Search Results (6,621)

Optimizing healthcare resources in neurodegenerative diseases requires balancing diagnostic performance with cost constraints. We introduce AHN-BudgetNet—a tiered, cost-aware assessment framework for Parkinson’s disease motor severity prediction—evaluated on 1387 simulated PPMI subjects via patient-level GroupKFold validation. Our analysis tested seven tier combinations encompassing demographic, self-reported, and clinical features. The baseline (T0) yields AUC = 0.65 (95% CI [0.629, 0.681]) at no cost. Self-assessments (T1) alone achieved an AUC = 0.69 (95% CI [0.643, 0.733]) at USD 75, with an efficiency of 1.07. The combined T0 + T1 set reached AUC = 0.75 (95% CI [0.729, 0.772]) at USD 75, with efficiency 1.43. T2 alone obtained AUC = 0.53 (95% CI [0.517, 0.542]) at USD 300 and efficiency 0.07. The full T0+T1+T2 set achieved the highest performance—AUC = 0.76 (95% CI [0.735, 0.774])—at USD 375, with efficiency 0.54, reflecting diminishing returns beyond T1. High-cost tiers (T3/T4) could not be empirically validated due to over 88% missing data, emphasizing the value of accessible assessments. Gaussian Mixture on Tier 0 features yielded a silhouette score of 0.54, compared to 0.53 for K-means, confirming that patient-reported outcomes can support clinical stratification. Our results underpin evidence-based resource allocation: budgets USD ≤75 prioritize T1, while budgets USD ≤375 justify a comprehensive assessment. This confirms that structured tier prioritization supports robust, resource-efficient diagnosis in resource-limited clinical environments. Full article

Mitochondria-associated membranes (MAMs) are essential for cellular homeostasis. MAMs are specialized contact sites located between the endoplasmic reticulum (ER) and mitochondria and control apoptotic pathways, lipid metabolism, autophagy initiation, and calcium signaling, processes critical to the survival and function of neurons. Although this area of membrane biology remains understudied, increasing evidence links MAM dysfunction to the etiology of major neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). MAMs consist of a network of protein complexes that mediate molecular exchange and ER–mitochondria tethering. MAMs regulate lipid flow in the brain, including phosphatidylserine and cholesterol; disruption of this process causes membrane instability and impaired synaptic function. Inositol 1,4,5-trisphosphate receptor—voltage-dependent anion channel 1 (IP3R-VDAC1) interactions at MAMs maintain calcium homeostasis, which is required for mitochondria to produce ATP; dysregulation promotes oxidative stress and neuronal death. An effective therapeutic approach for altering neurodegenerative processes is to restore the functional integrity of MAMs. Improving cell-to-cell interactions and modulating MAM-associated proteins may contribute to the restoration of calcium homeostasis and lipid metabolism, both of which are key for neuronal protection. MAMs significantly contribute to the progression of neurodegenerative diseases, making them promising targets for future therapeutic research. This review emphasizes the increasing importance of MAMs in the study of neurodegeneration and their potential as novel targets for membrane-based therapeutic interventions. Full article

The repeated head impacts experienced by athletes have attracted significant interest from both the public and the scientific community; however, the neurobiological effects following the games are not well understood. For example, a single football match carries the risk of repeated concussive and subconcussive head impacts, which can increase the risk of developing neurodegenerative diseases. Chronic traumatic encephalopathy (CTE) is one of the neurodegenerative conditions athletes often face or are unaware of. However, addressing the disease progression in CTE is difficult to determine due to several reasons, such as the failure to identify risk factors, difficulty in differentiating CTE from other neurodegenerative diseases, and the lack of a specific mechanism by which CTE leads to tau protein accumulation. In addition, CTE symptoms overlap with other neurodegenerative conditions, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), which poses a challenge to producing specific targeted therapy. In this case, ultrasound represents a promising non-invasive technique that enables clear visualization of brain structures and may modulate neuronal activity. The term ultrasound encompasses various modalities; for example, high-intensity focused ultrasound (HIFU) employs thermal energy to ablate cells, whereas low-intensity pulsed ultrasound (LIPUS) delivers mechanical energy that activates molecular signaling pathways to impede the progression of CTE. Therefore, the LIPUS application could potentially minimize the risk of damage in the surrounding tissues of the brain and reduce the disease progression in individuals with CTE. Nevertheless, limited studies have been reported in the literature, with a poor mechanistic approach. Hence, this review aims to highlight the molecular signaling pathways, such as AKT, MAPK, and ERK, affected by LIPUS and emphasize the need for additional research to clarify its mechanistic effects in CTE management. Ultimately, this review aims to contribute to a nuanced understanding of LIPUS as a therapeutic strategy in addressing the complexities of CTE and its associated neurodegenerative disorders. Full article

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) are marked by progressive network dysfunction that challenges conventional, protocol-based neurorehabilitation. In parallel, neuromodulation, encompassing deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and artificial intelligence (AI), has matured rapidly, offering complementary levers to tailor therapy in real time. This narrative review synthesizes current evidence at the intersection of AI and neuromodulation in neurorehabilitation, focusing on how data-driven models can personalize stimulation and improve functional outcomes. We conducted a targeted literature synthesis of peer-reviewed studies identified via PubMed, Embase, Scopus, and reference chaining, prioritizing recent clinical and translational reports on adaptive/closed-loop systems, predictive modeling, and biomarker-guided protocols. Across indications, convergent findings show that AI can optimize device programming, enable state-dependent stimulation, and support clinician decision-making through multimodal biomarkers derived from neural, kinematic, and behavioral signals. Key barriers include data quality and interoperability, model interpretability and safety, and ethical and regulatory oversight. Here we argue that AI-enhanced neuromodulation reframes neurorehabilitation from static dosing to adaptive, patient-specific care. Advancing this paradigm will require rigorous external validation, standardized reporting of control policies and artifacts, clinician-in-the-loop governance, and privacy-preserving analytics. Full article

Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder frequently associated with cognitive impairment. In the context of increasing interest in remote healthcare solutions, particularly after the COVID-19 pandemic, this preliminary study aimed to evaluate the feasibility of an online version of the Parkinson’s Disease—Cognitive Rating Scale (PD-CRS), a first-level neuropsychological screening tool for mild cognitive impairment (MCI) in individuals with PD. Methods: Seventy-nine patients with idiopathic PD were recruited between October 2020 and February 2024. A telematic version of the PD-CRS was administered via video call using adapted materials (e.g., slide-based instructions and webcam-mediated tasks). Both patients and examiners completed a Visual Analogue Scale (VAS) to rate perceived difficulty. Descriptive statistics and non-parametric tests were used to analyze data. Results: Difficulty ratings were low for both patients (mean VAS = 1.60, SD = 0.88) and the examiner (mean VAS = 1.43, SD = 0.61), with no significant difference (p = 0.176). No demographic or clinical variable predicted difficulty. Conclusions: These findings support the feasibility and usability of an online version of PD-CRS. This approach may facilitate wider access to cognitive screening for PD patients, particularly those with mobility limitations or living in underserved areas. Full article

Background/Objectives: Parkinson’s disease (PD) and multiple sclerosis (MS) are neurological conditions that result in debilitating non-motor symptoms, such as anxiety and depression, which significantly reduce quality of life and often persist despite pharmacological treatment. As a result, effective alternative treatment strategies are needed. Exercise therapy—particularly aerobic training—has shown promise in alleviating non-motor symptoms, potentially through neuroplastic adaptations. However, traditional aerobic exercise is often time-consuming and monotonous, limiting long-term adherence. High-intensity interval training (HIIT) offers a time-efficient and potentially more engaging alternative, though its effects on non-motor symptoms in PD and MS remain understudied. Methods: This transdiagnostic randomized controlled trial will enroll 48 participants (24 PD, 24 MS) with clinically significant affective symptoms (hospital anxiety and depression scale [HADS] ≥ 8). The participants will be randomly assigned to one of three 8-week interventions: (1) HIIT, 5–6 intervals of 45 s of high-intensity cycling; (2) continuous aerobic training (CAT), 50 min of low-intensity cycling; (3) movement advice (MA), step goals, and physical education. The primary (affective symptoms) and secondary outcomes (cognition, fatigue, sleep, motor function) will be assessed at four time points: 4 and 1 weeks pre intervention, and 1 and 4 weeks post intervention. Weekly blood samples and pre/post brain imaging will be collected to study biofluid and MRI measures for potential neuroplasticity. Linear mixed models will analyze the time and group effects. Discussion: This trial will assess whether HIIT can more effectively improve non-motor and motor symptoms in PD and MS than CAT or MA. A multimodal approach will explore both the clinical outcomes and underlying mechanisms, informing scalable and engaging rehabilitation strategies. Full article

Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration. Full article

Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood–brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy’s dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases. Full article

The aggregation of α-synuclein (αSyn) is a central feature of Parkinson’s disease (PD) and other synucleinopathies. The efficient clearance of αSyn depends largely on the autophagy–lysosomal pathway. Emerging genetic evidence highlights the role of pleckstrin homology and RUN domain-containing M1 protein (PLEKHM1), a critical regulator of autophagosome–lysosome fusion, in the pathogenesis of multiple neurodegenerative diseases. This study investigates the possible effects of increased PLEKHM1 expression on αSyn pathology and neurodegeneration in mice. We utilized a mouse model of PD that is based on A53T-αSyn overexpression, achieved by the stereotactic injection of recombinant adeno-associated viral vectors (rAAV) into the substantia nigra. Additionally, this study explores the effect of PLEKHM1 overexpression on the autophagy–lysosomal pathway under physiological conditions, using transgenic autophagy reporter mice. PLEKHM1 overexpression facilitated the αSyn-induced degeneration of dopaminergic somata in the substantia nigra and degeneration of dopaminergic axon terminals in the striatum. In concert with αSyn expression, PLEKHM1 also potentiated microglial activation. The extent of αSyn pathology, as reported by staining for phosphorylated αSyn, was not affected by PLEKHM1. Using RFP-EGFP-LC3 autophagy reporter mice, rAAV-mediated PLEKHM1 overexpression reduced lysosomal and autolysosomal area, increased LAMP1-LC3 colocalization, and decreased the autolysosome-to-autophagosome ratio. Concurrently, PLEKHM1 overexpression in both genotypes caused p62 accumulation, accompanied by reduced overlap with lysosomal and autophagosomal markers but increased colocalization with autolysosomal markers, indicating impaired cargo degradation during late-stage autophagy. Taken together, elevated PLEKHM1 levels exacerbate neurodegeneration in αSyn-overexpressing mice, possibly by impairing autophagic flux. Now, with in vivo evidence complementing genetic data, alterations in PLEKHM1 expression appear to compromise autophagy, potentially enhancing neuronal vulnerability to secondary insults like αSyn pathology. Full article

Iron is critical for brain development, metabolism, and function; however, dysregulated iron disposition contributes to neurological diseases. Many neuroimaging techniques have enabled detection of iron susceptibility, and quantitative susceptibility mapping (QSM) offers a sensitive magnetic resonance imaging (MRI) technique for quantifying brain iron. To elucidate the functional role of cerebral iron and clarify the utility of QSM in establishing iron as a potential biomarker, this review synthesizes cellular and regional behaviours of iron from physiological aging to disease conditions, with a focus on neurodegeneration such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), as well as cerebral small vessel disease (CSVD) as cerebrovascular manifestation. Distinct patterns of iron distribution in deep gray matter and selective cortical regions are associated with motor and cognitive impairment, while the interaction between iron, vascular integrity, and glial function further stresses its pathological relevance. QSM of iron may, thereby, serve as a marker to monitor iron-related disease progression and facilitate intervention. Temporal dynamics of iron in brain pathology remain underexplored, and we emphasized the need for longitudinal mapping and multi-modality biomarker integration. Establishing iron as a clinically relevant imaging biomarker requires continued investigation into its topographical, molecular, and functional correlates across aging and disease trajectories. Full article

Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD) diseases. And while all these diseases seem to have different genetic and environmental components, growing evidence shows that they share common underlying pathological features such as increased neuroinflammation and excessive oxidative stress. RAGE, the receptor for advanced glycation end-products, is a signal transduction receptor, and its activation triggers an increase in proinflammatory molecules, oxidative stressors, and cytokines. Diaph1, protein diaphanous homolog 1, is an actin modulator and an intracellular ligand of RAGE. Studies demonstrated that RAGE and Diaph1 act together, and their downstream signaling pathways play a role in neurodegeneration. Here, based on current evidence and our own research, we provide an overview of the RAGE–Diaph1 signaling and discuss the therapeutic potential of targeted therapy aimed at RAGE–Diaph1 signaling inhibition in the prevention and treatment of neurodegenerative diseases. Full article

Histone deacetylases (HDACs) are key epigenetic regulators that influence chromatin remodeling, gene expression, and cellular plasticity in the central nervous system (CNS). This review provides a comprehensive overview of the classification and functional diversity of HDACs, with particular emphasis on their roles in neural progenitor cells, mature neurons, and glial populations. In neural stem and progenitor cells, HDACs modulate neurogenesis, fate specification, and lineage commitment. In differentiated neurons, HDACs govern synaptic plasticity, memory formation, and survival. In glial cells, including astrocytes and microglia, HDACs orchestrate inflammatory responses, redox balance, and metabolic adaptations. We further examine the dysregulation of HDAC expression and activity in major neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Evidence from human post-mortem brain studies reveals region- and isoform-specific alterations in HDAC expression, which are closely associated with cognitive decline, mitochondrial dysfunction, and neuroinflammation. Preclinical studies support the use of HDAC inhibitors (HDACi) as neuroprotective agents, capable of restoring acetylation homeostasis, reducing neuroinflammation, and improving neuronal function. Given the relevance of HDACi, we summarize current clinical studies assessing the safety of these compounds in the context of tumor biology, as well as their potential future applications in neurodegenerative diseases. Together, this review underscores the dual significance of HDACs as biomarkers and therapeutic targets in the context of CNS disorders. Full article

Recent studies increasingly highlight the complex interaction between gut microbiota and mental health, drawing attention to the role of the microbiota–gut–brain axis (MGBA) in the pathophysiology of mental and neurodevelopmental disorders. Changes in the composition of the gut microbiota—dysbiosis—are associated with conditions such as depression, schizophrenia, bipolar disorder (BD), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and neurodegenerative diseases such as Parkinson’s and Alzheimer’s. These microbial imbalances can affect brain function through a variety of mechanisms, including activation of the immune system, alteration of intestinal permeability, modulation of the digestive and central nervous systems, and changes in the production of neuroactive metabolites such as short-chain fatty acids, serotonin, and tryptophan derivatives. The aim of this paper is to review the current state of knowledge on therapeutic strategies targeting the gut microbiome—including probiotics, prebiotics, synbiotics, personalized dietary interventions, and fecal microbiota transplantation (FMT)—which are becoming promising adjuncts or alternatives to conventional psychopharmacology, offering a forward-looking and individualized approach to mental health treatment. Understanding the bidirectional and multifactorial nature of MGBA may pave the way for new, integrative treatment paradigms in psychiatry and neurology, requiring further research and exploration of their scope of application. Full article

Parkinson’s disease (PD) is recognized as one of the most common neurodegenerative disorders globally. The primary factor contributing to this condition is the loss of dopaminergic neurons, which results in both motor and nonmotor symptoms. The etiology of neurodegeneration remains unclear. However, it is characterized by the elevated production of reactive oxygen species, which subsequently leads to oxidative stress, lipid peroxidation, mitochondrial dysfunction, and inflammation. The investigation of the applicability of natural compounds and their derivatives to various diseases is becoming increasingly important. The possible role of curcumin from Curcuma longa L. and its derivatives in the treatment of PD has been partially investigated, but there are no data on the action of synthetic cyclic C₅-curcuminoids and chalcones tested in a Parkinson’s model. Two chalcones and five synthetic cyclic C₅-curcuminoids with potential antioxidant properties were investigated in an in vitro model of 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in differentiated SH-SY5Y cells. Reactive oxygen species (ROS) production, total antioxidant capacity, antioxidant enzyme activity, thiol and ATP levels, caspase-3 activity, and cytokine release were examined after treatment with the test compounds. Based on these results, one cyclic chalcone (compound 5) and three synthetic cyclic C₅-curcuminoids (compounds 9, 12, and 13) decreased oxidative stress and apoptosis in our in vitro model of neurodegeneration. Compounds 5 and 9 were also successful in decreasing the production of pro-inflammatory cytokines (IL-6, IL-8, and TNF-α), while promoting the release of anti-inflammatory cytokines (IL-4 and IL-10). These findings indicate that these two compounds exhibit potential antioxidant, anti-apoptotic, and anti-inflammatory properties, rendering them promising candidates for drug development. Full article

Background: Although several epidemiological studies have suggested a potential association between infections and Parkinson’s disease (PD), relatively few have specifically examined the relationship between upper respiratory tract infections (URIs) and PD, apart from coronavirus disease 2019 (COVID-19). Objectives: We investigated whether a history of URI was associated with the diagnosis of PD among Korean individuals aged ≥40 years, using data from the Korean National Health Insurance Service–Health Screening Cohort. Methods: A total of 5844 patients newly diagnosed with PD were identified and matched with 23,376 control participants at a 1:4 ratio based on age, sex, income, and geographical region. Conditional logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for PD, adjusting for potential confounders including smoking, alcohol consumption, body mass index, blood pressure, comorbidity scores, blood glucose, and serum cholesterol levels. Results: Overall, no significant association was found between a history of URI and PD when considering a two-year exposure window. However, in the one-year window analysis, individuals with a history of URI had a modestly reduced odds of PD (≥1, ≥2, or ≥3 episodes: (adjusted OR: 0.93, 95% CI: 0.88–0.97, aOR: 0.91, 95% CI: 0.87–0.96 and aOR: 0.92, 95% CI: 0.87–0.98, respectively). Subgroup analyses revealed that the inverse association was more pronounced among women, older adults (≥65 years), and those with higher comorbidity scores. No clear dose–response trend was observed across increasing frequencies of URI diagnoses. Conclusions: Our findings suggest that the apparent protective association between recent URI history and PD is unlikely to be causal and may instead reflect confounding by medication use or reverse causation related to the prodromal phase of PD. These results should therefore be interpreted with caution and regarded as hypothesis-generating. Further prospective studies incorporating detailed prescription data and long-term follow-up are warranted to clarify the role of infections and anti-inflammatory medications in the pathogenesis of PD. Full article