Search Results (71)

Background: Deep brain stimulation (DBS) is increasingly understood as a precision-oriented neuromodulation therapy capable of influencing distributed basal ganglia–thalamo–cortical and cerebellothalamic networks. Although its symptomatic benefits in Parkinson’s disease, essential tremor, and dystonia are well established, the extent to which DBS supports motor learning, adaptive plasticity, and participation in rehabilitation remains insufficiently defined. Traditional interpretations of DBS as a focal or lesion-like intervention are being challenged by electrophysiological and imaging evidence demonstrating multiscale modulation of circuit dynamics. Objectives and methods: DBS may enhance rehabilitation outcomes by stabilizing pathological oscillations and reducing moment-to-moment variability in motor performance, thereby enabling more consistent task execution and more effective physiotherapy, occupational therapy, and speech–language interventions. However, direct comparative evidence demonstrating additive or synergistic effects of DBS combined with rehabilitation remains limited. As a result, this potential is not fully realized in clinical practice due to interindividual variability, limited insight into how individual circuit architecture shapes therapeutic response, and the limited specificity of current connectomic biomarkers for predicting functional gains. Results: Technological advances such as tractography-guided targeting, directional leads, sensing-enabled devices, and adaptive stimulation are expanding opportunities to align neuromodulation with individualized circuit dysfunction. Despite these developments, major conceptual and empirical gaps persist. Few controlled studies directly compare outcomes with versus without structured rehabilitation following DBS. Heterogeneity in therapeutic response and rehabilitation access further complicates the interpretation of outcomes. Clarifying these relationships is essential for developing precision-informed frameworks that integrate DBS with rehabilitative strategies, recognizing that current connectomic and physiological biomarkers remain incompletely validated for predicting functional outcomes. Conclusions: This review synthesizes mechanistic, imaging, and technological evidence to outline a network-informed perspective of DBS as a potential facilitator of rehabilitation-driven functional improvement and identifies priorities for future research aimed at optimizing durable functional restoration. Full article

Alzheimer’s disease (AD) represents an increasingly severe global health challenge. Recently, the role of the gut–brain axis in AD pathogenesis has garnered significant attention. Dysbiosis of the gut microbiota can exacerbate core pathologies such as neuroinflammation, amyloid beta (Aβ) deposition, and tau hyperphosphorylation through neural, endocrine, and immune pathways. Polyphenolic compounds have emerged as a focal point in neuroprotective research owing to their pronounced anti-inflammatory and antioxidant properties. Notably, polyphenols exert effects not only by directly influencing the central nervous system (CNS) but also through indirectly modulating the composition and function of the gut microbiota, thereby impacting bidirectional gut–brain communication. This dual mechanism offers a potential avenue for their application in the prevention and treatment of AD. This review aims to compile recent research on the relationship between polyphenols and the gut microbiota. We assessed the literature from PubMed, Google Scholar, and Web of Science databases, published from the establishment of the database to 24 November 2025. The keywords used include “Polyphenols”, “Gut–brain axis”, “Gut microbiota”, “Alzheimer’s disease”, “Epigallocatechin gallate”, “Quercetin”, “Curcumin”, “Ferulic acid”, “Resveratrol”, “Anthocyanin”, “Myricetin”, “Chlorogenic acid”, etc. This review discusses the various mechanisms by which polyphenols influence AD through modulating the gut microbiota. Polyphenols and gut microbiota exhibit critical bidirectional interactions. On one hand, the bioavailability and activity of polyphenols are highly dependent on metabolic conversion by gut microbiota. On the other hand, polyphenols selectively promote the proliferation of beneficial bacteria such as bifidobacteria and lactobacilli like prebiotics, while inhibiting the growth of pathogenic bacteria. This reshapes the intestinal microecology, enhances barrier function, and regulates beneficial metabolites. Utilizing a nanotechnology-based drug delivery system, the pharmacokinetic stability and brain targeting efficacy of polyphenols can be significantly enhanced, providing innovative opportunities for the targeted prevention and management of AD. Full article

Multiple sclerosis (MS) is a chronic, heterogeneous, multifactorial, immune-mediated neurodegenerative disease of the central nervous system that affects the working-age population. Its development is influenced by both genetic and environmental factors. A pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which are associated with neuronal damage caused by autoaggressive immune factors (T cells, B cells, and myeloid cells). Focal lesions are believed to be caused by the infiltration of immune cells into the central nervous system (CNS) parenchyma with concomitant tissue damage. Multiple sclerosis represents a significant social problem due to the high cost of available treatments, as well as the deterioration of employment prospects and job retention for both patients and their caregivers. Advances in MS diagnostic methods have enabled disease detection at early stages and correction of immune response impairments. Concurrently, treatments for MS patients are actively being studied, with the ongoing development of novel methods for targeted and cellular immunotherapy. This review primarily discusses approaches to cellular immunotherapy and methods of influencing the cellular arm of immunopathogenesis in multiple sclerosis. Full article

Alzheimer’s disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5–2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke. Full article

Stimulator of interferon genes (STING) is a cytosolic DNA sensor that activates type I interferon (IFN) signaling, which plays a key role in neuroinflammation. Although the role of STING in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), remains debated, its involvement in the development of CNS lesions, particularly within localized pathology, modeled here by targeting the corpus callosum, has yet to be explored. Using a focal EAE model, we compared the induction of lesions in wild-type and STING-deficient (STING^gt/gt) mice. Lesions were analyzed by immunohistochemistry, flow cytometry, and transcriptomics. STING-deficient mice had significantly larger demyelinated lesions, reduced ISG expression, and modified immune cell infiltration. STING signaling limits lesion severity in focal EAE by promoting IFN responses and regulating immune infiltration. These findings position STING as a potential target for MS therapy. Full article

Cerebral ischemia/reperfusion (I/R) injury remains a significant contributor to adult neurological morbidity, primarily due to exacerbated neuroinflammation and cell apoptosis. These processes amplify brain damage through the release of various pro-inflammatory cytokines and pro-apoptotic mediators. Although long non-coding RNAs (lncRNAs) are increasingly recognized for their involvement in regulating diverse biological pathways, their precise role in cerebral I/R injury has not been fully elucidated. In the current study, transcriptomic profiling was conducted using a rat model of focal cerebral I/R, leading to the identification of lncRNA-1810026B05Rik—also referred to as CHASERR—as a novel lncRNA responsive to ischemic conditions. The elevated expression of this lncRNA was observed in mouse brain tissues subjected to middle cerebral artery occlusion followed by reperfusion (MCAO/R), as well as in primary cortical neurons derived from rats exposed to oxygen-glucose deprivation and subsequent reoxygenation (OGD/R). The results suggested that lncRNA-1810026B05RiK mediates the activation of the nuclear factor-kappaB (NF-κB) signaling pathway by physically binding to NF-kappa-B inhibitor alpha (IκBα) and promoting its phosphorylation, thus leading to neuroinflammation and neuronal apoptosis during cerebral ischemia/reperfusion. In addition, lncRNA-1810026B05Rik knockdown acts as an NF-κB inhibitor in the OGD/R and MCAO/R pathological processes, suggesting that lncRNA-1810026B05Rik downregulation exerts a protective effect on cerebral I/R injury. In summary, the lncRNA-1810026B05Rik has been identified as a critical regulator of neuronal apoptosis and inflammation through the activation of the NF-κB signaling cascade. This discovery uncovers a previously unrecognized role of 1810026B05Rik in the molecular mechanisms underlying ischemic stroke, offering valuable insights into disease pathology. Moreover, its involvement highlights its potential as a novel therapeutic target, paving the way for innovative treatment strategies for stroke patients. Full article

Background/Objectives: Brain metastasis from uterine leiomyosarcoma (ULMS) is an exceptionally rare complication of an aggressive malignancy. With fewer than 40 cases previously documented, a significant knowledge gap exists regarding its clinical course, management, and outcomes. This study provides the largest analysis of ULMS brain metastases to date, integrating a systematic literature review with a novel case report illustrating the disease’s uniquely rapid progression. Methods: Following PRISMA guidelines, we systematically reviewed four major databases to identify all reported cases of intracranial metastasis from ULMS. Data on patient demographics, clinico-radiological features, treatments, and survival were extracted and analyzed. Methodological quality was assessed using a modified Joanna Briggs Institute (JBI) tool. Results: We analyzed 34 studies with 39 individual cases. Additionally, this review was supplemented by one new illustrative case from our institution. The median patient age was 51.5 years, and most presented with focal neurological symptoms. Common imaging findings included hyperdense lesions on CT and homogeneously enhancing, dural-based masses on MRI, which mimic other intracranial pathologies. Though surgery was the most frequent intervention (76.9%), median survival after a brain metastasis diagnosis was a grim 5 months, with no significant difference observed between treatment modalities. Our illustrative case was remarkable for an extremely rapid volumetric doubling time averaging just 7.3 days. Conclusions: Brain metastasis from ULMS is a lethal event with an extremely poor prognosis. Nonspecific imaging features create diagnostic challenges, necessitating histopathological confirmation. Current therapies, including surgery and radiotherapy, offer palliative benefit but do not significantly alter survival. The aggressive biological behavior demonstrated here underscores the urgent need for increased clinical awareness and collaborative research to develop more effective management strategies and improve outcomes for this devastating diagnosis. Full article

Background: Brain computed tomography (CT) is the primary imaging modality for patients with acute neurological complaints in emergency departments, despite having a low diagnostic yield for many conditions. This study aimed to assess the common indications for brain CT, evaluate the prevalence of acute pathologies, and explore whether certain patient groups may be overexposed to unnecessary scans, impacting both patient safety and healthcare costs. Methods: We conducted a retrospective review of brain CT requests from the General Emergency Department in a single center over a one-month period. We recorded patient demographics (sex, age), scan indications, presence of focal neurological symptoms, acute pathology on CT, and final diagnoses. Descriptive statistics, including means ± SEM, were calculated using GraphPad Prism version 10.4.1. Results: A total of 584 brain CT scans were requested, of which 532 (91.1%) were normal, and 52 (8.9%) showed acute pathology. The age of all included patients were 70.8 ± 0.7 years with women (n = 304, 52.1%) being 71.9 ± 1.0 years old and men (n = 280, 47.9%) 69.7 ± 1.0 years old (p > 0.1). The most common indication for CT was head trauma (265, 45.4%) followed by ischemic stroke (130, 22.3%). The most frequent pathologies were ischemic stroke (2.7%), subdural hematoma (1.7%), and other traumatic bleeds (1.7%). Of the 52 patients with acute pathology, 42 (80.8%) exhibited focal neurological deficits. Conclusions: 91.1% of the brain CT scans in the emergency department were normal and did not lead to further intervention. While this may indicate a low diagnostic yield in certain patient groups—particularly those presenting with mild or nonspecific neurological symptoms—it does not alone confirm overuse. These findings highlight the importance of careful clinical evaluation to optimize imaging decisions. Reducing potentially unnecessary brain CT scans could lower healthcare costs and minimize radiation exposure, but the health-economic impact depends on balancing the savings with the potential costs of missing critical diagnoses and the associated societal consequences. Full article

The focal “hot spot” neuropathologies in COVID-19 infection are revealing footprints of a hidden underlying collapse of a novel ultrafast ultradian Piezo2 signaling system within the nervous system. Paradoxically, the same initiating pathophysiology may underpin the systemic findings in COVID-19 infection, namely the multiorgan SARS-CoV-2 infection-induced vascular pathologies and brain–body-wide systemic pro-inflammatory signaling, depending on the concentration and exposure to infecting SARS-CoV-2 viruses. This common initiating microdamage is suggested to be the primary damage or the acquired channelopathy of the Piezo2 ion channel, leading to a principal gateway to pathophysiology. This Piezo2 channelopathy-induced neural switch could not only explain the initiation of disrupted cell–cell interactions, metabolic failure, microglial dysfunction, mitochondrial injury, glutamatergic synapse loss, inflammation and neurological states with the central involvement of the hippocampus and the medulla, but also the initiating pathophysiology without SARS-CoV-2 viral intracellular entry into neurons as well. Therefore, the impairment of the proposed Piezo2-induced quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling seems to be the principal and critical underlying COVID-19 infection-induced primary damage along the brain axes, depending on the loci of SARS-CoV-2 viral infection and intracellular entry. Moreover, this initiating Piezo2 channelopathy may also explain resultant autonomic dysregulation involving the medulla, hippocampus and heart rate regulation, not to mention sleep disturbance with altered rapid eye movement sleep and cognitive deficit in the short term, and even as a consequence of long COVID. The current opinion piece aims to promote future angles of science and research in order to further elucidate the not entirely known initiating pathophysiology of SARS-CoV-2 infection. Full article

Background: Cerebral aneurysm (CA) is a focal or diffuse pathological dilation of the cerebral arterial wall that arises due to various etiological factors. It represents a serious vascular condition, particularly affecting the elderly, and carries a high risk of rupture and neurological morbidity. Clonidine (CL), an α2-adrenergic receptor agonist, has been reported to suppress aneurysm progression; however, its underlying molecular mechanisms, especially in relation to cerebral endothelial dysfunction, remain unclear. This study aimed to investigate the potential of CL to mitigate CA development by modulating apoptosis, inflammation, and oxidative stress in an Angiotensin II (Ang II)-induced endothelial injury model. Methods: Human brain microvascular endothelial cells (HBMECs) were used to establish an in vitro model of endothelial dysfunction by treating cells with 1 µM Ang II for 48 h. CL was administered 2 h prior to Ang II exposure at concentrations of 0.1, 1, and 10 µM. Cell viability was assessed using the MTT assay. Oxidative stress markers, including reactive oxygen species (ROS) and Nitric Oxide (NO), were measured using 2′,7′–dichlorofluorescin diacetate (DCFDA). Gene expression levels of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP-2 and MMP-9), high mobility group box 1 (HMGB1), and nuclear factor kappa B (NF-κB) were quantified using RT-qPCR. Levels of proinflammatory cytokines; tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and interferon-gamma (IFN-γ); were measured using commercial ELISA kits. Results: Ang II significantly increased ROS production and reduced NO levels, accompanied by heightened proinflammatory cytokine release and endothelial dysfunction. MTT assay revealed a marked decrease in cell viability following Ang II treatment (34.18%), whereas CL preserved cell viability in a concentration-dependent manner: 44.24% at 0.1 µM, 66.56% at 1 µM, and 81.74% at 10 µM. CL treatment also significantly attenuated ROS generation and inflammatory cytokine levels (p < 0.05). Furthermore, the expression of VEGF, HMGB1, NF-κB, MMP-2, and MMP-9 was significantly downregulated in response to CL. Conclusions: CL exerts a protective effect on endothelial cells by reducing oxidative stress and suppressing proinflammatory signaling pathways in Ang II-induced injury. These results support the potential of CL to mitigate endothelial injury in vitro, though further in vivo studies are required to confirm its translational relevance. Full article

The temporary or permanent occlusion of cerebral blood vessels results in ischemic stroke (IS). Ischemia per se causes focal neuronal damage, and the subsequent ischemia–reperfusion injury that occurs after blood flow restoration further compromises brain tissue and cells in the neurovascular unit, significantly contributing to poor patient outcomes and functional impairments. Current research indicates that the ubiquitin–proteasome system (UPS) plays a crucial role in the pathological processes associated with cerebral ischemia–reperfusion injury (CIRI). Notably, E3 ubiquitin (Ub) ligases, which are essential in the UPS, have garnered increasing attention as potential novel therapeutic targets for treating ischemia–reperfusion damage in the brain. This review focuses primarily on the background of E3 Ub ligases and explores their intricate relationships with the pathological processes of CIRI. Full article

Background: Glioblastoma (GBM) is the most common primary brain tumor in adults, with a poor prognosis and survival. Although typically presenting with focal neurological deficits, seizures, or cognitive decline, GBM can occasionally mimic autoimmune encephalitis (AE), leading to significant diagnostic delay. The overlap in clinical, radiological, and serological findings between GBM and AE underscores the need for thorough evaluation. Methods: We retrospectively reviewed cases of patients diagnosed between 2016 and 2023 with pathology-confirmed GBM, critically rethinking those cases initially diagnosed with AE at symptom onset. The diagnostic workup included magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, autoantibody testing, and whole-body nuclear scanning to exclude extracranial malignancies. Results: We found five female patients diagnosed with GBM who initially presented with signs and symptoms suggestive for AE. Initial MRI showed non-specific brain tissue alterations, without definitive tumor features. CSF analysis was largely unremarkable, though some cases exhibited positive autoantibodies. Despite therapy, clinical deterioration and follow-up MRI revealed infiltrative intra-axial lesions with contrast enhancement, leading to pathology-confirmed GBM diagnoses. All patients had poor prognoses, with a mean survival of 10 ± 4 months. Conclusions: GBM can mimic AE, delaying appropriate treatment. In patients with atypical MRI findings and suboptimal response to therapy, early follow-up imaging and biopsy should be considered to exclude malignancy. A multidisciplinary approach is critical for timely diagnosis and improved management. Full article

Background: The current animal models of multiple sclerosis (MS) predominantly emphasize white matter inflammation, reflecting early-stage disease. However, progressive MS (PMS) is characterized by cortical pathology, including subpial demyelination, chronic meningeal inflammation, and microglial activation, which are underrepresented in the existing models. While alternative mouse models replicate the relapsing–remitting phenotype and gray matter pathology, pathology is frequently dispersed throughout the brain, complicating the analysis of the specific lesion sites. Methods: To address this gap, we developed a novel model that integrates laser-induced focal demyelination with cytokine-driven meningeal inflammation to replicate the key aspects of PMS cortical pathology. Results: Using two-photon laser irradiation, we induced controlled subpial cortical lesions in CX3CR1-GFP mice, leading to microglial activation, astrocytosis, and focal demyelination. The addition of IFNγ-expressing adenovirus to promote meningeal inflammation which resulted in prolonged glial responses, increased immune cell infiltration, and exacerbated demyelination, mimicking the PMS-associated pathology. Conclusions: This model provides a powerful tool to investigate the mechanisms underlying the cortical lesion development and immune-mediated neurodegeneration in PMS. By capturing the critical aspects of cortical pathology, it enables the evaluation of therapeutic strategies targeting neuroinflammation and demyelination, ultimately aiding in the development of new treatments of progression in PMS patients. Full article

Background: Cerebral amyloid angiopathy-related inflammation (CAA-RI) is a rare subtype of cerebral amyloid angiopathy (CAA), which presents mostly as a subacute and reversible encephalopathy. Primary symptoms include behavioral changes and cognitive decline in the form of rapidly progressive dementia, headache, seizures, and focal neurological deficits. It can also manifest as a varied range of typical and atypical presentations. Misdiagnosis is common because it shares symptoms with other infectious, ischemic and autoimmune pathologies and there is also a significant overlap of MRI findings. Methods: Gold standard diagnosis requires brain biopsy in appropriate clinical setting, but diagnostic criteria is established for probable and possible CAA-RI using clinical symptoms and MRI findings in the absence of other inflammatory, infectious or autoimmune processes. Immunomodulatory therapy is the mainstay of treatment, with variable response. Results: We present a case series of three patients with CAA-RI highlighting disease course, neuroradiological manifestation, treatment response, and clinical outcomes. We also provide a literature review to increase insight into this rare pathology. Conclusions: Early diagnosis and prompt initiation of immunosuppressive therapy is beneficial in most cases. Full article

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article