Early Stages Of Disease Research Articles

Experience of Family Caregivers in Long-Term Care Hospitals During the Early Stages of COVID-19: A Phenomenological Analysis.

This study investigated the experiences of inpatient family caregivers who experienced restrictions in meeting their family members owing to the changed visitation guidelines of long-term care hospitals during the early stages of the coronavirus disease 2019 (COVID-19). We aimed to deepen our understanding of the nature of these caregivers' experiences. The participants were family caregivers of patients in long-term care hospitals during the early stages of the COVID-19 pandemic. We collected data from nine inpatient caregivers from April to July 2021. Individual interviews and data were analyzed using Colaizzi's phenomenological method. Participants' experiences were classified into the following three themes: (1) a prison-like long-term care hospital bound by strict COVID-19 prevention rules; (2) growing affection for unreachable parents; and (3) adaptation to a new, safer daily life. Participants had difficulty communicating with their families living under quarantine conditions during COVID-19 due to non-face-to-face situations. However, amid the long-term COVID-19 situation, participants overcame these challenges through efforts to facilitate communication. The results of this study can be used as basic data to support the smooth communication between patients and caregivers in long-term care hospitals in the event of an infectious disease outbreak in the future, to alleviate emotional stress, and to minimize the weakening of families.

Abstract 4117032: Investigating the natural history and risk factors underlying deterioration in early-stage hypertrophic cardiomyopathy: findings from SOLENOID

Background: Understanding the natural history and factors contributing to heterogeneous outcomes in patients with early-stage hypertrophic cardiomyopathy (HCM) is crucial to improving patient management. Aim: Utilizing a real-world data cohort spanning multiple centers, we described the natural history of early-stage HCM patients and identified risk factors for disease progression. Methods: SOLENOID is an observational study conducted in five academic centers (two in France, UK, Spain and the US). Inclusion criteria were patients with confirmed HCM seen between 2010 and 2022 in NYHA class I, or in “early stage” NYHA class II (defined by an NT-pro BNP<300 pg/ml, resting or provoked LVOT<50 mmHg, LAVi<35 ml/m2, E/e’<14, without a history of atrial fibrillation (AF), and not on HCM-specific therapy). The endpoint was a composite of NYHA class worsening, new onset of AF and cardiovascular hospitalization. To identify risk factors, univariate analyses were conducted in each center, and then aggregated through a meta-analysis. Results: A total of 1044 patients were included with a median follow-up of 3.9 years (IQR 1.5-7.0). The mean age was 53±16 years, with 30% females and 42% of NYHA I were treated with beta-blockers. Genetic tests in 57% of patients revealed mutations, primarily in MYBPC3 (29%) and MYH7 (12%). During follow-up, the composite endpoint has an incidence of 27% and 41% at 3 and 5 years. The main contributor was NYHA class worsening with an incidence of 24% and 35% at 3 and 5 years. AF at inclusion (log-HR=1.56, p<0.001), baseline level of NT-proBNP (log-HR=0.75, p<0.001) and age at inclusion (log-HR=0.24, p=0.005) were the main predictors of the composite endpoint. Conclusion: Nearly 30% of the early-stage HCM patients experienced disease progression within a 3 year follow-up period, highlighting a medical unmet need. Further studies are needed to assess whether the population characterized by elevated NT-proBNP, or pre-existing AF at inclusion, may benefit from more intensive surveillance and, in future HCM-specific therapy.

Abstract 4139195: Tipping Point Analysis Identifies C-terminal src kinase-Collagen 22 Regulation by Inflammation in the Pathogenesis of Early-Stage Pulmonary Arterial Hypertension

Inflammatory injury to pulmonary artery endothelial cells (PAECs) is a key pathogenetic event that drives fibrotic vascular remodeling in pulmonary arterial hypertension (PAH), a progressive disease that lacks early stage-specific therapeutic targets. In an inflammatory rodent model of PAH, we established early-stage disease based on abnormalities in right ventricular (RV) afterload, pulmonary vascular resistance, and RV cardiomyocyte phenotype that were evident without substantial elevation in pulmonary artery pressure. We performed RNA-Seq on PAEC mRNA isolated ex vivo from control, early-stage, and advanced-stage PAH rats and deployed a ‘tipping point’ methodology to identify key pulmonary endothelial protein-protein interactions (PPIs) that regulate the transition from control to early-stage PAH in silico . Building on prior data on the intersection between glucose and proline signaling in fibrosis, we interrogated our early-stage PAH network for convergent PPIs involving metabolism and fibrosis endotypes. C-terminal src kinase (Csk), a conserved inhibitor of Src, was predicted to regulate PAEC fibrosis and was increased in early-stage PAH. In human PAECs, inflammatory stimuli affected markers of Src activation as well as collagen 22 (Col22A1). We observed that pulmonary arterial Col22A1 expression increased progressively across all PAH stages in vivo and that arterial Col22A1 expression is upregulated in human PAH. Further, although inflammation upregulated total Csk mRNA and protein expression in HPAECs, it decreased phosphorylation of Src at tyrosine 527 (pTyr527Src), a Csk-dependent brake on Src kinase activity. Targeting Src through small molecule inhibition or adenovirus overexpression of Csk to increase pTyr527Src, in turn, attenuated inflammation-induced Col22A1 in vitro . Taken together, these data suggest that acquired inhibition of Csk is a novel molecular mechanism by which inflammation induces pulmonary endothelial dysfunction, Src activation, and fibrosis. In early-stage PAH, disrupted Csk inhibition of Src may induce transcriptional upregulation of Csk as a negative feedback response to Src activation. These data suggest that the Csk-Src-Col22A1 axis is a novel target for advancing early-stage therapeutics in patients with PAH subtypes characterized by inflammatory vascular injury.

Optimization of upper respiratory tract cancer diagnosis method based on exhaled breath gas analysis

Introduction. Head and neck tumors comprise about 7 % of all malignant neoplasms. In the head and neck area, tumors are usually located on the tongue (25–40 %) and floor of mouth (15–20 %). In the majority of cases, diagnosis, especially at early disease stages, is based on clinical and histopathological evaluation of tumor process. However, recently development and implementation of non-invasive techniques of early diagnosis of upper respiratory tract tumors through detection of pathognomonic volatile tumor markers in the exhaled air has become topical.Aim. To evaluate diagnostic accuracy of sensory gas analysis device and artificial neural network for examination of exhaled gas samples from patients with oropharyngeal, laryngeal, laryngopharyngeal cancer and to establish the optimal conditions for sampling.Materials and methods. The study included 28 patients with oropharyngeal, laryngeal, laryngopharyngeal cancers and 25 healthy volunteers. The proposed technique is based on analysis of samples of exhaled gas from the studied individuals using a diagnostic device developed by the authors. The device detects volatile compounds in the exhaled air using a set of semiconductor sensors with subsequent analysis by a neural network. The exhaled air was sampled using two methods: in the morning in the fasted state before daily hygienic procedures and physical activity (prepared samples) and in the context of everyday life, nutrition and hygiene without restrictions before sampling (non-prepared samples).Results. Based on the signals from the sensors, the neural network classified and detected patients with malignant tumors. Accuracy of the prepared samples from healthy volunteers and patients with oropharyngeal, laryngeal, laryngopharyngeal cancers was 79.17 %, of non-prepared – 84.09 %.Conclusion. High diagnostic accuracy of the developed technique of non-invasive diagnosis of malignant tumors of the oropharyngeal, laryngeal, laryngopharyngeal areas using exhaled air samples which does not require special preparation of the studied samples was demonstrated.

Presentation and outcome of Gastric Cancer at a Tertiary Care Center

Introduction: Gastric cancer is the fifth most common cancer globally and the fourth leading cause of cancer-related deaths. Early-stage disease can be managed with endoscopic therapy or surgery, while advanced gastric cancer requires a multimodal treatment approach, including extensive lymphadenectomy. This study aims to evaluate the clinicodemographic profile and treatment outcomes of gastric cancer patients and to establish an effective therapeutic strategy. Methods: This retrospective descriptive cross-sectional study was conducted in the Department of Surgery at Shree Birendra Hospital. It included patients with gastric malignancies who had complete medical records. Data on patient history, AJCC staging, operative details, and postoperative findings were analyzed. Surgical choices were based on the clinical indication in each case. Clinicopathological characteristics and surgical outcomes were compared across tumor stages. Data were analyzed using Statistical Package for Social Sciences (SPSS) version 24. Results: The study included 90 patients (62 males, 28 females) aged between 23 and 82 years. The most common clinical presentations were abdominal pain (58%), gastric outlet obstruction (18%), lump (5%), anemia (5%), and peritonitis (4%). Adenocarcinoma was the predominant histological type (87.78%). Curative surgery was performed on 73 patients (81.11%), while 17 patients (18.89%) underwent palliative procedures. Morbidity occurred in 16 patients (17.7%), primarily due to chest complications and sepsis, and mortality was recorded in 5 patients (5.5%). Conclusion: This study highlights the predominance of locally advanced gastric cancer in males, with distal gastric cancer and well-differentiated adenocarcinoma being the most common. Chest complications and sepsis were the leading causes of morbidity and mortality. No patients received perioperative chemotherapy, underscoring the need for updated treatment protocols to improve outcomes.

Association of Urinary Epidermal Growth Factor, Fatty Acid-Binding Protein 3, and Vascular Cell Adhesion Molecule 1 Levels with the Progression of Early Diabetic Kidney Disease

Introduction: Diabetic kidney disease (DKD) is a common cause of chronic kidney disease with around 25–40% of patients with diabetes being affected. The course of DKD is variable, and estimated glomerular filtration rate (eGFR) and albuminuria, the currently used clinical markers, are not able to accurately predict the individual disease trajectory, in particular in early stages of the disease. The aim of this study was to assess the association of urine levels of selected protein biomarkers with the progression of DKD at an early stage of disease. Methods: We measured 22 protein biomarkers using the Mesoscale Discovery platform in 461 urine samples of the PROVALID cohort, an observational study of patients with type 2 diabetes mellitus followed at the primary health care level for a minimum of 4 years. Odds ratios (ORs) were estimated for the effect of marker values above median on fast progression using unadjusted and adjusted logistic regression models. RNA expression at the single-cell level in kidney biopsy samples obtained from a cohort of young persons with type 2 diabetes mellitus was in addition determined for markers showing significant associations with disease progression. Results: Increased urinary levels of epidermal growth factor (EGF) were linked to lower odds of fast progression (defined as annual eGFR decline greater than 2.58 mL/min per 1.73 m2) with an OR of 0.60 (95% CI: 0.46, 0.78). The association with outcome was even stronger when adjusting for a set of 14 baseline clinical parameters including age, biological sex, eGFR, body mass index, albuminuria, and HbA1c. Elevated urinary levels of fatty acid-binding protein 3 (FABP3) and vascular cell adhesion molecule 1 (VCAM1) were each significantly associated with fast progression with an OR of 1.44 (95% CI: 1.11, 1.87) and an OR of 1.41 (95% CI: 1.08, 1.83), respectively. Enriched expression of EGF and FABP3 was observed in distal convoluted tubular cells and VCAM1 in parietal epithelial cells at single-cell level from biopsies of patients with early DKD. Conclusion: In summary, we show that lower urinary levels of EGF and higher urinary levels of FABP3 and VCAM1 are significantly associated with DKD progression in early-stage disease.

A single-cell transcriptomic map of the murine and human multiple myeloma immune microenvironment across disease stages

BackgroundThe long-term effectiveness of immunotherapies against Multiple Myeloma (MM) remains elusive, demonstrated by the inevitable relapse in patients. This underscores the urgent need for an in-depth analysis of the MM tumor-immune microenvironment (TME). Hereto, a representative immunocompetent MM mouse model can offer a valuable approach to study the dynamic changes within the MM-TME and to uncover potential resistance mechanisms hampering effective and durable therapeutic strategies in MM.MethodsWe generated a comprehensive single-cell RNA-sequencing atlas of the MM-TME in bone marrow and spleen encompassing different stages of disease, using the immunocompetent 5T33MM mouse model. Through comparative analysis, we correlated our murine dataset with the pathogenesis in MM patients by reanalyzing publicly available datasets of human bone marrow samples across various disease stages. Using flow cytometry, we validated the dynamic changes upon disease progression in the 5T33MM model. Furthermore, interesting target populations, as well as the immune-boosting anti-CD40 agonist (αCD40) therapy were tested ex vivo on murine and human primary samples and in vivo using the 5T33MM model.ResultsIn this study, we identified the heterogenous and dynamic changes within the TME of murine and human MM. We found that the MM-TME was characterized by an increase in T cells, accompanied with an exhausted phenotype. Although neutrophils appeared to be rather innocuous at early disease stages, they acquired a pro-tumorigenic phenotype during MM progression. Moreover, conventional dendritic cells (cDCs) showed a less activated phenotype in MM, underscoring the potential of immune-boosting therapies such as αCD40 therapy. Importantly, we provided the first pre-clinical evaluation of αCD40 therapy and demonstrated successful induction of cDC- and T-cell activation, accompanied by a significant short-term anti-tumor response.ConclusionsThis resource provides a comprehensive and detailed immune atlas of the evolution in human and murine MM disease progression. Our findings can contribute to immune-based patient stratification and facilitate the development of novel and durable (immune) therapeutic strategies in MM.

Estimation methods of reproduction numbers for epidemics of varying strains of COVID-19

The estimation methods of reproduction numbers and serial intervals are important in the early stages of infectious diseases. During the COVID pandemic, China implemented a dynamic zero-COVID policy on the Chinese mainland until the end of 2022. This study compares three estimation methods of basic reproduction numbers on small-scale, short-duration COVID-19 epidemics in Fujian Province. Basic reproduction numbers were investigated using a varying-strain model via a next-generation matrix method. Serial intervals were derived using the infector–infectee pairs of two epidemics from the Fujian Provincial Center for Disease Control and Prevention. Basic reproduction numbers were estimated using the maximum likelihood estimation method and the exponential growth method. The curves of the effective reproduction numbers of the three epidemics were plotted by utilizing daily cases and the EpiEstim R package. The spatial heterogeneity of infection cases was described using the Gini coefficient. This study provides significant insights on the estimation methods of reproduction numbers for policymakers in the local government. The results reveal that social contacts between infectors and susceptible individuals should be reduced to avoid an increase in deaths and to fight against the spread of infectious diseases.

Real-world characteristics and treatment of cardiac transthyretin amyloidosis: A multicentre, observational study.

Data on the clinical profiles of patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM) in the post-approval era of tafamidis 61mg are lacking. Study aims were characterization of contemporary ATTR-CM patients, analysis of potential eligibility for the 'Transthyretin Amyloidosis Cardiomyopathy Clinical Trial' (ATTR-ACT) and identification of factors associated with the decision on tafamidis 61mg treatment. This retrospective study analysed ATTR-CM patients seen at eight University Hospitals in the first year after approval of tafamidis 61mg for ATTR-CM in Germany (April 2020 to March 2021). The cohort comprised 366 patients (median age 79 [74; 82] years, 84% male), with 47% and 45% of the cohort being in National Amyloidosis Centre ATTR stage≥II and NYHA class≥III, respectively. Sixty-four per cent of patients met key eligibility criteria of the pivotal ATTR-ACT. In recently diagnosed patients (58% with diagnosis ≤6months), the rate of variant ATTR was significantly lower than in patients diagnosed more than 6months ago (9.3% vs. 19.7%). Of the 293 patients without prior ATTR specific treatment, tafamidis 61mg was newly initiated in 77%. Patients with tafamidis 61mg treatment were significantly younger, were more often eligible for ATTR-ACT, had lower NYHA class and higher serum albumin levels. These variables explained 16% of the variance of treatment decision. Unadjusted survival was higher in patients with than those without treatment (1-year survival 98.6% vs. 87.3%, P<0.001). Wild-type ATTR was the primary aetiology amongst contemporary ATTR-CM patients and almost two-thirds of patients were in an advanced disease stage. Clinical profiles of 64% of patients in routine care matched those of the ATTR-ACT. Further effort is needed to detect patients at an earlier disease stage and to validate criteria justifying treatment initiation.

The management of adult and paediatric uveitis for rheumatologists.

Uveitis encompasses multiple different conditions that are all characterized by intra-ocular inflammation. Uveitis occurs in the context of many different rheumatological conditions and carries a substantial risk to vision. Uveitis can develop both at the early stages of rheumatic diseases, sometimes even preceding other clinical features, and at later stages of disease. Uveitis can also occur as either a direct or anindirect complication of therapies used to treat patients with rheumatic disease. Conversely, patients with uveitis of non-rheumatic aetiology sometimes require immunosuppression, a treatment option that is not readily accessible to ophthalmologists. Thus, collaborative working between rheumatologists and ophthalmologists is critical for optimal management of patients with uveitis. This Review is written with rheumatologists in mind, to assist in the care of patients with uveitis. We collate and summarize the latest evidence and best practice in the diagnosis, management and prognostication of uveitis, including future trends and research priorities.

Exploring the role of Cdk5 on striatal synaptic plasticity in a 3-NP-induced model of early stages of Huntington's disease.

Impaired mitochondrial function has been associated with the onset of neurodegenerative diseases. Specifically, certain mitochondrial toxins, such as 3-nitropropionic acid (3-NP), initiate cellular changes within the striatum that closely resemble the pathology observed in Huntington's disease (HD). Among the pivotal signaling molecules contributing to neurodegeneration, cyclin-dependent kinase 5 (Cdk5) stands out. In particular, Cdk5 has been implicated not only in cellular pathology but also in the modulation of synaptic plasticity. Given its widespread presence in the striatum, this study seeks to elucidate the potential role of Cdk5 in the induction of corticostriatal synaptic plasticity in murine striatal cells subjected to subchronic doses of 3-NP in vivo, aiming to mimic the early stages of HD. Immunostaining analyses revealed an increase in Cdk5 in tissues from animals treated with 3-NP, without a significant change in protein levels. Regarding striatal plasticity, long-term depression (LTD) was induced in both control and 3-NP cells when recorded in voltage clamp mode. The Cdk5 inhibitor roscovitine-reduced LTD in most cells. A minority subset of cells exhibited long-term potentiation (LTP) generation in the presence of roscovitine. The inhibitor of D1 receptors SCH23390 prevented LTP in three of nine cells, implying that MSN cells lacking D1/PKA activation were capable of LTP induction when Cdk5 was also blocked. Nevertheless, the co-administration of H89, a PKA inhibitor, along with roscovitine, prevented the generation of any type of plasticity in all recorded cells. These findings show the impact of 3-NP treatment on striatal plasticity and suggest that Cdk5 during early neurodegeneration may attenuate signaling pathways that lead neurons to increase their activity.

Dopamine Cell-Based Replacement Therapies.

Parkinson's disease (PD) is a common disorder that has, as part of its core pathology, the loss of the nigral dopaminergic nerve cells that project to the striatum. Replacing this loss with dopaminergic drugs has been the mainstay of therapy in PD for more than 50 years and while offering significant clinical benefit, especially in early-stage disease, leads to side effects over time. A conceptually more effective way to treat this aspect of the PD pathology would be to replace the missing dopaminergic system with grafts of new dopamine cells. This approach has been investigated for nearly 40 years using a variety of different dopamine cell sources. To date, a proof-of-principle has been shown using human fetal dopamine cells in patients with PD, but the more widespread adoption of this approach has been hampered by logistical reasons around tissue supply, the ethics of the cell source, and, most importantly, by the inconsistent results shown across trials, which in some cases have reported worrying side effects. Reasons for all this have been discussed extensively in the literature and one solution may lie in the development of new human stem cell-derived dopamine cells, which are now just entering first in human clinical trials.

Racial and Ethnic Differences in Prostate Cancer Epidemiology Across Disease States in the VA

Prostate cancer (PC) care has evolved rapidly as a result of changes in prostate-specific antigen testing, novel imaging, and newer treatments. The impact of these changes on PC epidemiology and racial disparities across disease states remains underexplored. To characterize racial and ethnic differences in the epidemiology of PC states, including nonmetastatic hormone-sensitive PC (nmHSPC), metastatic HSPC (mHSPC), nonmetastatic castration-resistant PC (nmCRPC), and metastatic CRPC (mCRPC). This is a retrospective, population-based cohort study of male US veterans aged 40 years and older with known race and ethnicity and no non-PC malignant neoplasm before study entry receiving care through the Veterans Health Administration. The study period was from 2012 to 2020, with follow-up through 2021. To identify active users, data capture included visits 18 months before and after the study period. Data analysis was performed from March to August 2023. Self-identified race and ethnicity, classified as Black, White, or Hispanic. The primary outcomes were annual age-adjusted incidence rates (IRs) and point prevalence for PC states by race and ethnicity. Trends were evaluated using joinpoint regression. Time to disease progression or death was estimated using nonparametric cumulative incidence. Competing risk models adjusted for age assessed the association of race and ethnicity on disease progression. The study included 6 539 001 veterans (median [IQR] age, 65 [56-74] years), of whom 476 227 had PC (median [IQR] age, 69 [63-75] years). IRs varied by time frame and disease state. Across all states and years, the relative risk among Black vs White patients ranged from 2.09 (95% CI, 2.01-2.18; P < .001) for nmHSPC in 2012 to 4.12 (95% CI, 3.39-5.02; P < .001) for nmCRPC in 2017. In nmHSPC, hazard ratios for progression to mHSPC and nmCRPC were 1.36 (95% CI, 1.33-1.40) and 1.60 (95% CI, 1.51-1.70), respectively, for Black patients and 1.38 (95% CI, 1.31-1.45) and 1.55 (95% CI, 1.40-1.72), respectively, for Hispanic patients vs White patients. In contrast, in mCRPC, the hazard ratio for death was lower for Black (0.84; 95% CI, 0.81-0.88) and Hispanic (0.76; 95% CI, 0.69-0.83) patients compared with White patients. This cohort study of veterans found that Black patients had more than 2-fold higher incidence of all disease states vs White patients. Progression risk was higher for Black and Hispanic patients in early-stage disease, but lower in later disease stages. Despite equal access, Black patients disproportionately experience PC, although progression risks relative to White patients differed according to disease state.

The Prognostic Value of the 31-Gene Expression Profile Test in Cutaneous Melanoma: A Systematic Review and Meta-Analysis.

Cutaneous melanoma is an increasingly common and potentially lethal form of skin cancer. Current staging systems based on clinical and pathological features have limitations in accurately predicting outcomes, particularly for early-stage disease. The 31-gene expression profile (31-GEP) test has emerged as a promising tool for improving risk stratification in melanoma patients. We conducted a systematic review and meta-analysis of studies evaluating the prognostic performance of the 31-GEP test in cutaneous melanoma. A comprehensive literature search was performed in multiple databases. Studies reporting survival outcomes stratified by 31-GEP class were included. Random-effects models were used to determine survival estimates across studies. Thirteen studies comprising 14,760 patients were included in the meta-analysis. The 31-GEP test consistently stratified patients into risk groups with significantly different outcomes. The 5-year melanoma-specific survival rates were 99.8% (95% CI: 98-100%) for Class 1A, 97.6% (95% CI: 92.4-99.3%) for Class 1B/2A, and 83.4% (95% CI: 66.5-92.7%) for Class 2B. Similar trends were observed for recurrence-free and distant metastasis-free survival. This meta-analysis supports the prognostic utility of the 31-GEP test in cutaneous melanoma prognostication. The test consistently stratified patients into clinically meaningful risk groups across multiple survival metrics. These findings support the potential clinical utility of the 31-GEP test in enhancing current staging systems and informing personalized management strategies for melanoma patients.

Oncologic outcomes of incidental serous tubal intraepithelial carcinoma and associated high-grade serous carcinoma in high-risk patients undergoing risk-reducing surgery

ObjectiveWe sought to describe the oncologic outcomes of isolated serous tubal intraepithelial carcinomas compared to an intraepithelial carcinoma found concurrently with microscopic high-grade serous carcinoma among patients with hereditary predisposition...

Neuroinflammatory Proteins in Huntington's Disease: Insights into Mechanisms, Diagnosis, and Therapeutic Implications.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG tract expansion in the huntingtin gene (HTT). HD is characterized by involuntary movements, cognitive decline, and behavioral changes. Pathologically, patients with HD show selective striatal neuronal vulnerability at the early disease stage, although the mutant protein is ubiquitously expressed. Activation of the immune system and glial cell-mediated neuroinflammatory responses are early pathological features and have been found in all neurodegenerative diseases (NDDs), including HD. However, the role of inflammation in HD, as well as its therapeutic significance, has been less extensively studied compared to other NDDs. This review highlights the significantly elevated levels of inflammatory proteins and cellular markers observed in various HD animal models and HD patient tissues, emphasizing the critical roles of microglia, astrocytes, and oligodendrocytes in mediating neuroinflammation in HD. Moreover, it expands on recent discoveries related to the peripheral immune system's involvement in HD. Although current immunomodulatory treatments and inflammatory biomarkers for adjunctive diagnosis in HD are limited, targeting inflammation in combination with other therapies, along with comprehensive personalized treatment approaches, shows promising therapeutic potential.

Lecanemab's Path Forward: Navigating the Future of Alzheimer's Treatment in Europe Amidst the EMA's Rejection.

Lecanemab (Leqembi©, Biogen), a humanized anti-amyloid-beta monoclonal antibody, has been approved for early-stage Alzheimer's disease (AD) in several countries, including the US and Japan. However, the European Medicines Agency (EMA) recently issued a negative opinion on its marketing authorization, reflecting concerns over the clinical value and manageability of anti-amyloid treatments. This decision highlights the ongoing disconnect between research advancements and clinical practice, where the focus on biological markers over tangible clinical improvements remains contentious. Despite promising biological effects, lecanemab's clinical outcomes have been modest, raising questions about its therapeutic role. The EMA's refusal underscores the need to address doubts surrounding the real-world effectiveness and safety of such treatments, especially concerning amyloid-related imaging abnormalities (ARIAs), a common side effect observed in clinical trials. The recent approval of lecanemab by the UK's Medicines and Healthcare products Regulatory Agency, despite the National Institute for Health and Care Excellence's rejection on cost-effectiveness grounds, further fuels the debate on the feasibility of anti-amyloid therapies. This commentary emphasizes the importance of real-world data on lecanemab's impact on cognitive decline, daily functioning, and side-effect management. As the global clinical use of lecanemab increases, continuous and standardized reporting on its outcomes is crucial for guiding future regulatory decisions and for potentially bridging the gap between research and practice in AD treatment.

CSF Parvalbumin Levels at Multiple Sclerosis Diagnosis Predict Future Worse Cognition, Physical Disability, Fatigue, and Gray Matter Damage.

Cognitive impairment (CI) in multiple sclerosis (MS) is frequent and determined by a complex interplay between inflammatory and neurodegenerative processes. We aimed to investigate whether CSF parvalbumin (PVALB), measured at the time of diagnosis, may have a prognostic role in patients with MS. In this cohort study, CSF analysis of PVALB and Nf-L levels was performed on all patients at diagnosis (T0) and combined with physical, cognitive, and MRI assessment after an average of 4 years of follow-up (T4) from diagnosis. Cognitive performance was evaluated with a comprehensive neuropsychologic battery: both global (cognitively normal, CN, mildly CI, mCI, and severely CI, sCI) and domain cognitive status (normal/impaired in memory, attention/information processing speed, and executive functions) were considered. Cortical thickness and gray matter volume data were acquired using 3T MRI scanner. A total of 72 patients with MS were included. At diagnosis, PVALB levels were higher in those patients who showed a worsening physical disability after 4 years of follow-up (p = 0.011). CSF PVALB levels were higher in sCI patients than in CN (p = 0.033). Moreover, higher PVALB levels significantly correlated with worse global cognitive (p = 0.024) and memory functioning (p = 0.044). A preliminary clinical threshold for PVALB levels at diagnosis was proposed (2.57 ng/mL), which maximizes the risk of showing CI (in particular, sCI) at follow-up, with a sensitivity of 91% (specificity 30%). No significant results were found for these associations with Nf-L. In addition, patients with higher levels of PVALB at diagnosis showed higher cognitive (p = 0.024) and global fatigue (p = 0.043) at follow-up. Finally, higher PVALB levels also correlated significantly with more pronounced CTh/volume at T4 in the inferior frontal gyrus (p = 0.044), postcentral gyrus (p = 0.025), frontal pole (p = 0.042), transverse temporal gyrus (p = 0.008), and cerebellar cortex (p = 0.041) and higher atrophy (change T0-T4) in the right thalamus (p = 0.038), pericalcarine cortex (p = 0.009), lingual gyrus (p = 0.045), and medial frontal gyrus (p = 0.028). The significant association found between parvalbumin levels in the CSF at diagnosis and cognitive, clinical, and neuroradiologic worsening after 4 years of follow-up support the idea that parvalbumin, in addition to Nf-L, might represent a new potential prognostic biomarker, reflecting MS neurodegenerative processes occurring since early disease stages.

Clinically Probable Multiple System Atrophy Presenting Ptosis as an Early Manifestation

Many ocular features were found in patients with multiple system atrophy (MSA), which include dry eye, blepharospasm, eye movement problems, and blink reflex dysfunction. Some of these symptoms are associated with autonomic dysfunctions seen in MSA. We report a young clinically-probable MSA patient with bilateral ptosis at an early disease stage. Although there is no clear evidence that ptosis, in this case, was caused by abnormalities in the sympathetic cholinergic system, the selective impairment of sudomotor function implied an injured sympathetic cholinergic system secondary to MSA pathology. Ocular manifestations need more attention in clinical examinations of patients with MSA.

Two for tau: Automated model discovery reveals two-stage tau aggregation dynamics in Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative disorder characterized by the presence of amyloid-β plaques and the accumulation of misfolded tau proteins and neurofibrillary tangles in the brain. A thorough understanding of the local accumulation of tau is critical to develop effective therapeutic strategies. Tau pathology has traditionally been described using reaction–diffusion models, which succeed in capturing the global spread, but fail to accurately describe the local aggregation dynamics. Current mathematical models enforce a single-peak behavior in tau aggregation, which does not align well with clinical observations. Here we identify a more accurate description of tau aggregation that reflects the complex patterns observed in patients. We propose an innovative approach that uses constitutive neural networks to autonomously discover bell-shaped aggregation functions with multiple peaks from clinical positron emission tomography (PET) data of misfolded tau protein. Our method reveals previously overlooked two-stage aggregation dynamics by uncovering a two-term ordinary differential equation that links the local accumulation rate to the tau concentration. When trained on data from amyloid-β positive and negative subjects, the neural network clearly distinguishes between both groups and uncovers a more subtle relationship between amyloid-β and tau than previously postulated. In line with the amyloid-tau dual pathway hypothesis, our results show that the presence of toxic amyloid-β influences the accumulation of tau, particularly in the earlier disease stages. We expect that our approach to autonomously discover the accumulation dynamics of pathological proteins will improve simulations of tau dynamics in Alzheimer’s disease and provide new insights into disease progression.Significance StatementIn Alzheimer’s disease, understanding the local dynamics of tau protein aggregation is crucial for developing effective treatments. Traditional models for tau protein dynamics use reaction-diffusion models that fail to accurately capture these local patterns. Our study introduces a novel approach that leverages constitutive neural networks to autonomously discover the complex, multi-peak aggregation dynamics from clinical PET data. This method reveals a previously overlooked two-stage tau accumulation process and a nuanced relationship between amyloid-β and tau. By distinguishing between amyloid-β positive and negative subjects, our model supports the amyloid-tau dual pathway hypothesis and offers novel insights into tau protein aggregation that have the potent to advance our understanding of Alzheimer’s disease progression.