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Formic acid treatment is widely used in diagnostic neuropathology to reduce the infectivity of prion-containing tissues; however, quantitative in vivo evidence supporting its effectiveness under routine laboratory conditions remains limited. Here, we assessed the impact of formalin fixation and formic acid treatment on the infectivity of type 1 sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD) prions using highly sensitive transgenic mouse models overexpressing human-PrP M129 (Hu-Tg340) or bovine PrP (Bo-Tg110). Brain tissues were processed under conditions closely resembling standard histopathological workflows and tested as untreated, formalin-fixed or formalin-plus-formic-acid-treated inocula. Untreated samples produced short incubation times and full attack rates, whereas formalin fixation caused only a modest prolongation of incubation times. In contrast, formic acid treatment markedly extended incubation times and reduced attack rates for sCJD. Based on incubation-time interpolation, the estimated infectivity reductions were on the order of 4.4 log₁₀ for vCJD and 5 log₁₀ for sCJD. These estimates indicate a major reduction in infectious titre under the conditions tested, although residual infectivity was still detected. The findings support formic acid treatment as an important risk-reduction step in routine neuropathology workflows for the two prion strains examined.

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are inflammatory disorders of the CNS with distinct immunopathologic mechanisms and treatment responses and partially overlapping clinical phenotypes. The identification of aquaporin-4 (AQP4)-IgG and MOG-IgG has transformed disease classification and diagnosis, enabled a classification of antibody-defined subgroups, and facilitated the development of targeted therapies. However, optimal use of these biomarkers in clinical practice requires careful interpretation within the appropriate clinical and radiologic context. This review synthesizes current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility. We review antibody detection using cell-based assays, highlighting differences between live and fixed platforms and the impact of antigen conformation on sensitivity and specificity, particularly for MOG-IgG. Common causes of false-positive and false-negative results are discussed, including low-titer reactivity, testing in low pretest probability populations, treatment-related antibody titer reduction, and assay-specific limitations. The diagnostic challenges posed by indiscriminate testing in adult cohorts with multiple sclerosis, in whom disease prevalence markedly exceeds that of MOGAD, are emphasized. We also discuss the role of repeat testing during acute attacks and paired serum-CSF analysis in improving diagnostic confidence when results are equivocal or discordant. Beyond disease-defining antibodies, we examine biomarkers of tissue injury and immune activation. Serum and CSF neurofilament light chain and glial fibrillary acidic protein provide complementary measures of neuroaxonal and astrocytic damage and show associations with attack severity, disease activity, relapse risk, and long-term disability. Cytokines, chemokines, and complement components reflect inflammatory pathways, including IL-6-driven immune activation in NMOSD and MOGAD and complement-mediated astrocytopathy in NMOSD, and may support mechanistic stratification and treatment monitoring in both conditions. We further review the contribution of CSF analysis, neuropathology, genetics, and antigen discovery platforms to refine disease classification, particularly in seronegative or atypical presentations. Finally, we outline priorities for future research, including assay harmonization, standardized sampling protocols, longitudinal biomarker profiling, and integrative multiomic approaches. Collectively, advances in biomarker science have the potential to improve diagnostic precision, guide individualized therapeutic strategies, and support de-escalation decisions in NMOSD and MOGAD.

Peak-width of skeletonized mean diffusivity (PSMD) and diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), reflecting white matter integrity and glymphatic function, are altered in Alzheimer's disease (AD). We evaluated whether these biomarkers differ between AD participants with and without concomitant cerebral amyloid angiopathy (CAA). The study included 50 AD participants with mild cognitive impairment/mild dementia, and intermediate to high AD neuropathologic change at autopsy. AD was categorized as AD with CAA and AD without CAA based on CAA neuropathology. We evaluated global and regional (frontal, parietal, temporal and occipital) PSMD; left, right and mean DTI-ALPS indices and their association with clinical measures [Clinical dementia rating sum-of-boxes (CDR-SB) from CDR Dementia Staging Instrument, mini mental state examination (MMSE), cognitive composites: memory, processing speed, executive function, and language]. AD participants with CAA (n = 17) had higher global [4.02 ± 1.44 (mean ± SD × 10-4 mm2/s) vs. 3.12 ± 0.91, β = -0.80, 95% CI (-1.42, -0.18), p = 0.012] and occipital PSMD [4.02 ± 1.10 vs. 3.00 ± 1.08, β = -0.88, 95% CI (-1.51, -0.26), p = 0.026] than those without CAA. No PSMD metric was associated with any clinical measure. However, imaging-by-group interactions showed global PSMD associated with language [β = -0.89, 95% CI (-1.53, -0.26), p = 0.027] and parietal PSMD with language [β = -1.05, 95% CI (-1.74, -0.36), p = 0.014] and memory [β = -0.83, 95% CI (-1.38, -0.28), p = 0.015]. DTI-ALPS indices did not differ by group. Higher mean and right DTI-ALPS indices were associated with preserved language function [mean: β = 9.33, 95% CI (2.05, 16.62), p = 0.036; right: β = 7.75, 95% CI (1.54, 13.95), p = 0.043] without imaging-by-group interactions. Global and occipital PSMD may help identify AD participants with concomitant CAA.

Sleep loss is a major risk factor for neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), accelerating cognitive impairment with neuropathology. Cumulative sleep loss impairs the glymphatic system, reduces amyloid-β clearance, and enhances the neuroinflammatory response, all of which contribute to the development of neurodegeneration. Given the orexin system's essential role in modulating sleep-wake rhythms, orexin receptor antagonists such as Suvorexant are potent candidates for treating sleep disturbances and cognitive decline associated with neurodegenerative conditions. Suvorexant promotes sustained sleep without the side effects commonly associated with sleep-inducing drugs, such as drowsiness and cognitive impairment, potentially offering a neuroprotective approach by selectively antagonizing orexin receptors. By inhibiting excessive orexin signaling in the brain, Suvorexant may benefit other neurodegenerative diseases. Preclinical studies support the idea that improving sleep quality, as seen with Suvorexant, can normalize sleep architecture, leading to reduced tau phosphorylation and amyloid plaque deposition, both of which are pathological hallmarks of AD. Furthermore, enhanced sleep quality may bolster synaptic plasticity and aid in memory consolidation, potentially counteracting cognitive deterioration. Although most research has been conducted in AD, the putative applications of Suvorexant in PD and other tauopathies are worth exploring, especially given the common involvement of sleep disturbances in these diseases. Animal studies show that Suvorexant not only promotes sleep but also prevents neuronal damage, suggesting its dual therapeutic potential. Long-term clinical trials are necessary, however, to prove its effectiveness in humans, especially in populations at risk for sleep disorders and early neurodegenerative alterations. Suvorexant could be a novel approach to slow cognitive decline and improve quality of life in patients with AD, PD, and related diseases, highlighting the vital interplay between sleep and brain health.

Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathological change (LATE-NC) is a cause of dementia resembling Alzheimer's disease (AD). The 90+ Study found women using hormone replacement therapy (HRT) two to three decades before death had lower odds of LATE-NC. We attempted to replicate this finding in a different cohort. Participants (n = 2056) included males (n = 640) and females (n = 1416) aged ≥65 from the Religious Orders Study and Memory and Aging Project with HRT and neuropathology data. We examined the association between HRT and LATE-NC in males and females and between HRT-related and reproductive variables in relation to LATE-NC in females using logistic regression. HRT use within 5 years before or after menopause (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.50 to 0.98, p = 0.03) or for 8 to 16 years (OR = 0.44, 95% CI = 0.24 to 0.79, p = 0.006) was associated with lower odds of LATE-NC. This finding identifies a potential factor related to LATE risk and highlights the importance of HRT timing and duration for its potential neuroprotective effects.

Manganese (Mn) is an essential metal required for many physiological functions, and deficiency or over-exposure is associated with neurological dysfunction and neuropathology. Tight homeostatic control of Mn in the body is required to maintain optimal physiological levels and protect against toxicity. Mn homeostasis has been studied for decades, but there has been limited knowledge of the molecular mechanisms until recently, when the first human genetic disorders of Mn metabolism were described. These discoveries led to the identification of the Mn transporters SLC30A10, SLC39A14, and SLC39A8, which spurred a transformation of research into Mn homeostatic mechanisms. This review will provide an overview of Mn physiology and homeostasis, the role of the critical Mn transporters, and discuss the progress made within recent years towards understanding how these transporters work together to regulate brain Mn biology under both physiological and pathophysiological Mn conditions.

Alzheimer's disease and related dementias (ADRD) typically involve multiple, overlapping pathologies-such as amyloid-β (Aβ), tau, cerebral amyloid angiopathy (CAA), TDP-43, hippocampal sclerosis, and alpha-synuclein-that complicate diagnosis and treatment. While PET and CSF biomarkers can detect abnormal levels of Aβ and tau, they are invasive, expensive, and not widely available. By contrast, structural magnetic resonance imaging (MRI) offers a non-invasive and scalable alternative, one that is now showing promise for neuropathological prediction when combined with artificial intelligence methods. Prior efforts have largely focused on inferring single pathologies such as abnormal Aβ; however, there is a pressing need for models that can jointly predict multiple co-occurring pathologies. In this work, we develop and evaluate a hybrid deep learning framework that integrates 3D T1-weighted brain MRI with demographic, clinical, and genetic covariates to make inferences, in living individuals, regarding the presence of six ADRD pathologies. The models are trained and tested using autopsy-confirmed neuropathology from individuals who were scanned while they were alive. Based on their strong performance on related tasks, we evaluate two machine learning models: (1) a deep learning algorithm based on a 3D convolutional neural network, a widely used model in computer vision applications, and (2) AutoGluon, an automated machine learning framework that automatically selects an approach for the problem. Each method can use both imaging and non-imaging covariates as inputs. To improve model transparency, we incorporate explainable AI methods-including occlusion sensitivity analysis (OSA), Grad-CAM, and Integrated Gradients (IG)-to interpret the spatial contribution of brain regions to model predictions. Finally, we compare the resulting feature importance maps ('salience maps') with traditional voxel-based morphometry (VBM) analyses to assess their biological plausibility. Our findings show the promise of multimodal, interpretable AI approaches for comprehensive, non-invasive profiling of dementia-related pathologies.

Zika virus (ZIKV) causes congenital disease and neurological complications, yet no approved vaccines or antivirals are available. Integrin β4 (ITGB4) has been identified as an entry receptor for ZIKV. Recombinant human ITGB4 ectodomain was expressed using a baculovirus-insect cell system and used to immunize BALB/c mice. Hybridoma screening identified monoclonal antibody 7C3. Binding affinity to ITGB4 was determined by biolayer interferometry. Epitope relationships between 7C3 and the previously reported anti-ITGB4 antibody 13H10 were assessed by competitive binding assay. Antiviral activity was evaluated in four cell lines by RT-qPCR quantification of cell-associated ZIKV RNA after antibody pretreatment and viral challenge. 7C3 bound ITGB4 with picomolar affinity (KD=30.9 pM) and high specificity. Competitive binding showed that 7C3 and 13H10 (KD=7.98 pM) recognize non-overlapping epitopes on ITGB4. Pretreatment with 7C3 significantly reduced cell-associated ZIKV RNA in all four cell lines compared with PBS and isotype controls. A second, independently generated anti-ITGB4 antibody with picomolar affinity can robustly block ZIKV entry across multiple cell types, including SY5Y neuroblastoma cells relevant to congenital neuropathology. The non-overlapping epitopes of 7C3 and 13H10 suggest potential for combination strategies to enhance ITGB4 blockade. High germline identity of the 7C3 variable regions (VH=94.46%, VL=95.82%) supports future humanization. These findings establish 7C3 as a host-directed antiviral candidate and provide a basis for ITGB4-targeting approaches against congenital ZIKV disease.

Primary microglia are essential for studying neuroinflammation and microglia-mediated neuropathology. However, conventional shaking-based isolation methods often yield unstable purity, astrocytic contamination, and heterogeneous activation states. We developed a multidimensional optimization strategy for primary rat microglia isolation by systematically integrating three key parameters: neonatal developmental stage, culture vessel geometry, and Percoll density gradient purification. Microglial purity, identity, viability, and functional responsiveness were evaluated by flow cytometry, immunofluorescence, Western blotting, qPCR, and ELISA. Compared with postnatal day 7 (P7), postnatal day 3 (P3) tissue provided higher isolation efficiency, greater culture homogeneity, and reduced astrocytic contamination. Culture in 6-cm dishes improved cell adhesion and morphological consistency. Percoll density gradient purification further increased microglial purity by approximately 20-30% while maintaining acceptable cell recovery. The optimized protocol consistently yielded cultures with stable purity (80-90%), high IBA1 positivity (>90%), increased metabolic activity, and lower basal activation. Following lipopolysaccharide stimulation, purified microglia exhibited robust inflammatory responses, including increased cytokine secretion and inflammatory gene expression. Compared with conventional shaking-based isolation, the optimized workflow improves purity, reduces contamination, enhances reproducibility, and preserves functional responsiveness without requiring specialized equipment. This study provides a practical and reproducible strategy for improving microglial purity and experimental consistency and offers a reliable experimental platform for neuroinflammation research and mechanistic studies.

A growing body of evidence indicates that the oral and gut microbiota are closely linked to central nervous system (CNS) diseases, and their bacterial extracellular vesicles (BEVs) play a significant role in disease pathogenesis. BEVs can cross the blood-brain barrier, deliver bioactive cargo to host cells, and participate in disease processes. Notably, BEVs exhibit a functional dichotomy in which pathogen-derived BEVs promote neuropathology while probiotic-derived and engineered BEVs exert protective effects. In this review, we systematically examine this dual role of oral- and gut-derived BEVs in CNS diseases, covering their pathogenic mechanisms, protective and therapeutic effects, and emerging applications as diagnostic biomarkers. We also highlight key challenges limiting clinical translation and outline future directions for the field.

Bilingualism offers a powerful test case for understanding how control systems adapt to sustained, variable attentional demands. Converging evidence across behavioral, structural, functional, and clinical literatures indicates that repeated demands for selection, conflict resolution, and language switching are associated with reorganization of control architecture in ways that are consistent with predictive and reinforcement-learning mechanisms, producing two interdependent outcomes. Efficiency emerges as control is redistributed from metabolically costly frontal regions to posterior and subcortical circuits, potentially supported by cortico-striatal learning, cerebellar calibration, and thalamic coordination. Reserve emerges as white matter tracts strengthen, functional connectivity becomes more integrated, and redundancy develops across distributed networks, enabling rerouting when primary pathways deteriorate. Together, these adaptations provide a candidate account for why bilinguals often show equal or greater neuropathology at diagnosis yet maintain cognition longer, exhibiting delayed, but not prevented, clinical expression of dementia. This article synthesizes evidence across domains to present a candidate mechanistic account of experience-driven neural adaptation and generates explicit testable predictions for longitudinal imaging, multimodal biomarkers, reinforcement-learning signatures, and clinical resilience. More broadly, bilingualism illustrates a general principle: attentional control systems reorganize in response to repeated demands, yielding more efficient and more resilient cognition across the lifespan.

Alzheimer's disease neuropathologic change (ADNC) and limbic-predominant age-related transactive response DNA-binding protein 43 kDa (TDP-43) encephalopathy neuropathologic change (LATENC) are common in older adults, yet differences in brain morphometry patterns when one or both pathologies are present remain unclear. We used deformation-based morphometry on ex-vivo MRI from 912 community-based older adults to compare groups with or without ADNC and/or LATENC. AD+LATE- and AD-LATE+ groups showed less tissue in the medial temporal lobe than AD-LATE-. The AD+LATE+ group had less tissue in temporal, frontal, and parietal lobes. The AD-LATE+ group exhibited smaller anterior hippocampi than the AD+LATE- group. These findings were less pronounced in individuals without dementia. Increments in LATENC stages were associated with smaller hippocampi than increments in ADNC severity, independent of the severity of comorbid ADNC or LATENC, respectively. These findings reveal distinct and overlapping brain morphometry patterns associated with ADNC and/or LATENC, with possible implications for diagnosis in older adults.

Nucleoporins (NUPs) constitute the nuclear pore complex (NPC) and are essentially involved in nuclear transport, chromatin organization, and context-dependent gene regulation. However, the role of NUPs in neuroendocrine (tumor)biology and related diagnostic potential is poorly defined. In this study, we comparatively analyzed immunohistochemical expression patterns of NUP98 and NUP153 (sharing structural and functional similarities) across a large variety of human tissues and tumors (total N > 600), with a focus on neuroendocrine neoplasms (NENs (n = 361)). While both NUPs showed a nuclear rim accentuated staining pattern, NUP98 exhibited ubiquitous and NUP153 a striking cell- and tissue/tumor-type-dependent immunoreactivity. More specifically, NUP153 immunoreactivity was consistently detectable in neuroendocrine tissues (e.g., pancreatic islets) and retained in neuroendocrine tumors (NETs) of the pancreas, lung, appendix, and small intestine, but almost completely absent in neuroendocrine carcinomas (NECs) and non-neuroendocrine carcinomas. Loss of NUP153 staining correlated with poorer clinical outcomes in pancreatic NETs. Further analyses revealed that NUP153 messenger ribonucleic acid (mRNA) and total protein levels were not significantly different between NETs and non-neuroendocrine carcinomas, as evaluated by quantitative real-time polymerase chain reaction and targeted proteomics. Differential isoform usage was ruled out by polymerase chain reaction and sequencing as another possible explanation for the discriminative immunohistochemical findings. Finally, a high density of post-translational modifications (PTMs) within the antigen sequence could be discovered and indicated PTM-dependent detection as the likely cause of differential staining. Collectively, our findings suggest that NUP153 is a differentiation-dependent and PTM-sensitive immunohistochemical marker in NENs with diagnostic and prognostic potential. It also emphasizes the importance of orthogonal molecular analyses for correct interpretation of IHC stainings.

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