Search Results (1,202)

In recent years, an increasing amount of research has investigated the impact of chronic inflammation on the development and progression of both neurological and psychiatric disorders, including epilepsy, depression, schizophrenia, and bipolar disorder. Moreover, growing attention is being paid to how inflammatory processes contribute to disease mechanisms, influence symptom severity, and interact with pharmacological treatments in these conditions. Changes in the levels of inflammatory biomarkers, such as cytokines and C-reactive protein, may signal the early stages of neurological disorder development. Furthermore, specific biomarker profiles have been identified for individual diseases, and chronic treatment may affect their blood levels. Over the last two decades, significant progress in the study of inflammatory biomarkers in psychiatric disorders and epilepsy has been achieved, demonstrating an association between biomarkers with symptoms, a potential prognostic role, and possible use in personalising therapy. Furthermore, widely used methods for biomarker evaluation, such as immunoenzymatic assays and flow cytometry, remain essential tools for current research. Despite numerous indications of the importance of inflammation in psychiatry and neurology, the available studies are characterised by considerable heterogeneity in terms of both population selection and methodology. Based on the available data, inflammatory biomarkers represent a promising diagnostic and therapeutic tool for epilepsy and psychiatric disorders. Although existing studies suggest a correlation between inflammation and the symptoms of various disorders, inconsistent results highlight the need for further research to enable wider implementation of these findings in psychiatric and epilepsy practice. Advancing knowledge of inflammatory biomarkers is essential for improving treatment outcomes and promoting the development of targeted interventions. 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

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

Deer tick virus (DTV) is a Tick-Borne Orthoflavivirus endemic to the United States, transmitted to humans through bites from the deer tick, Ixodes scapularis, which is also the primary vector of Borrelia burgdorferi s.l., the causative agent of Lyme disease. Human infection with DTV can result in acute febrile illness followed by central nervous system complications, such as encephalitis and meningoencephalitis. Currently, there are mouse models established for investigating the pathogenesis and clinical outcomes of DTV that mimic human infections, but the strains of mice utilized are refractory to infection with B. burgdorferi s.l. Here, we describe the pathogenesis and clinical outcomes of DTV infection in C3H/HeJ mice. Neurological clinical signs, mortality, and weight loss were observed in all DTV-infected mice during the investigation. Infected animals demonstrated consistent viral infection in their organs. Additionally, neuropathology of brain sections indicated the presence of meningoencephalitis throughout the brain. This data, along with the clinical outcomes for the mice, indicates successful infection and showcases the neuroinvasive nature of the virus. This is the first study to identify C3H/HeJ mice as an appropriate model for DTV infection. As C3H/HeJ mice are already an established model for B. burgdorferi s.l. infection, this model could serve as an ideal system for investigating disease progression and pathogenesis of co-infections. Full article

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29–41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a ‘one and done’ approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients. Full article

Background/Objectives: Wilson’s disease (WD) is a rare autosomal recessive disorder of copper metabolism that results in hepatic, neurological, and psychiatric manifestations. Despite being described globally, data from the Middle East remains limited. This study presents the first comprehensive national cohort analysis of WD in Oman, examining clinical features, diagnostic challenges, treatment patterns, and long-term outcomes. Methods: A retrospective cohort study was conducted on 36 Omani patients diagnosed with WD between 2013 and 2020 at Sultan Qaboos University Hospital using AASLD diagnostic criteria. Clinical presentation, biochemical parameters, treatment regimens, and progression-free survival were analyzed. Results: The median age at diagnosis was 14.5 years, with a slight female predominance (55.6%). Clinical presentation varied: 25% had hepatic symptoms, 22.2% had mixed hepatic-neurological features, and 16.7% presented with neurological symptoms alone. Asymptomatic cases identified via family screening accounted for 33.3%. Diagnostic delays were most pronounced among patients presenting with neurological symptoms. A positive family history was reported in 88.9% of cases, suggesting strong familial clustering despite a low rate of consanguinity (5.6%). Regional distribution was concentrated in Ash Sharqiyah North and Muscat. Chelation therapy with trientine or penicillamine, often combined with zinc, was the mainstay of treatment. Treatment adherence was significantly associated with improved progression-free survival (p = 0.012). Conclusions: WD in Oman is marked by heterogeneous presentations, frequent diagnostic delays, and strong familial clustering. Early detection through cascade screening and sustained treatment adherence are critical for favorable outcomes. These findings support the need for national screening policies and structured long-term care models for WD in the region. Full article

Background: Lysosomal storage diseases (LSDs) are a genetically and clinically heterogeneous group of inborn errors of metabolism caused by variants in genes encoding lysosomal hydrolases, membrane proteins, activator proteins, or transporters. These disease-causing variants lead to enzymatic deficiencies and the progressive accumulation of undegraded substrates within lysosomes, disrupting cellular function across multiple organ systems. While classical phenotypes typically manifest in infancy or early childhood with severe multisystem involvement, a combination of advances in molecular diagnostics [particularly next-generation sequencing (NGS)] and improved understanding of disease heterogeneity have enabled the identification of attenuated forms characterised by residual enzyme activity and later-onset presentations. These milder phenotypes often evade early recognition due to nonspecific or isolated symptoms, resulting in significant diagnostic delays and missed therapeutic opportunities. Objectives/Methods: This study characterises the clinical, biochemical, and molecular profiles of 10 adult patients diagnosed with LSDs, all representing attenuated forms, and discusses them alongside a narrative review. Results: Enzyme activity, molecular data, and phenotypic assessments are described to explore genotype–phenotype correlations and identify diagnostic challenges. Conclusions: These findings highlight the variable expressivity and organ involvement of attenuated LSDs and reinforce the importance of maintaining clinical suspicion in adults presenting with unexplained cardiovascular, neurological, ophthalmological, or musculoskeletal findings. Enhanced recognition of atypical presentations is critical to facilitate earlier diagnosis, guide management, and enable cascade testing for at-risk family members. Full article

Alzheimer’s Disease and Dementia (ADD) progresses along a continuum of cognitive decline, typically from Subjective Cognitive Impairment (SCI) to Mild Cognitive Impairment (MCI) and eventually to dementia. While many studies have focused on classifying these clinical stages, fewer have examined whether brain connectomes encode this continuum in a low-dimensional, interpretable form. Motivated by the hypothesis that structural brain connectomes undergo complex yet compact changes across cognitive decline, we propose a Graph Neural Network (GNN)-based framework that embeds these connectomes into a two-dimensional manifold to capture the evolving patterns of structural connectivity associated with cognitive deterioration. Using attention-based graph aggregation and Principal Component Analysis (PCA), we find that MCI subjects consistently occupy an intermediate position between SCI and ADD, and that the observed transitions align with known clinical biomarkers of ADD pathology. This hypothesis-driven analysis is further supported by the model’s robust separation performance, with ROC-AUC scores of 0.93 for ADD vs. SCI and 0.81 for ADD vs. MCI. These findings offer an interpretable and neurologically grounded representation of dementia progression, emphasizing structural connectome alterations as potential markers of cognitive decline. Full article

Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer’s disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases. Full article

About one billion people worldwide are affected by neurologic disorders. Among the various neurologic disorders, one of the most common is Alzheimer’s disease (AD). AD is a neurodegenerative disorder that progressively affects cognitive functions, disrupting the daily lives of millions of individuals. Mild cognitive impairment (MCI) is often considered a prodromal stage of Alzheimer’s disease. In this article, we retrieved data from the online available dataset GSE63060, which includes transcriptomic data of 329 blood samples, of which there are 104 cognitively normal controls, 80 MCI patients, and 145 AD patients. We used transcriptomic data related to all three groups to perform an over-representation analysis of the gene ontologies followed by a network analysis. The aim of our study is to pinpoint alterations, detectable through a non-invasive method, in biological processes affected in MCI that persist during AD. Our goal is to uncover transcriptomic changes that could support earlier diagnosis and the development of more effective therapeutic strategies, starting from the early stages of the disease, to slow down or mitigate its progression. Our work provides a consistent picture of the transcriptomic unbalance of many genes strongly involved in ribosomal formation and biogenesis and splicing processes both in patients with MCI and with AD. Full article

Parkinson’s disease (PD), a progressive neurodegenerative disorder, imposes growing clinical and socioeconomic burdens worldwide. Despite landmark discoveries in dopamine biology and α-synuclein pathology, translating mechanistic insights into effective, personalized interventions remains elusive. Recent advances in molecular profiling, neuroimaging, and computational modeling have broadened the understanding of PD as a multifactorial systems disorder rather than a purely dopaminergic condition. However, critical gaps persist in diagnostic precision, biomarker standardization, and the translation of bench side findings into clinically meaningful therapies. This review critically examines the current landscape of PD research, identifying conceptual blind spots and methodological shortfalls across pathophysiology, clinical evaluation, trial design, and translational readiness. By synthesizing evidence from molecular neuroscience, data science, and global health, the review proposes strategic directions to recalibrate the research agenda toward precision neurology. Here I highlight the urgent need for interdisciplinary, globally inclusive, and biomarker-driven frameworks to overcome the fragmented progression of PD research. Grounded in the Accelerating Medicines Partnership-Parkinson’s Disease (AMP-PD) and the Parkinson’s Progression Markers Initiative (PPMI), this review maps shared biomarkers, open data, and patient-driven tools to faster personalized treatment. In doing so, it offers actionable insights for researchers, clinicians, and policymakers working at the intersection of biology, technology, and healthcare delivery. As the field pivots from symptomatic relief to disease modification, the road forward must be cohesive, collaborative, and rigorously translational, ensuring that laboratory discoveries systematically progress to clinical application. Full article

Bruton Tyrosine Kinase (BTK) has emerged as a critical mediator in the pathophysiology of neuroinflammation associated with neurodegenerative diseases. BTK, a non-receptor tyrosine kinase predominantly expressed in cells of the hematopoietic lineage, modulates B-cell receptor signaling and innate immune responses, including microglial activation. Recent evidence implicates aberrant BTK signaling in the exacerbation of neuroinflammatory cascades contributing to neuronal damage in disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic stroke, and Huntington’s disease. Pharmacological inhibition of BTK has shown promise in attenuating microglial-mediated neurotoxicity, reducing pro-inflammatory cytokine release, and promoting neuroprotection in preclinical models. BTK inhibitors, originally developed for hematological malignancies, demonstrate favorable blood–brain barrier penetration and immunomodulatory effects relevant to central nervous system pathology. This therapeutic approach may counteract detrimental neuroimmune interactions without broadly suppressing systemic immunity, thus preserving host defense. Ongoing clinical trials are evaluating the safety and efficacy of BTK inhibitors in patients with neurodegenerative conditions, with preliminary results indicating potential benefits in slowing disease progression and improving neurological outcomes. This review consolidates current knowledge on BTK signaling in neurodegeneration and highlights the rationale for BTK inhibition as a novel, targeted therapeutic strategy to modulate neuroinflammation and mitigate neurodegenerative processes. Full article

Sporadic Parkinson’s Disease (PD) affects 3% of people over 65 years of age. People are living longer, thanks in large part to improvements in global health technology and health access for non-neurological diseases. Consequently, neurological diseases of senescence, such as PD, are representing an ever-increasing share of global disease burden. There is an intensifying research focus on the processes that underlie these conditions in the hope that neurological decay may be arrested at the earliest time point. The concept of neuronal death linked to ageing- neural senescence- first emerged in the 1800s. By the late 20th century, it was recognized that neurodegeneration was common to all ageing human brains, but in most cases, this process did not lead to clinical disease during life. Conditions such as PD are the result of accelerated neurodegeneration in particular brain foci. In the case of PD, degeneration of the substantia nigra pars compacta (SNpc) is especially implicated. Why neural degeneration accelerates in these particular regions remains a point of contention, though current evidence implicates a complex interplay between a vast array of neuronal cell functions, bioenergetic failure, and a dysfunctional brain immunological response. Their complexity is a considerable barrier to disease modification trials, which seek to intercept these maladaptive cell processes. This paper reviews current evidence in the domain of neurodegeneration in Parkinson’s disease, focusing on alpha-synuclein accumulation and deposition and the role of oxidative stress and inflammation in progressive brain changes. Recent approaches to disease modification are discussed, including the prevention or reversal of alpha-synuclein accumulation and deposition, modification of oxidative stress, alteration of maladaptive innate immune processes and reactive cascades, and regeneration of lost neurons using stem cells and growth factors. The limitations of past research methodologies are interrogated, including the difficulty of recruiting patients in the clinically quiescent prodromal phase of sporadic Parkinson’s disease. Recommendations are provided for future studies seeking to identify novel therapeutics with disease-modifying properties. Full article

Parkinson’s disease (PD) is a progressive neurological disorder with motor and non-motor symptoms that are inadequately addressed by current pharmacological and surgical therapies. Brain–computer interfaces (BCIs), particularly those based on electroencephalography (eBCIs), provide a promising, non-invasive approach to personalized neurorehabilitation. This narrative review explores the clinical potential of BCIs in PD, discussing signal acquisition, processing, and control paradigms. eBCIs are well-suited for PD due to their portability, safety, and real-time feedback capabilities. Emerging neurophysiological biomarkers—such as beta-band synchrony, phase–amplitude coupling, and altered alpha-band activity—may support adaptive therapies, including adaptive deep brain stimulation (aDBS), as well as motor and cognitive interventions. BCIs may also aid in diagnosis and personalized treatment by detecting these cortical and subcortical patterns associated with motor and cognitive dysfunction in PD. A structured search identified 11 studies involving 64 patients with PD who used BCIs for aDBS, neurofeedback, and cognitive rehabilitation, showing improvements in motor function, cognition, and engagement. Clinical translation requires attention to electrode design and user-centered interfaces. Ethical issues, including data privacy and equitable access, remain critical challenges. As wearable technologies and artificial intelligence evolve, BCIs could shift PD care from intermittent interventions to continuous, brain-responsive therapy, potentially improving patients’ quality of life and autonomy. This review highlights BCIs as a transformative tool in PD management, although more robust clinical evidence is needed. Full article