Search Results (134)

Adeno-associated virus (AAV) vectors have emerged as powerful tools for in vivo gene therapy, enabling long-term transgene expression in targeted tissues with minimal pathogenicity. This review examines the AAV serotypes used in clinical gene therapy trials for neurodegenerative (central nervous system, CNS) diseases, highlighting their tropisms, engineering advances, and translational progress. We discuss how capsid modifications, cell-specific promoters, and novel delivery routes are enhancing AAV tropism and reducing immunogenicity to overcome current limitations. Key clinical trials in neurodegenerative disorders (such as Parkinson’s, Alzheimer’s, and Huntington’s disease) are summarized, including delivery methods (intravenous, intracoronary, intrathecal, etc.) and outcomes. We further outline the regulatory landscape with recent approvals of AAV-based therapies and ongoing efforts to address safety challenges like immune responses and vector dose toxicity. A more translational, forward-looking perspective is adopted to consider combination therapies (e.g., AAV with immune modulation or genome editing) and strategic directions to improve the next generation of AAV vectors. Overall, continued innovation in AAV vector design and delivery, alongside careful clinical evaluation, is accelerating the translation of gene therapies for neurodegenerative diseases. Full article

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting countless individuals worldwide. PD is characterized by the onset of a marked motor symptomatology in association with several non-motor manifestations. The clinical phase of the disease is usually preceded by a long prodromal phase, devoid of overt motor symptomatology but often showing some conditions such as sleep disturbance, constipation, anosmia, and phonatory changes. To date, speech analysis appears to be a promising digital biomarker to anticipate even 10 years before the onset of clinical PD, as well serving as a useful prognostic tool for patient follow-up. That is why, the voice can be nominated as the non-invasive method to detect PD from healthy subjects (HS). Methods: Our study was based on cross-sectional study to analysis voice impairment. A dataset comprising 81 voice samples (41 from healthy individuals and 40 from PD patients) was utilized to train and evaluate common machine learning (ML) models using various types of features, including long-term (jitter, shimmer, and cepstral peak prominence (CPP)), short-term features (Mel-frequency cepstral coefficient (MFCC)), and non-standard measurements (pitch period entropy (PPE) and recurrence period density entropy (RPDE)). The study adopted multiple machine learning (ML) algorithms, including random forest (RF), K-nearest neighbors (KNN), decision tree (DT), naïve Bayes (NB), support vector machines (SVM), and logistic regression (LR). Cross-validation technique was applied to ensure the reliability of performance metrics on train and test subsets. These metrics (accuracy, recall, and precision), help determine the most effective models for distinguishing PD from healthy subjects. Result: Among all the algorithms used in this research, random forest (RF) was the best-performing model, achieving an accuracy of 82.72% with a ROC-AUC score of 89.65%. Although other models, such as support vector machine (SVM), could be considered with an accuracy of 75.29% and a ROC-AUC score of 82.63%, RF was by far the best one when evaluated across all metrics. The K-nearest neighbor (KNN) and decision tree (DT) performed the worst. Notably, by combining a comprehensive set of long-term, short-term, and non-standard acoustic features, unlike previous studies that typically focused on only a subset, our study achieved higher predictive performance, offering a more robust model for early PD detection. Conclusions: This study highlights the potential of combining advanced acoustic analysis with ML algorithms to develop non-invasive and reliable tools for early PD detection, offering substantial benefits for the healthcare sector. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression remain incompletely understood, emerging evidence suggests that the buildup of nuclear DNA damage, especially DNA double-strand breaks (DDSBs), plays a key role in contributing neurodegeneration, promoting senescence and neuroinflammation. Despite the pathogenic role for DDSB in neurodegenerative disease, targeting DNA repair mechanisms in PD is largely unexplored as a therapeutic approach. Ataxia telangiectasia mutated (ATM), a key kinase in the DNA damage response (DDR), plays a crucial role in neurodegeneration. In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy. Four-month-old C57BL/6J mice were unilaterally injected with either an empty AAV1/2 vector (control) or AAV1/2 expressing human A53T α-synuclein to the substantia nigra, followed by daily AZD1390 treatment for six weeks. In AZD1390-treated α-synuclein mice, we observed a significant reduction in the protein level of γ-H2AX, a DDSB marker, along with downregulation of senescence-associated markers, such as p53, Cdkn1a, and NF-κB, suggesting improved genomic integrity and attenuation of cellular senescence, indicating enhanced genomic stability and reduced cellular aging. AZD1390 also significantly dampened neuroinflammatory responses, evidenced by decreased expression of key pro-inflammatory cytokines and chemokines. Interestingly, mice treated with AZD1390 showed significant improvements in behavioral asymmetry and motor deficits, indicating functional recovery. Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative condition that impairs motor and non-motor functions. Early and accurate diagnosis is critical for effective management and care. Leveraging machine learning (ML) techniques, this study aimed to develop a robust prediction system for PD using a stacked ensemble learning approach, addressing challenges such as imbalanced datasets and feature optimization. Methods: An open-access PD dataset comprising 22 vocal attributes and 195 instances from 31 subjects was utilized. To prevent data leakage, subjects were divided into training (22 subjects) and testing (9 subjects) groups, ensuring no subject appeared in both sets. Preprocessing included data cleaning and normalization via min–max scaling. The synthetic minority oversampling technique (SMOTE) was applied exclusively to the training set to address class imbalance. Feature selection techniques—forward search, gain ratio, and Kruskal–Wallis test—were employed using subject-wise cross-validation to identify significant attributes. The developed system combined support vector machine (SVM), random forest (RF), K-nearest neighbor (KNN), and decision tree (DT) as base classifiers, with logistic regression (LR) as the meta-classifier in a stacked ensemble learning framework. Performance was evaluated using both recording-wise and subject-wise metrics to ensure clinical relevance. Results: The stacked ensemble learning model achieved realistic performance with a recording-wise accuracy of 84.7% and subject-wise accuracy of 77.8% on completely unseen subjects, outperforming individual classifiers including KNN (81.4%), RF (79.7%), and SVM (76.3%). Cross-validation within the training set showed 89.2% accuracy, with the performance difference highlighting the importance of proper validation methodology. Feature selection results showed that using the top 10 features ranked by gain ratio provided optimal balance between performance and clinical interpretability. The system’s methodological robustness was validated through rigorous subject-wise evaluation, demonstrating the critical impact of validation methodology on reported performance. Conclusions: By implementing subject-wise validation and preventing data leakage, this study demonstrates that proper validation yields substantially different (and more realistic) results compared to flawed recording-wise approaches. The findings underscore the critical importance of validation methodology in healthcare ML applications and provide a template for methodologically sound PD classification research. Future research should focus on validating the model with larger, multi-center datasets and implementing standardized validation protocols to enhance clinical applicability. Full article

Background/Objectives: Glycogen synthase kinase-3 beta (GSK3β) is a key enzyme involved in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, contributing to tau hyperphosphorylation, amyloid-beta (Aβ) aggregation, and neuronal dysfunction. Methods: This study applied a machine learning-driven virtual screening approach to identify potent natural inhibitors of GSK3β. A dataset of 3092 natural compounds was analyzed using Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbors (KNN), with feature selection focusing on key molecular descriptors, including lipophilicity (ALogP: −0.5 to 5.0), hydrogen bond acceptors (0–10), and McGowan volume (0.5–2.5). RF outperformed SVM and KNN, achieving the highest test accuracy (83.6%), specificity (87%), and lowest RMSE (0.3214). Results: Virtual screening using AutoDock Vina and molecular dynamics simulations (100 ns, GROMACS 2022) identified artemisinin as the top GSK3β inhibitor, with a binding affinity of −8.6 kcal/mol, interacting with key residues ASP200, CYS199, and LEU188. Dihydroartemisinin exhibited a binding affinity of −8.3 kcal/mol, reinforcing its neuroprotective potential. Pharmacokinetic predictions confirmed favorable drug-likeness (TPSA: 26.3–70.67 Ų) and non-toxicity. Conclusions: While these findings highlight artemisinin-based inhibitors as promising candidates, experimental validation and structural optimization are needed for clinical application. This study demonstrates the effectiveness of machine learning and computational screening in accelerating neurodegenerative drug discovery. Full article

The recent proliferation of novel machine learning techniques in quantitative marker-based 3D gait analysis (3DGA) has shown promise for improving interpretations of clinical gait analysis. The objective of this study was to characterize the state of the literature on using machine learning in the analysis of marker-based 3D gait analysis to provide clinical insights that may be used to improve clinical analysis and care. Methods: A scoping review of the literature was conducted using the PubMed and Web of Science databases. Search terms from eight relevant articles were identified by the authors and added to by experts in clinical gait analysis and machine learning. Inclusion was decided by the adjudication of three reviewers. Results: The review identified 4324 articles matching the search terms. Adjudication identified 105 relevant papers. The most commonly applied techniques were the following: support vector machines, neural networks (NNs), and logistic regression. The most common clinical conditions evaluated were cerebral palsy, Parkinson’s disease, and post-stroke. Conclusions: ML has been used broadly in the literature and recent advances in deep learning have been more successful in larger datasets while traditional techniques are robust in small datasets and can outperform NNs in accuracy and explainability. XAI techniques can improve model interpretability but have not been broadly used. Full article

This research aims to explore the interdisciplinary connection between the field of neurology and artificial intelligence (AI) through machine learning (ML) algorithms. The central objective is to evaluate the current state of research in the Neuro-ML field and identify gaps in the literature that require additional approaches. To achieve this objective, 10 analyses were introduced that analyze the distribution of articles based on keywords, countries, years, publishers, and ML algorithms used in the context of neurological diseases. Surveys were also conducted to identify the diseases most frequently studied through ML algorithms. Thus, it was found that Alzheimer’s disease (37 articles for Support Vector Regression—SVR; 31 for Random Forest—RF), Parkinson’s disease (46 articles for SVM and 48 for RF), and multiple sclerosis (9 articles for SVM) are the most studied diseases in the field of Neuro-ML. The study analyzes Alzheimer’s, Parkinson’s, and multiple sclerosis in detail by focusing on diagnosis. The overall results highlight an increase in researchers’ interest in applying ML in neurology, with models such as SVM (597 articles), Artificial Neural Network (525 articles), and RF (457 articles) being the most used. The results highlighted three major gaps: the underrepresentation of rare diseases, the lack of standardization in evaluating the performance of ML models, and the lack of exploration of algorithms with greater implementation difficulty, such as Extreme Gradient Boosting and Multilayer Perceptron. The value analysis of the performance metrics of ML models demonstrates the ability to correctly classify neuro-degenerative diseases, with high accuracy in some cases (for example, 97.46% accuracy in Alzheimer’s diagnosis), but there may still be improvements. Future directions include exploring rare diseases, investigating underutilized algorithms, and developing standardized protocols for evaluating the performance of ML models, which will facilitate the comparison of results across different studies. Full article

Background: This work presents an artificial intelligence-based algorithm for detecting Parkinson’s disease (PD) from voice signals. The detection of PD at pre-symptomatic stages is imperative to slow disease progression. Speech signal processing-based PD detection can play a crucial role here, as it has been reported in the literature that PD affects the voice quality of patients at an early stage. Hence, speech samples can be used as biomarkers of PD, provided that suitable voice features and artificial intelligence algorithms are employed. Methods: Advanced signal-processing techniques are used to extract audio features from the sustained vowel ‘/a/’ sound. The extracted audio features include baseline features, intensities, formant frequencies, bandwidths, vocal fold parameters, and Mel-frequency cepstral coefficients (MFCCs) to form a feature vector. Then, this feature vector is further enriched by including wavelet-based features to form the second feature vector. For classification purposes, two popular machine learning models, namely, support vector machine (SVM) and k-nearest neighbors (kNNs), are trained to distinguish patients with PD. Results: The results demonstrate that the inclusion of wavelet-based voice features enhances the performance of both the SVM and kNN models for PD detection. However, kNN provides better accuracy, detection speed, training time, and misclassification cost than SVM. Conclusions: This work concludes that wavelet-based voice features are important for detecting neurodegenerative diseases like PD. These wavelet features can enhance the classification performance of machine learning models. This work also concludes that kNN is recommendable over SVM for the investigated voice features, despite the inclusion and exclusion of the wavelet features. Full article

Background/Objectives: The implementation of artificial intelligence-based systems for disease detection using biomedical signals is challenging due to the limited availability of training data. This paper deals with the generation of synthetic EEG signals using deep learning-based models, to be used in future research for training Parkinson’s disease detection systems. Methods: Linear models, such as AR, MA, and ARMA, are often inadequate due to the inherent non-linearity of time series. To overcome this drawback, long short-term memory (LSTM) networks are proposed to learn long-term dependencies in non-linear EEG time series and subsequently generate synthetic signals to enhance the training of detection systems. To learn the forward and backward time dependencies in the EEG signals, a Bidirectional LSTM model has been implemented. The LSTM model was trained on the UC San Diego Resting State EEG Dataset, which includes samples from two groups: individuals with Parkinson’s disease and a healthy control group. Results: To determine the optimal number of cells in the model, we evaluated the mean squared error (MSE) and cross-correlation between the original and synthetic signals. This method was also applied to select the length of the hidden state vector. The number of hidden cells was set to 14, and the length of the hidden state vector for each cell was fixed at 4. Increasing these values did not improve MSE or cross-correlation and unnecessarily increased computational complexity. The proposed model’s performance was evaluated using the mean-squared error (MSE), Pearson’s correlation coefficient, and the power spectra of the synthetic and original signals, demonstrating the suitability of the proposed method for this application. Conclusions: The proposed model was compared to Autoregressive Moving Average (ARMA) models, demonstrating superior performance. This confirms that deep learning-based models, such as LSTM, are strong alternatives to statistical models like ARMA for handling non-linear, multifrequency, and non-stationary signals. Full article

This study explores an innovative approach to early Parkinson’s disease (PD) detection by analyzing speech data collected using a mixed reality (MR) system. A total of 57 Polish participants, including PD patients and healthy controls, performed five speech tasks while using an MR head-mounted display (HMD). Speech data were recorded and analyzed to extract acoustic and linguistic features, which were then evaluated using machine learning models, including logistic regression, support vector machines (SVMs), random forests, AdaBoost, and XGBoost. The XGBoost model achieved the best performance, with an F1-score of 0.90 ± 0.05 in the story-retelling task. Key features such as MFCCs (mel-frequency cepstral coefficients), spectral characteristics, RASTA-filtered auditory spectrum, and local shimmer were identified as significant in detecting PD-related speech alterations. Additionally, state-of-the-art deep learning models (wav2vec2, HuBERT, and WavLM) were fine-tuned for PD detection. HuBERT achieved the highest performance, with an F1-score of 0.94 ± 0.04 in the diadochokinetic task, demonstrating the potential of deep learning to capture complex speech patterns linked to neurodegenerative diseases. This study highlights the effectiveness of combining MR technology for speech data collection with advanced machine learning (ML) and deep learning (DL) techniques, offering a non-invasive and high-precision approach to PD diagnosis. The findings hold promise for broader clinical applications, advancing the diagnostic landscape for neurodegenerative disorders. Full article

Normal pressure hydrocephalus (NPH) is a neurological disorder characterized by altered cerebrospinal fluid accumulation in the brain’s ventricles, leading to symptoms such as gait disturbance and cognitive impairment. Artificial intelligence (AI), including machine learning (ML) and deep learning (DL), shows promise in diagnosing NPH using medical images. In this systematic review, we examined 21 papers on the use of AI in detecting NPH. The studies primarily focused on differentiating NPH from other neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease. We found that traditional ML methods like Support Vector Machines, Random Forest, and Logistic Regression were commonly used, while DL methods, particularly Deep Convolutional Neural Networks, were also widely employed. The accuracy of these approaches varied, ranging from 70% to 95% in differentiating NPH from other conditions. Feature selection techniques were used to identify relevant parameters for diagnosis. MRI scans were more frequently used than CT scans, but both modalities showed promise. Evaluation metrics like Dice similarity coefficients and ROC-AUC were the most typical metrics of model performance. Challenges in implementing AI in clinical practice were identified, and the authors suggested that a hybrid deep-traditional ML framework could enhance NPH diagnosis. Further research is needed to maximize the benefits of AI while addressing limitations. Full article

Background: Parkinson’s disease (PD) is one of the most prevalent, widespread, and intricate neurodegenerative disorders. According to the experts, at least 1% of people over the age of 60 are affected worldwide. In the present time, the early detection of PD remains difficult due to the absence of a clear consensus on its brain characterization. Therefore, there is an urgent need for a more reliable and efficient technique for early detection of PD. Using the potential of electroencephalogram (EEG) signals, this study introduces an innovative method for the detection or classification of PD patients through machine learning, as well as a more accurate deep learning approach. Methods: We propose an innovative EEG-based PD detection approach by integrating advanced spectral feature engineering with machine learning and deep learning models. Using (a) the UC San Diego Resting State EEG dataset and (b) IOWA dataset, we extract a standardized EEG feature from five key frequency bands—alpha, beta, theta, gamma, delta ($\alpha ,\beta ,\theta ,\gamma ,\delta$) and employ an SVM (Support Vector Machine) classifier as a baseline, achieving a notable accuracy. Furthermore, we implement a deep learning classifier (CNN) with a complex multi-dimensional feature set by combining power values from all frequency bands, which gives superior performance in distinguishing PD patients (both with medication and without medication states) from healthy patients. Results: With the five-fold cross-validation on these two datasets, our approaches successfully achieve promising results in a subject dependent scenario. The SVM classifier achieves competitive accuracies of 82% and 94% in the UC San Diego Resting State EEG dataset (using gamma band) and IOWA dataset, respectively in distinguishing PD patients from non-PD patients in subject. With the CNN classifier, our model is able to capture major cross-frequency dependencies of EEG; therefore, the classification accuracies reach beyond 96% and 99% with those two datasets, respectively. We also perform our experiments in a subject independent environment, where the SVM generates 68.09% accuracy. Conclusions: Our findings, coupled with advanced feature extraction and deep learning, have the potential to provide a non-invasive, efficient, and reliable approach for diagnosing PD, with further work aimed at enhancing feature sets, inclusion of a large number of subjects, and improving model generalizability across more diverse environments. Full article

Biomimetic nanoassemblies derived from natural products are considered promising nanomaterials due to their self-assembling ability and their favorable interactions with biological molecules leading to their numerous applications as therapeutic agents or as molecular probes. In this work, we have created peptide nanoconjugates of two natural products, β-Boswellic acid (BA) and β-glycyrrhetinic acid (GH). Both BA and GH are known for their medicinal value, including their role as strong antioxidants, anti-inflammatory, neuroprotective and as anti-tumor agents. To enhance the bioavailability of these molecules, they were functionalized with three short peptides (YYIVS, MPDAHL and GSGGL) to create six conjugates with amphiphilic structures capable of facile self-assembly. The peptides were also derived from natural sources and have been known to display antioxidant activity. Depending upon the conjugate, nanofibers, nanovesicles or a mixture of both were formed upon self-assembly. The binding interactions of the nanoconjugates with α-Synuclein, a protein implicated in Parkinson’s disease (PD) was examined through in silico studies and FTIR, circular dichroism and imaging studies. Our results indicated that the nanoassemblies interacted with alpha-synuclein fibrils efficaciously. Furthermore, the nanoassemblies were found to demonstrate high viability in the presence of microglial cells, and were found to enhance the uptake and interactions of α-Synuclein with microglial cells. The nanoconjugates designed in this work may be potentially utilized as vectors for peptide-based drug delivery or for other therapeutic applications. Full article

Parkinson’s disease (PD) is a neurological disorder that severely affects motor function, especially gait, requiring accurate diagnosis and assessment instruments. This study presents Dense Multiscale Sample Entropy (DM-SamEn) as an innovative method for diminishing feature dimensions while maintaining the uniqueness of signal features. DM-SamEn employs a weighting mechanism that considers the dynamic properties of the signal, thereby reducing redundancy and improving the distinctiveness of features extracted from vertical ground reaction force (VGRF) signals in patients with Parkinson’s disease. Subsequent to the extraction process, correlation-based feature selection (CFS) and sequential backward selection (SBS) refine feature sets, improving algorithmic accuracy. To validate the feature extraction and selection stage, three classifiers—Adaptive Weighted K-Nearest Neighbors (AW-KNN), Radial Basis Function Support Vector Machine (RBF-SVM), and Multilayer Perceptron (MLP)—were employed to evaluate classification efficacy and ascertain optimal performance across selection strategies, including CFS, SBS, and the hybrid SBS-CFS approach. K-fold cross-validation was employed to provide improved evaluation of model performance by assessing the model on various data subsets, thereby mitigating the risk of overfitting and augmenting the robustness of the results. As a result, the model demonstrated a significant ability to differentiate between PD patients and healthy controls, with classification accuracy reported as ACC [CI 95%: 97.82–98.5%] for disease identification and ACC [CI 95%: 96.3–97.3%] for severity assessment. Optimal performance was primarily achieved through feature sets chosen using SBS and the integrated SBS-CFS methods. The findings highlight the model’s potential as an effective instrument for diagnosing PD and assessing its severity, contributing to advancements in clinical management of the condition. Full article

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are debilitating conditions that affect millions worldwide, and the number of cases is expected to rise significantly in the coming years. Because early detection is crucial for effective intervention strategies, this study investigates whether the structural analysis of selected brain regions, including volumes and their spatial relationships obtained from regular T1-weighted MRI scans (N = 168, PPMI database), can model stages of PD using standard machine learning (ML) techniques. Thus, diverse ML models, including Logistic Regression, Random Forest, Support Vector Classifier, and Rough Sets, were trained and evaluated. Models used volumes, Euclidean, and Cosine distances of subcortical brain structures relative to the thalamus to differentiate among control (HC), prodromal (PR), and PD groups. Based on three separate experiments, the Logistic Regression approach was optimal, providing low feature complexity and strong predictive performance (accuracy: 85%, precision: 88%, recall: 85%) in PD-stage recognition. Using interpretable metrics, such as the volume- and centroid-based spatial distances, models achieved high diagnostic accuracy, presenting a promising framework for early-stage PD identification based on MRI scans. Full article