconstruction enforces a combination of an explicit low-rank subspace-constraint and a temporal sparsity constraint. The temporal basis used to construct the subspace is learned from an intermediate reconstruction step using the low-resolution portion of radial k-space, which eliminates the need for generating the basis using auxiliary data or a physical signal model. A convolutional neural network was trained to generate the contrast enhancement curve in the artery, from which clinically relevant contrast phases are automatically selected for evaluation. The performance of GRASP-Pro was demonstrated for high spatiotemporal resolution DCE-MRI of the prostate and was compared against standard GRASP in terms of overall image quality, image sharpness, and residual streaks and/or noise level. RESULTS: Compared to GRASP, GRASP-Pro reconstructed dynamic images with enhanced sharpness, less residual streaks and/or noise, and finer delineation of the prostate without prolonging reconstruction time. The image quality improvement reached statistical significance (P < 0.05) in all the assessment categories. The neural network successfully generated contrast enhancement curves in the artery, and corresponding peak enhancement indexes correlated well with that from the manual selection. CONCLUSION: GRASP-Pro is a promising method for rapid and continuous DCE-MRI. It enables superior reconstruction performance over standard GRASP and allows reliable generation of artery enhancement curve to guide the selection of desired contrast phases for improving the efficiency of GRASP MRI workflow.

Rotating single-shot acquisition (RoSA) with composite reconstruction for fast high-resolution diffusion imaging.

PURPOSE: To accelerate high-resolution diffusion imaging, rotating single-shot acquisition (RoSA) with composite reconstruction is proposed. Acceleration was achieved by acquiring only one rotating single-shot blade per diffusion direction, and high-resolution diffusion-weighted (DW) images were reconstructed by using similarities of neighboring DW images. A parallel imaging technique was implemented in RoSA to further improve the image quality and acquisition speed. RoSA performance was evaluated by simulation and human experiments. METHODS: A brain tensor phantom was developed to determine an optimal blade size and rotation angle by considering similarity in DW images, off-resonance effects, and k-space coverage. With the optimal parameters, RoSA MR pulse sequence and reconstruction algorithm were developed to acquire human brain data. For comparison, multishot echo planar imaging (EPI) and conventional single-shot EPI sequences were performed with matched scan time, resolution, field of view, and diffusion directions. RESULTS: The simulation indicated an optimal blade size of 48 × 256 and a 30 ° rotation angle. For 1 × 1 mm2 in-plane resolution, RoSA was 12 times faster than the multishot acquisition with comparable image quality. With the same acquisition time as SS-EPI, RoSA provided superior image quality and minimum geometric distortion. CONCLUSION: RoSA offers fast, high-quality, high-resolution diffusion images. The composite image reconstruction is model-free and compatible with various diffusion computation approaches including parametric and nonparametric analyses. Magn Reson Med 79:264-275, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Comparison of ADC metrics and their association with outcome for patients with newly diagnosed glioblastoma being treated with radiation therapy, temozolomide, erlotinib and bevacizumab.

To evaluate metrics that describe changes in apparent diffusion coefficient (ADC) and to examine their association with clinical outcome for patients with newly diagnosed GBM who were participating in a Phase II clinical trial of treatment with radiation (RT), temozolomide, erlatonib and bevacizumab. Thirty six patients were imaged after surgery but prior to therapy and at regular follow-up time points. The following ADC metrics were evaluated: (1) histogram percentiles within the T2-hyperintense lesion (T2L) at serial follow-ups; (2) parameters obtained by fitting a two-mixture normal distribution to the histogram within the contrast-enhancing lesion (CEL) at baseline; (3) parameters obtained using both traditional and graded functional diffusion maps within the CEL and T2L. Cox Proportional Hazards models were employed to assess the association of the ADC parameters with overall survival (OS) and progression-free survival (PFS). A lower ADC percentile value within the T2L at early follow-up time points was associated with worse outcome. Of particular interest is that, even when adjusting for clinical prognostic factors, the ADC10% within the T2L at 2 months was strongly associated with OS (p < 0.001) and PFS (p < 0.007). fDM metrics showed an association with OS and PFS within the CEL when considered by univariate analysis, but not in the T2L. Our study emphasizes the value of ADC metrics obtained from the T2L at the post-RT time point as non-invasive biomarkers for assessing residual tumor in patients with newly diagnosed GBM being treated with combination therapy that includes the anti-angiogenic agent bevacizumab.

Contribution of Direct Cerebral Vascular Transport in Brain Substance Clearance.

The accumulation of harmful substances has long been recognized as a likely cause of many neurodegenerative diseases. The two classic brain clearance pathways are cerebrospinal fluid (CSF) and vascular circulation systems. Since the discovery of the glymphatic system, research on the CSF pathway has gained momentum, and impaired CSF clearance has been implicated in virtually all neurodegenerative animal models. However, the contribution of the direct participation of vascular transport across the blood-brain barrier in clearing substances is often ignored in glymphatic papers. Supportive evidence for the direct involvement of parenchymal vasculature in substance clearance is accumulated. First, multiple mechanisms have been proposed for the vascular drainage of exogenous and endogenous substances across the blood-brain barriers. Second, the "traditional" role of arachnoid villi and granulations as the main site for CSF draining into the vasculature system has been questioned. Third, MRI studies using different CSF tracers indicate that parenchymal vasculature directly participates in tracer efflux, consistent with immunohistochemical findings. Here we will review evidence in the literature that supports the direct participation of the parenchymal vascular system in substance clearance, in addition to the CSF clearance pathways.

Spatial transcriptomic patterns underlying amyloid-ß and tau pathology are associated with cognitive dysfunction in Alzheimer's disease.

Amyloid-ß (Aß) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aß and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aß (gene-to-Aß associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aß and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aß and the gene-to-tau associations. These findings may explain the discordance between regional Aß and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.

Paeoniflorin protects 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mice by inhibiting oxidative stress and neuronal apoptosis through activating the Nrf2/HO-1 signaling pathway.

OBJECTIVES: This study aimed to explore the neuroprotective effects of paeoniflorin on oxidative stress and apoptosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mice. METHODS: The effects of paeoniflorin on motor function in mice were evaluated by behavioral test. Then substantia nigra of mice were collected and neuronal damage was assessed using Nissl staining. Positive expression of tyrosine hydroxylase (TH) was detected by immunohistochemistry. Levels of malondialdehyde, superoxide dismutase (SOD) and glutathione were measured by biochemical method. terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay was used to detect apoptosis of dopaminergic neurons. Western blotting and real-time fluorescence quantitative PCR were used to detect the protein and mRNA expressions of Nrf2, heme oxygenase-1 (HO-1), B-cell lymphoma-2(Bcl-2), Bax and cleaved caspase-3. RESULTS: Paeoniflorin treatment significantly ameliorated the motor performance impairment in MPTP-induced PD mice. Moreover, it notably increased the positive expression rate of TH and reduced the damage and apoptosis of dopaminergic neurons in the substantia nigra. Furthermore, paeoniflorin increased the levels of SOD and glutathione and decreased the malondialdehyde content. It also promoted Nrf2 nuclear translocation, increased the protein and mRNA expressions of HO-1 and Bcl-2 and reduced the protein and mRNA expressions of BCL2-Associated X2 (Bax) and cleaved caspase-3. Treatment with the Nrf2 inhibitor, ML385, notably reduced the effects of paeoniflorin in MPTP-induced PD mice. CONCLUSIONS: Neuroprotective effects of paeoniflorin in MPTP-induced PD mice may be mediated via inhibition of oxidative stress and apoptosis of dopaminergic neurons in substantia nigra through activation of the Nrf2/HO-1 signaling pathway.

INHBA gene silencing inhibits proliferation, migration, and invasion of osteosarcoma cells by repressing TGF-ß signaling pathway activation.

BACKGROUND: Osteosarcoma (OS) is a refractory malignancy. This study aimed to explore the roles and mechanisms of Inhibin subunit beta A (INHBA) in OS. METHODS: INHBA expression levels in OS tissues and cells were assessed using RT-qPCR and western blotting. The impact of INHBA silencing on OS development was then explored by transfecting the OS cell lines U2OS and MG63 with INHBA-small interfering RNA (siRNA). The influence of INHBA silencing on U2OS and MG63 cell proliferation, migration, and invasion was examined using MTT and Transwell assays. Epithelial-mesenchymal transition (EMT) markers (E-cadherin and N-cadherin) were analyzed by RT-qPCR. The expression of genes involved in cell proliferation, migration, invasion, and the TGF-ß signaling pathway was evaluated by western blotting and RT-qPCR. RESULTS: INHBA levels were elevated in the OS tissues and cells. Furthermore, the transforming growth factor-ß (TGF-ß) signaling pathway of OS cells was suppressed in response to INHBA-siRNA, whereas proliferation, migration, and invasion of OS cells were inhibited. Besides, INHBA-siRNA significantly inhibited OS cell EMT, evidenced by enhanced E-cadherin mRNA expression and reduced N-cadherin mRNA expression. Further mechanistic studies revealed that the TGF-ß1 agonist SRI-011381 hydrochloride increased OS cell proliferation, migration, and invasion after INHBA downregulation. CONCLUSION: We found that INHBA silencing could play a vital role in OS via TGF-ß1-regulated proliferation, migration, and invasion.

Single-Institution Comparative Study of Magnetic Resonance-Guided Laser Interstitial Thermal Therapy and Open Corpus Callosotomy.

OBJECTIVE: Open corpus callosotomy (CC) poses a higher risk of perioperative morbidity than does magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) for treatment of drop and generalized seizures without documented superiority. We present a single-institution comparison between open and MRgLITT CC. METHODS: A 2-year retrospective review was performed of patients who underwent open and MRgLITT CC (January 2019-January 2021). Demographics, surgical outcome data, hospital costs, and interhemispheric connectivity with diffusion tensor imaging were compared. RESULTS: The average age in years was 9.3 and 11.4 for CC (n = 4) and MRgLITT (n = 9), respectively. Preoperative drop seizure frequency was higher in CC (25 vs. 14.5 seizures/day; P = 0.59). At 10 months follow-up, the reduction in drop seizure frequency was better in open CC, but not statistically significant (93.8% vs. 64.3%; P = 0.21). The extent of CC ablation did not correlate with seizure reduction (Pearson coefficient = 0.09). An inverse correlation between interhemispheric connectivity change (diffusion tensor imaging analysis) and drop seizure frequency reduction was noted (Pearson coefficient = -0.97). Total hospital cost was significantly lower in MRgLITT ($67,754 vs. $107,111; P = 0.004), attributed to lower intensive care unit (1.1 vs. 4 days; P= 0.004) and total hospital stay (1.8 vs. 10.5 days; P = 0.0001). Postoperative hydrocephalus was present in 75% of patients in the CC group compared with zero in the MRgLITT group. CONCLUSIONS: Our middle-volume single-institution experience shows the safety, efficacy, and cost-effective benefit of MRgLITT compared with the traditional CC with therapeutic equipoise. This study is limited by the number of patients and, hence, further patient enrollment or multicenter study is warranted.

Spatial transcriptomic patterns underlying regional vulnerability to amyloid-ß and tau pathologies and their relationships to cognitive dysfunction in Alzheimer's disease.

Amyloid-ß (Aß) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aß and tau pathologies than others, gene expression may play a role. We studied the association between brain-wide gene expression profiles and regional vulnerability to Aß (gene-to-Aß associations) and tau (gene-to-tau associations) pathologies leveraging two large independent cohorts (n = 715) of participants along the AD continuum. We identified several AD susceptibility genes and gene modules in a gene co-expression network with expression profiles related to regional vulnerability to Aß and tau pathologies in AD. In particular, we found that the positive APOE -to-tau association was only seen in the AD cohort, whereas patients with AD and frontotemporal dementia shared similar positive MAPT -to-tau association. Some AD candidate genes showed sex-dependent negative gene-to-Aß and gene-to-tau associations. In addition, we identified distinct biochemical pathways associated with the gene-to-Aß and the gene-to-tau associations. Finally, we proposed a novel analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations. Taken together, our study identified distinct gene expression profiles and biochemical pathways that may explain the discordance between regional Aß and tau pathologies, and filled the gap between gene-to-pathology associations and cognitive dysfunction in individual AD patients that may ultimately help identify novel personalized pathogenetic biomarkers and therapeutic targets. One Sentence Summary: We identified replicable cognition-related associations between regional gene expression profiles and selectively regional vulnerability to amyloid-ß and tau pathologies in AD.

Longitudinal Associations Between Blood Biomarkers and White Matter MRI in Sport-Related Concussion: A Study of the NCAA-DoD CARE Consortium.

BACKGROUND AND OBJECTIVES: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play. METHODS: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes. RESULTS: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (ß = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (ß = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|ß|s > 0.12, SEs <0.09, psFDR-adjusted < 0.05) and GFAP showed a significant association only at 7 days after return to play (ßs > 0.14, SEs <0.06, psFDR-adjusted < 0.05). The p values for the associations of early tau and later RD were not significant after multiple comparison adjustment, but were less than 0.1 in 7 white matter tracts. DISCUSSION: This prospective study using data from the CARE Consortium demonstrated that in the early phase of SRC, white matter microstructural integrity detected by DTI neuroimaging was associated with elevated levels of blood-based biomarkers of traumatic brain injury. Total tau in the blood showed the strongest association with white matter microstructural changes.