Brain organoids are valuable research models for human development and disease since they mimic the various cell compositions and structures of the human brain; however, they have challenges in presenting aging phenotypes for degenerative diseases. This study analyzed the association between aging and the gut metabolite trimethylamine N-oxide (TMAO), which is highly found in the midbrain of elderly and Parkinson’s disease (PD) patients. TMAO treatment in midbrain organoid induced aging-associated molecular changes, including increased senescence marker expression (P21, P16), p53 accumulation, and epigenetic alterations. In addition, TMAO-treated midbrain organoids have shown parts of neurodegeneration phenotypes, including impaired brain-derived neurotrophic factor (BDNF) signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Moreover, we found TMAO treatment-induced pathophysiological phosphorylation of α-synuclein protein at Ser-129 residues and Tau protein at Ser202/Thr205. These results suggest a role of TMAO in the aging and pathogenesis of the midbrain and provide insight into how intestinal dysfunction increases the risk of PD. Furthermore, this system can be utilized as a novel aging model for induced pluripotent stem cell (iPSC)-based modeling of late-onset diseases.
Background: Timely and accurate prediction of delayed cerebral ischemia is critical for improving the prognosis of patients with aneurysmal subarachnoid hemorrhage. Machine learning (ML) algorithms are increasingly regarded as having a higher prediction power than conventional logistic regression (LR). This study aims to construct LR and ML models and compare their prediction power on delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH).
Methods: This was a multicenter, retrospective, observational cohort study that enrolled patients with aneurysmal subarachnoid hemorrhage from five hospitals in China. A total of 404 aSAH patients were prospectively enrolled. We randomly divided the patients into training (N = 303) and validation cohorts (N = 101) according to a ratio of 75–25%. One LR and six popular ML algorithms were used to construct models. The area under the receiver operating characteristic curve (AUC), accuracy, balanced accuracy, confusion matrix, sensitivity, specificity, calibration curve, and Hosmer–Lemeshow test were used to assess and compare the model performance. Finally, we calculated each feature of importance.
Results: A total of 112 (27.7%) patients developed DCI. Our results showed that conventional LR with an AUC value of 0.824 (95%CI: 0.73–0.91) in the validation cohort outperformed k-nearest neighbor, decision tree, support vector machine, and extreme gradient boosting model with the AUCs of 0.792 (95%CI: 0.68–0.9, P = 0.46), 0.675 (95%CI: 0.56–0.79, P < 0.01), 0.677 (95%CI: 0.57–0.77, P < 0.01), and 0.78 (95%CI: 0.68–0.87, P = 0.50). However, random forest (RF) and artificial neural network model with the same AUC (0.858, 95%CI: 0.78–0.93, P = 0.26) were better than the LR. The accuracy and the balanced accuracy of the RF were 20.8% and 11% higher than the latter, and the RF also showed good calibration in the validation cohort (Hosmer-Lemeshow: P = 0.203). We found that the CT value of subarachnoid hemorrhage, WBC count, neutrophil count, CT value of cerebral edema, and monocyte count were the five most important features for DCI prediction in the RF model. We then developed an online prediction tool (https://dynamic-nomogram.shinyapps.io/DynNomapp-DCI/) based on important features to calculate DCI risk precisely.
Conclusions: In this multicenter study, we found that several ML methods, particularly RF, outperformed conventional LR. Furthermore, an online prediction tool based on the RF model was developed to identify patients at high risk for DCI after SAH and facilitate timely interventions.
Clinical Trial Registration: http://www.chictr.org.cn, Unique identifier: ChiCTR2100044448.
With the aging process, brain functions, such as attention, memory, and cognitive functions, degrade over time. In a super-aging society, the alteration of neural activity owing to aging is considered crucial for interventions for the prevention of brain dysfunction. The complexity of temporal neural fluctuations with temporal scale dependency plays an important role in optimal brain information processing, such as perception and thinking. Complexity analysis is a useful approach for detecting cortical alteration in healthy individuals, as well as in pathological conditions, such as senile psychiatric disorders, resulting in changes in neural activity interactions among a wide range of brain regions. Multi-fractal (MF) and multi-scale entropy (MSE) analyses are known methods for capturing the complexity of temporal scale dependency of neural activity in the brain. MF and MSE analyses exhibit high accuracy in detecting changes in neural activity and are superior with regard to complexity detection when compared with other methods. In addition to complex temporal fluctuations, functional connectivity reflects the integration of information of brain processes in each region, described as mutual interactions of neural activity among brain regions. Thus, we hypothesized that the complementary relationship between functional connectivity and complexity could improve the ability to detect the alteration of spatiotemporal patterns observed on electroencephalography (EEG) with respect to aging. To prove this hypothesis, this study investigated the relationship between the complexity of neural activity and functional connectivity in aging based on EEG findings. Concretely, MF and MSE analyses were performed to evaluate the temporal complexity profiles, and phase lag index analyses assessing the unique profile of functional connectivity were performed based on the EEGs conducted for young and older participants. Subsequently, these profiles were combined through machine learning. We found that the complementary relationship between complexity and functional connectivity improves the classification accuracy among aging participants. Thus, the outcome of this study could be beneficial in formulating interventions for the prevention of age-related brain dysfunction.