The role of the parenchymal vascular system in cerebrospinal fluid tracer clearance.

OBJECTIVES: The current understanding of cerebral waste clearance (CWC) involves cerebrospinal fluid (CSF) participation but lacks convincing evidence for the direct participation of the parenchymal vascular system. The objective of this study was to evaluate the role of the parenchymal vascular system in CSF tracer clearance in rats. METHODS: We used superparamagnetic iron oxide-enhanced susceptibility-weighted imaging (SPIO-SWI) and quantitative susceptibility mapping (QSM) methods to simultaneously study 7 T MRI signal changes in parenchymal veins, arteries, and their corresponding para-vascular spaces in 26 rats, following intra-cisterna magna (ICM) infusion of different CSF tracers (FeREX, Ferumoxytol, Fe-Dextran) to determine the amount of tracer in the artery and vein quantitatively. RESULTS: We observed that the parenchymal venous system participated in CSF tracer clearance following ICM infusion of different MRI tracers with different concentrations of iron. Parenchymal venous participation was more obvious when 75 µg iron was injected. In the parenchymal veins, the relative mean (± SE) value of the susceptibility increased by 13.5 (± 1.0)% at 15 min post-tracer infusion (p < 0.01), and 33.6 (± 6.7)% at 45 min post-tracer infusion (p = 0.01), compared to baseline. In contrast to the parenchymal veins, a negligible amount of CSF tracer entered the parenchymal arteries: 1.3 (± 2.6)% at 15 min post-tracer infusion (p = 0.6), and 12 (± 19)% at 45 min post-tracer infusion (p = 0.5), compared to baseline. CONCLUSIONS: MRI tracers can enter the parenchymal vascular system and more MRI tracers were observed in the cerebral venous than arterial vessels, suggesting the direct participation of parenchymal vascular system in CWC. KEY POINTS: • MRI results revealed that the parenchymal venous system directly participates in cerebrospinal fluid tracer clearance following ICM infusion of MRI tracer. • Different sizes of MRI tracers can enter the parenchymal venous system.

Magnetic Resonance Imaging Quantification of Accumulation of Epicardial Adipose Tissue Adds Independent Risks for Diastolic Dysfunction among Dialysis Patients.

BACKGROUND: Diastolic dysfunction (DD) frequently occurs in dialysis patients; however, the risk factors of DD remain to be further explored in such a population. Epicardial adipose tissue (EAT) volume has proven to be an independent clinical risk factor for multiple cardiac disorders. PURPOSE: To assess whether EAT volume is an independent risk factor for DD in dialysis patients. STUDY TYPE: Case-control study. POPULATION: A total of 113 patients (mean age: 54.5 ± 14.4 years; 41 women) who had underwent dialysis for at least 3 months due to uremia. FIELD STRENGTH: A 3 T, steady-state free precession (SSFP) sequence for cine imaging, modified Look-Locker imaging (MOLLI) for T1 mapping and gradient-recalled-echo for T2*. ASSESSMENT: All participants were performed cardiac magnetic resonance imaging (MRI) and echocardiogram. For MRI images analysis, borders of the EAT were manually delineated, as well as, pericardial adipose tissue (PeAT) and paracardial adipose tissue (PaAT), T1 mapping, T2* mapping, global longitudinal strain (GLS), and left atrial strain. For echocardiogram assessments, the thickness of PaAT, e' velocity, E velocity, E/e ratio, A velocity, and deceleration time were measured. STATISTICAL TESTS: Univariate and multivariate logistic regressions were performed to explore the independent risk factors for DD. P value less than 0.05 was considered as significant. RESULTS: Compared with the DD(-) group, the DD(+) group had significantly more epicardial tissue fat (18.5 ± 1.3 vs. 30.9 ± 2.3) In addition, EAT volumes increased significantly with the grades of DD (grade 1 vs. grade 2 and 3: 27.9 ± 15.9 vs. 35.4 ± 13.1). Moreover, EAT had significant correlations with T1 mapping, T2* mapping, GLS, left atrial strain, e' velocity, and E/e ratio. EAT accumulation added an independent risk for DD (Odds Ratio = 1.03) over conventional clinical risk factors including age, diabetes mellitus, and hemodialysis. DATA CONCLUSION: EAT was associated with diastolic function, and its accumulation may be an independent risk factor for DD among dialysis patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

All Central Nervous System Neuro- and Vascular-Communication Channels Are Surrounded With Cerebrospinal Fluid.

Background: Recent emerging evidence has highlighted the potential critical role of cerebrospinal fluid (CSF) in cerebral waste clearance and immunomodulation. It is already very well-established that the central nervous system (CNS) is completely submerged in CSF on a macro-level; but to what extent is this true on a micro-level? Specifically, within the peri-neural and peri-vascular spaces within the CNS parenchyma. Therefore, the objective of this study was to use magnetic resonance imaging (MRI) to simultaneously map the presence of CSF within all peri-neural (cranial and spinal nerves) and peri-vascular spaces in vivo in humans. Four MRI protocols each with five participants were used to image the CSF in the brain and spinal cord. Our findings indicated that all CNS neuro- and vascular-communication channels are surrounded with CSF. In other words, all peri-neural spaces surrounding the cranial and spinal nerves as well as all peri-vascular spaces surrounding MRI-visible vasculature were filled with CSF. These findings suggest that anatomically, substance exchange between the brain parenchyma and outside tissues including lymphatic ones can only occur through CSF pathways and/or vascular pathways, warranting further investigation into its implications in cerebral waste clearance and immunity.

Waste Clearance in the Brain.

Waste clearance (WC) is an essential process for brain homeostasis, which is required for the proper and healthy functioning of all cerebrovascular and parenchymal brain cells. This review features our current understanding of brain WC, both within and external to the brain parenchyma. We describe the interplay of the blood-brain barrier (BBB), interstitial fluid (ISF), and perivascular spaces within the brain parenchyma for brain WC directly into the blood and/or cerebrospinal fluid (CSF). We also discuss the relevant role of the CSF and its exit routes in mediating WC. Recent discoveries of the glymphatic system and meningeal lymphatic vessels, and their relevance to brain WC are highlighted. Controversies related to brain WC research and potential future directions are presented.

Texture Analysis of Native T1 Images as a Novel Method for Noninvasive Assessment of Uremic Cardiomyopathy.

BACKGROUND: Noncontrast cardiac T1 times are increased in dialysis patients which might indicate fibrotic alterations in uremic cardiomyopathy. PURPOSE: To explore the application of the texture analysis (TA) of T1 images in the assessment of myocardial alterations in dialysis patients. STUDY TYPE: Case-control study. POPULATION: A total of 117 subjects, including 22 on hemodialysis, 44 on peritoneal dialysis, and 51 healthy controls. FIELD STRENGTH: A 3 T, steady-state free precession (SSFP) sequence, modified Look-Locker imaging (MOLLI). ASSESSMENT: Two independent, blinded researchers manually delineated endocardial and epicardial borders of the left ventricle (LV) on midventricular T1 maps for TA. STATISTICAL TESTS: Texture feature selection was performed, incorporating reproducibility verification, machine learning, and collinearity analysis. Multivariate linear regressions were performed to examine the independent associations between the selected texture features and left ventricular function in dialysis patients. Texture features' performance in discrimination was evaluated by sensitivity and specificity. Reproducibility was estimated by the intraclass correlation coefficient (ICC). RESULTS: Dialysis patients had greater T1 values than normal (P < 0.05). Five texture features were filtered out through feature selection, and four showed a statistically significant difference between dialysis patients and healthy controls. Among the four features, vertical run-length nonuniformity (VRLN) had the most remarkable difference among the control and dialysis groups (144 ± 40 vs. 257 ± 74, P < 0.05), which overlap was much smaller than Global T1 times (1268 ± 38 vs. 1308 ± 46 msec, P < 0.05). The VRLN values were notably elevated (cutoff = 170) in dialysis patients, with a specificity of 97% and a sensitivity of 88%, compared with T1 times (specificity = 76%, sensitivity = 60%). In dialysis patients, VRLN was significantly and independently associated with left ventricular ejection fraction (P < 0.05), global longitudinal strain (P < 0.05), radial strain (P < 0.05), and circumferential strain (P < 0.05); however, T1 was not. DATA CONCLUSION: The texture features obtained by TA of T1 images and VRLN may be a better parameter for assessing myocardial alterations than T1 times. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 3.

Diagnostic Utility of the Simplified Perfusion Fraction for Identifying Myocardial Injury in Patients With Reperfused ST-segment Elevation Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a disease with high morbidity and mortality worldwide and the evaluation of myocardial injury and perfusion status following myocardial ischemia and reperfusion is of clinical value. PURPOSE: To assess the diagnostic utility of simplified perfusion fraction (SPF) in differentiating salvage and infarcted myocardium and its predictive value for left ventricular remodeling in patients with reperfusion ST-segment elevation myocardial infarction (STEMI). STUDY TYPE: Prospective. POPULATION: Forty-one reperfused STEMI patients and 20 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3.0T MRI. The MR examination included cine, T2 -short tau inversion recovery (T2 -STIR), first pass perfusiong (FPP)，phase sensitive inversion recovery (PSIR), and diffusion-weighted imaging (DWI). ASSESSMENT: SPF values among different myocardium regions (infarcted, salvaged, remote, and MVO) and stages of reperfused STEMI patients as well as normal controls were measured. The diagnostic utility of SPF values in differentiating salvaged and infarcted myocardium was assessed. STATISTICAL ANALYSIS: Independent t-test and the Mann-Whitney U-test. Logistic regression. RESULTS: SPF values in healthy controls were not significantly different than SPF values in the remote myocardium of patients (40.09 ± 1.47% vs. 40.28 ± 1.93%, P = 0.698). In reperfusion STEMI patients, SPF values were lower in infarcted myocardium compared to remote and salvaged myocardium (32.15 ± 2.36% vs. 40.28 ± 1.93%, P < 0.001; 32.15 ± 2.36% vs. 36.68 ± 2.71%, P < 0.001). SPF values of infarcted myocardium showed a rebound increase from acute to convalescent stages (32.15 ± 2.36% vs. 34.69 ± 3.69%, P < 0.001). When differentiating infarcted and salvaged myocardium, SPF values demonstrated an area under the curve (AUC) of 0.89 (sensitivity 85.4%, specificity 80.5%, cutoff 34.42%). Lower SPF values were associated with lower odds ratio (OR = 0.304) of left ventricular remodeling after adjusting for potential confounders with a confidence interval (CI) of 0.129-0.717, P = 0.007. DATA CONCLUSION: SPF might be able to differentiate salvaged and infarcted myocardium and is a strong predictor of left ventricular remodeling in reperfused STEMI patients. Level of Evidence 2 Technical Efficacy Stage 2.

Magnetic Resonance Imaging and Modeling of the Glymphatic System.

The glymphatic system is a newly discovered waste drainage pathway in the brain; it plays an important role in many neurological diseases. Ongoing research utilizing various cerebrospinal fluid tracer infusions, either directly or indirectly into the brain parenchyma, is investigating clearance pathways by using distinct imaging techniques. In the present review, we discuss the role of the glymphatic system in various neurological diseases and efflux pathways of brain waste clearance based on current evidence and controversies. We mainly focus on new magnetic resonance imaging (MRI) modeling techniques, along with traditional computational modeling, for a better understanding of the glymphatic system function. Future sophisticated modeling techniques hold the potential to generate quantitative maps for glymphatic system parameters that could contribute to the diagnosis, monitoring, and prognosis of neurological diseases. The non-invasive nature of MRI may provide a safe and effective way to translate glymphatic system measurements from bench-to-bedside.

Association of Early Postdonation Renal Function With Subsequent Risk of End-Stage Renal Disease in Living Kidney Donors.

Importance: Living kidney donation is associated with increased long-term risk of end-stage renal disease (ESRD). An early postdonation marker of ESRD risk could improve postdonation risk assessment and counseling for kidney donors and allow early intervention for donors at increased risk. Objective: To determine the association between renal function in the first 6 months postdonation and subsequent risk of ESRD in kidney donors. Design, Setting, and Participants: This secondary analysis of a prospective national cohort uses a population-based registry of all living kidney donors in the United States between October 26, 1999, and January 1, 2018, with follow-up through December 31, 2018. All kidney donors who had donated in the date range and had serum creatinine measured at 6 months (±3 months) postdonation were included. Exposures: Renal function as measured by estimated glomerular filtration rate 6 months after donation (eGFR6). Main Outcomes and Measures: End-stage renal disease, ascertained via linkage to Centers for Medicare & Medicaid Services data. Results: A total of 71 468 living kidney donors were included (of 109 065 total donors over this period). Their median (interquartile range) eGFR6 was 63 (54-74) mL/min/1.73 m2. Cumulative incidence of ESRD at 15 years postdonation ranged from 11.7 donors per 10 000 donors with eGFR6 values greater than 70 mL/min/1.73 m2 to 33.1 donors per 10 000 donors with eGFR6 values of 50 mL/min/1.73 m2 or less. Adjusting for age, race, sex, body mass index, and biological relationship, every 10 mL/min/1.73 m2 reduction in eGFR6 was associated with a 28% increased risk of ESRD (adjusted hazard ratio, 1.28 [95% CI, 1.06-1.54]; P = .009). The association between predonation eGFR and ESRD was not significant and was fully mediated by eGFR6 (adjusted hazard ratio, 1.00 [95% CI, 0.86-1.17]; P = .97). The postdonation eGFR value was a better marker of ESRD than eGFR decline after donation or the ratio of eGFR6 to predonation eGFR, as determined by the Akaike information criterion (in which a lower value indicates a better model fit; eGFR6, 1495.61; predonation eGFR - eGFR6, 1503.58; eGFR6 / predonation eGFR, 1502.30). Conclusions and Relevance: In this study, there was an independent association of eGFR6 with subsequent ESRD risk in living kidney donors, even after adjusting for predonation characteristics. The findings support measurement of early postdonation serum creatinine monitoring in living kidney donors, and the use of these data to help identify donors who might need more careful surveillance and early intervention.

Correction: Individual Case Analysis of Postmortem Interval Time on Brain Tissue Preservation.

[This corrects the article DOI: 10.1371/journal.pone.0151615.].

Long-term Renal Function in Living Kidney Donors Who Had Histological Abnormalities at Donation.

BACKGROUND: Recent evidence suggests that living kidney donors are at an increased risk of end-stage renal disease. However, predicting which donors will have renal dysfunction remains challenging, particularly among those with no clinical evidence of disease at the time of donation. Although renal biopsies are not routinely performed as part of the donor evaluation process, they may yield valuable information that improves the ability to predict renal function in donors. METHODS: We used implantation protocol biopsies to evaluate the association between histological abnormalities in the donated kidney and postdonation renal function (estimated glomerular filtration rate, eGFR) of the remaining kidney in living kidney donors. Longitudinal analysis using mixed-effects linear regression was used to account for multiple eGFR measures per donor. RESULTS: Among 310 donors between 1997 and 2012, median (IQR) follow-up was 6.2 (2.5-8.7; maximum 14.0) years. In this cohort, the overall prevalence of histological abnormalities was 65.8% (19.7% abnormal glomerulosclerosis, 23.9% abnormal interstitial fibrosis and tubular atrophy (IFTA), 4.8% abnormal mesangial matrix increase, 32.0% abnormal arteriolar hyalinosis, and 32.9% abnormal vascular intimal thickening). IFTA was associated with a 5-mL/min/1.73 m decrease of postdonation eGFR after adjusting for donor age at donation, sex, race, preoperative systolic blood pressure, preoperative eGFR, and time since donation (P < 0.01). CONCLUSIONS: In this single-center study, among healthy individuals cleared for living donation, IFTA was associated with decreased postdonation eGFR, whereas no other subclinical histological abnormalities provided additional information.

Individual Case Analysis of Postmortem Interval Time on Brain Tissue Preservation.

At autopsy, the time that has elapsed since the time of death is routinely documented and noted as the postmortem interval (PMI). The PMI of human tissue samples is a parameter often reported in research studies and comparable PMI is preferred when comparing different populations, i.e., disease versus control patients. In theory, a short PMI may alleviate non-experimental protein denaturation, enzyme activity, and other chemical changes such as the pH, which could affect protein and nucleic acid integrity. Previous studies have compared PMI en masse by looking at many different individual cases each with one unique PMI, which may be affected by individual variance. To overcome this obstacle, in this study human hippocampal segments from the same individuals were sampled at different time points after autopsy creating a series of PMIs for each case. Frozen and fixed tissue was then examined by Western blot, RT-PCR, and immunohistochemistry to evaluate the effect of extended PMI on proteins, nucleic acids, and tissue morphology. In our results, immunostaining profiles for most proteins remained unchanged even after PMI of over 50 h, yet by Western blot distinctive degradation patterns were observed in different protein species. Finally, RNA integrity was lower after extended PMI; however, RNA preservation was variable among cases suggesting antemortem factors may play a larger role than PMI in protein and nucleic acid integrity.

Mislocalization of CDK11/PITSLRE, a regulator of the G2/M phase of the cell cycle, in Alzheimer disease.

Post-mitotic neurons are typically terminally differentiated and in a quiescent status. However, in Alzheimer disease (AD), many neurons display ectopic re-expression of cell cycle-related proteins. Cyclin-dependent kinase 11 (CDK11) mRNA produces a 110-kDa protein (CDK11(p110)) throughout the cell cycle, a 58-kDa protein (CDK11(p58)) that is specifically translated from an internal ribosome entry site and expressed only in the G(2)/M phase of the cell cycle, and a 46-kDa protein (CDK11(p46)) that is considered to be apoptosis specific. CDK11 is required for sister chromatid cohesion and the completion of mitosis. In this study, we found that the expression patterns of CDK11 vary such that cytoplasmic CDK11 is increased in AD cellular processes, compared to a pronounced nuclear expression pattern in most controls. We also investigated the effect of amyloid precursor protein (APP) on CDK11 expression in vitro by using M17 cells overexpressing wild-type APP and APP Swedish mutant phenotype and found increased CDK11 expression compared to empty vector. In addition, amyloid-ß(25-35) resulted in increased CDK11 in M17 cells. These data suggest that CDK11 may play a vital role in cell cycle re-entry in AD neurons in an APP-dependent manner, thus presenting an intriguing novel function of the APP signaling pathway in AD.