Search Results (2,187)

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD’s, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies. Full article

Background/Objective: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive impairment, and psychiatric symptoms. As the disease progresses, weight loss, cachexia, and musculoskeletal atrophy are common, reducing quality of life, decreasing their autonomy in their activities of daily living (ADLs), and increasing morbidity and mortality risk. To describe and compare energy expenditure (EE) during ADLs and resting conditions in individuals with HD and healthy controls, and to examine its associations with quality of life, cognitive status, motor function, and functional capacity. Methods: A cross-sectional observational study was conducted with 16 people with manifest HD and 10 healthy controls. Participants completed five ADLs: resting, dressing, combing hair, feeding, and walking under laboratory conditions. EE during ADLs was measured using a portable indirect calorimetry system. Results: Statistically significant between-group differences in EE were found only during feeding, with individuals with HD showing higher EE than controls (p = 0.021). In the exploratory correlation analysis, cognitive status was significantly associated with EE during dressing (p = 0.033). Conclusions: This exploratory study contributes to the limited evidence on EE during ADLs in adults with HD. The findings suggest that individuals with HD may expend more energy than healthy controls during specific daily activities, particularly feeding. However, these results should be interpreted with caution due to the small sample size and preliminary nature of the study. Larger, multicenter, and longitudinal studies are needed to confirm these findings and determine their clinical relevance. Full article

Parkinson’s disease is a progressive neurodegenerative disorder characterized by motor impairments that significantly affect handwriting and fine motor control. Recent advances in artificial intelligence have enabled the non-invasive analysis of handwritten patterns as reliable digital biomarkers for early Parkinson’s disease detection. However, existing deep-learning approaches often struggle with diagnostic uncertainty and lack interpretability, limiting their clinical reliability and practical adoption. Moreover, models trained on single datasets frequently exhibit poor generalization across heterogeneous handwriting sources. This study uses two image-based handwriting datasets and one CSV-based HandPD feature dataset, including the Parkinson’s Augmented Handwriting Dataset, Parkinson’s Drawings Dataset, and HandPD Spiral/Meander feature records. A Transformer-based architecture is employed to learn global motor patterns from handwriting images, followed by a fuzzy-logic-based decision layer to handle uncertainty and improve robustness. The novelty of this work lies in integrating Transformer-driven deep feature learning with fuzzy clinical reasoning, supported by an AIC-based handcrafted feature analysis for interpretability. The model performance is evaluated using accuracy, precision, recall, F1-score, MCC, and AUC metrics. The experimental results demonstrate that the proposed Transformer–Fuzzy framework consistently outperforms CNN and Transformer-only baselines, achieving superior classification performance and robust generalization across all datasets, thereby establishing its effectiveness for reliable and interpretable Parkinson’s disease screening. Full article

Understanding how brain activity varies across neurological and neurodevelopmental disorders requires tools capable of revealing patterns hidden in complex electroencephalographic (EEG) data. Conditions such as epilepsy, Alzheimer’s disease, dementia, and autism exhibit distinct alterations in neural oscillations and connectivity, which remain difficult to interpret in real time; therefore, this study proposes an interactive interface for intuitive exploration and analysis of disease-specific EEG dynamics. The system integrates classical signal processing techniques and computational modeling to extract spectral features, inter-electrode coherence, and spatial activation patterns, which are visualized through spectrograms, topographic maps, and connectivity graphs that update continuously. In addition, a web-based platform is incorporated to enable clinicians and technicians to store and manage patient information, including diagnosis, severity level, number of recordings, sampling frequency, recording duration, and acquisition dates, supporting structured data organization and longitudinal monitoring. The results demonstrate that the interface captures meaningful differences between disorders, with epileptic patterns showing strong synchronization and burst activity, while neurodegenerative conditions exhibit spectral slowing and reduced connectivity. Overall, the proposed framework provides an effective and accessible tool for EEG visualization, combining interactive analysis with clinical data management to support research, education, and potential clinical applications. Full article

Papaver nudicaule L. is a medicinal plant traditionally used in Asian ethnomedicine, yet its phytochemical composition and biological activity remain insufficiently explored. This study bridges phytochemistry and neuroactive potential. It includes metabolite profiling with bioactivity-guided fractionation, performed to evaluate its potential as a source of acetylcholinesterase (AChE) inhibitors. The methanolic extract of the aerial parts was analysed using HPLC–ESI–QTOF-MS/MS, which enabled the tentative identification of 34 compounds, predominantly isoquinoline alkaloids and flavonoid derivatives. The extract was subsequently fractionated by centrifugal partition chromatography (CPC) using an optimised biphasic solvent system, yielding fractions enriched in alkaloid constituents. The obtained fractions were evaluated for AChE inhibitory activity, revealing significantly higher activity than that of the crude extract. The most active fractions exhibited marked inhibition based on the comparison with the reference compound berberine, indicating effective enrichment of bioactive metabolites. Further analysis demonstrated that the activity of the most potent fraction was associated with the presence of amurensinine, which was purified by preparative HPLC and subsequently identified by NMR and LC-MS. The Papaver nudicaule extract showed no significant cytotoxicity toward SH-SY5Y neuronal cells up to 200 µg/mL, whereas the amurensinine-containing fraction reduced cell viability only at higher concentrations (≥100 µg/mL). Notably, when expressed in the micromolar range, this effect corresponds to relatively weak cytotoxicity, suggesting a potential safety margin at lower, biologically relevant concentrations. These findings demonstrate that P. nudicaule possesses a highly diverse alkaloid profile and represents a promising natural source of compounds with potential relevance for the development of agents targeting neurodegenerative disorders. Full article

The glymphatic system has been proposed as a brain-wide pathway that promotes the exchange between cerebrospinal and interstitial fluids and facilitates the clearance of metabolic waste products, including amyloid-β and tau proteins. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) has emerged as a non-invasive magnetic resonance imaging technique proposed to indirectly assess glymphatic-related fluid dynamics. This systematic review evaluated the methodological consistency and clinical applicability of the ALPS index in neurodegenerative diseases. A structured search of PubMed (MEDLINE) and Web of Science identified human studies published up to January 2026 investigating DTI-ALPS in neurodegenerative conditions. Data regarding study populations, MRI acquisition parameters, image-processing methods, statistical approaches, and clinical associations were extracted and synthesized. Ten studies met the inclusion criteria. Across studies, lower ALPS index values were generally associated with cognitive impairment, amyloid burden, and disease severity, particularly in Alzheimer’s disease. Several studies incorporated multimodal biomarkers, including amyloid positron emission tomography and cerebrospinal fluid markers, thereby improving the biological interpretation of DTI-ALPS findings. However, substantial methodological heterogeneity was identified across studies, including variability in region-of-interest placement, diffusion acquisition protocols, and image-processing pipelines. Furthermore, the interpretation of diffusivity metrics as direct measures of glymphatic flow remains controversial. Current evidence suggests that DTI-ALPS may represent a promising non-invasive imaging marker of glymphatic-related alterations; however, its biological specificity and clinical applicability remain insufficiently established. Standardized acquisition protocols, harmonized analytical pipelines, and longitudinal multicenter studies are required to clarify its role in neurodegenerative disease research. Full article

Background/Objectives: Constructional apraxia (CA) is an impairment in combining simple elements into coherent spatial configurations without basic motor deficits. Although common in neurodegenerative disorders, the qualitative features of visuo-constructional errors and their role in differentiating dementia types remain unclear. This systematic review aimed to synthesize patterns of visuo-constructional errors in dementia and mild cognitive impairment (MCI), exploring distinctive qualitative features associated with different neurodegenerative conditions. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 1990 and January 2026, following PRISMA guidelines. Studies on adults with dementia or MCI assessing drawing/copying abilities through standardized tasks and qualitative error analysis were included. Reviews, meta-analyses, case reports, non-English articles, and studies not explicitly assessing constructional apraxia were excluded. The quality of evidence was assessed using an adapted version of the Newcastle–Ottawa Scale. Results: A total of 25 studies were included, showing heterogeneous and condition-specific visuo-constructional deficits. Spatial errors and simplifications were the most common across disorders, while perseverations, rotations, and closing-in phenomena were less frequent. Alzheimer’s disease was mainly associated with spatial disorganization, omissions, and conceptual errors linked to temporo-parietal dysfunction; frontotemporal dementia with executive deficits such as perseverations and planning impairments; Lewy body and Parkinson’s disease dementias with visuospatial and attentional alterations; and Huntington’s disease with simplifications and executive dysfunction related to fronto-striatal involvement. Conclusions: No single error pattern was pathognomonic, but qualitative assessment of constructional errors may provide clinically useful information when integrated with the broader neuropsychological profile. Full article

Background/Objectives. Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuron loss, α-synuclein pathology, neuroinflammation, and cognitive decline. Synaptamide (N-Docosahexaenoylethanolamine (DHEA)) is an endogenous lipid mediator with documented anti-inflammatory and neurogenic properties, but its effects in PD models remain unexplored. This study aimed to evaluate the neuroprotective potential of synaptamide in a subchronic MPTP-induced mouse model of PD. Methods. Male C57BL/6 mice received MPTP (30 mg/kg/day, i.p., 5 days) with or without synaptamide (10 mg/kg/day, s.c., 13 days). Behavioral tests (open field, Y-maze, elevated plus maze, novel object recognition (NOR)) were performed, followed by immunohistochemical analysis of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, and Western blotting for α-synuclein, p-α-synuclein, TH, and IL1β in brain homogenates and serum. In vitro Neuro-2a cells were co-treated with MPP⁺ (100 µM) and synaptamide (0.1–10 µM) for cytotoxicity assessment (MTS assay). Results. Synaptamide (10 µM) significantly attenuated MPP⁺-induced cytotoxicity in Neuro-2a cells. In vivo, MPTP caused a marked loss of TH⁺-neurons in the substantia nigra, which was prevented by synaptamide treatment. Importantly, this subchronic MPTP model recapitulates early biochemical alterations (e.g., α-synuclein phosphorylation at Ser129) rather than mature Lewy body pathology, a limitation that should be considered when interpreting these findings. Although no motor deficits or anxiety-like behavior were observed, the NOR test revealed MPTP-induced long-term memory impairment, which was fully restored by synaptamide. Conclusions. These findings suggest that synaptamide may exert effects on pathological processes associated with PD, warranting further investigation into its potential role in combination or supportive therapy for this disease. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and a breakdown of mitochondrial homeostasis. Vitamin K2 (VK2) has emerged as a potential neuroprotective agent, yet the specific molecular cascades linking its intervention to the restoration of mitochondrial integrity remain poorly understood. This study utilizes an AD Drosophila model to investigate the efficacy of VK2 and elucidates its multidimensional regulatory mechanisms. Behavioral analysis showed that VK2 significantly rescued locomotor impairments, improving both vertical climbing and horizontal walking performance. Crucially, VK2 intervention achieved a systemic rescue of mitochondrial health: transmission electron microscopy (TEM) confirmed the preservation of mitochondrial ultrastructure and cristae density, while biochemical assays demonstrated a robust recovery of bioenergetic markers, including ATP levels and the NAD⁺/NADH ratio. Furthermore, VK2 treatment stabilized the mitochondrial membrane potential (MMP) and effectively attenuated the accumulation of reactive oxygen species (ROS). To identify the molecular drivers of this recovery, an unbiased integration of human clinical transcriptomic data and network pharmacology prioritized the EGFR-Ras-ERK signaling axis as a central hub. In vivo validation confirmed that VK2 suppresses the pathological overactivation of this cascade. VK2 reduced EGFR phosphorylation in parallel with the effects observed for the EGFR inhibitor Gefitinib. Collectively, our findings show that VK2 ameliorates locomotor deficits and mitochondrial dysfunction in Aβ42-expressing flies and that these effects are associated with suppression of the EGFR-Ras-ERK signaling axis. Further studies are required to establish direct target engagement and pathway causality. Full article

Positron emission tomography (PET) of muscarinic acetylcholine receptors has evolved from a receptor-mapping exercise into a potential translational tool for probing cholinergic dysfunction in neurodegenerative disease. However, the field still lacks a clear hierarchy of clinical value across receptor subtypes, tracers, and quantitative analysis strategies, including acquisition protocols and kinetic modeling approaches. In the M₂ arena, [¹⁸F]FP-TZTP has been associated with higher distribution volumes in older APOE-ε4 carriers, but the biological meaning of this signal remains uncertain in the absence of longitudinal conversion data and with quantification approaches that are difficult to implement routinely. Among M₄ ligands, [¹¹C]MK-6884 is the most advanced and reproducible tracer to date, yet its clinical evidence still rests on proof-of-concept studies, mainly in moderate-to-severe Alzheimer’s disease, with important methodological limitations. In our view, muscarinic PET should now be reframed less as a stand-alone diagnostic biomarker and more as a platform for mechanistic and pharmacodynamic studies, especially for the development and monitoring of muscarinic-positive allosteric modulators. Future progress will depend on longitudinal multicenter validation, simplified quantification pipelines, and next-generation PET systems capable of capturing tracer kinetics more efficiently. Full article

Hydroperoxides (R–OOH, organic hydroperoxides) constitute a relatively small but structurally diverse class of natural metabolites occurring in higher plants, fungi, and marine organisms. Their formation is closely associated with oxidative processes involving redox-active metal ions, particularly iron and copper, which promote reactive oxygen species (ROS) generation and the oxidative transformation of steroids and triterpenoids. In the present study, approximately 1500 naturally occurring steroids and triterpenoids were screened using the PASS (Prediction of Activity Spectra for Substances) platform to identify compounds with potential relevance to neurodegenerative disorders. Among the analyzed compounds, only 17 hydroperoxide-containing steroids and triterpenoids exhibited notable predicted anti-dementia activity and were selected for detailed evaluation. The selected compounds displayed a broad spectrum of predicted biological activities, including antineoplastic, anti-inflammatory, antiulcerative, antithrombotic, hepatoprotective, and neuroprotective effects. Several hydroperoxide-containing triterpenoids demonstrated particularly high predicted anti-dementia activity, with a norlupane-type hydroperoxide exhibiting the highest probability of activity (Pa = 0.972). The biological significance of these compounds may be related to the unique redox properties of the hydroperoxide functionality, which can participate in both oxidative and adaptive signaling processes. Because hydroperoxides interact with transition metal ions and reactive oxygen species, they occupy a complex position at the interface between oxidative stress, cellular defense mechanisms, and neurodegeneration. The present analysis highlights hydroperoxide-containing steroids and triterpenoids as an underexplored class of natural products with potential relevance to dementia research. However, the reported activities are based primarily on computational predictions and should be interpreted as indicators of pharmacological potential rather than experimentally validated therapeutic effects. Further investigations involving blood–brain barrier permeability assessment, biochemical studies, cellular assays, animal models, and clinical evaluation will be required to determine the true therapeutic value of these compounds in neurodegenerative diseases. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor control, balance, and gait impairments that significantly elevate fall risk. Traditional gait analysis focuses on spatiotemporal parameters, while gait variability, asymmetry, and balance measures offer more sensitive indicators of PD-related motor deficits. Machine learning studies using wearable gait data frequently report high classification accuracy but lack biomechanical interpretability and methodological rigor. Using the PhysioNet Gait in Parkinson’s Disease database, 93 individuals with PD and 72 healthy controls were analyzed during level-ground walking. Key biomechanical differences were identified: stride time coefficient of variation was significantly higher in PD bilaterally (left p = 0.001; right p = 0.003); swing-phase time was significantly reduced in both limbs (left p = 0.003; right p = 0.001); anterior–posterior center of pressure (COP) variability was significantly lower in PD for both limbs (p < 0.001); and COP path symmetry index was the most prominent asymmetry marker, significantly elevated in PD relative to controls (p = 0.003). A machine-learning analysis pipeline identified HistGradientBoosting as the best-performing classifier (AUC = 0.992; accuracy = 97.6%), but leave-one-study-out evaluation exposed substantial cross-protocol heterogeneity (AUC: 0.500–1.000), indicating that the model relied partly on dataset-specific patterns and may not generalize to independent acquisition protocols. Shapley Additive Explanations (SHAP) analysis showed classification was driven by a multimodal combination of clinical severity measures and biomechanical gait features rather than wearable metrics alone. A pre-specified gait-only sensitivity analysis that excluded clinical severity variables (UPDRS, UPDRSM, Hoehn and Yahr) confirmed that biomechanical features alone retained moderate, but substantially reduced, discriminative ability (gait-only holdout AUC = 0.844), supporting the interpretation that the headline performance reflects multimodal clinical separation rather than a stand-alone wearable-gait biomarker. These findings indicate that Parkinsonian gait impairment is characterized by timing instability and constrained forward COP progression. The combination of biomechanical analysis with interpretable predictive modeling represents a structured analysis pipeline for gait-based PD assessment; however, external validation in independent cohorts and prospective testing across acquisition protocols are required before such a pipeline can be deployed as a clinically generalizable digital biomarker. Full article

Neuroinflammation is a key hallmark of both neurodegenerative and neurospecific autoimmune diseases, including multiple sclerosis (MS), where immune dysregulation contributes to cellular stress, autophagy, and disease progression in Alzheimer’s disease (AD), Parkinson’s disease (PD), and MS. Emerging evidence suggests a shared mechanism behind MS, AD, and PD, driven by chronic interaction between the peripheral immune system and the central nervous system (CNS). While MS was traditionally viewed as a primary autoimmune condition, recent research indicated that all three disorders involve a breakdown of the blood–brain barrier (BBB). This structural failure enables peripheral immune cells and cytokines to enter the brain, causing sustained neuroinflammation and accelerating disease progression. Here, we propose an end-to-end framework for identification of the diagnostic and therapeutic cell-specific protein markers commonly regulated in mild–moderate AD (MMAD), early-stage PD (ESPD), and MS within peripheral blood mononuclear cells (PBMCs). PBMC markers were first identified based on shared differential protein expression, followed by filtering for BBB permeability. Subsequently, sorted cell markers were mapped to disease-specific neural cell types. Our analysis suggests that PBMC-derived cells, including astrocyte- and monocyte-like populations, share overlapping transcriptional signatures and functional similarity with macrophages and neuroglial cells, indicating potential transcriptional similarity or functional convergence. Furthermore, intra- and inter-cellular pathway analysis suggested both shared and disease-specific signaling mechanisms, with kinase–integrin interactions emerging as key regulatory factors. Selected potential seed markers, primarily kinases and immunoglobulins, were further analyzed through evolutionary sequence–structure space to identify druggable structural features. Next, protein moonlighting possibilities were tested to enhance the temporal functional trajectory of the markers for precise therapeutic impact. Hence, the framework provides a robust strategy to identify immune-based disease-specificcandidate diagnostic andpotential therapeutic targets. Full article

Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer’s disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders. Full article

Background: Chronic pain and early cognitive vulnerability frequently co-occur in older women and may share inflammatory mechanisms. Objective: We examined whether dietary inflammatory load, assessed using the dietary inflammatory index (DII), and Mediterranean-derived dietary patterns (Mediterranean diet (MED), Dietary Approaches to Stop Hypertension (DASH), Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) and anti-inflammatory Mediterranean Diet (AnMED)) are associated with pain and early cognitive outcomes. Methods: We conducted a cross-sectional study among women aged ≥50 years recruited from community pharmacies and healthcare centers in the Comunidad Valenciana (Spain). Dietary intake was assessed using the PREDIMED Food Frequency Questionnaire to derive DII and dietary pattern scores. Outcomes included pain intensity, subjective memory complaints (SMC) and semantic verbal fluency (SVF). Analyses were adjusted for sociodemographic, clinical and lifestyle covariates, with false discovery rate correction. Results: Complete case samples comprised 470 women for SMC and SVF, with 328 also included for pain. Higher DII was consistently associated with greater pain intensity, increased odds of SMC, and lower SVF scores. No dietary pattern was associated with pain after correction. AnMED was associated with lower odds of SMC and higher SVF, while DASH was also positively associated with SVF. Bridge analysis showed that lower DII was associated with both MIND and AnMED, with a stronger association for AnMED. Conclusions: Dietary inflammatory load showed the most consistent associations with pain and early cognitive vulnerability, whereas Mediterranean-derived patterns differed in their inflammatory and cognitive relevance. Full article