Accuracy of Noncontrast T2 SPACE in Active MS Cord Lesion Detection.

BACKGROUND AND PURPOSE: The diagnosis of active MS lesions is often based on postgadolinium T1-weighted MR imaging. Recent studies suggest a risk of IV gadolinium to patients, predominantly based on gadolinium deposition in tissue. Noncontrast sequences have shown promise in MS diagnosis, but none differentiate acute from chronic MS lesions. We hypothesized that 3D T2 sampling perfection with application-optimized contrasts by using different flip angle evolution (SPACE) MR imaging can help detect and differentiate active-versus-chronic MS lesions without the need for IV contrast. MATERIALS AND METHODS: In this single-center retrospective study, 340 spinal MR imaging cases of MS were collected in a 24-month period. Two senior neuroradiologists blindly and independently reviewed postcontrast T1-weighted sagittal and T2-SPACE sagittal images for the presence of MS lesions, associated cord expansion/atrophy on T2-SPACE, and enhancement on postcontrast T1WI. Discrepancies were resolved by consensus between the readers. Sensitivity, specificity, and accuracy of T2-SPACE compared with postcontrast T1WI were computed, and interobserver agreement was calculated. RESULTS: The sensitivity of lesion detection on T2-SPACE was 85.71%, 95% CI, 63.66%-96.95%; with a specificity of 93.52%, 95% CI, 90.06%-96.05%; and an accuracy of 92.99%, 95% CI, 89.58%-95.56. Additionally, 16/21 (84.2%) acute enhancing cord lesions showed cord expansion on T2-SPACE. The interobserver agreement was 92%. CONCLUSIONS: Our study shows that T2-SPACE facilitates noncontrast detection of acute MS lesions with high accuracy compared with postcontrast T1WI and with high interobserver agreement. The lack of gadolinium use provides an advantage, bypassing any potential adverse effects of repetitive contrast administration.

A Comparative Analysis of Functional and Patient-Reported Outcomes Following Lisfranc and Chopart Amputations in High-Risk Limb Salvage Patients.

Midfoot amputations provide an opportunity for limb salvage through preservation of a weightbearing limb. However, the longevity of midfoot amputations is threatened by restrictions in surface area and risks of skin breakdown. To better inform decisions surrounding the level of amputation, we sought to compare outcomes of high-risk individuals who underwent Lisfranc or Chopart amputations. A single-center retrospective cohort study was performed from November 2013 to September 2022 of adult patients who underwent Lisfranc or Chopart amputations. Patients were stratified into cohorts based on the amputation type. Outcomes included postoperative rates of re-amputation, functional status, mortality and patient-reported outcome measures in the form of Lower Extremity Functional Scale scores. Sixty-six patients were identified; of which, 45 underwent Lisfranc amputation, and 21 underwent Chopart amputation. Median Charlson Comorbidity Index was 7, signifying a substantial comorbidity burden. By median follow-up of 14 (Interquartile range: 28) months, 31 patients (36%) progressed to higher-level amputation, and most patients were ambulatory (n = 38, 58%). Overall rates of re-amputation, ambulatory status, and mortality were comparable between groups. Re-amputation to another midfoot amputation was more common among the Lisfranc cohort (n = 16, 36% vs n = 1, 5%), whereas re-amputation to BKA was more prevalent among the Chopart cohort (Chopart: n = 7, 33% vs Lisfranc: n = 7, 16%; p = .011). Average Lower Extremity Functional Scale scores were similar between groups and corresponded to a maximal function of 48%. Lisfranc and Chopart amputations have the potential to be efficacious limb salvage options in high-risk patient populations in conjunction with intraoperative biomechanical optimization and optimal preoperative patient selection.

Lysine Acetylation Changes the Mechanism of Aß25-35 Peptide Binding and Dimerization in the DMPC Bilayer.

The impact of Lys28 acetylation on Alzheimer's Aß peptide binding to the lipid bilayer has not been previously studied, either experimentally or computationally. To probe this common post-translational modification, we performed all-atom replica exchange molecular dynamics simulations targeting binding and aggregation of acetylated acAß25-35 peptide within the DMPC bilayer. Using the unmodified Aß25-35 studied previously as a reference, our results can be summarized as follows. First, Lys28 acetylation strengthens the Aß25-35 hydrophobic moment and consequently promotes the helical structure across the peptide extending it into the N-terminus. Second, because Lys28 acetylation disrupts electrostatic contact between Lys28 and lipid phosphate groups, it reduces the binding affinity of acAß25-35 peptides to the DMPC bilayer. Accordingly, although acetylation preserves the bimodal binding featuring a preferred inserted state and a less probable surface bound state, it decreases the stability of the former. Third, acetylation promotes acAß25-35 aggregation and eliminates monomers as thermodynamically viable species. More importantly, acAß25-35 retains as the most thermodynamically stable the inserted dimer with unique head-to-tail helical aggregation interface. However, due to enhanced helix structure, this dimer state becomes less stable and is less likely to propagate into higher order aggregates. Thus, acetylation is predicted to facilitate the formation of low-molecular-weight oligomers. Other post-translational modifications, including phosphorylation and oxidation, reduce helical propensity and have divergent impact on aggregation. Consequently, acetylation, when considered in its totality, has distinct consequences on Aß25-35 binding and aggregation in the lipid bilayer.

Met35 Oxidation Hinders Aß25-35 Peptide Aggregation within the Dimyristoylphosphatidylcholine Bilayer.

Using all-atom explicit solvent replica exchange molecular dynamics simulations, we studied the aggregation of oxidized (ox) Aß25-35 peptides into dimers mediated by the zwitterionic dimyristoylphosphatidylcholine (DMPC) lipid bilayer. By comparing oxAß25-35 aggregation with that observed for reduced and phosphorylated Aß25-35 peptides, we elucidated plausible impact of post-translational modifications on cytotoxicity of Aß peptides involved in Alzheimer's disease. We found that Met35 oxidation reduces helical propensity in oxAß25-35 peptides bound to the lipid bilayer and enhances backbone fluctuations. These factors destabilize the wild-type head-to-tail dimer interface and lower the aggregation propensity. Met35 oxidation diversifies aggregation pathways by adding monomeric species to the bound conformational ensemble. The oxAß25-35 dimer becomes partially expelled from the DMPC bilayer and as a result inflicts limited disruption to the bilayer structure compared to wild-type Aß25-35. Interestingly, the effect of Ser26 phosphorylation is largely opposite, as it preserves the wild-type head-to-tail aggregation interface and strengthens, not weakens, aggregation propensity. The differing effects can be attributed to the sequence locations of these post-translational modifications, since in contrast to Ser26 phosphorylation, Met35 oxidation directly affects the wild-type C-terminal aggregation interface. A comparison with experimental data is provided.

Phosphorylation Promotes Aß25-35 Peptide Aggregation within the DMPC Bilayer.

The consequences of phosphorylation of the Aß25-35 peptide at the position Ser26 on its aggregation have not been examined. To investigate them, we performed all-atom replica exchange simulations probing the binding of phosphorylated Aß25-35 (pAß25-35) peptides to the dimyristoyl phosphatidylcholine (DMPC) bilayer and their subsequent aggregation. As a control, we used our previous study of unmodified peptides. We found that phosphorylation moderately reduces the helical propensity in pAß25-35 and its binding affinity to the DMPC bilayer. Phosphorylation preserves the bimodal binding observed for unmodified Aß25-35, which features a preferred inserted state and a less probable surface bound state. Phosphorylation also retains the inserted dimer with a head-to-tail helical aggregation interface as the most thermodynamically stable state. Importantly, this post-translation modification strengthens interpeptide interactions by adding a new aggregation "hot spot" created by cross-bridging phosphorylated Ser26 with water, cationic ions, or Lys28. The cross-bridging constitutes the molecular mechanism behind most structural phosphorylation effects. In addition, phosphorylation eliminates pAß25-35 monomers and diversifies the pool of aggregated species. As a result, it changes the binding and aggregation mechanism by multiplying pathways leading to stable inserted dimers. These findings offer a plausible molecular rationale for experimental observations, including enhanced production of low molecular weight oligomers and cytotoxicity of phosphorylated Aß peptides.

Do Cholesterol and Sphingomyelin Change the Mechanism of Aß25-35 Peptide Binding to Zwitterionic Bilayer?

Using replica exchange with solute tempering all-atom molecular dynamics, we studied the equilibrium binding of Aß25-35 peptide to the ternary bilayer composed of an equimolar mixture of dimyristoylphosphatidylcholine (DMPC), N-palmitoylsphingomyelin (PSM), and cholesterol. Binding of the same peptide to the pure DMPC bilayer served as a control. Due to significant C-terminal hydrophobic moment, binding to the ternary and DMPC bilayers promotes helical structure in the peptide. For both bilayers a polarized binding profile is observed, in which the N-terminus anchors to the bilayer surface, whereas the C-terminus alternates between unbound and inserted states. Both ternary and DMPC bilayers feature two Aß25-35 bound states, surface bound, S, and inserted, I, separated by modest free energy barriers. Experimental data are in agreement with our results but indicate that cholesterol impact is Aß fragment dependent. For Aß25-35, we predict that its binding mechanism is independent of the inclusion of PSM and cholesterol into the bilayer.

Diagnosing growth in low-grade gliomas with and without longitudinal volume measurements: A retrospective observational study.

BACKGROUND: Low-grade gliomas cause significant neurological morbidity by brain invasion. There is no universally accepted objective technique available for detection of enlargement of low-grade gliomas in the clinical setting; subjective evaluation by clinicians using visual comparison of longitudinal radiological studies is the gold standard. The aim of this study is to determine whether a computer-assisted diagnosis (CAD) method helps physicians detect earlier growth of low-grade gliomas. METHODS AND FINDINGS: We reviewed 165 patients diagnosed with grade 2 gliomas, seen at the University of Alabama at Birmingham clinics from 1 July 2017 to 14 May 2018. MRI scans were collected during the spring and summer of 2018. Fifty-six gliomas met the inclusion criteria, including 19 oligodendrogliomas, 26 astrocytomas, and 11 mixed gliomas in 30 males and 26 females with a mean age of 48 years and a range of follow-up of 150.2 months (difference between highest and lowest values). None received radiation therapy. We also studied 7 patients with an imaging abnormality without pathological diagnosis, who were clinically stable at the time of retrospective review (14 May 2018). This study compared growth detection by 7 physicians aided by the CAD method with retrospective clinical reports. The tumors of 63 patients (56 + 7) in 627 MRI scans were digitized, including 34 grade 2 gliomas with radiological progression and 22 radiologically stable grade 2 gliomas. The CAD method consisted of tumor segmentation, computing volumes, and pointing to growth by the online abrupt change-of-point method, which considers only past measurements. Independent scientists have evaluated the segmentation method. In 29 of the 34 patients with progression, the median time to growth detection was only 14 months for CAD compared to 44 months for current standard of care radiological evaluation (p < 0.001). Using CAD, accurate detection of tumor enlargement was possible with a median of only 57% change in the tumor volume as compared to a median of 174% change of volume necessary to diagnose tumor growth using standard of care clinical methods (p < 0.001). In the radiologically stable group, CAD facilitated growth detection in 13 out of 22 patients. CAD did not detect growth in the imaging abnormality group. The main limitation of this study was its retrospective design; nevertheless, the results depict the current state of a gold standard in clinical practice that allowed a significant increase in tumor volumes from baseline before detection. Such large increases in tumor volume would not be permitted in a prospective design. The number of glioma patients (n = 56) is a limitation; however, it is equivalent to the number of patients in phase II clinical trials. CONCLUSIONS: The current practice of visual comparison of longitudinal MRI scans is associated with significant delays in detecting growth of low-grade gliomas. Our findings support the idea that physicians aided by CAD detect growth at significantly smaller volumes than physicians using visual comparison alone. This study does not answer the questions whether to treat or not and which treatment modality is optimal. Nonetheless, early growth detection sets the stage for future clinical studies that address these questions and whether early therapeutic interventions prolong survival and improve quality of life.