Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder, yet it remains unclear whether cortical architecture can reveal biologically distinct subtypes with distinct molecular and serum biomarker signatures. Two hundred PD patients and 121 healthy controls underwent structural MRI. Subject-specific cortical similarity networks were constructed using Morphometric INverse Divergence (MIND), and subtypes were identified with HYDRA. Spatial patterns were linked to regional gene expression from the Allen Human Brain Atlas through partial least squares regression, followed by functional and cell-type enrichment analyses. Serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified using single-molecule array assays. No significant MIND differences emerged when PD patients were analysed as a single group. HYDRA identified two subtypes (ARI = 0.85) with divergent cortical organization that only partially overlapped with conventional motor phenotypes. Cluster 1 exhibited temporo-parietal MIND increases associated with synaptic and oligodendroglial signatures, without serum biomarker associations. Cluster 2 showed widespread fronto-cingulate MIND reductions enriched for mitochondrial, lysosomal, and proteostatic pathways, including the KEGG Parkinson's disease pathway, and these reductions correlated with higher serum NfL and GFAP. These findings reveal two biologically distinct PD subtypes with divergent molecular architecture and systemic neurodegeneration beyond conventional motor phenotyping.
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The epidermal growth factor receptor (EGFR; ErbB1/HER1) is a receptor tyrosine kinase that regulates cell proliferation, survival, differentiation, and tissue repair. In the nervous system, EGFR is expressed in neural progenitors, astrocytes, oligodendrocyte precursor cells, and neuronal populations, where its functions are context dependent. EGFR signaling contributes to neural regeneration by promoting progenitor proliferation, neuronal survival, neurogenesis, and remyelination following injury. However, sustained or excessive EGFR activation can drive reactive astrogliosis, neuroinflammation, glial scar formation, and neurotoxicity. Emerging evidence suggests that transient, regulated EGFR activation supports neural repair, whereas chronic or dysregulated signaling may contribute to neurodegeneration. These apparently opposing effects likely reflect differences in timing, duration, cellular context, ligand availability, and downstream signaling pathways engaged by EGFR activation, rather than inherently contradictory biological functions. In experimental models of Parkinson's disease, Alzheimer's disease, and Multiple sclerosis-like conditions, EGFR modulation has shown therapeutic potential, although the mechanisms remain incompletely understood. While EGFR ligands often exert neurotrophic and pro-remyelinating effects, disease-associated EGFR activation may promote maladaptive signaling pathways. In this review, we summarize current knowledge of EGFR signaling in neural repair and neurodegenerative diseases, discuss the context-dependent roles of this pathway, and highlight therapeutic strategies. We further propose a conceptual framework in which EGFR functions as a context-dependent signaling hub, with its outcomes determined by the spatiotemporal regulation of receptor activation. Although challenges remain, including optimal timing, dosing, and safety considerations, preclinical evidence suggests that modulation of EGFR signaling may be a therapeutic approach to promote neural repair while limiting neurodegenerative pathology.
Dietary patterns increasingly influence research on neurodegenerative diseases, with attention shifting from isolated nutrients to integrative nutritional models. The Amazonian Diet, a biodiversity-based dietary pattern rich in native fruits, seeds, freshwater fish, and cassava-derived foods, is naturally enriched in bioactive compounds including polyphenols, anthocyanins, carotenoids, methylxanthines, selenium, vitamins, and unsaturated fatty acids. This review aimed to investigate the potential relevance of key foods derived from the Amazonian Diet to Parkinson's disease (PD) by integrating compositional nutritional analysis, multivariate analytical approaches, and mechanistic evidence synthesis. In Stage 1, the composition of 36 Amazonian foods was analyzed using TBCA and FAO data, followed by hierarchical clustering analysis (Ward's linkage, Euclidean distance). Distinct compositional patterns were identified, highlighting foods with high bioactive diversity, relevant lipid composition, and dietary fiber. In Stage 2, an integrative literature review (PubMed/MEDLINE, SciELO) of in vitro, in vivo, observational, and clinical studies suggested that açaí berry, guaraná, cocoa/cacao, camu-camu, and Brazil nuts contain nutrients and bioactive compounds that intersect with biological pathways implicated in PD, including oxidative stress, mitochondrial dysfunction, and neuroinflammation. However, this review does not evaluate the effects of the Amazonian Diet on PD incidence, progression, symptoms, levodopa response, or biomarkers.
Parkinson's disease (PD) is characterised by the pathological aggregation of α-synuclein (α-syn) into Lewy body inclusions, yet no disease-modifying therapy exists. To address this, we developed an integrated computational pipeline combining quantitative structure-activity relationship (QSAR) modelling, structure-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations to repurpose FDA-approved drugs as α-syn fibril inhibitors. Two complementary QSAR model families were trained on 501 α-syn binding affinity records from BindingDB: Morgan extended-connectivity fingerprint (ECFP4) classifiers and a frozen ChemBERTa-77M-MLM transformer encoder, each using Random Forest and Logistic Regression. The applicability domain (AD) was assessed using Morgan-Tanimoto similarity (Tc ≥ 0.40) and calibrated ChemBERTa cosine distance (θ ≤ 0.367). A three-stage funnel applying central nervous system (CNS) permeability filters, a consensus QSAR probability threshold (≥0.80), and AD gating reduced 2241 FDA-approved drugs to 205 candidates for AutoDock Vina 1.2.6 docking against two sites on the cryo-electron microscopy (cryo-EM) α-syn fibril structure, PDB 6SSX: the inter-protofilament cleft (Site 1) and the non-amyloid-beta component (NAC) groove (Site 2). The Morgan fingerprint models achieved an area under the receiver operating characteristic curve (AUROC) of up to 0.940 and a balanced accuracy of 0.810; the ChemBERTa models achieved an AUROC of 0.785 and a balanced accuracy of 0.728. Notably, ChemBERTa AD covered 76.8% of the FDA drugs versus only 5.5% for Morgan-Tanimoto, enabling broad-spectrum screening. The top docking candidates were Olaparib (-7.91 kcal/mol), Paliperidone (-7.75 kcal/mol), Niraparib (-7.18 kcal/mol), Dordaviprone (-7.06 kcal/mol), and Parecoxib (-6.89 kcal/mol). The MD simulations over 200 ns across three independent replicates confirmed stable NAC groove binding, and replicate-averaged MM-PBSA calculations yielded ΔG = -20.6 ± 1.9 kcal/mol for Olaparib at Site 2, -17.1 ± 0.9 kcal/mol for Risperidone, and -16.9 ± 0.8 kcal/mol for Paliperidone, reported as the mean ± standard error of the mean (SEM) across replicates. Olaparib additionally formed five hydrogen bonds in the representative pose, while MD trajectories maintained approximately 2-5 hydrogen bonds, together with a halogen bond within the NAC groove, the largest contact count of any screened compound. These findings identify Olaparib as a novel high-affinity repurposing lead, while Paliperidone and Risperidone are reported as chemically informative secondary NAC-groove binders rather than proposed antiparkinsonian therapeutics, given that their dopamine D2-antagonist pharmacology is clinically associated with drug-induced parkinsonism. All of the candidates warrant experimental validation via thioflavin-T fluorescence or nuclear magnetic resonance (NMR) spectroscopy.
The increased activity of δ-aminolevulinic acid synthase-1 (ALAS1) leads to the accumulation of δ-aminolevulinic acid (ALA), which may reduce the iron(III) retention ability of ferritin, resulting in iron(III) overload. The accumulation of ALA occurs in the condition of attenuation of the heme negative feedback loop over ALAS1 activity in concert with the induction of ALAS1 expression. Attenuation of the heme negative feedback loop is maintained by elevated quantities of the heme catabolizing enzyme, heme oxygenase-1 (HO-1), which, in turn, may be induced by highly increased heme concentration. The upregulation of brain HO-1 occurs in patients with Alzheimer's and Parkinson's diseases. A mouse with overexpressed human HMOX1 is a model of schizophrenia with concurrent iron overload. HO-1 inhibitors reduce oxidative damage to whole cells and mitochondrial compartments of rat astrocytes transfected with the HMOX1 gene. Iron reduction within the heme prosthetic moiety of P450 cytochromes in microsomes is facilitated by NADPH-cytochrome P450 oxidoreductase (CPR), while adrenodoxin reductase performs this function in the mitochondria. In partial CPR-deficient conditions, the half-life of apocytochromes is prolonged while HO-1 is induced due to the elevated heme release from unreduced cytochromes. This study posits that, before being degraded by HO-1, the released hemin triggers the oligomerization of cytochromes, as well as other oxidative damages, by producing hydroperoxyl radicals from hydrogen peroxide produced in uncoupling reaction. After reaching a specific level, iron(III) overload may trigger the saturation of CPR, resulting in the development of neuropathologies.
The perivascular and neurofluid-related tissue environment is implicated in neurodegeneration, but its clinical relevance in spinocerebellar ataxia type 3 (SCA3) remains unclear. We investigated alterations in diffusion tensor image analysis along the perivascular space (DTI-ALPS) across disease stages, and its longitudinal associations with clinical progression and brain atrophy. We included 129 SCA3 (44 preclinical, 85 ataxic) at baseline, 51 with longitudinal follow-up, and 78 controls. Cross-sectional, longitudinal, and structural equation modeling (SEM) analyses examined group differences, clinical correlates, progression, associations with regional brain volumes, and relationships among age, genetic burden, DTI-ALPS index, brainstem volume, and severity. DTI-ALPS index was reduced in SCA3 and showed stage-dependent pattern. Ataxic SCA3 exhibited lower DTI-ALPS index than preclinical SCA3 and controls, whereas preclinical SCA3 did not differ from controls. Lower DTI-ALPS index was associated with greater clinical severity (r = -0.208, p < 0.05) and reduced volumes of the brainstem, thalamus, hippocampus, caudate, amygdala, pallidum, and putamen (p < 0.05). SEM showed that lower DTI-ALPS index was associated with greater clinical severity (β = -0.151, p < 0.05) and reduced brainstem volume (β = 0.160, p < 0.05). Longitudinally, lower baseline DTI-ALPS index was associated with faster clinical progression (β = -2.59, p < 0.01). Reduced DTI-ALPS index emerged predominantly during SCA3 symptomatic stage and was associated with greater severity, brainstem atrophy, and faster longitudinal disease progression. These findings supported DTI-ALPS index as a promising imaging marker for characterizing disease-related tissue environment changes and providing adjunctive prognostic information in SCA3.
Blood flow restriction (BFR) training induces beneficial adaptations at low exercise intensities. However, studies on its effects during walking exercise in individuals with Parkinson's disease (PD) remain limited. Twenty-four individuals with PD (Hoehn and Yahr stages 2-3) were randomly assigned to a walking exercise (WALK, n = 8), walking with BFR (WALK-BFR, n = 8), or control group (CON, n = 8). Both exercise groups performed supervised training twice weekly for 8 weeks; the WALK-BFR group was trained with BFR applied at 40-60% of the arterial occlusion pressure. The outcomes included vascular, neurotrophic, functional, and quality-of-life parameters. Exercise-related adverse events were recorded. The WALK group did not show significant improvements in brain-derived neurotrophic factor (BDNF), flow-mediated dilation (FMD), brachial-ankle pulse wave velocity (baPWV), Five Times Sit-to-Stand Test, Timed Up and Go Test (TUGT), or 10-Meter Walk Test (10MWT) [all p > 0.05]. Although total Unified Parkinson's Disease Rating Scale (UPDRS) scores decreased in the WALK group, a similar reduction was observed in the CON group, with the only distinct improvement observed in UPDRS Part I. In contrast, WALK-BFR demonstrated significant improvements in BDNF and FMD (both p < 0.05), as well as functional performance (TUGT and 10MWT), quality of life (PDQ-8), and total UPDRS scores, with additional reductions in UPDRS Parts II-IV. However, baPWV did not significantly change in any group (p > 0.05). Both interventions were well tolerated, with a similar incidence of mild and transient lower-extremity muscle soreness in WALK and WALK-BFR groups. WALK-BFR was associated with concurrent improvements in neurotrophic, vascular, and functional outcomes and quality of life in individuals with PD. Furthermore, the intervention was well tolerated and may represent a feasible rehabilitation strategy.
Dementia with Lewy Bodies (DLB) is the most common neurodegenerative dementia after Alzheimer's disease (AD), but it remains challenging to diagnose due to overlapping symptoms and mixed pathologies. This pilot study tested whether DLB has different metabolic blood proteomic profiles compared to AD and controls. Serum was analysed from people with DLB (n = 20), a group with AD (either with Alzheimer's disease dementia or Mild Cognitive Impairment with a positive amyloid positron emission tomography scan (MCI+/AD) (n = 15), and similarly aged controls (n = 15) using the Olink Metabolism panel encompassing 92 proteins. Six proteins (PILRB, LRIG1, NECTIN2, TINAGL1, SSC4D, and FKBP4) were significantly different in DLB compared with the controls, and one protein (SERPINB8) was differentially expressed when compared with MCI+/AD. Receiver operating characteristic curves for biologically relevant proteins that have previously established roles in neurodegenerative and cognitive properties showed that RNASE3 levels could differentiate DLB from MCI+/AD (area under the curve (AUC) = 0.717, sensitivity = 0.850, and specificity = 0.600). A multimarker model incorporating RNASE3 with phosphorylated tau 217 (pTau217) and polygenic risk scores for LBD achieved improved accuracy in discriminating DLB from MCI+/AD (AUC = 0.963, sensitivity = 1.000, and specificity = 0.900). Pathway analyses revealed dysregulation in cortisol signalling, inflammation resolution, and ErbB4-mediated neuroplasticity, which point towards peripheral protein alterations related to the adaptation to stress, immune regulation, and synaptic integrity in DLB. The present exploratory study highlights potential pathophysiological mechanisms implicated in DLB, suggesting that a multimodal biomarker panel may perform better compared to single proteins. Considering the small sample sizes, the findings will need to be replicated in larger cohorts.
Family proteins - α-, β, γ-synucleins shown to play important roles in metabolism, signal transduction and dopamine handling. Aggregated α-synuclein is neurotoxic and involved in pathogenesis of Parkinson's disease. The mechanism toxicity of aggregated α-synuclein includes lipid peroxidation, oxidative stress and ferroptosis but effect of monomeric synucleins on the basal lipid peroxidation is unclear. Using acute brain slices and primary cortical co-culture of neurons and astrocytes from α-, β- and γ-synuclein deficient mice and live cell imaging we studied how lack of synucleins changes the rate of lipid peroxidation and level of reduced glutathione (GSH) in basal conditions and under dopamine treatment. We have found that lack of synucleins leads to significant reduction in the basal rate of lipid peroxidation and dopamine-induced further decrease of lipid peroxidation in these brain slices. The level of GSH in neurons and astrocytes with synuclein deficiency was higher or similar to wild type cells, the level of NADPH and rate of NADH production also were unchanged. Thus, synuclein deficiency induces alteration of process of lipid peroxidation in brain cells independently of oxidative stress.
Objectives: Accurate severity classification is important for sensor-based assessment of Parkinson's disease, but overlap between adjacent stages and class imbalance can reduce model robustness. This study aimed to develop and evaluate a dual-task gait fusion framework that integrates signals collected during self-selected walking and walking with turning. Methods: The primary cohort comprised 87 participants with Parkinson's disease across mild, mild-to-moderate, and moderate stages. Task-specific temporal representations were learned from the two gait conditions, concatenated and optimized using delayed class re-weighting. Performance was evaluated using subject-level stratified five-fold cross-validation with five random seeds. Generalizability was further assessed using an independent PhysioNet cohort of 93 participants with Parkinson's disease. Results: The proposed method achieved an accuracy of 90.23 ± 1.27, balanced accuracy of 89.61 ± 1.13, macro F1-score of 89.10 ± 1.35, and probability-based macro AUC of 94.43 ± 1.42 on WearGait-PD. Confusion matrix and ablation analyses indicated balanced class-level performance and complementary contributions from dual-task fusion and delayed re-weighting. On the external PhysioNet cohort, accuracy, balanced accuracy, macro F1-score, and macro AUC were 84.34 ± 1.82, 82.13 ± 1.92, 81.68 ± 1.98, and 88.93 ± 2.14, respectively. Conclusions: Integrating turning-related gait information with self-selected walking signals improved wearable sensor-based severity classification and showed cross-dataset robustness, although validation in larger cohorts with complete severity stage coverage remains necessary.
Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is characterized by progressive loss of dopaminergic neurons in the substantia nigra. Although the molecular mechanisms of PD remain incompletely understood, mitochondrial dysfunction has emerged as a central pathological driver, highlighting the urgent need for therapies targeting mitochondrial homeostasis. In this study, we demonstrate that rhynchophylline (Rhy), a bioactive alkaloid from Uncaria species, exerts neuroprotective effects by restoring mitochondrial dynamics. Thermal proteome profiling identified dihydrolipoamide acetyltransferase (DLAT) as a direct target of Rhy. Genetic ablation of DLAT induced mitochondrial fragmentation and abolished Rhy-mediated beneficial effects on mitochondrial structure and function. Mechanically, Rhy binds to the N-terminal lipoyl domain of DLAT, allosterically disrupting its interaction with sirtuin 4 (SIRT4) and subsequently enhancing DLAT lipoylation, a critical post-translational modification for mitochondrial energy metabolism. In vivo, Rhy administration ameliorated motor deficits and dopaminergic neurodegeneration in both the 6-OHDA-induced and A53T α-synuclein transgenic PD mouse models. Single-nucleus RNA sequencing further highlighted the clinical relevance of DLAT dysregulation in PD. Collectively, our findings establish Rhy as a promising PD therapeutic candidate and delineate DLAT as a pivotal node in therapeutic targets by promoting mitochondrial fusion and bioenergetics, offering a novel mechanistic avenue for neuroprotection.
Neurological and neuro-oncological brain disorders like Alzheimer's disease (AD), Parkinson's disease (PD), and brain tumors are challenging to diagnose due to overlapping symptoms and the limitations of conventional imaging techniques. Magnetic resonance imaging (MRI) with convolutional neural networks (CNNs) has emerged as a powerful approach, enabling automated and high-precision detection and staging. This review critically integrates recent developments in CNN architectures, such as hybrid models, attention mechanisms, and 3D CNNs for MRI-based diagnosis of these disorders. It further examines preprocessing methods, datasets, and performance metrics across studies, with emphasis on innovations such as transformer-based models and lightweight architectures. While CNNs show impressive accuracy, issues remain in generalizability, interpretability, and clinical integration. This review highlights the need for multimodal data fusion, explainable artificial intelligence, and real-world validation to narrow the gap between research and clinical practice. By defining future directions, this review aims to guide the development of robust, scalable neurodiagnostic systems for early intervention and better patient outcomes.
Parkinson's disease (PD) is a progressive neurodegenerative disorder in which early gastrointestinal dysfunction and oxidative stress are increasingly implicated through the gut-brain axis. Zebrafish (Danio rerio) offer a tractable model for PD research; However, to our knowledge, there is currently no consensus on the rotenone concentration that effectively mimics both brain and gut pathology, leaving the dose required to induce integrated central-peripheral pathology unresolved. Adult zebrafish were exposed to 2.5 or 5µg/L rotenone for 28 days, and behavioral, biochemical, histological, and transcriptional changes were assessed in the brain and intestine. Rotenone induced concentration-dependent impairments in locomotion, anxiety-like behavior, and cognition, with pronounced deficits at 5µg/L. Histopathological damage in both the brain and intestine was observed at 2.5 & 5µg/L. Oxidative stress was evident, with elevated reactive oxygen species (ROS) levels in the brain at both concentrations and in the intestine only at 5µg/L, accompanied by increased lipid peroxidation (LPO) at the higher concentration. Antioxidant enzyme activities, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were significantly disrupted. Transcriptional analysis revealed upregulation of γ1-synuclein and top2b alongside downregulation of nr4a2a (Nurr1) in both tissues. Pro-inflammatory cytokines il6 and tnfa were also markedly elevated. In conclusion, these findings establish 5µg/L rotenone as an optimized exposure for inducing reproducible, systemically integrated PD-like pathology in zebrafish and underscore NURR1-TOP2B dysregulation as a molecular correlate of gut-brain axis-associated dysfunction.
The prevalence of frailty is high among older patients receiving hemodialysis and there is a widespread agreement that frailty may be alleviated by interventions, yet frailty assessment and management are not consistently conducted among these patients. The objective of this study was to assess perceptions and attitudes regarding frailty assessment and physical activity interventions among patients receiving hemodialysis and their clinicians in a large dialysis unit. Focus groups or interviews were conducted with patients (n= 9) and dialysis unit staff and providers (n= 26) from the Hines Veterans Affairs dialysis unit. Recordings from the focus groups and interviews were transcribed verbatim. Deductive and inductive qualitative analyses were used to identify emergent themes. Emerging themes were organized into; 1) Perspectives and current practices about frailty testing reported by clinicians; 2) perspectives and current practices about physical activity reported by patients and clinicians, and 3) practical suggestions to increase frailty testing and physical activity interventions also reported by patients and clinicians. The clinicians in our study were supportive about frailty assessments in the dialysis unit. However, they were skeptical about the implications of the assessment to inform patient care and additional burden in an already constraint dialysis unit. Patients and clinicians also noted that at the health center, physical activity was mostly supported in the context for rehabilitation from acute illnesses. They spoke about the relevance for individualized exercise routines based on patients' preferences, capabilities and situation, as well as convenience. Clinicians also spoke about the importance of multidisciplinary approach for designing frailty reduction interventions including aspects of physical, mental and social wellbeing. While there is broad stakeholder acceptability and interest in frailty assessment and frailty reduction interventions, significant operational, educational, and patient-, clinician- and systemic-level barriers must be addressed before implementation is feasible in routine dialysis unit care.
Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration associated with oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and impaired proteostasis. In this study, we investigated the role of Up-Regulated Gene 7 (URG7), an ER-resident protein, in regulating cellular stress responses in SH-SY5Y neuroblastoma cells exposed to 6-hydroxydopamine (6-OHDA), a widely used in vitro model of PD. URG7 overexpression significantly enhanced activation of the adaptive unfolded protein response (UPR), particularly the PERK/eIF2α/ATF4 pathway, while limiting ER stress-induced damage. Moreover, URG7 promoted protein quality control mechanisms by stimulating both the ubiquitin-proteasome system and autophagy, as demonstrated by increased ubiquitination, proteasome activity, and upregulation of Beclin-1 and LC3-II. URG7 also prevented intracellular calcium overload and reduced the expression of proteins involved in the SOCE pathway, thereby preserving calcium homeostasis under oxidative stress conditions. In addition, URG7 attenuated G1 cell cycle arrest and reduced the expression of pro-apoptotic markers, including p53, p21, Bax, and cleaved PARP, while promoting pro-survival signaling pathways such as AKT and ERK1/2. Collectively, these findings identify URG7 as an important regulator of adaptive stress responses and suggest its possible involvement in neuroprotective mechanisms associated with neurodegenerative disorders characterized by oxidative stress.
The cholinergic basal forebrain and subcortical gray matter have previously been implicated in Parkinson's disease (PD), but the relationship between the symptomology of PD, including cognitive impairment, and specific patterns of damage remains unclear. Additionally, understanding the impact of fitness, including motor skills, on brain structure remains a knowledge gap. In this study, we examine a longitudinal cohort of PD patients using advanced microstructural analysis derived from diffusion MRI, alongside volumetric and connectivity components. These imaging metrics are compared to comprehensive cognitive and motor skill fitness metrics. Although the volumetric components well characterize change across the longitudinal timescale, the microstructural analysis was related to a number of composite cognitive scores, including attention, executive function, cognition, language, and the level of motor skill fitness. We further assess the connectivity of the cholinergic basal forebrain, particularly the nucleus basalis of Meynert in area 4 (CH4), and find that connectivity between CH4 and the thalamus is associated with motor skill fitness. The pattern of microstructural results suggests that increased cellularity may support reduced cognitive decline in individuals with PD and greater motor skill fitness.
Background/Objectives: Dilated cardiomyopathy (DCM) is a genetically heterogeneous myocardial disorder. Emerging evidence suggests that some genes implicated in DCM may also be associated with neurological disorders, supporting the concept of genetic pleiotropy. This study explored the intersection between cardiac and neurological genetics, with the aim of identifying candidate genes that may contribute to shared pathogenic pathways linking these clinically distinct conditions. Methods: We performed exome sequencing in 149 patients with echocardiographically confirmed DCM and subsequently applied an in silico filter to a predefined list of 211 genes associated with inherited cardiomyopathies. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Genes with validated evidence for DCM according to the Clinical Genome Resource (ClinGen) were further investigated through the Human Gene Mutation Database (HGMD) and a focused literature review to identify reported associations with neurological disorders. Results: Genetic variants in DCM-associated genes were identified in 105 patients. Overall, 137 variants were detected, including pathogenic variants and variants of uncertain significance. The most frequently involved genes were TTN, FLNC, and MYH6. Several DCM-associated genes also showed reported associations with neurological disorders, including autism spectrum disorder, Alzheimer's disease, Parkinson's disease, epilepsy, and schizophrenia. Among them, TTN, FLNC, RYR2, and SCN5A displayed the broadest overlap between cardiac and neurological phenotypes. Conclusions: These descriptive findings show that variants were most frequently observed in TTN, FLNC, and MYH6 and that several genes included in the ClinGen DCM curation framework have also been independently reported in neurological disorders. Because most identified variants were VUS and no control group or systematic neurological phenotyping was available, the findings indicate gene-level co-annotation only and do not establish variant enrichment, shared pathogenic mechanisms, or clinical overlap.