Search Results (1,898)

In light of the growing interest in the bidirectional relationship between epilepsy and dementia, this review aims to provide an overview of the role of hyperphosphorylated tau (pTau) in cognition in human epilepsy. A literature search identified five relevant studies. All of them examined pTau burden in surgical biopsy specimens from patients with temporal lobe epilepsy. The prevalence of pTau reported across the five studies, encompassing a total of 142 patients, ranged from 3.5% to 95%. Findings also varied regarding the location of pTau in the hippocampus and/or temporal cortex. Two of five studies (40%) demonstrated an inverse relationship between pTau burden and cognitive performance, one study with regard to executive functions and the other with regard to naming and verbal short-term memory. The only longitudinal study found a significant link between pTau and cognitive decline in verbal learning and memory, and in part also in naming, from the pre- to the postoperative assessment and from three to 12 months postoperatively. Given the heterogeneity of the study cohorts and the neuropsychological and neuropathological methodologies and findings, no clear picture emerges regarding the association between pTau and cognition in temporal lobe epilepsy. Added to this is the multifactorial etiology of cognitive impairment in epilepsy, including the active epilepsy, the underlying and sometimes dynamic pathology, and anti-seizure medication. Some of these factors may affect pTau expression. Further research should aim to investigate pTau longitudinally and noninvasively on a whole-brain level, using targeted neuropsychological outcome measures and controlling for age and other factors potentially influencing cognitive trajectories in epilepsy. Full article

Recent research highlights compelling links between oral health, particularly periodontitis, and systemic diseases, including Alzheimer’s disease (AD). Although the biological mechanisms underlying these associations remain unclear, the role of periodontal pathogens, particularly Porphyromonas gingivalis, has garnered significant attention. P. gingivalis, a major driver of periodontitis, is recognized for its potential systemic effects and its putative role in AD pathogenesis. This review examines evidence connecting P. gingivalis to hallmark AD features, such as amyloid β accumulation, tau hyperphosphorylation, neuroinflammation, and other neuropathological features consistent with AD. Virulence factors, such as gingipains and lipopolysaccharides, were shown to be implicated in blood–brain barrier disruption, neuroinflammation, and neuronal damage. P. gingivalis-derived outer membrane vesicles may serve to disseminate virulence factors to brain tissues. Indirect mechanisms, including systemic inflammation triggered by chronic periodontal infections, are also supposed to exacerbate neurodegenerative processes. While the exact pathways remain uncertain, studies detecting P. gingivalis virulence factors and its other components in AD-affected brains support their possible role in disease pathogenesis. This review underscores the need for further investigation into P. gingivalis-mediated mechanisms and their interplay with host responses. Understanding these interactions could provide critical insights into novel strategies for reducing AD risk through periodontal disease management. Full article

Background: Intracranial choroid plexus tumors (CPT) are rare and primarily affect young children. Leptomeningeal dissemination (LMD) has been reported not only in high-grade choroid plexus carcinoma (CPC) but also in lower histological grades; however, a systematic evaluation of CPT-specific imaging characteristics remains lacking. Methods: We analyzed the imaging characteristics of LMD in a single-center pediatric cohort of 22 CPT patients (thirteen choroid plexus papilloma (CPP), six atypical choroid plexus papilloma (aCPP), three CPC), comparing LMD features with those of the primary tumor. Additionally, we examined the correlation between resection status and LMD development during follow-up. Results: At diagnosis, we observed true LMD in three (two CPCs, one CPP) and pseudo-LMD in one case (CPP). During follow-up, two CPP patients developed cystic LMD, and one aCPP patient developed a solid metastasis. LMD had characteristics of the primary tumor in 3/4 cases. Incomplete resection was associated with a higher risk of LMD (p = 0.025). Conclusions: LMD can occur in both high- and lower-grade CPT, presenting at diagnosis as well as in relapsed lower-grade cases. Notable MR-imaging features include pseudo-LMD at diagnosis and cystic LMD in relapsed CPP cases. Incomplete tumor resection may increase the risk of LMD, although further validation is needed. Full article

The neuropathological diagnosis of Alzheimer’s disease (AD) relies on amyloid beta (Aβ) deposition in brain tissues. To study the relationship between Aβ deposition and brain structure, as determined using ¹¹C-Pittsburgh compound B (PiB) and magnetic resonance imaging (MRI), respectively, we developed a regression model with PiB and MRI data as the predictor and response variables, respectively, and proposed a regression method for studying the association between them based on a supervised sparse multivariate analysis with dimension reduction based on a composite paired basis function. By applying this method to imaging data of 61 patients with AD (age: 55–85), the first component showed the strongest correlation with the composite score, owing to the supervised feature. The spatial pattern included the hippocampal and parahippocampal regions for MRI. The peak value was observed in the posterior cingulate and precuneus for PiB. The differences in PiB scores among the diagnosis groups 12 months after PiB imaging were significant between the normal and AD groups (p = 0.0284), but not between the normal and mild cognitive impairment (MCI) groups or the MCI and AD groups (p = 0.3508). Our method may facilitate the development of a dementia biomarker from brain imaging data. Scoring imaging data allows for visualization and the application of traditional analysis, facilitating clinical analysis for better interpretation of results. Full article

Background: Age-related changes to the orbicularis oculi muscle include impaired eyelid function, such as lagophthalmos, alterations in tear film dynamics, and aesthetic changes like wrinkles, festoons, and the descent of soft tissue. To date, the structural and functional changes that would comprehensively increase our understanding of orbicularis aging have not been analyzed. This study aims to investigate functional outcomes using surface electromyography and correlate them with ultrastructural changes in orbicularis during aging. Methods: This study enrolled 26 patients aged 37 to 78 years with a clinical diagnosis of dermatochalasis. Patients were divided into two age groups (<60 years; ≥60 years). Ultrastructural and electromyographical examinations were performed, and the electromyographical signals were correlated with the ultrastructural damage in the orbicularis. Results: This study revealed significantly lower values of average voluntary contraction and RMS of the surface electromyography signals in the older age group compared to the younger age group (p = 0.029 and p = 0.045, respectively). There was no statistically significant association between age and muscle damage (χ²(2) = 2.86, p > 0.05). There was no correlation between average voluntary contraction and the degree of ultrastructural damage in both groups (Spearman’s coefficient equaled 0.06923 and 0.64366, respectively). Conclusions: sEMG measurements are valuable for monitoring age-related functional changes in the orbicularis. Aging diminishes the functional capacity of the orbicularis, as evidenced by reduced contraction strength. This study, the first to compare ultrastructural and electromyographical changes in the orbicularis among dermatochalasis patients of different ages, finds that ultrastructural damage to muscle fibers is not directly responsible for the contraction strength decline. Full article

The latest World Health Organization (WHO) classification of central nervous system tumors (WHO2021/5th) has incorporated molecular information into the diagnosis of each brain tumor type including diffuse glioma. Therefore, an artificial intelligence (AI) framework for learning histological patterns and predicting important genetic events would be useful for future studies and applications. Using the concept of multiple-instance learning, we developed an AI framework named GLioma Image-level and Slide-level gene Predictor (GLISP) to predict nine genetic abnormalities in hematoxylin and eosin sections: IDH1/2, ATRX, TP53 mutations, TERT promoter mutations, CDKN2A/B homozygous deletion (CHD), EGFR amplification (EGFRamp), 7 gain/10 loss (7+/10−), 1p/19q co-deletion, and MGMT promoter methylation. GLISP consists of a pair of patch-level GLISP-P and patient-level GLISP-W models, each pair of which is for a genetic prediction task, providing flexibility in clinical utility. In this study, the Cancer Genome Atlas whole-slide images (WSIs) were used to train the model. A total of 108 WSIs from the Tokyo Women’s Medical University were used as the external dataset. In cross-validation, GLISP yielded patch-level/case-level predictions with top performances in IDH1/2 and 1p/19q co-deletion with average areas under the curve (AUCs) of receiver operating characteristics of 0.75/0.79 and 0.73/0.80, respectively. In external validation, the patch-level/case-level AUCs of IDH1/2 and 1p/19q co-deletion detection were 0.76/0.83 and 0.78/0.88, respectively. The accuracy in diagnosing IDH-mutant astrocytoma, oligodendroglioma, and IDH-wild-type glioblastoma was 0.66, surpassing the human pathologist average of 0.62 (0.54–0.67). In conclusion, GLISP is a two-stage AI framework for histology-based prediction of genetic events in adult gliomas, which is helpful in providing essential information for WHO 2021 molecular diagnoses. Full article

Traumatic brain injury (TBI) remains one of the leading causes of death. Because of the individual nature of the trauma (brain, circumstances and forces), humans experience individual TBIs. This makes it difficult to generalise therapies. Clinical management issues such as whether intracranial pressure (ICP), cerebral perfusion pressure (CPP) or decompressive craniectomy improve patient outcome remain partly unanswered. Experimental drug approaches for the treatment of secondary brain injury (SBI) have not found clinical application. The complex, cellular and molecular pathways of SBI remain incompletely understood, and there are insufficient experimental (animal) models that reflect the pathophysiology of human TBI to develop translational therapeutic approaches. Therefore, we investigated different injury patterns after acute subdural hematoma (ASDH) as TBI in a post-hoc approach to assess the impact on SBI in a long-term, human-sized porcine TBI animal model. Post-mortem brain tissue analysis, after ASDH, bilateral ICP, CPP, cerebral oxygenation and temperature monitoring, and biomarker analysis were performed. Extracerebral, intraparenchymal–extraventricular and intraventricular blood, combined with brainstem and basal ganglia injury, influenced the experiment and its outcome. Basal ganglia injury affects the duration of the experiment. Recognition of these different injury patterns is important for translational interpretation of results in this animal model of SBI after TBI. Full article

Background: Sphenoid wing meningiomas (SWM) frequently compress structures of the optic pathway, resulting in significant visual dysfunction characterized by vision loss and visual field deficits, which profoundly impact patients’ quality of life (QoL), daily activities, and independence. The objective of this study was to assess the impact of SWM surgery on patient-reported outcome measures (PROMs) regarding postoperative visual function. Methods: The Visual Function Score Questionnaire (VFQ-25) is a validated tool designed to assess the impact of visual impairment on quality of life. The questionnaire was distributed to a previously published study population in which shape radiomics were correlated with new cranial nerve deficits after SWM surgery. Results: A total of 42 patients (42/74; 56.8%) responded to the questionnaire. Of the 42 patients, 30 were female (71%) and 12 were male (29%). The multivariable analysis demonstrated that lower sphericity reflecting irregular SWM shape was associated with poorer VFQ-25 (OR: 6.8, 95% CI: 1.141.8, p = 0.039), while age was associated with lower VFQ-25 (OR: 27, 95% CI: 2.7−272.93, p = 0.005), too. Analysis of the subcategories of the VFQ-25 revealed significantly reduced general vision (p = 0.045), social functioning (p = 0.045), and peripheral vision (p = 0.017) in those with SWM with low sphericity. Conclusions: The study highlights that SWM surgery impacts postoperative visual function, with age and irregular SWM shape being associated with poorer postoperative VFQ-25 scores. VFQ-25 is a feasible tool to assess vision outcome in SWM surgery and has clinical potential for longitudinal follow-up evaluations. Irregular SWM shape should be considered during preoperative treatment planning and patient consultation regarding functional outcome. Full article

Despite the fact that there are published case reports and model work providing evidence of inflammation in Charcot–Marie–Tooth disorders (CMTs), in clinical practice, CMT and inflammatory neuropathies are always classified as two separate groups of disorders. This sharp separation of chronic neuropathies into two groups has serious clinical implications. As a consequence, the patients harboring CMT mutations are practically excluded from pharmacological anti-inflammatory treatments. In this review, we present that neuropathological studies of peripheral nerves taken from some patients representing familial aggregation of CMTs revealed the presence of inflammation within the nerves. This shows that neurodegeneration resulting from germline mutations and the inflammatory process are not mutually exclusive. We also point to reports demonstrating that, at the clinical level, a positive response to anti-inflammatory therapy was observed in some patients diagnosed with CMTs, confirming the role of the inflammatory component in CMT. We narrowed a group of more than 100 genes whose mutations were found in CMT-affected patients to the seven most common (MPZ, PMP22, GJB1, SEPT9, LITAF, FIG4, and GDAP1) as being linked to the coexistence of hereditary and inflammatory neuropathy. We listed studies of mouse models supporting the idea of the presence of an inflammatory process in some CMTs and studies demonstrating at the cellular level the presence of an inflammatory response. In the following, we discuss the possible molecular basis of some neuropathies involving neurodegenerative and inflammatory processes at both the clinical and morphological levels. Finally, we discuss the prospect of a therapeutic approach using immunomodulation in some patients affected by CMTs. Full article

Background/Objectives: Toxoplasma gondii (T. gondii), an obligate food-borne intracellular parasite, causes severe neuropathology by establishing a persistent infection in the host brain. We have previously shown that T. gondii infection induces severe neuropathology in the brain manifested by increased nitric oxide production, oxidative stress, glial activation/BBB damage, increased pro-inflammatory cytokine glia maturation factor-beta and induced apoptosis. Methods: The aim of this experimental study was to investigate the serum amyloid P (SAP) components, nuclear factor kappa B (NF-κB), interleukin-1 beta (IL-1β), caspase 1 (Casp 1), tumor necrosis factor-alpha (TNF-α) and complement 3 (C3) gene expressions on the 10th, 20th and 30th days after infection with T. gondii in the neuroimmunopathogenesis of toxoplasmic encephalitis (TE) in mouse brains by real-time quantitative polymerase chain reaction. The study also aimed to determine whether there was a correlation between the markers included in the study on these critical days, which had not previously been investigated. The mRNA expression levels of SAP components, NF-κB, IL-1β, Casp 1, TNF-α and C3 were examined. Results: The most notable outcome of this investigation was the observation that SAP components exhibited a 13.9-fold increase on day 10 post-infection, followed by a rapid decline in the subsequent periods. In addition, IL-1β expression increased 20-fold, while SAP components decreased 13-fold on day 20 after infection. Additionally, the TNF-α, Casp 1 and NF-κB expression levels were consistently elevated to above normal levels at each time point. Conclusions: This study identified SAP components, NF-κB, IL-1β, Casp 1 and TNF-α expressions as playing critical roles in TE neuroimmunopathogenesis. Furthermore, to the best of our knowledge, this is the first study to investigate SAP components during the transition from acute systemic infection to early/medium chronic and chronic infection and to explore the relationship between SAP components and other nuclear factors/pro-cytokines. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management. Full article

Background: Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy, often associated with hippocampal sclerosis (HS), which involves selective neuronal loss in the Cornu Ammonis subregion 1 CA1 and CA4 regions of the hippocampus. Granule cells show migration and mossy fiber sprouting, though the mechanisms remain unclear. Microglia play a role in neurogenesis and synaptic modulation, suggesting they may contribute to epilepsy. This study examines the role of microglia and axonal guidance molecules in neuronal reorganization in TLE. Methods: Nineteen hippocampal samples from patients with TLE undergoing epilepsy surgery were analyzed. Microglial activity (M1/M2-like microglia) and neuronal guidance molecules were assessed using microscopy and semi-automated techniques. Gene expression was evaluated using the nCounter Expression Profiling method. Results: Neuronal cell loss was correlated with decreased activity of the M1 microglial phenotype. In the CA2 region, neuronal preservation was linked to increased mossy fiber sprouting and microglial presence. Neuronal markers such as Deleted in Colorectal Cancer (DCC) and Synaptopodin were reduced in areas of cell death, while Netrin-1 was elevated in the granule cell layer, potentially influencing mossy fiber sprouting. The nCounter analysis revealed downregulation of genes involved in neuronal activity (e.g., NPAS4, BCL-2, GRIA1) and upregulation of IκB, indicating reduced neuroinflammation. Conclusions: This study suggests reduced neuroinflammation in areas of neuronal loss, while regions with preserved neurons showed mossy fiber sprouting associated with microglia, Netrin-1, and DCC. Full article

(1) Background: Impeded resolution of inflammation contributes substantially to the pathogenesis of Alzheimer’s disease (AD); consequently, resolving inflammation is pivotal to the amelioration of AD pathology. This can potentially be achieved by the treatment with specialized pro-resolving lipid mediators (SPMs), which should resolve neuroinflammation in brains. (2) Methods: Here, we report the histological effects of long-term treatment with an SPM, maresin-like 1 (MarL1), on AD pathogenesis in a transgenic 5xFAD mouse model. (3) Results: MarL1 treatment reduced Aβ overload, curbed the loss of neurons in brains especially cholinergic neurons associated with cleaved-caspase-3-associated apoptotic degeneration, reduced microgliosis and the pro-inflammatory M1 polarization of microglia, curbed the AD-associated decline in anti-inflammatory Iba1⁺Arg-1⁺-M2 microglia, inhibited phenotypic switching to pro-inflammatory N1 neutrophils, promoted the blood–brain barrier-associated tight-junction protein claudin-5 and decreased neutrophil leakage in 5xFAD brains, and induced the switch of neutrophils toward the inflammation-resolving N2 phenotype. (4) Conclusions: Long-term administration of MarL1 mitigates AD-related neuropathogenesis in brains by curbing neuroinflammation and neurodegeneration, based on the histological results. These findings provide preclinical leads and mechanistic insights for the development of MarL1 into an effective modality to ameliorate AD pathogenesis. Full article

The overlapping molecular pathophysiology of Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph of 33+ million biomedical journal articles. The unsupervised learning rank aggregation algorithm from SemNet 2.0 compared the most important amino acid, peptide, and protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% of its nodes with ALS and AD; AD shared 64.2% of its nodes with FTD and ALS; and ALS shared 68.3% of its nodes with AD and FTD. The results were validated and mapped to functional biological processes using supervised human supervision and an external large language model. The overall percentages of mapped intersecting biological processes were as follows: inflammation and immune response, 19%; synapse and neurotransmission, 19%; cell cycle, 15%; protein aggregation, 12%; membrane regulation, 11%; stress response and regulation, 9%; and gene regulation, 4%. Once normalized for node count, biological mappings for cell cycle regulation and stress response were more prominent in the intersection of AD and FTD. Protein aggregation, gene regulation, and energetics were more prominent in the intersection of ALS and FTD. Synapse and neurotransmission, membrane regulation, and inflammation and immune response were greater at the intersection of AD and ALS. Given the extensive molecular pathophysiology overlap, small differences in regulation, genetic, or environmental factors likely shape the underlying expressed disease phenotype. The results help prioritize testable hypotheses for future clinical or experimental research. Full article