Aims: We mainly evaluate retinal alterations in Alzheimer's disease (AD) patients, investigate the associations between retinal changes with AD biomarkers, and explore an optimal machine learning (ML) model for AD diagnosis based on retinal thickness.Methods: A total of 159 AD patients and 299 healthy controls were enrolled. The retinal parameters of each participant were measured using optical coherence tomography (OCT). Additionally, cognitive impairment severity, brain atrophy, and cerebrospinal fluid (CSF) biomarkers were measured in AD patients.Results: AD patients demonstrated a significant decrease in the average, superior, and inferior quadrant peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL) thicknesses, as well as total macular volume (TMV) (all p < 0.05). Moreover, TMV was positively associated with Mini‐Mental State Examination and Montreal Cognitive Assessment scores, IPL thickness was correlated negatively with the medial temporal lobe atrophy score, and the GCL thickness was positively correlated with CSF Aβ₄₂/Aβ₄₀ and negatively associated with p‐tau level. Based on the significantly decreased OCT variables between both groups, the XGBoost algorithm exhibited the best diagnostic performance for AD, whose four references, including accuracy, area under the curve, f1 score, and recall, ranged from 0.69 to 0.74. Moreover, the macular retinal thickness exhibited an absolute superiority for AD diagnosis compared with other enrolled variables in all ML models.Conclusion: We identified the retinal alterations in AD patients and found that macular thickness and volume were associated with AD severity and biomarkers. Furthermore, we confirmed that OCT combined with ML could serve as a potential diagnostic tool for AD.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and aging and genetic and environmental exposure can contribute to its pathogenesis. DNA methylation has been suggested to play a pivotal role in neurodevelopment and neurodegenerative diseases. 5-hydroxymethylcytosine (5hmC) is generated through 5-methylcytosine (5mC) oxidization by ten-eleven translocation proteins and is particularly enriched in the brain. Although 5hmC has been linked to multiple neurological disorders, little is known about 5hmC alterations in the substantia nigra of patients with PD. To determine the specific alterations in DNA methylation and hydroxymethylation in PD brain samples, we examined the genome-wide profiles of 5mC and 5hmC in the substantia nigra of patients with PD and Alzheimer’s disease (ad). We identified 4119 differentially hydroxymethylated regions (DhMRs) and no differentially methylated regions (DMRs) in the postmortem brains of patients with PD compared with those of controls. These DhMRs were PD-specific when compared with the results of AD. Gene ontology analysis revealed that several signaling pathways, such as neurogenesis and neuronal differentiation, were significantly enriched in PD DhMRs. KEGG enrichment analysis revealed substantial alterations in multiple signaling pathways, including phospholipase D (PLD), cAMP and Rap1. In addition, using a PD Drosophila model, we found that one of the 5hmC-modulated genes, PLD1, modulated α-synuclein toxicity. Our analysis suggested that 5hmC may act as an independent epigenetic marker and contribute to the pathogenesis of PD.

Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson’s disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy.