INTRODUCTION:Lecanemab, the first disease-modifying therapy for Alzheimer's disease (AD), mitigates pathology primarily by clearing amyloid plaques, but its impact on peripheral immunity remains unclear. METHODS:To assess Lecanemab's immunological effects, we performed antibody array analysis of serum and single-cell RNA sequencing of peripheral blood mononuclear cells collected from healthy controls and patients with AD at baseline, 3, and 6 months post-treatment. RESULTS:Lecanemab restored multiple serum chemokines to healthy levels in patients with AD. Compared to controls, baseline samples from patients with AD showed altered frequencies and functions of naïve and unswitched memory (UswM) B cells. Lecanemab treatment corrected the abnormal naïve and UswM B cell proportions and rebuilt their functional homeostasis by alleviating chronic inflammation and reversing the dysregulation of key pathways including immune response, NF-κB, RAGE, and cell adhesion. DISCUSSION:These findings uncover a novel peripheral immunomodulatory mechanism of Lecanemab, offering new insights into AD therapeutics.

Background Template-based PET metrics quantify Alzheimer disease (AD) amyloid-β (Aβ) and tau burden but compress whole-brain data into a single scalar, overlooking disease heterogeneity and sometimes causing imaging-clinical discordance. Artificial intelligence (AI) approaches capture richer patterns but often lack biologic interpretability. Purpose To develop and validate an interpretable deep-learning framework that separates AD-specific abnormalities from physiologic uptake using pathophysiologic constraints, generating a clinically meaningful AI biomarker. Materials and Methods In this retrospective study, Aβ and tau PET scans from the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging Biomarkers and Lifestyle study, Global Alzheimer's Association Interactive Network, and the authors' center were analyzed. An adversarial decomposition learning (ADL) network generated voxel-level pathologic maps and an AD adversarial decomposition (ADAD) score. Discriminatory performance for clinical AD versus cognitively normal individuals was evaluated using the area under the curve (AUC). Clinical relevance was assessed with cognitive, hippocampal volume, cerebrospinal fluid (CSF), and neuropathologic measures using longitudinal mixed-effects models and Spearman correlations. Results The study included 7457 Aβ PET scans from 3595 patients (median age, 71.4 years; IQR, 65.7-77.0 years; 1637 female patients) and 1894 tau PET scans from 1127 patients (median age, 72.0 years; IQR, 66.9-78.5 years; 545 female patients). External testing AUCs were 0.94 (95% CI: 0.89, 0.98) for Aβ and 0.98 (95% CI: 0.95, 1.00) for tau. ADL generated interpretable pathologic attribution maps that correlated with expert rankings (Aβ and tau, Spearman ρ = 0.79 and 0.63, respectively). Although Centiloid and CenTauRz showed numerically higher correlations with postmortem neuropathologic structure and stronger associations with CSF biomarkers, the ADAD score demonstrated independent baseline and longitudinal associations with cognitive outcomes and hippocampal atrophy after adjustment. Conclusion Pathophysiologic-constrained ADL provided interpretable, personalized pathologic maps and an AI-derived ADAD score that more closely linked PET pathologic abnormalities with multimodal clinical measures. © RSNA, 2026 Supplemental material is available for this article.

Due to the low abundance of biomarkers, reliance on expensive instruments, and low reliability of singlebiomarker detection, it is necessary to develop economical, accurate, and user-friendly blood-based Alzheimer's disease (AD) diagnostic methods. In this study, a highly sensitive colorimetric and surface-enhanced Raman scattering (SERS) dual-readout lateral flow immunoassay (LFIA) was developed to simultaneously detect two core AD biomarkers in plasma samples within 25 min, including A beta 42 oligomers (A beta 42O) and tau phosphorylated at Ser396 and Ser404 (p-tau396,404). The assay leverages conformation-selective antibody pairs and high signal-to-noise ratio SERS nanotags to achieve femtomolar sensitivity, long signal lifetime, and strong anti-interference performance. Clinical evaluations demonstrated that the dual-target LFIA method effectively differentiated AD patients from cognitively normal elderly individuals, with a sensitivity and specificity of 86.7 % and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.933, which is superior to the single-target assay. The economical and portable design of the dual-target LFIA enables rapid, accurate, and scalable detection, highlighting its potential as a practical tool for point-of-care diagnostics and large-scale community self-screening of AD.

Background: Post-stroke depression (PSD) is a common complication of stroke, in which neuroinflammation plays a crucial role. Depression resilience has garnered significant attention in recent years, yet its relevance to PSD remains unexplored. Methods: In this study, we assessed emotional behaviors in C57BL/6 mice subjected to stereotaxic injection of endothelin-1 (ET1). Subsequently, hippocampal samples were collected to analyze the levels of NLRP3/NF-κB, along with microglial activation in the hippocampus. Results: The results showed that ET1 injection induced depressive-like behaviors in a subset of rodents. However, a subset of mice showed no statistically significant differences from the control group in measures from the open field test (OFT), elevated plus maze (EPM), tail suspension test (TST), and forced swim test (FST), demonstrating depression resilience to PSD. Furthermore, PSD animals exhibited activated microglia and NLRP3/NF-κB activation, whereas these markers in the resilient group showed no significant difference compared to controls. Conclusions: This study provides evidence that depression resilience exists in a PSD model, and it suggests that the microglia-NLRP3 signaling axis may participate in this resilient phenotype. These findings offer potential intervention targets for the clinical prevention and treatment of PSD.

Abstract Blood-based biomarkers have great potential for the early diagnosis of Alzheimer’s disease (AD); however, their implementation in primary healthcare screening remains largely limited owing to their reliance on sophisticated instruments and complex procedures. Furthermore, the complexity of the biological matrix poses a significant challenge to detection without washing and the use of reagents. Herein, we report a single-pot electrochemical sensing platform that enables rapid and ultrasensitive quantitative detection of AD biomarkers directly from untreated blood or plasma within 20 min of collection, without sample preparation, washing, or using additional reagents. This platform integrated high-affinity antibodies with an electric field-driven sensing mechanism based on a molecular pendulum. Upon the application of a potential, a negatively charged DNA scaffold moved directionally toward the electrode, enabling the real-time dynamic detection of surface-confined redox reporters and precise biomarker quantification. We validated the platform in 80 clinical plasma samples using Aβ42 and p-tau217 as representative biomarkers. We found that combined biomarker analysis outperformed single-analyte detection and achieved an area under the curve of 0.9475, with 82.5% sensitivity and 92.5% specificity. This work establishes a truly wash-free and reagentless electrochemical sensing strategy, showing great potential for early diagnosis of AD in community or home settings.

BACKGROUND:Neuropsychiatric symptoms (NPS) in mild cognitive impairment (MCI) are associated with accelerated Alzheimer's disease (AD) progression. Identifying multimodal brain imaging patterns associated with NPS in MCI may help understand pathophysiology correlates AD. METHODS:This cross-sectional resting-state functional magnetic resonance imaging study included 376 participants: 130 MCI with neuropsychiatric symptoms (MCI+NPS), 154 MCI without neuropsychiatric symptoms (MCI-NPS), 92 cognitively normal (CN). NPS were assessed by the Neuropsychiatric Inventory Questionnaire (NPI-Q). Functional connectivity between default mode network (DMN) and salience network (SN) was compared among MCI+NPS, MCI-NPS and CN. Then, the morphometric measurements of abnormal node in default mode and salience networks was explored. Furthermore, correlation analysis was performed to investigate the relationship between NPS and functional and structural alterations in DMN and SN in MCI. RESULTS:In the MCI+NPS group, the most frequently endorsed NPS was anxiety (46.2 %), the less prevalent NPS was euphoria/elation (1.44 %). Compared with the MCI-NPS group, there was abnormal FC between medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) (P < 0.05) in the MCI+NPS group, which was significantly associated with total NPI-Q score (r = 0.244, p = 0.000), affective symptoms (r = 0.212, p = 0.000), and hyperactivity symptoms (r = 0.196 p = 0.000). The mPFC area of MCI-NPS group was smaller than that of CN group (p < 0.05), and the area of mPFC was significantly associated with hyperactivity symptoms in MCI group. CONCLUSIONS:Dysfunction of DMN and SN may partly contribute to the NPS in MCI patients, especially affective symptoms and hyperactivity symptoms. Our results complement the evidence linking NPS with Alzheimer's disease biomarkers.

The characteristic events in neurodegenerative diseases (NDDs) encompass protein misfolding, aggregation, accumulation, and their related cellular dysfunction, synaptic function loss. While distinct proteins are implicated in the pathological processes of different NDDs, the process of protein misfolding and aggregation remains notably similar across various conditions. Specifically, proteins undergo misfolding into beta-folded (β-folded) conformation, resulting in the formation of insoluble amyloid proteins. Despite advancements in comprehending protein aggregation, certain facets of this intricate process remain incompletely elucidated. In recent years, the concept that long non-coding RNAs (lncRNAs) contribute to protein aggregation has gained recognition. LncRNAs influence the formation of protein aggregates by facilitating protein overexpression through the regulation of gene transcription and translation, inhibiting protein degradation via lysosomal and autophagic pathways, and targeting aberrant modifications and phase transitions of proteins. A better understanding of the relationship between lncRNAs and aberrant protein aggregation is an important step in dissecting the underlying molecular mechanisms and will contribute to the discovery of new therapeutic targets and strategies. HIGHLIGHTS: NDDs are marked by protein misfolding, aggregation, and accumulation, leading to cellular dysfunction and loss of synaptic function. Despite different proteins being involved in various NDDs, the process of misfolding into β-folded conformations and forming insoluble amyloid proteins is consistent across conditions. The role of lncRNAs in protein aggregation has gained attention, as they regulate gene transcription and translation, inhibit protein degradation, and target aberrant protein modifications. Understanding the link between lncRNAs and protein aggregation is crucial for uncovering molecular mechanisms and developing new therapeutic targets.

The molecular mechanisms of early-onset multigenerational diabetes remain unknown. This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations. From 1296 inpatients with diabetes, we selected individuals who were ≤ 30 years of age and who were clinically suspected of having familial monogenic diabetes. Clinical data were collected from the probands and their family members. Whole-exome sequencing (WES) was used to identify possible causal variants for diabetes. Candidate pathogenic variants were verified by Sanger sequencing, assessed for cosegregation in family members, and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Moreover, missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2. RNAfold was used to predict RNA structural alterations for synonymous variants. Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled. Pathogenic/likely pathogenic variants (p.Gly292fs in HNF1A, p.Gly245Argfs*22 in PDX1, p.Asp329His in KCNJ11, p.Leu734Phe and p.Val606Gly in WFS1) were detected in four patients, who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results. The variants of uncertain significance (ABCC8 c.3039 G > A (p.Ser1013 = Ser), MAPK8IP1 p.Gln144_Gly145insSerGln, and TBC1D4 p.Arg1249Trp) were identified in three probands. Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants. Genetic testing in this population enables precision diagnosis, informs individualized treatment, and facilitates genetic counseling.

BACKGROUND:Cushing's syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters. METHODS:A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD. RESULTS:A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p < 0.001). CS patients had noticeably increased visceral fat but decreased skeletal muscle in comparison to their healthy counterparts. Higher prevalence of LVDD was found in CS patients based on LV diastolic function evaluated by E/A ratio (p < 0.001). EATV was proved to be an independent risk factor for LVDD in CS patients (OR = 1.015, 95%CI 1.003-1.026, p = 0.011). If the cut-point of EATV was set as 139.252 cm3 in CS patients, the diagnostic sensitivity and specificity of LVDD were 84.00% and 55.60%, respectively. CONCLUSION:CS was associated with marked accumulation of EAT and visceral fat, reduced skeletal muscle mass, and increased prevalence of LVDD. EATV was an independent risk factor for LVDD, suggesting the potential role of EAT in the development of LVDD in CS.

Blood exosomes are emerging as potential biomarkers for diagnosing brain diseases such as Alzheimer’s disease (AD). There is currently a lack of an ultrasensitive technology for identifying core AD biomarkers in blood exosomes to optimize the utility of biomarkers in clinical practice. Here, an immunomagnetic exosomal polymerase chain reaction (iMEP) platform was developed using DNA-conjugated antibodies for the rapid detection of amyloid-β (Aβ 1–40 and Aβ 1–42 ) and phosphorylated tau (p-tau 396,404 and p-tau 181 ) in clinical blood exosomes. The toehold shift–mediated DNA affinity pulldown eliminates the high detection background, which allows the detection of biomarkers at concentrations down to 10 femtograms per milliliter. With the iMEP assay, exosomal Aβ 1–42 was more accurate in differentiating patients with AD from healthy individuals compared with exosomal p-tau 181 and p-tau 396,404 , with a sensitivity of 95.0% and a specificity of 95.0%. The iMEP technique is also adept at quantifying the levels of different exosomal biomarkers associated with disease pathogenesis.

Purpose Early-onset Alzheimer disease (EOAD) is rare, highly heterogeneous, and associated with poor prognosis. This AT(N) Framework–based study aimed to compare multiprobe PET/MRI findings between EOAD and late-onset Alzheimer disease (LOAD) patients and explore potential imaging biomarkers for characterizing EOAD. Methods Patients with AD who underwent PET/MRI in our PET center were retrospectively reviewed and grouped according to the age at disease onset: EOAD, younger than 60 years; and LOAD, 60 years or older. Clinical characteristics were recorded. All study patients had positive β-amyloid PET imaging; some patients also underwent 18 F-FDG and 18 F-florzolotau PET. Imaging of the EOAD and LOAD groups was compared using region-of-interest and voxel-based analysis. Correlation of onset age and regional SUV ratios were also evaluated. Results One hundred thirty-three patients were analyzed (75 EOAD and 58 LOAD patients). Sex ( P = 0.515) and education ( P = 0.412) did not significantly differ between groups. Mini-Mental State Examination score was significantly lower in the EOAD group (14.32 ± 6.74 vs 18.67 ± 7.20, P = 0.004). β-Amyloid deposition did not significantly differ between groups. Glucose metabolism in the frontal, parietal, precuneus, temporal, occipital lobe, and supramarginal and angular gyri was significantly lower in the EOAD group (n = 49) than in the LOAD group (n = 44). In voxel-based morphometry analysis, right posterior cingulate/precuneus atrophy was more obvious in the EOAD ( P < 0.001), although no voxel survived family-wise error correction. Tau deposition in the precuneus, parietal lobe, and angular, supramarginal, and right middle frontal gyri was significantly higher in the EOAD group (n = 18) than in the LOAD group (n = 13). Conclusions Multiprobe PET/MRI showed that tau burden and neuronal damage are more severe in EOAD than in LOAD. Multiprobe PET/MRI may be useful to assess the pathologic characteristics of EOAD.

Background and purpose:Executive function impairment, a slight but noticeable cognitive deficit in mild cognitive impairment (MCI) patients, is influenced by gamma-aminobutyric acid (GABA) levels. Reduced cognitive function is accompanied by thinning of the cerebral cortex, which has higher GABA levels than white matter. However, the relationships among GABA levels, cortical thickness, and executive function in MCI patients have not yet been elucidated. We investigated the relationships among GABA levels, cortical thickness, and executive function in MCI patients.Methods:In this study, a total of 36 MCI patients and 36 sex-, age-, and education-matched healthy controls (HC) were recruited. But 33 MCI patients and 35 HC were included because of head motion or poor data quality for three MCI patients and one HC. The levels of gamma-aminobutyric acid plus relative to creatine (GABA+/Cr) and glutamate-glutamine relative to creatine (Glx/Cr) in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) were measured using the Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence. Metabolite ratios, cortical thickness, and executive function and their interrelationships were determined in the MCI and HC groups.Results:Patients with MCI showed lower GABA+/Cr levels in the ACC and PCC. Combined levels of GABA+ and Glx in the ACC and GABA+ in the PCC showed good diagnostic efficacy for MCI (AUC: 0.82). But no differences in cortical thickness were found between the two groups. In the MCI group, lower GABA+/Cr level was correlated to worse performance on the digit span test backward, and the shape trail test-B. The cortical thickness was not associated with GABA+ levels and executive function in patients.Conclusion:These results implied that decreased GABA levels in the ACC and PCC had a critical role in the early diagnosis of impaired executive function of MCI. Therefore, GABA in the ACC and PCC could be a potential diagnostic marker of the executive function decline of MCI.

Background: Stickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is an ultra-rare disease, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few pathogenic COL11A2 variants reported to date. Case presentation: A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in COL11A2, both of which were predicted to be splicing mutations. One is synonymous mutation c.3774C>T (p.Gly1258Gly) supposed to be a splice site mutation, the other is a novel intron mutation c.4750 + 5 G>A, which is a highly conservative site across several species. We also present a review of the current known pathogenic mutation spectrum of COL11A2 in patients with type 3 SS. Conclusion: Both synonymous extonic and intronic variants are easily overlooked by whole-exome sequencing. For patients with clinical manifestations suspected of SS syndrome, next-generation whole-genome sequencing is necessary for precision diagnosis and genetic counseling.

The complement system is crucial to the innate immune system. It has the function of destroying pathogens by activating the classical, alternative, and lectin pathways. The complement system is important in nervous system diseases such as cerebrovascular and neurodegenerative diseases. Activation of the complement system involves a series of intercellular signaling and cascade reactions. However, research on the source and transport mechanisms of the complement system in neurological diseases is still in its infancy. Studies have increasingly found that extracellular vesicles (EVs), a classic intercellular communication paradigm, may play a role in complement signaling disorders. Here, we systematically review the EV-mediated activation of complement pathways in different neurological diseases. We also discuss the prospect of EVs as future immunotherapy targets.

Astrocytes, an integral component of the central nervous system (CNS), contribute to the maintenance of physiological homeostasis through their roles in synaptic function, K+ buffering, blood-brain barrier (BBB) maintenance, and neuronal metabolism. Reactive astrocytes refer to astrocytes undergoing morphological, molecular and functional remodelling in response to pathological stimuli. The activation and differentiation of astrocytes are implicated in the pathogenesis of multiple neurodegenerative diseases. However, there are still controversies regarding their subset identification, function and nomenclature in neurodegeneration. In this review, we revisit the multidimensional roles of reactive astrocytes in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Furthermore, we propose a precise linkage between astrocyte subsets and their functions based on single-cell sequencing analyses.

Purpose Early-onset Alzheimer disease (EOAD) is rare, highly heterogeneous, and associated with poor prognosis. This AT(N) Framework–based study aimed to compare multiprobe PET/MRI findings between EOAD and late-onset Alzheimer disease (LOAD) patients and explore potential imaging biomarkers for characterizing EOAD. Methods Patients with AD who underwent PET/MRI in our PET center were retrospectively reviewed and grouped according to the age at disease onset: EOAD, younger than 60 years; and LOAD, 60 years or older. Clinical characteristics were recorded. All study patients had positive β-amyloid PET imaging; some patients also underwent 18F-FDG and 18F-florzolotau PET. Imaging of the EOAD and LOAD groups was compared using region-of-interest and voxel-based analysis. Correlation of onset age and regional SUV ratios were also evaluated. Results One hundred thirty-three patients were analyzed (75 EOAD and 58 LOAD patients). Sex (P = 0.515) and education (P = 0.412) did not significantly differ between groups. Mini-Mental State Examination score was significantly lower in the EOAD group (14.32 ± 6.74 vs 18.67 ± 7.20, P = 0.004). β-Amyloid deposition did not significantly differ between groups. Glucose metabolism in the frontal, parietal, precuneus, temporal, occipital lobe, and supramarginal and angular gyri was significantly lower in the EOAD group (n = 49) than in the LOAD group (n = 44). In voxel-based morphometry analysis, right posterior cingulate/precuneus atrophy was more obvious in the EOAD (P < 0.001), although no voxel survived family-wise error correction. Tau deposition in the precuneus, parietal lobe, and angular, supramarginal, and right middle frontal gyri was significantly higher in the EOAD group (n = 18) than in the LOAD group (n = 13). Conclusions Multiprobe PET/MRI showed that tau burden and neuronal damage are more severe in EOAD than in LOAD. Multiprobe PET/MRI may be useful to assess the pathologic characteristics of EOAD.

[This corrects the article DOI: 10.3389/fcvm.2021.682389.].

Background and Purpose Currently, acute ischemic stroke (AIS) is one of the most common and serious diseases in the world and is associated with very high mortality and morbidity even after thrombolysis therapy. This study aims to research the relationship between lactic dehydrogenase (LDH) and prognosis in AIS patients treated with intravenous rtPA. Method This study (a Multicenter Clinical Trial of Revascularization Treatment for Acute Ischemic Stroke, TRAIS) included 527 AIS patients in 5 cooperative medical institutions in China from January 2018 to February 2021. The primary outcome was major disability and death within 3 months (mRS score of 3–6), and the secondary outcomes were early neurological improvement (ENI), early neurological deterioration (END), moderate-severe cerebral edema (CE), and symptomatic intracranial hemorrhage (sICH). Results The mean age of the 527 patients was 65.6 ± 11.7 years, and the median baseline NIHSS score was 4 (interquartile range, 2–7). The median serum LDH level was 184 U/L (interquartile range, 163–212 U/L). In total, 287 (54.5%) patients acquired ENI, 68 (13.0%) patients suffered END, 53 (12.1%) patients were observed with moderate-severe CE, and 28 (6.2%) patients showed sICH. Within 3 months, 127 (25.15%) patients experienced the primary outcome and 42 (8.3%) patients died. Serum LDH levels before thrombolysis showed an independent association with the risk of primary outcome [adjusted odds ratio, 3.787; (95% CI, 1.525–9.404); P = 0.014]. When log-transformed LDH increased each standard deviation, the risk of primary outcome was raised by 80.1% (95% CI, 28.9–251.7%). A positive linear dependence between the risk of primary outcome and serum LDH levels (P of linearity = 0.0248, P of non-linearity = 0.8284) was shown in multivariable-adjusted spline regression models. Pre-thrombolysis LDH quartile also provided a conventional risk model and significant improvement of the prediction for clinical outcomes, with a net reclassification improvement index (NRI) = 41.86% (P < 0.001) and integrated discrimination improvement (IDI) = 4.68% (P < 0.001). Conclusions Elevated serum LDH levels predicted unfavorable clinical outcomes after intravenous thrombolysis in AIS patients.