The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
Humans ; Prions ; Neurodegenerative Diseases/pathology* ; Amyloid beta-Peptides ; Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; Parkinson Disease

Nicotinamide adenine dinucleotide（NADH） in its reduced form of is a key coenzyme in redox reactions, essential for maintaining energy homeostasis.NADH and its oxidized counterpart, NAD+, form a redox couple that regulates various biological processes, including calcium homeostasis, synaptic plasticity, anti-apoptosis, and gene expression. The reduction of NAD+/NADH levels is closely linked to mitochondrial dysfunction, which plays a pivotal role in the cascade of various neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease.Auditory neuropathy（AN） is recognized as a clinical biomarker in neurodegenerative disorders. Furthermore, mitochondrial dysfunction has been identified in patients with mutations in genes like OPA1and AIFM1. However, effective treatments for these conditions are still lacking. Increasing evidence suggests that administratering NAD+ or its precursors endogenously may potentially prevent and slow disease progression by enhancing DNA repair and improving mitochondrial function. Therefore, this review concentrates on the metabolic pathways of NAD+/NADH production and their biological functions, and delves into the therapeutic potential and mechanisms of NADH in treating AN.
Humans ; NAD/metabolism* ; Neurodegenerative Diseases/metabolism* ; Mitochondria ; Oxidation-Reduction ; Mitochondrial Diseases

Background: Creutzfeldt-Jakob disease is a rapidly progressive, fatal, transmissible neurodegenerative disorder caused by a prion protein. It is characterized by cognitive decline, motor dysfunction, and eventually, death. It occurs globally with 1 case per one million population/year. And It is still considered rare in countries like the Philippines due to challenges in its diagnosis and the under recognition of its clinical features. As of now, the local prevalence or incidence of this disease in our country remains unknown, as only a single case report has been documented. As of now, the local prevalence or incidence of this disease in our country remains unknown, as only a single case report has been documented. Objective: To report a series of patients with probable sporadic CJD from a tertiary hospital in the Philippines. Materials and Methods: Patients with rapidly developing dementia fulfilling the diagnostic criteria for sCJD were included. All were investigated in detail to find out any possible treatable cause, including electroencephalography (EEG), magnetic resonance imaging (MRI) of the brain, and cerebrospinal fluid analysis. Results: A total of 3 patients with probable sCJD were diagnosed using the European diagnostic criterion from January 2022 to April 2023. The clinical features are consistent with other reported series. All 3 patients had the classical EEG findings, typical MRI features, and positive for 14-3-3 assay, and one was positive for RT-QuIC. Two patients died within 13 months from the disease onset. Conclusion This is the first reported case series of probable sCJD in the Philippines from a tertiary hospital in Metro Manila. Like in our patients, this disease should be considered in individuals with rapidly progressive dementia associated with myoclonus, neuropsychiatric symptoms, akinetic mutism, visual abnormality, and ataxia with signs of pyramidal and extra-pyramidal dysfunction. Although a definitive diagnosis must be histopathological, there are ancillary tests that are currently available that allow us to make a probable diagnosis of sCJD possible. Our study raises question about the prevalence of this disease in the Philippines which needs more validated studies from other parts of the country.
Creutzfeldt-Jakob Syndrome ; Neurodegenerative Diseases

Previous studies mainly used β-amyloid and α-synuclein as the biomarkers for the diagnosis of neurodegenerative diseases. In recent years，studies have shown that telomeres at the end of chromosome can be used as an index to measure the degree of biological aging，and telomere length and telomerase activity may also be used as the blood markers to evaluate the risk，progression，and poor prognosis of neurodegenerative diseases in the elderly；however，there is still a lack of consistency between the research findings in China and globally. Understanding the role of telomere-related biomarkers in age-related diseases can help clinicians learn more about the mechanism of disease development and progression. This article reviews the latest research advances in the telomere-telomerase system in neurodegenerative diseases，in order to introduce the influence of telomere length and telomerase activity on neurodegenerative diseases and their potential mechanisms of action.
Telomere ; Telomerase ; Neurodegenerative Diseases ; Alzheimer Disease ; Parkinson Disease

Parkinson's disease(PD)is the second most common neurodegenerative disease after Alzheimer's disease,with high morbidity and high disability rate.Since the early symptoms of PD are not typical and often similar to those of normal aging or other diseases.It is easy to missed diagnosis and misdiagnosis,which seriously affects the diagnosis and treatment of this disease and aggravetes the burden on the patients' life.MicroRNAs(miRNA)are a class of endogenous non-coding RNAs that are involved in post-transcriptional regulation by binding to target messenger RNAs(mRNA).They are highly conserved,short,easy to obtain,and can stably exist in peripheral body fluids.They have been used as biomarkers for a variety of diseases.Recent studies have demonstrated that miRNA play an important role in the development of PD.This paper reviews the recent research progress of miR-7/124/155,three mature miRNA in PD,aiming to provide reference for clarifying the pathogenesis and guiding the diagnosis and treatment of PD.
Humans ; Parkinson Disease ; Neurodegenerative Diseases ; MicroRNAs/genetics* ; Gene Expression Regulation ; Biomarkers/metabolism*

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. Neuroimaging based on magnetic resonance imaging (MRI) is one of the most intuitive and reliable methods to perform AD screening and diagnosis. Clinical head MRI detection generates multimodal image data, and to solve the problem of multimodal MRI processing and information fusion, this paper proposes a structural and functional MRI feature extraction and fusion method based on generalized convolutional neural networks (gCNN). The method includes a three-dimensional residual U-shaped network based on hybrid attention mechanism (3D HA-ResUNet) for feature representation and classification for structural MRI, and a U-shaped graph convolutional neural network (U-GCN) for node feature representation and classification of brain functional networks for functional MRI. Based on the fusion of the two types of image features, the optimal feature subset is selected based on discrete binary particle swarm optimization, and the prediction results are output by a machine learning classifier. The validation results of multimodal dataset from the AD Neuroimaging Initiative (ADNI) open-source database show that the proposed models have superior performance in their respective data domains. The gCNN framework combines the advantages of these two models and further improves the performance of the methods using single-modal MRI, improving the classification accuracy and sensitivity by 5.56% and 11.11%, respectively. In conclusion, the gCNN-based multimodal MRI classification method proposed in this paper can provide a technical basis for the auxiliary diagnosis of Alzheimer's disease.
Humans ; Alzheimer Disease/diagnostic imaging* ; Neurodegenerative Diseases ; Magnetic Resonance Imaging/methods* ; Neural Networks, Computer ; Neuroimaging/methods* ; Cognitive Dysfunction/diagnosis*

Objective: To analyze the clinical features of children with uridine responsive developmental epileptic encephalopathy 50 (DEE50) caused by CAD gene variants. Methods: A retrospective study was conducted on 6 patients diagnosed with uridine-responsive DEE50 caused by CAD gene variants at Beijing Children's Hospital and Peking University First Hospital from 2018 to 2022. The epileptic seizures, anemia, peripheral blood smear, cranial magnetic resonance imaging (MRI), visual evoked potential (VEP), genotype features and the therapeutic effect of uridine were descriptively analyzed. Results: A total of 6 patients, including 3 boys and 3 girls, aged 3.5(3.2,5.8) years, were enrolled in this study. All patients presented with refractory epilepsy, anemia with anisopoikilocytosis and global developmental delay with regression. The age of epilepsy onset was 8.5 (7.5, 11.0) months, and focal seizures were the most common seizure type (6 cases). Anemia ranged from mild to severe. Four patients had peripheral blood smears prior to uridine administration, showing erythrocytes of variable size and abnormal morphology, and normalized at 6 (2, 8) months after uridine supplementation. Two patients suffered from strabismus, 3 patients had VEP examinations, indicating of suspicious optic nerve involvement, and normal fundus examinations. VEP was re-examined at 1 and 3 months after uridine supplementation, suggesting significant improvement or normalization. Cranial MRI were performed at 5 patients, demonstrating cerebral and cerebellar atrophy. They had cranial MRI re-examined after uridine treatment with a duration of 1.1 (1.0, 1.8) years, indicating significant improvement in brain atrophy. All patients received uridine orally at a dose of 100 mg/(kg·d), the age at initiation of uridine treatment was 1.0 (0.8, 2.5) years, and the duration of treatment was 2.4 (2.2, 3.0) years. Immediate cession of seizures was observed within days to a week after uridine supplementation. Four patients received uridine monotherapy and were seizure free for 7 months, 2.4 years, 2.4 years and 3.0 years respectively. One patient achieved seizure free for 3.0 years after uridine supplementation and had discontinued uridine for 1.5 years. Two patients were supplemented with uridine combined with 1 to 2 anti-seizure medications and had a reduced seizure frequency of 1 to 3 times per year, and they had achieved seizure free for 8 months and 1.4 years respectively. Conclusions: The clinical manifestations of DEE50 caused by CAD gene variants present a triad of refractory epilepsy, anemia with anisopoikilocytosis, and psychomotor retardation with regression, accompanied by suspected optic nerve involvement, all of which respond to uridine treatment. Prompt diagnosis and immediate uridine supplementation could lead to significant clinical improvement.
Male ; Female ; Humans ; Child ; Infant ; Epilepsy/genetics* ; Retrospective Studies ; Drug Resistant Epilepsy ; Uridine ; Evoked Potentials, Visual ; Anemia ; Electroencephalography/adverse effects* ; Neurodegenerative Diseases

Humans ; Cerebral Cortex ; Hallucinations/pathology* ; Neurodegenerative Diseases/pathology* ; Atrophy/pathology* ; Magnetic Resonance Imaging

Neurodegenerative diseases (NDs) have become a significant threat to an aging human society. Numerous studies have been conducted in the past decades to clarify their pathologic mechanisms and search for reliable biomarkers. Magnetic resonance imaging (MRI) is a powerful tool for investigating structural and functional brain alterations in NDs. With the advantages of being non-invasive and non-radioactive, it has been frequently used in both animal research and large-scale clinical investigations. MRI may serve as a bridge connecting micro- and macro-level analysis and promoting bench-to-bed translational research. Nevertheless, due to the abundance and complexity of MRI techniques, exploiting their potential is not always straightforward. This review aims to briefly introduce research progress in clinical imaging studies and discuss possible strategies for applying MRI in translational ND research.
Animals ; Humans ; Neurodegenerative Diseases/pathology* ; Translational Research, Biomedical ; Magnetic Resonance Imaging/methods* ; Brain/pathology* ; Head/pathology*

As prominent immune cells in the central nervous system, microglia constantly monitor the environment and provide neuronal protection, which are important functions for maintaining brain homeostasis. In the diseased brain, microglia are crucial mediators of neuroinflammation that regulates a broad spectrum of cellular responses. In this review, we summarize current knowledge on the multifunctional contributions of microglia to homeostasis and their involvement in neurodegeneration. We further provide a comprehensive overview of therapeutic interventions targeting microglia in neurodegenerative diseases. Notably, we propose microglial depletion and subsequent repopulation as promising replacement therapy. Although microglial replacement therapy is still in its infancy, it will likely be a trend in the development of treatments for neurodegenerative diseases due to its versatility and selectivity.
Humans ; Microglia/physiology* ; Central Nervous System ; Neurodegenerative Diseases/therapy* ; Brain/physiology* ; Homeostasis