Neuronal Pentraxin Research Articles

Hypometabolic mismatch with atrophy and tau pathology in mixed Alzheimer and Lewy body disease.

Polypathology is a major driver of heterogeneity in clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer Disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as α-synuclein (S) in mixed AD with Lewy Body Disease (LBD). Patients with Mixed Etiology Dementia (MED) such as AD+LBD have faster progression and potentially differential responses to targeted treatments, though the diagnosis of AD+LBD can be challenging given overlapping clinical and imaging features. Development and validation of improved in vivo biomarkers are required to study relationships between N and S and identify imaging patterns reflecting mixed AD+LBD pathologies. We hypothesize that individual proteinopathies, such as T and S, are associated with commensurate levels of N. Thus, we assessed biomarkers of A, T, N and S with positron emission tomography (PET), magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) seeding amplification assay (SAA) data to determine molecular presentations of mixed A+S+ vs. A+S- cognitively impaired patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found A+S+ patients had parieto-occipital 18F-Fluorodeoxyglucose hypometabolism (a measure of N) disproportionate to the degree of regional atrophy or T burden, highlighting worse hypometabolism associated with S+ SAA. Following up on this hypometabolic mismatch with CSF metabolite and proteome analyses, we found that A+S+ patients exhibited lower CSF levels of dopamine metabolites and synaptic markers like neuronal pentraxin-2 (NPTX2), suggesting that altered neurotransmission and neuron integrity contribute to this dissociation between metabolic PET and MRI. Potential confounders exist when studying relations between N, AD and LBD pathologies, including neuroinflammation and other non-Alzheimer pathologies in MED, though our findings imply posterior hypometabolic mismatch is related more to S than vascular or TDP-43 pathology. A+S+ patients had posterior mismatch with excessive 18F-Fluorodeoxyglucose hypometabolism relative to atrophy or T load, possibly reflecting impaired neuron integrity. Further research must disentangle the impact of multiple proteinopathies and clinicopathologic factors on hypometabolism and atrophy. Cumulatively, patients with mixed AD+LBD etiologies harbor a unique metabolic PET mismatch signature.

Molecular signature underlying (R)-ketamine rapid antidepressant response on anhedonic-like behavior induced by sustained exposure to stress

Anhedonia induced by sustained stress exposure is a hallmark symptom of major depressive disorder (MDD) and in rodents, it can be accessed through the sucrose preference test (SPT). (R)-ketamine is a fast-acting antidepressant with less detrimental side effects and abuse liability compared to racemic ketamine. The present study combined high-throughput proteomics and network analysis to identify molecular mechanisms involved in chronic variable stress (CVS)-induced anhedonia and promising targets underlying (R)-ketamine rapid antidepressant response. Male Wistar rats were subjected to CVS for five weeks. Based on the SPT, animals were clustered into resilient or anhedonic-like (ANH) groups. ANH rats received a single dose of saline or (R)-ketamine (20 mg/kg, i.p.), which was proceeded by treatment response evaluation. After prefrontal cortex collection, proteomic analysis was performed to uncover the differentially expressed proteins (DEPs) related to both anhedonic-like behavior and pharmacological response. The behavioral assessment showed that the ANH animals had a significant decrease in SPT, and that (R)-ketamine responders showed a reversal of anhedonic-like behavior. On a molecular level, anhedonia-like behavior was associated with the downregulation of Neuronal Pentraxin Receptor (Nptxr) and Galectin−1 (Gal-1). These data reinforce a disruption in the inflammatory response, neurotransmitter receptor activity, and glutamatergic synapses in chronic stress-induced anhedonia. (R)-ketamine response-associated DEPs included novel potential targets involved in the modulation of oxidative stress, energetic metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length, converging to biological themes extensively documented in MDD physiopathology. Our data provide valuable insights into the molecular mechanisms underlying the response to (R)-ketamine and highlight these pathways as potential therapeutic targets for anhedonia. By addressing proteins involved in oxidative stress, energy metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length, we can target multiple key factors involved in the pathophysiology of MDD. Modulating these proteins could open avenues for novel therapeutic strategies and deepen our understanding of anhedonia, offering hope for improved outcomes in individuals facing this challenging condition. However, additional studies will be essential to validate these findings and further explore their therapeutic implications.

Plasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways.

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

Membrane trafficking of synaptic adhesion molecules.

Synapse formation and stabilization are aided by several families of adhesion molecules, which are generally seen as specialized surface receptors. The function of most surface receptors, including adhesion molecules, is modulated in non-neuronal cells by the processes of endocytosis and recycling, which control the number of active receptors found on the cell surface. These processes have not been investigated extensively at the synapse. This review focuses on the current status of this topic, summarizing general findings on the membrane trafficking of the most prominent synaptic adhesion molecules. Remarkably, evidence for endocytosis processes has been obtained for many synaptic adhesion proteins, including dystroglycans, latrophilins, calsyntenins, netrins, teneurins, neurexins, neuroligins and neuronal pentraxins. Less evidence has been obtained on their recycling, possibly because of the lack of specific assays. We conclude that the trafficking of the synaptic adhesion molecules is an important topic, which should receive more attention in the future.

Alternative translation initiation produces synaptic organizer proteoforms with distinct localization and functions

While many mRNAs contain more than one translation initiation site (TIS), the functions of most alternative TISs and their corresponding protein isoforms (proteoforms) remain undetermined. Here, we showed that alternative usage of CUG and AUG TISs in neuronal pentraxin receptor (NPR) mRNA produced two proteoforms, of which the ratio was regulated by RNA secondary structure and neuronal activity. Downstream AUG initiation truncated the N-terminal transmembrane domain and produced a secreted NPR proteoform sufficient in promoting synaptic clustering of AMPA-type glutamate receptors. Mutations that altered the ratio of NPR proteoforms reduced AMPA receptors in parvalbumin-positive interneurons and affected learning behaviors in mice. In addition to NPR, upstream AUU-initiated N-terminal extension of C1q-like synaptic organizers anchored these otherwise secreted factors to the membrane. Together, these results uncovered the plasticity of N-terminal signal sequences regulated by alternative TIS usage as a potentially widespread mechanism in diversifying protein localization and functions.

MiR-133b as a potential regulator of a synaptic NPTX2 protein in Alzheimer's disease.

A synaptic protein, Neuronal Pentraxin 2 (NPTX2), has emerged as a pivotal biomarker for Alzheimer's dementia (AD). We identified candidate miRNAs targeting NPTX2 and performed association and mediation analyses using multi-omics data (N = 702). Among 44 candidate miRNAs, miR-133b was significantly associated with AD and Braak positivity. Higher miR-133b expression was also associated with higher NPTX2 gene expression and better cognition. Mediation analysis showed that miR-133b partially influences AD and cognition through the NPTX2 protein. Our integrated approach suggests a potential role of miR-133b in synaptic integrity and offers new insights into AD pathogenesis.

High-Speed Atomic Force Microscopy Reveals Fluctuations and Dimer Splitting of the N-Terminal Domain of GluA2 Ionotropic Glutamate Receptor-Auxiliary Subunit Complex.

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors (AMPARs) enable rapid excitatory synaptic transmission by localizing to the postsynaptic density of glutamatergic spines. AMPARs possess large extracellular N-terminal domains (NTDs), which are crucial for AMPAR clustering at synaptic sites. However, the dynamics of NTDs and the molecular mechanism governing their synaptic clustering remain elusive. Here, we employed high-speed atomic force microscopy (HS-AFM) to directly visualize the conformational dynamics of NTDs in the GluA2 subunit complexed with TARP γ2 in lipid environments. HS-AFM videos of GluA2-γ2 in the resting and activated/open states revealed fluctuations in NTD dimers. Conversely, in the desensitized/closed state, the two NTD dimers adopted a separated conformation with less fluctuation. Notably, we observed individual NTD dimers transitioning into monomers, with extended monomeric states in the activated/open state. Molecular dynamics simulations provided further support, confirming the energetic stability of the monomeric NTD states within lipids. This NTD-dimer splitting resulted in subunit exchange between the receptors and increased the number of interaction sites with synaptic protein neuronal pentraxin 1 (NP1). Moreover, our HS-AFM studies revealed that NP1 forms a ring-shaped octamer through N-terminal disulfide bonds and binds to the tip of the NTD. These findings suggest a molecular mechanism in which NP1, upon forming an octamer, is secreted into the synaptic region and binds to the tip of the GluA2 NTD, thereby bridging and clustering multiple AMPARs. Thus, our findings illuminate the critical role of NTD dynamics in the synaptic clustering of AMPARs and contribute valuable insights into the fundamental processes of synaptic transmission.

Biomarkers in Alzheimer’s disease progression: a longitudinal cohort study of NPTX2, GRIA1, and GRIA4

Early diagnosis and intervention are vital for slowing Alzheimer’s disease progression and improving the quality of life in older people. Mild cognitive impairment, an early stage of Alzheimer’s disease, offers a key opportunity for research and intervention. However, current diagnostic methods are typically applied after significant symptoms appear, limiting the effectiveness of early intervention. The data of middle-aged and older individuals collected from the publicly available NCBI datasets GSE5281 and GSE1297 were included in this longitudinal cohort study. The cognitive status changes in participants over time were assessed using standard cognitive assessment tools, such as the Mini-Mental State Examination, along with mild cognitive impairment-specific tools. There was a significant negative correlation between Mini-Mental State Examination scores and the expression levels of neuronal pentraxin 2, glutamate receptor ionotropic AMPA 1 and 4. These results suggest that higher expression levels of these genes are associated with more severe cognitive impairment, highlighting their potential as biomarkers for the early detection of mild cognitive impairment. This study provides new insights into the molecular mechanisms underlying cognitive decline in older people and suggests directions for future research.

A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer-secreted protein that becomes overexpressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig-like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical, and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia-inducible factor-1α (HIF1α) nuclear retention and function. NPTX1 is overexpressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1α hypoxic response in PDAC. Significance: We identified the NPTX1-AMIGO2 axis as a regulatory mechanism upstream of HIF1α-driven hypoxia response that promotes PDAC liver metastasis. Therapeutic NPTX1 targeting outperformed a common chemotherapy regimen in inhibiting liver metastasis and suppressed primary tumor growth in preclinical models, revealing a novel therapeutic strategy targeting hypoxic response in PDAC.

Expression of activity-regulated transcripts in pyramidal neurons across the cortical visuospatial working memory network in unaffected comparison individuals and individuals with schizophrenia

Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by multiple cortical regions including the primary (V1) and association (V2) visual, posterior parietal (PPC) and dorsolateral prefrontal (DLPFC) cortices. In these regions, parvalbumin (PV) or somatostatin (SST) GABA neurons are altered in SZ as reflected in lower levels of activity-regulated transcripts. As PV and SST neurons receive excitatory inputs from neighboring pyramidal neurons, we hypothesized that levels of activity-regulated transcripts are also lower in pyramidal neurons in these regions. Thus, we quantified levels of four activity-regulated, pyramidal neuron-selective transcripts, namely adenylate cyclase-activating polypeptide-1 (ADCYAP1), brain-derived neurotrophic factor (BDNF), neuronal pentraxin-2 (NPTX2) and neuritin-1 (NRN1) mRNAs, in V1, V2, PPC and DLPFC from unaffected comparison and SZ individuals. In SZ, BDNF and NPTX2 mRNA levels were lower across all four regions, whereas ADCYAP1 and NRN1 mRNA levels were lower in V1 and V2. The regional pattern of deficits in BDNF and NPTX2 mRNAs was similar to that in transcripts in PV and SST neurons in SZ. These findings suggest that lower activity of pyramidal neurons expressing BDNF and/or NPTX2 mRNAs might contribute to alterations in PV and SST neurons across the vsWM network in SZ.

Effects of time of the day at sampling on CSF and plasma levels of Alzheimer’ disease biomarkers

BackgroundStudies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels.MethodsWe included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aβ42/Aβ40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer’ disease (AD) biomarkers, including Aβ42, Aβ40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins.ResultsCSF Aβ42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aβ40 (MD, 1.85 ng/mL; p < 0.001), plasma Aβ42 (MD, 1.65 pg/mL; p = 0.002) and plasma Aβ40 (MD, 0.01 ng/mL, p = 0.002) were increased by 4.2-17.0% in evening compared with morning samples. Further, CSF levels of 14 synaptic and endo-lysosomal proteins, including neurogranin and neuronal pentraxin-1, were increased by 4.5-13.3% in the evening samples (MDrange, 0.02-0.56 fmol/µl; p < 0.042). However, no significant differences were found between morning and evening levels for the Aβ42/Aβ40 ratio, different p-tau variants, GFAP and NfL. There were no significant interaction between sampling time and Aβ status for any of the biomarkers, except that CSF t-tau was increased (by 5.74%) in the evening samples compared to the morning samples in Aβ-positive (MD, 16.46 ng/ml; p = 0.009) but not Aβ-negative participants (MD, 1.89 ng/ml; p = 0.47). There were no significant interactions between sampling time and order in which samples were obtained.DiscussionOur findings provide evidence for diurnal fluctuations in Aβ peptide levels, both in CSF and plasma, while CSF and plasma p-tau, GFAP and NfL were unaffected. Importantly, Aβ42/Aβ40 ratio remained unaltered, suggesting that it is more suitable for implementation in clinical workup than individual Aβ peptides. Additionally, we show that CSF levels of many synaptic and endo-lysosomal proteins presented a diurnal rhythm, implying a build-up of neuronal activity markers during the day. These results will guide the development of unified sample collection procedures to avoid effects of diurnal variation for future implementation of AD biomarkers in clinical practice and drug trials.

Cerebrospinal fluid biomarkers and cognitive trajectories in patients with Alzheimer’s disease and a history of traumatic brain injury

Traumatic brain injury (TBI) and Alzheimer’s disease (AD) have overlapping mechanisms but it remains unknown if pathophysiological characteristics and cognitive trajectories in AD patients are influenced by TBI history. Here, we studied AD patients (stage MCI or dementia) with TBI history (ADTBI+, n=110), or without (ADTBI-, n=110) and compared baseline CSF concentrations of amyloid beta 1–42 (Aβ42), phosphorylated tau181 (pTau181), total tau, neurofilament light chain (NfL), synaptosomal associated protein-25kDa (SNAP25), neurogranin (Ng), neuronal pentraxin-2 (NPTX2) and glutamate receptor-4 (GluR4), as well as differences in cognitive trajectories using linear mixed models. Explorative, analyses were repeated within stratified TBI groups by TBI characteristics (timing, severity, number). We found no differences in baseline CSF biomarker concentrations nor in cognitive trajectories between ADTBI+ and ADTBI- patients. TBI >5 years ago was associated with higher NPTX2 and a tendency for higher SNAP25 concentrations compared to TBI ≤ 5 years ago, suggesting that TBI may be associated with long-term synaptic dysfunction only when occurring before onset or in a pre-clinical disease stage of AD.

NARP-related alterations in the excitatory and inhibitory circuitry of socially isolated mice: developmental insights and implications for autism spectrum disorder.

Social isolation during critical periods of development is associated with alterations in behavior and neuronal circuitry. This study aimed to investigate the immediate and developmental effects of social isolation on firing properties, neuronal activity-regulated pentraxin (NARP) and parvalbumin (PV) expression in the prefrontal cortex (PFC), social behavior in juvenile socially isolated mice, and the biological relevance of NARP expression in autism spectrum disorder (ASD). Mice were subjected to social isolation during postnatal days 21-35 (P21-P35) and were compared with group-housed control mice. Firing properties in the PFC pyramidal neurons were altered in P35 socially isolated mice, which might be associated with alterations in NARP and PV expression. In adulthood, mice that underwent juvenile social isolation exhibited difficulty distinguishing between novel and familiar mice during a social memory task, while maintaining similar levels of social interaction as the control mice. Furthermore, a marked decrease in NARP expression in lymphoblastoid cell lines derived from adolescent humans with ASD as compared to typically developing (TD) humans was found. Our study highlights the role of electrophysiological properties, as well as NARP and PV expression in the PFC in mediating the developmental consequences of social isolation on behavior.

YB-800, a monoclonal antibody targeting the human neuronal pentraxin receptor (NPTXR), as a potential candidate for the design of a first in class antibody drug conjugate (ADC) as novel therapeutic intervention in gastro-intestinal cancers.

e15022 Background: The human neuronal pentraxin receptor (NPTXR) gene encodes a type II transmembrane protein that functions as a trans-synaptic organizer and anchors neuronal pentraxin complexes to plasma membranes. Beside a subset of neuronal cells (Hippocampus and Cerebral Cortex), expression of NPTXR is not detected in all other tissues [ The Human Protein Atlas database]. In recent studies [Kanda et al. (2020) Mol. Cancer. doi: 10.1186/s12943-020-01251-0], transcriptome and bioinformatics analysis of gastric cancer (GC) tissues from patients with or without metastasis have revealed that NPTXR expression was associated with disease progression. NPTXR expression was also correlated negatively with survival in GC patients. It appears that NPTXR does not have a major physiological function; e.g., NPTXR−/− mice showed no abnormalities in reproduction, development, metabolism, or motor function. NPTXR is expressed in a number of GI cancers, i.e., gastric, esophageal, colorectal, pancreatic, bladder, liver, as well as breast and thyroid cancer. YB-800 is a fully humanized monoclonal antibody against NPTXR (identified by in silico analysis). Methods: The present studies were conducted to provide a rationale for the design of a YB-800-based antibody drug conjugate (ADC) for therapeutic intervention in oncology. Hence, YB-800 binding to and internalization in selected tumor cells, as well as immunohistochemistry (IHC) in tumor biopsies, were evaluated. Results: Taken together experimental data confirm that: (i) YB-800 binds to a new target (NPTXR) on selected tumor cells; confirmed by FACS analysis; (ii) IHC analysis in tumor samples demonstrates specific immunoreaction in bladder, gastric, prostate, hepatocellular carcinoma, colorectal cancer and cervical cancer, but not in adjacent healthy tissues; and (iii) once YB-800 binds to NPTXR, the conjugate is internalized in selected tumor cells in a time-dependent manner. Conclusions: In conclusion, YB-800 represents a first in class ADC candidate that could be used as novel treatment for gastro-intestinal cancers. Hence, as initial proof of concept, tesirine (DNA intercalating agent) and deruxtecan (topoisomerase I inhibitor) containing protease-sensitive linkers were coupled to YB-800 by stochastic maleimide conjugations to interchain cysteines. Initial results with YB-800-based ADCs will be discussed.

NPTX1 Mediates the Facilitating Effects of Hypoxia-Stimulated Human Adipocytes on Adipose-Derived Stem Cell Activation and Autologous Adipose Graft Survival Rate.

Autologous adipose tissue is an ideal material for soft tissue filling and transplantation; however, high volumes of fat absorption over time lead to a relatively low overall survival percentage. The survival and differentiation of adipose-derived stem cells (ADSCs) in the transplanted microenvironment might improve adipose graft survival. Adipocytes have been reported to affect ADSC activation. However, its underlying mechanisms remain unclear. Human ADSCs were incubated in a culture medium supplemented with hypoxic or normoxic conditioned culture medium (CM) derived from human adipocytes. Neuronal Pentraxin 1 (NPTX1) was overexpressed or knocked down in human adipocytes using an overexpression vector (NPTX1 OE) or small interfering RNA (siRNA) transfection, respectively. ADSC differentiation and paracrine secretion were assessed. Nude mice were implanted with human adipocytesand ADSCs. The adipose tissue was subsequently evaluated by histological analysis. CM from hypoxic-stimulated human adipocytes significantly facilitated the differentiation ability and paracrine levels of ADSCs. NPTX1 was significantly up-regulated in human adipocytes exposed to hypoxic conditions. In vitro, CM derived from hypoxia-stimulated human adipocytes or NPTX1-overexpressing human adipocytes exposed to normoxia promoted ADSC differentiation and paracrine; after silencing NPTX1, the facilitating effects of hypoxia-treated human adipocytes on ADSC activation were eliminated. Similarly, in vivo, the NPTX1 OE + normoxia-CM group saw improved histological morphology and fat integrity, less fibrosis and inflammation, and increased vessel numbers compared with the OE NC + normoxia-CM group; the adipocyte grafts of the si-NC + hypoxia-CM group yielded the most improved histological morphology, fat integrity, and the most vessel numbers. However, these enhancements of ADSC activation and adipose graft survival were partially abolished by NPTX1 knockdown in human adipocytes. NPTX1 might mediate the facilitating effects of hypoxia-stimulated human adipocytes on ADSC activation, thereby improving adipose tissue survival rate after autologous fat transplantation and the effectiveness of autologous fat transplantation through promoting ADSC activation. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

ASO Visual Abstract: Therapeutic Potential of Antibody Targeting Neuronal Pentraxin Receptor in Esophageal Squamous Cell Carcinoma.

ASO Visual Abstract: Therapeutic Potential of Antibody Targeting Neuronal Pentraxin Receptor in Esophageal Squamous Cell Carcinoma.

Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid of de novo Parkinson’s disease

Lysosomal and synaptic dysfunctions are hallmarks in neurodegeneration and potentially relevant as biomarkers, but data on early Parkinson’s disease (PD) is lacking. We performed targeted mass spectrometry with an established protein panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) of drug-naïve de novo PD, and sex-/age-matched healthy controls (HC) cross-sectionally (88 PD, 46 HC) and longitudinally (104 PD, 58 HC) over 10 years. Multiple markers of autophagy, synaptic plasticity, and secretory pathways were reduced in PD. We added samples from prodromal subjects (9 cross-sectional, 12 longitudinal) with isolated REM sleep behavior disorder, revealing secretogranin-2 already decreased compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins in PD correlated with clinical progression, showing predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials.

Therapeutic Potential of Antibody Targeting Neuronal Pentraxin Receptor in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite advances in multidisciplinary treatments and immune checkpoint inhibitors. We previously reported that neural pentraxin receptor (NPTXR), a transmembrane protein mainly expressed in the brain and involved in synaptic transmission, is implicated in gastric cancer malignancy. This study evaluated the expression and function of NPTXR in ESCC, the therapeutic potential of monoclonal antibody (mAb) against NPTXR, and its prognostic value in ESCC patients. The study involved analyzing the NPTXR expression in 21 ESCC cell lines and total 371 primary ESCC tissue samples using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. The impact of NPTXR on the malignant behavior of ESCC was examined using small interfering RNA-mediated knockdown and a subsequent assessment of cell proliferation, apoptosis, and adhesion. This study further investigated the efficacy of anti-NPTXR mAb in vitro and associations between the expression of NPTXR messenger RNA (mRNA) and protein with clinicopathological factors and the prognosis. NPTXR was overexpressed in several ESCC cell lines and primary ESCC tissues. Knockdown of NPTXR in ESCC cells resulted in reduced proliferation, increased apoptosis, and decreased cell adhesion. The mAb against NPTXR significantly inhibited ESCC cell proliferation in vitro. A high NPTXR expression in patient tissues was correlated with a worse overall survival, suggesting its potential as a prognostic biomarker. NPTXR influences the malignant behavior of ESCC cells. Anti-NPTXR mAb may be a promising therapeutic agent, and its expression in ESCC tissues may serve as a prognostic biomarker.

Cerebrospinal fluid synaptic biomarker changes in bipolar disorder – A longitudinal case-control study

BackgroundThis exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections. MethodsFifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14–3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes. ResultsThe synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up. LimitationIt is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect. ConclusionThis first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.

Serum NPTX2 as a Potential Predictive Biomarker for Postoperative Delirium in Patients with Acute Type A Aortic Dissection.

Postoperative delirium (POD) significantly impacts patient outcomes after acute type A aortic dissection (ATAAD) surgeries. This study investigates the role of Neuronal Pentraxin 2 (NPTX2) as a potential biomarker for POD in ATAAD patients. This secondary analysis involved ATAAD patients from a prospective observational study. Serum NPTX2 levels were measured preoperatively and immediately postoperatively using Enzyme-Linked Immunosorbent Assay (ELISA). Delirium was assessed using the Confusion Assessment Method (CAM) or CAM for the ICU (CAM-ICU). Statistical analyses included the Pearson Correlation Coefficient and multivariate logistic regression to evaluate the association between NPTX2 levels and POD. Among the 62 patients included, 46.77% developed POD. Patients with POD had significantly lower preoperative and postoperative serum NPTX2 levels. The Receiver Operating Characteristic (ROC) curve analysis showed that postoperative NPTX2 had a strong predictive capability for POD (AUC = 0.895). The optimal cutoff for postoperative NPTX2 in predicting POD was less than 421.4 pg/mL. Preoperative NPTX2 also demonstrated predictive value, albeit weaker (AUC = 0.683). Serum NPTX2 levels, both preoperatively and postoperatively, are promising biomarkers for predicting POD in ATAAD patients. These findings suggest that NPTX2 could be instrumental in early POD detection and intervention strategies.