Search Results (6,819)

Background: The primary effect of Botulinum toxin (BoNT) is to cause weakness in the injected muscles by inhibiting the release of acetyl choline from presynaptic nerve terminals. Its effect on sensorimotor integration (SMI) has largely been confined to small studies. The aim of this review is to highlight effect of BoNT on SMI in the context of Parkinson’s disease (PD), Cervical dystonia (CD), and Writer’s cramp (WC). Methods: Using keywords “Botulinum toxin” and “sensorimotor integration” or “Freezing of gait (FOG)” or ‘Tremor”or “Cervical dystonia” or “Parkinson’s disease”, or “Writer’s cramp”, PubMed database was searched for relevant articles supporting our view. The abstracts of all resultant articles (case reports, case series, randomized trials, observational studies) were reviewed to look for evidence of effects of botulinum toxin on SMI. The relevant articles were charted in excel sheet for further full text review. Results: In FOG, chronic BoNT injections may alter central motor patterns with inclusion of alternative striatal systems, cerebellum, and its connections. In tremor, the afferent proprioceptive input may be modified with reduction of intracortical facilitation and increment of intracortical inhibition. In CD, BoNT can restore disorganized cortical somatotrophy, the key pathophysiology behind cervical dystonia. Similarly, in WC, both the deficient sensory system and abnormal reorganization of the sensorimotor cortex may be altered following chronic BoNT injections. Conclusions: There is preliminary evidence that BoNT may modulate SMI in PD, CD, and WC by altering inputs from the muscle spindles in short term and modifying circuits/particular anatomic cerebral cortices in the long term. Properly conducted randomized trials comparing BoNT with placebo or prospective large-scale studies to look for effect on various surrogate markers reflective of changes in SMI should be the next step to confirm these findings. Targeting the system of afferents like spindles and golgi tendon organs in muscles may be a better way of injecting BoNT, with lower amounts of toxin needed and potential for lesser side-effects like weakness and atrophy. However, this needs to be proven in controlled trials. Full article

Background: Freezing of gait (FoG) is one of the most debilitating motor symptoms in Parkinson’s disease (PD). It often leads to falls and reduces quality of life due to the risk of injury and loss of independence. Several types of wearable sensors have emerged as promising tools for the detection of FoG in clinical and real-life settings. Objective: The main objective of this systematic review was to critically evaluate the current usability of wearable sensor technologies for FoG detection in PD patients. The focus of the study is on sensor types, sensor combinations, placement on the body and the applications of such detection systems in a naturalistic environment. Methods: PubMed, IEEE Explore and ACM digital library were searched using a search string of Boolean operators that yielded 328 results, which were screened by title and abstract. After the screening process, 43 articles were included in the review. In addition to the year of publication, authorship and demographic data, sensor types and combinations, sensor locations, ON/OFF medication states of patients, gait tasks, performance metrics and algorithms used to process the data were extracted and analyzed. Results: The number of patients in the reviewed studies ranged from a single PD patient to 205 PD patients, and just over 65% of studies have solely focused on FoG + PD patients. The accelerometer was identified as the most frequently utilized wearable sensor, appearing in more than 90% of studies, often in combination with gyroscopes (25.5%) or gyroscopes and magnetometers (20.9%). The best overall sensor configuration reported was the accelerometer and gyroscope setup, achieving nearly 100% sensitivity and specificity for FoG detection. The most common sensor placement sites on the body were the waist, ankles, shanks and feet, but the current literature lacks the overall standardization of optimum sensor locations. Real-life context for FoG detection was the focus of only nine studies that reported promising results but much less consistent performance due to increased signal noise and unexpected patient activity. Conclusions: Current accelerometer-based FoG detection systems along with adaptive machine learning algorithms can reliably and consistently detect FoG in PD patients in controlled laboratory environments. The transition of detection systems towards a natural environment, however, remains a challenge to be explored. The development of standardized sensor placement guidelines along with robust and adaptive FoG detection systems that can maintain accuracy in a real-life environment would significantly improve the usefulness of these systems. Full article

Apolipoprotein A (ApoA) proteins, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V, play critical roles in lipid metabolism, neuroinflammation, and blood–brain barrier integrity, making them pivotal in neurological diseases such as Alzheimer’s disease (AD), stroke, Parkinson’s disease (PD), and multiple sclerosis (MS). This review synthesizes current evidence on their structural and functional contributions to neuroprotection, highlighting their dual roles as biomarkers and therapeutic targets. ApoA-I, the most extensively studied, exhibits anti-inflammatory, antioxidant, and amyloid-clearing properties, with reduced levels associated with AD progression and cognitive decline. ApoA-II modulates HDL metabolism and stroke risk, while ApoA-IV influences neuroinflammation and amyloid processing. ApoA-V, although less explored, is implicated in stroke susceptibility through its regulation of triglycerides. Genetic polymorphisms (e.g., APOA1 rs670, APOA5 rs662799) further complicate disease risk, showing population-specific associations with stroke and neurodegeneration. Therapeutic strategies targeting ApoA proteins, including reconstituted HDL, mimetic peptides, and gene-based approaches, show promise in preclinical models but face translational challenges in human trials. Clinical trials, such as those with CSL112, highlight the need for neuro-specific optimization. Further research should prioritize human-relevant models, advanced neuroimaging techniques, and functional assays to elucidate ApoA mechanisms inside the central nervous system. The integration of genetic, lipidomic, and clinical data offers potential for enhancing precision medicine in neurological illnesses by facilitating the generation of ApoA-targeted treatments and bridging current deficiencies in disease comprehension and therapy. Full article

Cathepsins, a family of lysosomal proteases, play critical roles in maintaining cellular homeostasis through protein degradation and modulation of immune responses. In the central nervous system (CNS), their functions extend beyond classical proteolysis, influencing neuroinflammation, synaptic remodeling, and neurodegeneration. Emerging evidence underscores the crucial role of microglial cathepsins in the pathophysiology of several neurological disorders. This review synthesizes current knowledge on the involvement of cathepsins in a spectrum of CNS diseases, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, Huntington’s disease, and ischemic stroke. We highlight how specific cathepsins contribute to disease progression by modulating key pathological processes such as α-synuclein and amyloid-β clearance, tau degradation, lysosomal dysfunction, neuroinflammation, and demyelination. Notably, several cathepsins demonstrate both neuroprotective and pathogenic roles depending on disease context and expression levels. Additionally, the balance between cathepsins and their endogenous inhibitors, such as cystatins, emerges as a critical factor in CNS pathology. While cathepsins represent promising biomarkers and therapeutic targets, significant gaps remain in our understanding of their mechanistic roles across diseases. Future studies focusing on their regulation, substrate specificity, and interplay with genetic and epigenetic factors may yield novel strategies for early diagnosis and disease-modifying treatments in neurology. Full article

Background/Objectives: Early diagnosis of Parkinson’s Disease (PD) is essential for initiating interventions that may slow its progression and enhance patient quality of life. Gait analysis provides a non-invasive means of capturing subtle motor disturbances, enabling the prediction of both disease presence and severity. This study evaluates and contrasts Bayesian-optimized convolutional neural network (CNN) and long short-term memory (LSTM) models applied directly to Vertical Ground Reaction Force (VGRF) signals for Parkinson’s disease detection and staging. Methods: VGRF recordings were segmented into fixed-length windows of 5, 10, 15, 20, and 25 s. Each segment was normalized and supplied as input to CNN and LSTM network. Hyperparameters for both architectures were optimized via Bayesian optimization using five-fold cross-validation. Results: The Bayesian-optimized LSTM achieved a peak binary classification accuracy of 99.42% with an AUC of 1.000 for PD versus control at the 10-s window, and 98.24% accuracy with an AUC of 0.999 for Hoehn–Yahr (HY) staging at the 5-s window. The CNN model reached up to 98.46% accuracy (AUC = 0.998) for binary classification and 96.62% accuracy (AUC = 0.998) for multi-class severity assessment. Conclusions: Bayesian-optimized CNN and LSTM models trained on VGRF data both achieved high accuracy in Parkinson’s disease detection and staging, with the LSTM exhibiting a slight edge in capturing temporal patterns while the CNN delivered comparable performance with reduced computational demands. These results underscore the promise of end-to-end deep learning for non-invasive, gait-based assessment in Parkinson’s disease. Full article

Parkinson’s disease (PD) is a disorder that causes a decrease in motor skills. Among the symptoms that have been observed, the most significant is the occurrence of Freezing of Gait (FoG), which manifests as an abrupt cessation of walking. This study investigates the impact of spatiotemporal gait parameters using wearable inertial measurement units (IMUs). Notably, 30 PD patients (15 with FoG, 15 without) and 20 healthy controls were enrolled. Gait data were acquired using two foot-mounted IMUs and key parameters such as stride time, gait phase distribution, cadence, stride length, speed, and foot clearance were extracted. Results indicated a tangible decline in motor abilities in PD patients, especially in those with FoG. Differences were observed in the segmentation of gait phases, with diminished swing phase duration observed in patients, and in the diminished spatial parameters of stride length, velocity, and foot clearance. Additionally, to validate the results, the accuracy of IMU-derived clearance measurements was validated against an optoelectronic system. While the IMUs accurately detected maximum points, the minimum clearance showed a higher measurement error. These findings support the use of wearable IMUs as a reliable and low-cost alternative to laboratory systems for the assessment of gait abnormalities in PD. Moreover, they highlight the potential for early detection and monitoring of FoG in both clinical and home settings. Full article

Background: The use of neuromodulation for the treatment of psychiatric disorders has become increasingly common, but this emerging treatment modality comes with ethical concerns. This scoping review aims to synthesize the neuroethical discourse from the past 10 years on the use of neurotechnologies for psychiatric conditions. Methods: A total of 4496 references were imported from PubMed, Embase, and Scopus. The inclusion criteria required a discussion of the neuroethics of neuromodulation and studies published between 2014 and 2024. Results: Of the 77 references, a majority discussed ethical concerns of patient autonomy and informed consent for neuromodulation, with neurotechnologies being increasingly seen as autonomy enablers. Concepts of changes in patient identity and personality, especially after deep brain stimulation, were also discussed extensively. The risks and benefits of neurotechnologies were also compared, with deep brain stimulation being seen as the riskiest but also possessing the highest efficacy. Concerns about equitable access and justice were raised regarding the rise of private transcranial magnetic stimulation clinics and the current experimental status of deep brain stimulation. Conclusions: Neuroethics discourse, particularly for deep brain stimulation, has continued to focus on how post-intervention changes in personality and behavior influence patient identity. Multiple conceptual frameworks have been proposed, though each faces critiques for addressing only parts of this complex phenomenon, prompting calls for pluralistic models. Emerging technologies, especially those involving artificial intelligence through brain computer interfaces, add new dimensions to this debate by raising concerns about neuroprivacy and legal responsibility for actions, further blurring the lines for defining personal identity. Full article

Background/Objectives: We have previously shown that motor and non-motor symptoms of patients with Parkinson’s disease (PD) improved after a two-week in-patient multimodal intensive neurorehabilitation and care (iMINC). This program includes five hours/day for five days/week of multimodal neurorehabilitation and drug adjustments, taking advantage of extensive patient observation. In this study, we ascertained whether the improvements observed after iMINC similarly occurred in patients with and without drug adjustments. Methods: With a retrospective approach, the scores of UPDRS Total and Part III, Beck’s Depression Inventory (BDI), PDQ-39, Parkinson’s Disease Sleep Scale (PDSS), and Vocal Volume before and after two weeks of iMINC were compared in two groups of patients with moderate to advanced PD (H&Y Stage 3–4). In one group, drug adjustment was not necessary (PD no drug adjustment, PDnda, 38 patients), and another group underwent drug changes (PD with drug adjustment, PDda, 93 patients). Scores of all tests were compared using ANOVAs (within subject: before iMINC, after iMINC; between subject: PDda, PDnda). Results: Following iMINC, all outcome measures improved in both groups. Conclusions: Pharmacological adjustment is not the major factor that drives the improvement of motor and non-motor outcome scores following iMINC. These findings suggest that this comprehensive in-patient approach addresses most parkinsonian symptoms and that proper medication status may enhance the positive effects of iMINC. Full article

Objectives: This study aimed to establish a transgenic mouse model expressing nucleus-localized human α-synuclein (α-syn) to investigate its impact on the central nervous system and behavior and the underlying mechanisms involved. Methods: A nuclear localization sequence (NLS) was added to the end of the human SNCA (hSNCA) gene. Subsequently, an empty vector and a mammalian lentiviral vector of the hSNCA-NLS were constructed. Transgenic mice were generated via microinjection, with genotyping and protein expression confirmed by PCR and western blotting. Only male mice were used in subsequent behavioral and molecular experiments. Immunofluorescence identified the colocalization of human α-syn with the cell nucleus in mouse brain tissues. Behavioral changes in transgenic mice were assessed using open field, rotarod, and O-maze tests. qPCR and Western blotting detected expression levels of genes and proteins related to inflammation, endoplasmic reticulum stress (ERS), and apoptosis. Bulk RNA sequencing was used to screen for differentially expressed genes and signaling pathways. Results: We successfully constructed a transgenic mouse model expressing human α-syn. Human α-syn was widely expressed in the heart, liver, spleen, kidneys, and brain of the mice, with distinct nuclear localization observed. Behavioral assessments demonstrated that, by 2 months of age, the mice exhibited motor dysfunction alongside astrocyte proliferation and neuroinflammation. At 6 months, the elevated expression of ERS-related genes (ATF6, PERK, and IRE1) and activation of the PERK-Beclin1-LC3II pathway indicated progressive ERS. By 9 months, apoptotic events had occurred, accompanied by significant anxiety-like behaviors. Bulk RNA sequencing further identified key differentially expressed genes, including IL-1α, TNF, PERK, BECLIN, GABA, IL-6α, P53, LC3II, NOS, and SPAG, suggesting their involvement in the observed pathological and behavioral phenotypes. Conclusions: The nuclear localization human α-syn transgenic mice were successfully established. These findings demonstrate that nucleus-localized α-syn induces early motor deficits, which are likely mediated by neuroinflammation, whereas later anxiety-like behaviors may result from ERS-induced apoptosis. This model provides a valuable tool for elucidating the role of nuclear α-syn in Parkinson’s disease and supports further mechanistic and therapeutic research. Full article

The three pathological hallmarks of multiple sclerosis (MS) are inflammation, demyelination, and progressive neurodegeneration. None of the approved disease-modifying therapies for MS counters all three pathologies, and, more specifically, none is approved for neuroprotection. Axonal loss is the most significant contributor to chronic and irreversible disability in MS. A tantalizing molecular target has emerged to uniquely counter all three MS pathologies: tumor necrosis factor receptor 2 (TNFR2). Agonism or activation of TNFR2 has been shown in MS models to induce immunosuppression, oligodendrocyte precursor differentiation, and neuroprotection. Further, in basic science studies stemming from the past 15 years, TNFR2 agonism is known to be a strong inducer of T-regulatory cells (Tregs). Treg cells, and especially those expressing TNFR2, are known to confer the strongest suppression per cell type. TNFR2 is even more attractive as a therapeutic target because of its restricted expression by only a handful of CNS and immune cell subsets, thereby minimizing the likelihood of systemic and other adverse effects. Recent antibody design work suggests many of the hurdles of Treg agonism may have been overcome. This review covers the current treatment landscape for MS, the basic science of TNFR2, the rationale for and evidence behind TNFR2 agonism to treat multiple sclerosis, the design of potent TNFR2 agonist antibodies, and the treatment applications for other neurological, autoimmune, or inflammatory diseases. Full article

Seed amplification assays (SAA) targeting misfolded α-synuclein have emerged as powerful tools for the diagnosis and study of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies, and multipßle system atrophy. These assays exploit the prion-like seeding properties of pathological α-synuclein to detect minute amounts of misfolded protein in biological specimens. the PubMed database was searched according to our study criteria, and 55 clinical studies comprised the final literature review. the majority of studies have focused on patients at various stages of PD, with cerebrospinal fluid (CSF) being the most commonly investigated biological specimen. Diagnostic utility was most pronounced in the CSF of PD patients, whereas results from other biological samples and across different synucleinopathies have been more modest. α-syn SAA demonstrate significant diagnostic potential in synucleinopathies. Additional applications may include monitoring disease progression. Future studies should explore the utility of α-syn SAA in alternative biological specimens, assess its performance across various synucleinopathies and other neurodegenerative diseases, and determine its comparative diagnostic value. Full article

Background/Objectives: Persons with Parkinson’s disease (PD) are at elevated risk of falling due to deficits in postural control, lower limb strength, and sensory integration. While community-based boxing programs (CBPs) have shown promise in improving strength and balance, their feasibility and potential role in addressing fall risk remain unclear. This preliminary, prospective cohort study explored the feasibility of a CBP enhanced with individualized balance training tailored to somatosensory deficits and explored early indications of potential impact on fall risk and related outcomes. Methods: Twenty individuals with mild-to-moderate PD participated in a 12-week exercise program consisting of group-based boxing, functional circuit training, and one-on-one balance training based on the Modified Clinical Test of Sensory Interaction in Balance. Self-reported falls were collected at baseline and 3 months post-intervention. Secondary outcomes included standard measures of balance, gait, and functional mobility. Results: Participants demonstrated significant improvements in balance and functional mobility including the Timed Up and Go (F(2, 40.85) = 24.83, p < 0.001, η² = 0.580), Five Times Sit-to-Stand Test (F(2, 78.13) = 50.22, p < 0.001, η² = 0.736), and Berg Balance Scale (F(2, 193.39) = 12.72, p < 0.001, η² = 0.414), among others. 4 participants experienced a decrease in falls, 2 experienced an increase, and the remainder had no change. Conclusions: These preliminary findings suggest that integrating individualized balance training with a CBP is feasible and may positively influence functional mobility and balance in persons with PD. However, effects on fall reduction remain inconclusive. These results should be interpreted as exploratory and used to inform the design of future structured clinical trials. Full article

This study used NMR-based metabolomics to investigate the mode of action (MoA) of 6-hydroxydopamine (6-OHDA) toxicity in the SH-SY5Y neuroblastoma cell model. 6-OHDA, a structural analogue of dopamine, has been used to create a Parkinson’s disease model since 1968. Its selective uptake via catecholaminergic transporters leads to intracellular oxidative stress and mitochondrial dysfunction. SH-SY5Y cells were treated with 6-OHDA at its IC₅₀ concentration of 60 μM, and samples of treated and untreated groups were collected after 24 h. The endo metabolome was extracted using a methanol–water mixture, while the exo metabolome was represented by the culture media. Further, endo- and exo metabolomes of treated and untreated cells were analysed for metabolic changes. Our results demonstrated significantly high levels of glutathione, acetate, propionate, and NAD⁺, which are oxidative stress markers, enhanced due to ROS production in the system. In addition, alteration of myoinositol, taurine, and o-phosphocholine could be due to oxidative stress-induced membrane potential disturbance. Mitochondrial complex I inhibition causes electron transport chain (ETC) dysfunction. Changes in key metabolites of glycolysis and energy metabolism, such as glucose, pyruvate, lactate, creatine, creatine phosphate, glycine, and methionine, respectively, demonstrated ETC dysfunction. We also identified changes in amino acids such as glutamine, glutamate, and proline, followed by nucleotide metabolism such as uridine and uridine monophosphate levels, which were decreased in the treated group. Full article

Extrapyramidal symptoms encompass features of Parkinsonism, including bradykinesia, cogwheel rigidity, and resting tremors, which contribute to motor impairments hindering handwriting and speech. In this study, we analyzed voice data captured using a voice sensor setup from 94 patients exhibiting varying levels of EPS and 30 unaffected controls. Each participant provided 13 recordings of repeated vowel and consonant sounds. The Drug-Induced Extrapyramidal Side Effect Scale and Glasgow Antipsychotic Side Effect Scales were used when grading patients into mild, moderate, and severe extrapyramidal symptoms, both administered by trained clinicians. To develop an objective assessment tool, we employed a transfer learning approach using a DenseNet architecture for feature extraction and classification. Its architecture enables the hierarchical concatenation of features at each layer. In this study, we identified that key acoustic features, MFCC, chroma, and spectral contrast vary significantly with the severity of extrapyramidal symptoms. Based on these findings, we developed a DenseNet-based model capable of predicting extrapyramidal symptoms from voice data. This model can classify with an accuracy of 81.9% and a precision of 82.0%. To the best of our knowledge, this is the first study to introduce a voice-based model for assessing the severity of extrapyramidal symptoms. Full article

The increasing global health crisis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s disease is worsening because of a rapidly increasing aging population. Disease-modifying therapies continue to face development challenges due to the blood–brain barrier (BBB), which prevents more than 98% of small molecules and all biologics from entering the central nervous system. The therapeutic landscape for neurodegenerative diseases has recently undergone transformation through advances in targeted drug delivery that include ligand-decorated nanoparticles, bispecific antibody shuttles, focused ultrasound-mediated BBB modulation, intranasal exosomes, and mRNA lipid nanoparticles. This review provides an analysis of the molecular pathways that cause major neurodegenerative diseases, discusses the physiological and physicochemical barriers to drug delivery to the brain, and reviews the most recent drug targeting strategies including receptor-mediated transcytosis, cell-based “Trojan horse” approaches, gene-editing vectors, and spatiotemporally controlled physical methods. The review also critically evaluates the limitations such as immunogenicity, scalability, and clinical translation challenges, proposing potential solutions to enhance therapeutic efficacy. The recent clinical trials are assessed in detail, and current and future trends are discussed, including artificial intelligence (AI)-based carrier engineering, combination therapy, and precision neuro-nanomedicine. The successful translation of these innovations into effective treatments for patients with neurodegenerative diseases will require essential interdisciplinary collaboration between neuroscientists, pharmaceutics experts, clinicians, and regulators. Full article