Human Meibum Age, Lipid-Lipid Interactions and Lipid Saturation in Meibum from Infants.

Tear stability decreases with increasing age and the same signs of instability are exacerbated with dry eye. Meibum lipid compositional changes with age provide insights into the biomolecules responsible for tear film instability. Meibum was collected from 69 normal donors ranging in age from 0.6 to 68 years of age. Infrared spectroscopy was used to measure meibum lipid phase transition parameters. Nuclear magnetic resonance spectroscopy was used to measure lipid saturation. Increasing human meibum lipid hydrocarbon chain unsaturation with age was related to a decrease in hydrocarbon chain order, cooperativity, and in the phase transition temperature. The change in these parameters was most dramatic between 1 and 20 years of age. Meibum was catalytically saturated to determine the effect of saturation on meibum lipid phase transition parameters. Hydrocarbon chain saturation was directly related to lipid order, phase transition temperature, cooperativity, changes in enthalpy and entropy, and could account for the changes in the lipid phase transition parameters observed with age. Unsaturation could contribute to decreased tear film stability with age.

MRI-Based Prediction of Clinical Improvement Following Ventricular Shunt Placement for Normal Pressure Hydrocephalus (NPH): Development and Evaluation of an Integrated Multi-Sequence Machine Learning Algorithm.

BACKGROUND AND PURPOSE: Symptoms of normal pressure hydrocephalus (NPH) are sometimes refractory to shunt placement, with limited ability to predict improvement for individual patients. We evaluated an MRI-based artificial intelligence method to predict post-shunt NPH symptom improvement. MATERIALS AND METHODS: NPH patients who underwent magnetic resonance imaging (MRI) prior to shunt placement at a single center (2014-2021) were identified. Twelve-month post-shunt improvement in modified Rankin Scale (mRS), incontinence, gait, and cognition were retrospectively abstracted from clinical documentation. 3D deep residual neural networks were built on skull stripped T2-weighted and fluid attenuated inversion recovery (FLAIR) images. Predictions based on both sequences were fused by additional network layers. Patients from 2014-2019 were used for parameter optimization, while those from 2020-2021 were used for testing. Models were validated on an external validation dataset from a second institution (n=33). RESULTS: Of 249 patients, n=201 and n=185 were included in the T2-based and FLAIR-based models according to imaging availability. The combination of T2-weighted and FLAIR sequences offered the best performance in mRS and gait improvement predictions relative to models trained on imaging acquired using only one sequence, with AUROC values of 0.7395 [0.5765-0.9024] for mRS and 0.8816 [0.8030-0.9602] for gait. For urinary incontinence and cognition, combined model performances on predicting outcomes were similar to FLAIR-only performance, with AUROC values of 0.7874 [0.6845-0.8903] and 0.7230 [0.5600-0.8859]. CONCLUSIONS: Application of a combined algorithm using both T2-weighted and FLAIR sequences offered the best image-based prediction of post-shunt symptom improvement, particularly for gait and overall function in terms of mRS. ABBREVIATIONS: NPH = normal pressure hydrocephalus; iNPH = idiopathic NPH; sNPH = secondary NPH; AI = artificial intelligence; ML = machine learning; CSF = cerebrospinal fluid; AUROC = area under the receiver operating characteristic; FLAIR = fluid attenuated inversion recovery; BMI = body mass index; CCI = Charlson Comorbidity Index; SD = standard deviation; IQR = interquartile range.

Charlson comorbidity index applied to shunted idiopathic normal pressure hydrocephalus.

A series of epidemiological studies have shown the limited life expectancy of patients suffering from idiopathic normal pressure hydrocephalus (iNPH). In most cases, comorbid medical conditions are the cause of death, rather than iNPH. Though it has also been shown that shunting improves both life quality and lifetime. We sought to investigate the utility of the Charlson comorbidity index (CCI) for improved preoperative risk-benefit assessment of shunt surgery in individual iNPH cases. 208 shunted iNPH cases were prospectively investigated. Two in-person follow up visits at 3 and 12 months assessed postoperative clinical status. The correlation of the age adjusted CCI with survival was investigated over the median observation time of 2.37 years (IQR 1.16-4.15). Kaplan Meier statistics revealed that patients with a CCI score of 0-5 have a 5-year survival rate of 87%, compared to only 55% in patients with CCI > 5. Cox multivariate statistics revealed that the CCI was an independent predictor of survival, while common preoperative iNPH scores (modified Rankin Scale (mRS), gait score, and continence score) are not. As expected, mRS, gait, and continence scores improved during the postoperative follow up period, though relative improvement on any of these was not predicted by baseline CCI. The CCI is an easily applicable preoperative predictor of survival time in shunted iNPH patients. The lack of a correlation between the CCI and functional outcome means that even patients with multiple comorbidities and limited remaining lifetime may appreciate benefit from shunt surgery.

tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory.

Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA modifying enzyme that methylates wobble uridines in specific tRNAs to modulate translation. Through methylation of tRNA-selenocysteine, ALKBH8 promotes selenoprotein synthesis and regulates redox homeostasis. Pathogenic variants in ALKBH8 have been linked to intellectual disability disorders in the human population, but the role of ALKBH8 in the nervous system is unknown. Through in vivo studies in Drosophila, we show that ALKBH8 controls oxidative stress in the brain to restrain synaptic growth and support learning and memory. ALKBH8 null animals lack wobble uridine methylation and exhibit a global reduction in protein synthesis, including a specific decrease in selenoprotein levels. Loss of ALKBH8 or independent disruption of selenoprotein synthesis results in ectopic synapse formation. Genetic expression of antioxidant enzymes fully suppresses synaptic overgrowth in ALKBH8 null animals, confirming oxidative stress as the underlying cause of dysregulation. ALKBH8 animals also exhibit associative learning and memory impairments that are reversed by pharmacological antioxidant treatment. Together, these findings demonstrate the critical role of tRNA modification in redox homeostasis in the nervous system and reveal antioxidants as a potential therapy for ALKBH8-associated intellectual disability.

Meibum Lipid Composition and Conformation in Parkinsonism.

PURPOSE: Patients with Parkinson's disease (PD) exhibit unstable tear films. Tear film lipid composition and structure are related to tear film stability and dry eye and tear lipids have not been characterized in people with PD. The aim of this study is to characterize Meibum tear lipids in donors with PD using 1H-NMR and infrared spectroscopy. METHODS: Three cohorts were compared: meibum from donors with PD (Mp) n = 10, meibum from donors with PD and dry eye (Mpd) n = 3, meibum from donors without PD (Mn) n = 29. RESULTS: There were no significant differences, P > 0.05, in hydrocarbon branching for Mp compared with Mn. Mn contained twice as much cholesteryl esters compared with Mp, P < 0.0001. The cooperativity of the phase transition was significantly 37% lower for Mp compared with Mn, P < 0.0001. Mpd was much more ordered (stiffer) with compared with Mp and Mn, P < 0.0001. CONCLUSION: Changes in meibum lipid composition and structure could be a marker for and/or contribute to increase the susceptibility of dry eye in patients with PD. A less cooperative phase transition for Mp compared with Mn indicates that Mp was more heterogeneous and/or contained more contaminants than Mn. The data support the idea that more ordered lipid contributes to dry eye.