Incorporation of view sharing and KWIC filtering into GRASP-Pro improves spatial resolution of single-shot, multi-TI, late gadolinium enhancement MRI.

While single-shot late gadolinium enhancement (LGE) is useful for imaging patients with arrhythmia and/or dyspnea, it produces low spatial resolution. One approach to improve spatial resolution is to accelerate data acquisition using compressed sensing (CS). Our previous work described a single-shot, multi-inversion time (TI) LGE pulse sequence using radial k-space sampling and CS, but over-regularization resulted in significant image blurring that muted the benefits of data acceleration. The purpose of the present study was to improve the spatial resolution of the single-shot, multi-TI LGE pulse sequence by incorporating view sharing (VS) and k-space weighted contrast (KWIC) filtering into a GRASP-Pro reconstruction. In 24 patients (mean age = 61 ± 16 years; 9/15 females/males), we compared the performance of our improved multi-TI LGE and standard multi-TI LGE, where clinical standard LGE was used as a reference. Two clinical raters independently graded multi-TI images and clinical LGE images visually on a five-point Likert scale (1, nondiagnostic; 3, clinically acceptable; 5, best) for three categories: the conspicuity of myocardium or scar, artifact, and noise. The summed visual score (SVS) was defined as the sum of the three scores. Myocardial scar volume was quantified using the full-width at half-maximum method. The SVS was not significantly different between clinical breath-holding LGE (median 13.5, IQR 1.3) and multi-TI LGE (median 12.5, IQR 1.6) (P = 0.068). The myocardial scar volumes measured from clinical standard LGE and multi-TI LGE were strongly correlated (coefficient of determination, R2 = 0.99) and in good agreement (mean difference = 0.11%, lower limit of the agreement = -2.13%, upper limit of the agreement = 2.34%). The inter-rater agreement in myocardial scar volume quantification was strong (intraclass correlation coefficient = 0.79). The incorporation of VS and KWIC into GRASP-Pro improved spatial resolution. Our improved 25-fold accelerated, single-shot LGE sequence produces clinically acceptable image quality, multi-TI reconstruction, and accurate myocardial scar volume quantification.

Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status.

This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer's disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aß42 and arterial Aß40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

SCMR expert consensus statement for cardiovascular magnetic resonance of patients with a cardiac implantable electronic device.

Cardiovascular magnetic resonance (CMR) is a proven imaging modality for informing diagnosis and prognosis, guiding therapeutic decisions, and risk stratifying surgical intervention. Patients with a cardiac implantable electronic device (CIED) would be expected to derive particular benefit from CMR given high prevalence of cardiomyopathy and arrhythmia. While several guidelines have been published over the last 16 years, it is important to recognize that both the CIED and CMR technologies, as well as our knowledge in MR safety, have evolved rapidly during that period. Given increasing utilization of CIED over the past decades, there is an unmet need to establish a consensus statement that integrates latest evidence concerning MR safety and CIED and CMR technologies. While experienced centers currently perform CMR in CIED patients, broad availability of CMR in this population is lacking, partially due to limited availability of resources for programming devices and appropriate monitoring, but also related to knowledge gaps regarding the risk-benefit ratio of CMR in this growing population. To address the knowledge gaps, this SCMR Expert Consensus Statement integrates consensus guidelines, primary data, and opinions from experts across disparate fields towards the shared goal of informing evidenced-based decision-making regarding the risk-benefit ratio of CMR for patients with CIEDs.

RNA editing of microtubule-associated protein tau circular RNAs promotes their translation and tau tangle formation.

Aggregation of the microtubule-associated protein tau characterizes tauopathies, including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-Tau). Gene expression regulation of tau is complex and incompletely understood. Here we report that the human tau gene (MAPT) generates two circular RNAs (circRNAs) through backsplicing of exon 12 to either exon 7 (12→7 circRNA) or exon 10 (12→10 circRNA). Both circRNAs lack stop codons. The 12→7 circRNA contains one start codon and is translated in a rolling circle, generating a protein consisting of multimers of the microtubule-binding repeats R1-R4. For the 12→10 circRNA, a start codon can be introduced by two FTLD-Tau mutations, generating a protein consisting of multimers of the microtubule-binding repeats R2-R4, suggesting that mutations causing FTLD may act in part through tau circRNAs. Adenosine to inosine RNA editing dramatically increases translation of circRNAs and, in the 12→10 circRNA, RNA editing generates a translational start codon by changing AUA to AUI. Circular tau proteins self-aggregate and promote aggregation of linear tau proteins. Our data indicate that adenosine to inosine RNA editing initiates translation of human circular tau RNAs, which may contribute to tauopathies.

Gender differences in diet quality and the association between diet quality and BMI: an analysis in young Australian adults who completed the Healthy Eating Quiz.

BACKGROUND: Many young adults report poor diet quality. However, research evaluating whether young adult males and females differ in diet quality is limited. Additionally, although diet quality has a known inverse association with body mass index (BMI), it is unclear whether this association is observed in young adults and whether it varies by gender. The present study aimed to evaluate gender differences in diet quality in young adults, as well as the associations between diet quality and BMI. METHODS: Data collected via the Healthy Eating Quiz (HEQ) in respondents aged 18-35 years between July 2019 and December 2021 were analysed, including demographics, and diet quality calculated using the Australian Recommended Food Score (ARFS). Differences in characteristics were analysed using a two-sample t-test, chi-squared and one-way analysis of covariance. Linear regressions were performed to estimate associations between diet quality and BMI. An interaction term was included in the model to test differences between genders. RESULTS: The respondents (n = 28,969) were predominantly female (70.8%) with a mean ± SD age of 25.9 ± 5.0 years and BMI of 24.6 ± 5.2 kg/m2. The mean ± SD ARFS was significantly different between females and males (33.1 ± 8.6 vs. 31.4 ± 9.3 points out of 70; p < 0.001). Diet quality had a small, significant inverse association with BMI in both genders. The interaction effect between diet quality score and gender in predicting BMI was significant (p < 0.001), suggesting the impact of diet quality on BMI varies by gender, with lower diet quality more strongly associated with higher BMI in females compared to males. CONCLUSION: Interventions that target young adults are needed to improve diet quality and its potential contribution to BMI status. As a result of the small observed effect sizes, caution should be applied in interpreting these findings.

Assessment of Beat-To-Beat Variability in Left Atrial Hemodynamics Using Real Time Phase Contrast MRI in Patients With Atrial Fibrillation.

BACKGROUND: Hemodynamic assessment of left atrial (LA) flow using phase contrast MRI provides insight into thromboembolic risk in atrial fibrillation (AF). However, conventional flow imaging techniques are averaged over many heartbeats. PURPOSE: To evaluate beat-to-beat variability and LA hemodynamics in patients with AF using real time phase contrast (RTPC) MRI. STUDY TYPE: Prospective. SUBJECTS: Thirty-five patients with history of AF (68 ± 10 years, nine female), 10 healthy controls (57 ± 19 years, four female). FIELD STRENGTH/SEQUENCE: 5T, 2D RTPC with through-plane velocity-encoded gradient echo sequence and 4D flow MRI with three-directional velocity-encoded gradient echo sequence. ASSESSMENT: RTPC was continuously acquired for a mid-LA slice in all subjects. 4D flow data were interpolated at the RTPC location and normally projected for comparison with RTPC. RR intervals extracted from RTPC were used to calculate heart rate variability (HRV = interquartile range over median × 100%). Patients were classified into low (<9.7%) and high (>9.7%) HRV groups. LA peak/mean velocity and stasis (%velocities < 5.8 cm/sec) were calculated from segmented 2D images. Variability in RTPC flow metrics was quantified by coefficient of variation (CV) over all cycles. STATISTICAL TESTS: Pearson's correlation coefficient (r), Bland-Altman analysis, Kruskal-Wallis test. A P value < 0.05 was considered statistically significant. RESULTS: RTPC and 4D flow measurements were strongly/significantly correlated for all hemodynamic parameters (R2  = 0.75-0.83) in controls. Twenty-four patients had low HRV (mean = 4 ± 2%) and 11 patients had high HRV (27 ± 9%). In patients, increased HRV was significantly correlated with CV of peak velocity (r = 0.67), mean velocity (r = 0.51), and stasis (r = 0.41). A stepwise decrease in peak/mean velocity and increase in stasis was observed when comparing controls vs. low HRV vs. high HRV groups. Mean velocity and stasis differences were significant for control vs. high HRV groups. CONCLUSIONS: RTPC may be suitable for assessing the impact of HRV on hemodynamics and provide insight for AF management in highly arrhythmic patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Optimal saturation recovery time for minimizing the underestimation of arterial input function in quantitative cardiac perfusion MRI.

PURPOSE: The purpose of this study was to determine an optimal saturation-recovery time (TS) for minimizing the underestimation of arterial input function (AIF) in quantitative cardiac perfusion MRI without multiple gadolinium injections per subject. METHODS: We scanned 18 subjects (mean age = 59 ± 14 years, 9/9 males/females) to acquire resting perfusion data and 1 additional subject (age = 38 years, male) to obtain stress-rest perfusion data using a 5-fold accelerated pulse sequence with radial k-space sampling and applied k-space weighted image contrast (KWIC) filters on the same k-space data to retrospectively reconstruct five AIF images with effective TS ranging from 10 to 21.2 ms (2.8 ms steps). Undersampled images were reconstructed using a compressed sensing framework with temporal-total-variation and temporal-principal-component as 2 orthogonal sparsifying transforms. The image processing steps included, same motion correction across five different AIF images, signal normalization by the proton-density-weighted-image, signal-to-T1 conversion using a Bloch equation, T1 -to-gadolinium-concentration conversion assuming fast water exchange, T2 * correction to the AIF, and gadolinium-concentration to myocardial blood flow (MBF) conversion based on a Fermi model. RESULTS: Among five TS values, the shortest TS (10 ms) produced significantly (P < 0.05) higher peak AIF and lower resting MBF (13.73 mM, 0.73 mL g-1 min-1 ) than 12.8 ms (11.24 mM, 0.89 mL g-1 min-1 ), 15.6 ms (9.56 mM, 1.05 mL g-1 min-1 ), 18.4 ms (8.55 mM, 1.17 mL g-1 min-1 ), and 21.2 ms (7.95 mM, 1.27 mL g-1 min-1 ). Similarly, shorter TS reduced underestimation of AIF (or overestimation of MBF) for both during stress and at rest, but this effect was canceled in myocardial-perfusion-reserve (MPR). CONCLUSION: This study demonstrates that TS of 10 ms reduces the underestimation of AIF and, hence, the overestimation of MBF compared with longer TS values (12.8-21.2 ms).

Wearing Compression Garment Enhances Central Hemodynamics? A Systematic Review and Meta-Analysis.

ABSTRACT: Lee, DCW, Ali, A, Sheridan, S, Chan, DKC, and Wong, SHS. Wearing compression garment enhances central hemodynamics? a systematic review and meta-analysis. J Strength Cond Res 36(8): 2349-2359, 2022-Compression garments (CG) are believed to enhance exercise performance and recovery by improving central hemodynamic responses. However, evidence is inconclusive. We performed a systematic review and meta-analysis to determine the effect of wearing CG at rest or after a physiological challenge on central hemodynamic responses, including cardiac output, stroke volume (SV), heart rate (HR), systolic blood pressure, diastolic blood pressure (DBP), and systemic vascular resistance in healthy individuals. The English language searches of the electronic databases SPORTDiscus, MEDLINE, and Web of Science were conducted from November 2018-February 2019. The studies involved were limited to the following: (a) original articles; (b) randomized controlled trials; (c) monitoring of central hemodynamic responses (either at rest or after a physiological challenge: maximal exercise or orthostatic challenge); and (d) healthy individuals. Of the 786 studies identified, 12 were included in the systematic review and meta-analysis. Meta-analysis was performed by the restricted maximum likelihood method. The results indicated that the effect size (ES) of wearing CG on improving central hemodynamic responses was large overall (Hedges' g = 0.55) and was large in SV (Hedges' g = 1.09) and HR (Hedges' g = 0.65). Subgroup analysis showed that the ESs in "post-physiological challenge" was large in overall (Hedges' g = 0.98), SV (Hedges' g = 1.78), HR (Hedges' g = 1.10), and DBP (Hedges' g = 0.75). Their ESs in "at rest" were not significant in all central hemodynamic responses, apart from a significant medium ES observed in SV (Hedges' g = 0.44). Healthy individuals who wear CG have marked improvement in central hemodynamic responses, particularly after a physiological challenge. More pronounced effects of CG are observed in increasing SV and reducing HR.

A theoretical framework for retrospective T2∗ correction to the arterial input function in quantitative myocardial perfusion MRI.

PURPOSE: To develop and evaluate a flexible, Bloch-equation based framework for retrospective T2∗ correction to the arterial input function (AIF) obtained with quantitative cardiac perfusion pulse sequences. METHODS: Our framework initially calculates the gadolinium concentration [Gd] based on T1 measurements alone. Next, T2∗ is estimated from this initial calculation of [Gd] while assuming fast water exchange and using the literature native T2 and static magnetic field variation (ΔB0 ) values. Finally, the [Gd] is recalculated after performing T2∗ correction to the Bloch equation signal model. Using this approach, we performed T2∗ correction to historical phantom and in vivo, dual-imaging perfusion data sets from 3 different patient groups obtained using different pulse sequences and imaging parameters. Images were processed to quantify both the AIF and resting myocardial blood flow (MBF). We also performed a sensitivity analysis of our T2∗ correction to ±20% variations in native T2 and ΔB0 . RESULTS: Compared with the ground truth [Gd] of phantom, the normalized root-means-square-error (NRMSE) in measured [Gd] was 5.1%, 1.3%, and 0.6% for uncorrected, our corrected, and Kellman's corrected, respectively. For in vivo data, both the peak AIF (7.0 ± 3.0 mM vs. 8.6 ± 7.1 mM, 7.2 ± 0.9 mM vs. 8.6 ± 1.7 mM, 7.7 ± 1.8 mM vs. 10.3 ± 5.1 mM, P < .001) and resting MBF (1.3 ± 0.1 mL/g/min vs. 1.1 ± 0.1 mL/g/min, 1.3 ± 0.1 mL/g/min vs. 1.1 ± 0.1 mL/g/min, 1.2 ± 0.1 mL/g/min vs. 0.9 ± 0.1 mL/g/min, P < .001) values were significantly different between uncorrected and corrected for all 3 patient groups. Both the peak AIF and resting MBF values varied by <5% over the said variations in native T2 and ΔB0 . CONCLUSION: Our theoretical framework enables retrospective T2∗ correction to the AIF obtained with dual-imaging, cardiac perfusion pulse sequences.

Rapid reconstruction of highly undersampled, non-Cartesian real-time cine k-space data using a perceptual complex neural network (PCNN).

Highly accelerated real-time cine MRI using compressed sensing (CS) is a promising approach to achieve high spatio-temporal resolution and clinically acceptable image quality in patients with arrhythmia and/or dyspnea. However, its lengthy image reconstruction time may hinder its clinical translation. The purpose of this study was to develop a neural network for reconstruction of non-Cartesian real-time cine MRI k-space data faster (<1 min per slice with 80 frames) than graphics processing unit (GPU)-accelerated CS reconstruction, without significant loss in image quality or accuracy in left ventricular (LV) functional parameters. We introduce a perceptual complex neural network (PCNN) that trains on complex-valued MRI signal and incorporates a perceptual loss term to suppress incoherent image details. This PCNN was trained and tested with multi-slice, multi-phase, cine images from 40 patients (20 for training, 20 for testing), where the zero-filled images were used as input and the corresponding CS reconstructed images were used as practical ground truth. The resulting images were compared using quantitative metrics (structural similarity index (SSIM) and normalized root mean square error (NRMSE)) and visual scores (conspicuity, temporal fidelity, artifacts, and noise scores), individually graded on a five-point scale (1, worst; 3, acceptable; 5, best), and LV ejection fraction (LVEF). The mean processing time per slice with 80 frames for PCNN was 23.7 ± 1.9 s for pre-processing (Step 1, same as CS) and 0.822 ± 0.004 s for dealiasing (Step 2, 166 times faster than CS). Our PCNN produced higher data fidelity metrics (SSIM = 0.88 ± 0.02, NRMSE = 0.014 ± 0.004) compared with CS. While all the visual scores were significantly different (P < 0.05), the median scores were all 4.0 or higher for both CS and PCNN. LVEFs measured from CS and PCNN were strongly correlated (R2 = 0.92) and in good agreement (mean difference = -1.4% [2.3% of mean]; limit of agreement = 10.6% [17.6% of mean]). The proposed PCNN is capable of rapid reconstruction (25 s per slice with 80 frames) of non-Cartesian real-time cine MRI k-space data, without significant loss in image quality or accuracy in LV functional parameters.

Dual-Stimuli Responsive Single-Chain Polymer Folding via Intrachain Complexation of Tetramethoxyazobenzene and ß-Cyclodextrin.

We synthesize and characterize a triblock polymer with asymmetric tetramethoxyazobenzene (TMAB) and ß-cyclodextrin functionalization, taking advantage of the well-characterized azobenzene derivative-cyclodextrin inclusion complex to promote photoresponsive, self-contained folding of the polymer in an aqueous system. We use 1H NMR to show the reversibility of (E)-to-(Z) and (Z)-to-(E) TMAB photoisomerization, and evaluate the thermal stability of (Z)-TMAB and the comparatively rapid acid-catalyzed thermal (Z)-to-(E) isomerization. Important for its potential use as a functional material, we show the photoisomerization cyclability of the polymeric TMAB chromophore and calculate isomerization quantum yields by extinction spectroscopy. To verify self-inclusion of the polymeric TMAB and cyclodextrin, we use two-dimensional 1H NOESY NMR data to show proximity of TMAB and cyclodextrin in the (E)-state only; however, (Z)-TMAB is not locally correlated with cyclodextrin. Finally, the observed decrease in photoisomerization quantum yield for the dual-functionalized polymer compared to the isolated chromophore in an aqueous solution confirms TMAB and ß-cyclodextrin not only are in proximity to one another, but also form the inclusion complex.

Validation of electrocardiographic criteria for identifying left ventricular dysfunction in patients with previous myocardial infarction.

BACKGROUND: Eleven criteria correlating electrocardiogram (ECG) findings with reduced left ventricular ejection fraction (LVEF) have been previously published. These have not been compared head-to-head in a single study. We studied their value as a screening test to identify patients with reduced LVEF estimated by cardiac magnetic resonance (CMR) imaging. METHODS: ECGs and CMR from 548 patients (age 61 + 11 years, 79% male) with previous myocardial infarction (MI), from the DETERMINE and PRE-DETERMINE studies, were analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each criterion for identifying patients with LVEF ≤ 30% and ≤ 40% were studied. A useful screening test should have high sensitivity and NPV. RESULTS: Mean LVEF was 40% (SD = 11%); 264 patients (48.2%) had LVEF ≤ 40%, and 96 patients (17.5%) had LVEF ≤ 30%. Six of 11 criteria were associated with a significant lower LVEF, but had poor sensitivity to identify LVEF ≤ 30% (range 2.1%-55.2%) or LVEF ≤ 40% (1.1%-51.1%); NPVs were good for LVEF ≤ 30% (range 82.8%-85.9%) but not for LVEF ≤ 40% (range 52.1%-60.6%). Goldberger's third criterion (RV4/SV4 < 1) and combinations of maximal QRS duration > 124 ms + either Goldberger's third criterion or Goldberger's first criterion (SV1 or SV2 + RV5 or RV6 ≥ 3.5 mV) had high specificity (95.4%-100%) for LVEF ≤ 40%, although seen in only 48 (8.8%) patients; predictive values were similar on subgroup analysis. CONCLUSIONS: None of the ECG criteria qualified as a good screening test. Three criteria had high specificity for LVEF ≤ 40%, although seen in < 9% of patients. Whether other ECG criteria can better identify LV dysfunction remains to be determined.

Wearing compression tights post-exercise enhances recovery hemodynamics and subsequent cycling performance.

PURPOSE: To investigate sports compression garment (CG)-induced recovery hemodynamics and their potential impact on subsequent cycling performance. METHODS: In a randomized crossover design, 13 physically active men (20.9 ± 1.4 years; 65.9 ± 7.8 kg; 173.3 ± 4.8 cm; peak power output 254.2 ± 27.2 W) underwent 2 experimental trials. During each experimental trial, the subjects performed 20-min fatiguing preload cycling followed by 60-min passive recovery wearing either a sports CG (28.6 ± 9.4 mmHg) or gymnastic pants (CON). A 5-min all-out cycling performance test was subsequently conducted and power output and cadence were recorded. Cardiac output (CO) and stroke volume (SV) were measured using Doppler ultrasound (USCOM®). Heart rate (HR), blood lactate [BLa-], ratings of perceived exertion (RPE), leg muscle soreness (LMS), mean arterial pressure (MAP) and systemic vascular resistance (SVR) were monitored at 5, 15, 30, 45, 60 min during passive recovery. RESULTS: During the subsequent 5-min all-out cycling performance test, power output (215.2 ± 24.0 vs. 210.8 ± 21.5 W, CG vs. CON) and cadence (72.5 ± 3.8 vs. 71.2 ± 4.8 rpm, CG vs. CON) were higher in CG than CON (P < 0.05). SV was higher at 15, 30 and 45 min (P < 0.05), CO was higher at 5 and 45 min (P < 0.05), HR was lower at 15 and 30 min (P < 0.05) and [BLa-] was lower at 5 and 15 min (P < 0.05) during passive recovery, while LMS was lower at all time-points (P < 0.05) compared with CON. CONCLUSION: Sports CG improves subsequent cycling performance by enhancing hemodynamic responses and attenuating perceived muscle soreness during passive recovery in physically active men.

Overexpression of human wtTDP-43 causes impairment in hippocampal plasticity and behavioral deficits in CAMKII-tTa transgenic mouse model.

AIMS: The current study utilizes the adeno-associated viral gene transfer system in the CAMKIIα-tTA mouse model to overexpress human wild type TDP-43 (wtTDP-43) and α-synuclein (α-Syn) proteins. The co-existence of these proteins is evident in the pathology of neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD), Parkinson disease (PD), and dementia with Lewy bodies (DLB). METHODS: The novel bicistronic recombinant adeno-associated virus (rAAV) serotype 9 drives wtTDP-43 and α-Syn expression in the hippocampus via "TetO" CMV promoter. Behavior, electrophysiology, and biochemical and histological assays were used to validate neuropathology. RESULTS: We report that overexpression of wtTDP-43 but not α-Syn contributes to hippocampal CA2-specific pyramidal neuronal loss and overall hippocampal atrophy. Further, we report a reduction of hippocampal long-term potentiation and decline in learning and memory performance of wtTDP-43 expressing mice. Elevated wtTDP-43 levels induced selective degeneration of Purkinje cell protein 4 (PCP-4) positive neurons while both wtTDP-43 and α-Syn expression reduced subsets of the glutamate receptor expression in the hippocampus. CONCLUSIONS: Overall, our findings suggest the significant vulnerability of hippocampal neurons toward elevated wtTDP-43 levels possibly via PCP-4 and GluR-dependent calcium signaling pathways. Further, we report that wtTDP-43 expression induced selective CA2 subfield degeneration, contributing to the deterioration of the hippocampal-dependent cognitive phenotype.

Simple electrocardiographic measures improve sudden arrhythmic death prediction in coronary disease.

AIMS: To determine whether the combination of standard electrocardiographic (ECG) markers reflecting domains of arrhythmic risk improves sudden and/or arrhythmic death (SAD) risk stratification in patients with coronary heart disease (CHD). METHODS AND RESULTS: The association between ECG markers and SAD was examined in a derivation cohort (PREDETERMINE; N = 5462) with adjustment for clinical risk factors, left ventricular ejection fraction (LVEF), and competing risk. Competing outcome models assessed the differential association of ECG markers with SAD and competing mortality. The predictive value of a derived ECG score was then validated (ARTEMIS; N = 1900). In the derivation cohort, the 5-year cumulative incidence of SAD was 1.5% [95% confidence interval (CI) 1.1-1.9] and 6.2% (95% CI 4.5-8.3) in those with a low- and high-risk ECG score, respectively (P for Δ < 0.001). A high-risk ECG score was more strongly associated with SAD than non-SAD mortality (adjusted hazard ratios = 2.87 vs. 1.38 respectively; P for Δ = 0.003) and the proportion of deaths due to SAD was greater in the high vs. low risk groups (24.9% vs. 16.5%, P for Δ = 0.03). Similar findings were observed in the validation cohort. The addition of ECG markers to a clinical risk factor model inclusive of LVEF improved indices of discrimination and reclassification in both derivation and validation cohorts, including correct reclassification of 28% of patients in the validation cohort [net reclassification improvement 28 (7-49%), P = 0.009]. CONCLUSION: For patients with CHD, an externally validated ECG score enriched for both absolute and proportional SAD risk and significantly improved risk stratification compared to standard clinical risk factors including LVEF. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01114269. ClinicalTrials.gov ID NCT01114269.

TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model.

BACKGROUND: Neuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases. METHODS: To investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected to a low-dose (500 µg/kg) intraperitoneal E. coli lipopolysaccharide (LPS) administration challenge for 2 weeks to mimic a chronically altered low-grade systemic inflammatory state. Mice were then subjected to neurobehavioral studies, followed by biochemical and immunohistochemical analyses of the brain tissue. RESULTS: In the present study, we report that elevated neuronal TDP-43 levels induced microglial and astrocytic activation in the cortex of injected mice followed by increased RANTES signaling. Moreover, overexpression of TDP-43 exerted abundant mouse immunoglobulin G (IgG), CD3, and CD4+ T cell infiltration as well as endothelial and pericyte activation suggesting increased blood-brain barrier permeability. The BBB permeability in TDP-43 overexpressing brains yielded the frontal cortex vulnerable to the systemic inflammatory response following LPS treatment, leading to marked neutrophil infiltration, neuronal loss, reduced synaptosome-associated protein 25 (SNAP-25) levels, and behavioral impairments in the radial arm water maze (RAWM) task. CONCLUSIONS: These results reveal a novel role for TDP-43 in BBB permeability and leukocyte recruitment, indicating complex intermolecular interactions between an altered systemic inflammatory state and pathologically prone TDP-43 protein to promote disease progression.

Rapid dealiasing of undersampled, non-Cartesian cardiac perfusion images using U-net.

Compressed sensing (CS) is a promising method for accelerating cardiac perfusion MRI to achieve clinically acceptable image quality with high spatial resolution (1.6 × 1.6 × 8 mm3 ) and extensive myocardial coverage (6-8 slices per heartbeat). A major disadvantage of CS is its relatively lengthy processing time (~8 min per slice with 64 frames using a graphics processing unit), thereby making it impractical for clinical translation. The purpose of this study was to implement and test whether an image reconstruction pipeline including a neural network is capable of reconstructing 6.4-fold accelerated, non-Cartesian (radial) cardiac perfusion k-space data at least 10 times faster than CS, without significant loss in image quality. We implemented a 3D (2D + time) U-Net and trained it with 132 2D + time datasets (coil combined, zero filled as input; CS reconstruction as reference) with 64 time frames from 28 patients (8448 2D images in total). For testing, we used 56 2D + time coil-combined, zero-filled datasets (3584 2D images in total) from 12 different patients as input to our trained U-Net, and compared the resulting images with CS reconstructed images using quantitative metrics of image quality and visual scores (conspicuity of wall enhancement, noise, artifacts; each score ranging from 1 (worst) to 5 (best), with 3 defined as clinically acceptable) evaluated by readers. Including pre- and post-processing steps, compared with CS, U-Net significantly reduced the reconstruction time by 14.4-fold (32.1 ± 1.4 s for U-Net versus 461.3 ± 16.9 s for CS, p < 0.001), while maintaining high data fidelity (structural similarity index = 0.914 ± 0.023, normalized root mean square error = 1.7 ± 0.3%, identical mean edge sharpness of 1.2 mm). The median visual summed score was not significantly different (p = 0.053) between CS (14; interquartile range (IQR) = 0.5) and U-Net (12; IQR = 0.5). This study shows that the proposed pipeline with a U-Net is capable of reconstructing 6.4-fold accelerated, non-Cartesian cardiac perfusion k-space data 14.4 times faster than CS, without significant loss in data fidelity or image quality.

Formulation of thrombin-inhibiting hydrogels via self-assembly of ionic peptides with peptide-modified polymers.

Cell therapy for spinal cord injuries offers the possibility of replacing lost cells after trauma to the central nervous system (CNS). In preclinical studies, synthetic hydrogels are often co-delivered to the injury site to support survival and integration of the transplanted cells. These hydrogels ideally mimic the mechanical and biochemical features of a healthy CNS extracellular matrix while also providing the possibility of localized drug delivery to promote healing. In this work, we synthesize peptide-functionalized polymers that contain both a peptide sequence for incorporation into self-assembled peptide hydrogels along with bioactive peptides that inhibit scar formation. We demonstrate that peptide hydrogels formulated with the peptide-functionalized polymers possess similar mechanical properties (soft and shear-thinning) as peptide-only hydrogels. Small angle neutron scattering analysis reveals that polymer-containing hydrogels possess larger inhomogeneous domains but small-scale features such as mesh size remain the same as peptide-only hydrogels. We further confirm that the integrated hydrogels containing bioactive peptides exhibit thrombin inhibition activity, which has previously shown to reduce scar formation in vivo. Finally, while the survival of encapsulated cells was poor, cells cultured on the hydrogels exhibited good viability. Overall, the described composite hydrogels formed from self-assembling peptides and peptide-modified polymers are promising, user-friendly materials for CNS applications in regeneration.

Left ventricular extracellular volume expansion does not predict recurrence of atrial fibrillation following catheter ablation.

INTRODUCTION: A recent study reported that diffuse left ventricular (LV) fibrosis is a predictor of atrial fibrillation (AF) recurrence following catheter ablation, by measuring postcontrast cardiac T1 (an error prone metric as per the 2017 Society for Cardiovascular Magnetic Resonance consensus statement) using an inversion-recovery pulse sequence (an error prone method in arrhythmia) in AF ablation candidates. The purpose of this study was to verify the prior study, by measuring extracellular volume (ECV) fraction (an accurate metric) using a saturation-recovery pulse sequence (accurate method in arrhythmia). METHODS AND RESULTS: This study examined 100 AF patients (mean age = 62 ± 11 years, 69 males and 31 females, 67 paroxysmal [pAF] and 33 persistent [peAF]) who underwent a preablation cardiovascular magnetic resonance (CMR) exam. LV ECV and left atrial (LA) and LV functional parameters were quantified using standard analysis methods. During an average follow-up period of 457 ± 261 days with 4 ± 3 rhythm checks per patient, 72 patients maintained sinus rhythm. Between those who maintained sinus rhythm (n = 72) and those who reverted to AF (n = 28), the only clinical characteristic that was significantly different was age (60 ± 12 years vs 66 ± 9 years); for CMR metrics, neither mean LV ECV (25.1 ± 3.3% vs 24.7 ± 3.7%), native LV T1 (1093.8 ± 73.5 ms vs 1070.2 ± 115.9 ms), left ventricular ejection fraction (54.1 ± 11.2% vs 55.7 ± 7.1%), nor LA end diastolic volume/body surface area (42.4 ± 14.8 mL/m2 vs 43.4 ± 19.6 mL/m2 ) were significantly different (P ≥ .23). According to Cox regression tests, none of the clinical and imaging variables predict AF recurrence. CONCLUSION: Neither LV ECV nor other CMR metrics predict recurrence of AF following catheter ablation.

Compression Garment-induced Leg Changes Increase Hemodynamic Responses in Healthy Individuals.

This study evaluated the morphological changes of the lower limb and associated hemodynamic responses to different lower-body compression pressures (COMPs) in physically active, healthy individuals at rest. Each of the 32 participants underwent three trials with three different degrees of lower-body compression applied: "Low" (2.2±1.4 mmHg), "Medium" (12.9±3.9 mmHg), and "High" (28.8±8.3 mmHg). In each COMP, a cross-sectional area of leg muscles (CSAmuscle), subcutaneous fat (CSAfat), superficial vessels (SupV), deep arteries (DA), and deep veins (DV) at the calf, knee, and thigh levels were measured using magnetic resonance imaging (MRI). Additionally, blood pressure (BP), heart rate (HR), cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR) were measured using Doppler ultrasound (USCOM®). With High COMP, calf CSAmuscle and SupV were smaller (p<0.01), whereas DA and DV were larger (p<0.05). Calf CSAfat, however, was similar among all COMPs. There were no major changes in CSAmuscle and CSAfat at knee and thigh levels. CO (3.2±0.9 L/min) and SV (51.9±16.4 mL) were higher (p<0.05) only with High COMP, but other hemodynamic variables showed no significant changes across different COMPs. The High COMP at the lower limb induces leg morphological changes and increases associated hemodynamic responses of physically active healthy individuals at rest.