Prodromal Research Articles

Abstract 1085: Vagal Nerve Schwannoma Presenting As A Syncope In A Young Patient

Introduction: Vagal schwannomas are rare, benign masses that usually develop in the cervical region but can arise anywhere along the vagus nerve. Patients may be asymptomatic; however, in most cases, patients present in their third to sixth decades, with neck swelling, hoarseness or cough. Herein, we discuss a case report of a 26-year-old male who presented after an abrupt syncopal episode with sinus bradycardia and was diagnosed with vagal schwannoma. Case Presentation: A 26-year-old male with a past medical history of bipolar disorder was brought to the hospital after an abrupt syncopal episode while driving. He denied any palpitations or prodromal symptoms prior to loss of consciousness. Inpatient cardiac monitoring revealed persistent sinus bradycardia, without high degree AV block. Treadmill EKG stress test confirmed chronotropic competence. CT head did not reveal other etiology of syncope. CT chest revealed a 2.4 x 2.0 cm left superior mediastinal mass. Cardiothoracic surgery was consulted for concern of thoracic outlet mass/mediastinal mass. Robotic-assisted left thoracoscopy was performed for mediastinal mass excision, which revealed a left vagus nerve schwannoma on frozen section. Discussion: Most vagus nerve schwannomas have been found to arise within the cervical course of the vagus nerve. Intrathoracic vagal schwannomas are rare. These tumors are usually asymptomatic, however varied symptoms such as pain, dysphagia and shortness of breath have been reported. In this case presented, the tumor possibly contributed to the heightened vagal tone and neurogenic syncope (with vasovagal syncope). It is also notable that our patient's resting heart rate normalized following excision of the mass. Of note, with a high reported incidence of peri-perioperative vocal cord paralysis, surgical excision remains a challenging mainstay of treatment in symptomatic patients. Conclusion: Vagal neoplasms should be hence considered as a differential diagnosis in patients with otherwise unexplained bradycardia with history of syncope. Reference: Neurocardiogenic syncope; Carol Chen-Scarabelli, cardiovascular nurse practitioner and Tiziano M Scarabelli, associate professor of internal medicine. BMJ 2004 Aug 7; 329 (7461):336-341.

Prodromal Status of Rapid Eye Movement Sleep Behavior Disorder: Clinical Significance and Future Perspectives

Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal stage for major neurodegenerative diseases, particularly α-synucleinopathies. Recently, the spectrum of RBD is expanding and its prodromal state has been recognized and categorized into isolated REM sleep without atonia and isolated dream-enacting behavior. Although unclear, prodromal RBD frequently occurs in the aged population, with a significantly high phenoconversion rate to RBD and an increased risk of developing neurodegenerative disorders. More active and structured general surveillance of this condition may contribute to the effective modulation of major neurodegenerative diseases. However, the clinical and polysomnographic profiles of prodromal RBD, methods for effective screening and diagnosis of prodromal RBD, and biomarkers for disease progression and phenoconversion must be investigated.

Novel Variants Linked to the Prodromal Stage of Parkinson's Disease (PD) Patients.

The symptoms of most neurodegenerative diseases, including Parkinson's disease (PD), usually do not occur until substantial neuronal loss occurs. This makes the process of early diagnosis very challenging. Hence, this research used variant call format (VCF) analysis to detect variants and novel genes that could be used as prognostic indicators in the early diagnosis of prodromal PD. Data were obtained from the Parkinson's Progression Markers Initiative (PPMI), and we analyzed prodromal patients with gVCF data collected in the 2021 cohort. A total of 304 participants were included, including 100 healthy controls, 146 prodromal genetic individuals, 21 prodromal hyposmia individuals, and 37 prodromal individuals with RBD. A pipeline was developed to process the samples from gVCF to reach variant annotation and pathway and disease association analysis. Novel variant percentages were detected in the analyzed prodromal subgroups. The prodromal subgroup analysis revealed novel variations of 1.0%, 1.2%, 0.6%, 0.3%, 0.5%, and 0.4% for the genetic male, genetic female, hyposmia male, hyposmia female, RBD male, and RBD female groups, respectively. Interestingly, 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300, and PPP6R2) that were recently detected in PD patients were detected in the prodromal stage of PD. Genetic biomarkers are crucial for the early detection of Parkinson's disease and its prodromal stage. The novel PD genes detected in prodromal patients could aid in the use of gene biomarkers for early diagnosis of the prodromal stage without relying only on phenotypic traits.

Executive functions and brain morphology of male and female dominant and subordinate cichlid fish.

Living in a social dominance hierarchy presents different benefits and challenges for dominant and subordinate males and females, which might in turn affect their cognitive needs. Despite the extensive research on social dominance in group-living species, there is still a knowledge gap regarding how social status impacts brain morphology and cognitive abilities. Here, we tested male and female dominants and subordinates of Neolamprologus pulcher, a social cichlid fish species with size-based hierarchy. We ran three executive cognitive function tests for cognitive flexibility (reversal learning test), self-control (detour test), and working memory (object permanence test), followed by brain and brain region size measurements. Performance was not influenced by social status or sex. However, dominants exhibited a brain-body slope that was relatively steeper than that of subordinates. Furthermore, individual performance in reversal learning and detour tests correlated with brain morphology, with some trade-offs among major brain regions like telencephalon, cerebellum, and optic tectum. As individuals' brain growth strategies varied depending on social status without affecting executive functions, the different associated challenges might yield a potential effect on social cognition instead. Overall, the findings highlight the importance of studying the individual and not just species to understand better how the individual's ecology might shape its brain and cognition.

Epidemiology of autoimmune liver disease in Korea: evidence from a nationwide real-world database

BackgroundAutoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are all immune-mediated chronic inflammatory liver diseases. Autoimmune liver diseases are rare, making identification and treatment difficult. To improve clinical outcomes and enhance patient quality of life, we performed an epidemiological study of autoimmune liver diseases based on real-world comprehensive data.ResultsWe used National Health Insurance Service claims data in Korea from 2005 to 2019. Patients were identified using the International Classification of Disease 10th Revision code, and rare intractable disease codes assigned according to the strict diagnostic criteria. In the AIH cohort, 8,572 (83.9%) were females and the mean age at diagnosis was 56.3 ± 14.3 years. PBC also showed female dominance (83.3%) and the mean age was 57.8 ± 12.6 years. Patients with PSC showed no sex predominance and had a mean age of 57.8 ± 21.5 years. During the study period, there were 10,212, 6,784, and 888 AIH, PBC, and PSC patients, respectively. The prevalence of AIH, PBC, and PSC in 2019 were 18.4, 11.8, and 1.5 per 100,000 population, while the corresponding incidences were 2.3, 1.4, and 0.3 per 100,000 population, respectively. Analysis of sex-age-standardized data showed that the annual prevalence of these diseases is increasing. The 10-year survival rates were 89.8%, 74.9%, and 73.4% for AIH, PBC, and PSC, respectively.ConclusionsThe number of patients with autoimmune liver disease in South Korea is increasing over time. Further research on autoimmune liver disease is needed to fulfill unmet clinical needs.

When are females dominant over males in rats (Rattus norvegicus)?

In group-living animals, males are assumed to be dominant over females when they are larger than females. Despite this, females have sometimes been proven to be dominant over some males via the winner-loser effect, which becomes stronger when the intensity of aggression in the group is higher. To test whether the winner-loser effect leads to (partial) female dominance in a species with a pronounced sexual dimorphism, we studied the hierarchy in 12 rat colonies (Rattus norvegicus) in which the rats could freely interact with their group members within a spacious area. To investigate the underlying mechanisms, we compared the empirical data to hypotheses generated by the agent-based model ‘DomWorld’. We show that females dominated on average 55% of the males, and occupied the alpha position in four colonies, in three of them they shared it with one or several males. Moreover, in line with the predictions of the computational model, females dominated a higher percentage of males when the intensity of aggression of the colony was higher. This shows that although females are only half as heavy as males, they dominate part of the males probably through the winner-loser effect. We suggest that this effect may be widespread in many other species and can be tested experimentally.Significance statementIt is often assumed that males automatically dominate females because males are bigger and stronger than females in many species. However, the present study shows that females can dominate males due to the winner-loser effect. We used an agent-based computational model to generate specific hypotheses that we empirically tested in a large sample of rat colonies. Despite this species having a pronounced male-biased sex dimorphism, some females dominated males – with one female even occupying an unshared alpha position. Such partial female dominance was stronger in colonies with higher intensity of aggression. Here, defeated males may suffer a drastic decrease in their fighting capability and consequently give females more opportunities to surpass them in the hierarchy.

Clinical trajectories preceding incident dementia up to 15 years before diagnosis: a large prospective cohort study.

Dementia has a long prodromal stage with various pathophysiological manifestations; however, the progression of pre-diagnostic changes remains unclear. We aimed to determine the evolutional trajectories of multiple-domain clinical assessments and health conditions up to 15 years before the diagnosis of dementia. Data was extracted from the UK-Biobank, a longitudinal cohort that recruited over 500,000 participants from March 2006 to October 2010. Each demented subject was matched with 10 healthy controls. We performed logistic regressions on 400 predictors covering a comprehensive range of clinical assessments or health conditions. Their evolutional trajectories were quantified using adjusted odds ratios (ORs) and FDR-corrected p-values under consecutive timeframes preceding the diagnosis of dementia. During a median follow-up of 13.7 [Interquartile range, IQR 12.9-14.2] years until July 2022, 7620 subjects were diagnosed with dementia. In general, upon approaching the diagnosis, demented subjects witnessed worse functional assessments and a higher prevalence of health conditions. Associations up to 15 years preceding the diagnosis comprised declined physical strength (hand grip strength, OR 0.65 [0.63-0.67]), lung dysfunction (peak expiratory flow, OR 0.78 [0.76-0.81]) and kidney dysfunction (cystatin C, OR 1.13 [1.11-1.16]), comorbidities of coronary heart disease (OR 1.78 [1.67-1.91]), stroke (OR 2.34 [2.1-1.37]), diabetes (OR 2.03 [1.89-2.18]) and a series of mental disorders. Cognitive functions in multiple tests also demonstrate decline over a decade before the diagnosis. Inadequate activity (3-5 year, overall time of activity, OR 0.82 [0.73-0.92]), drowsiness (3-5 year, sleep duration, OR 1.13 [1.04-1.24]) and weight loss (0-5 year, weight, OR 0.9 [0.83-0.98]) only exhibited associations within five years before the diagnosis. In addition, serum biomarkers of enriched endocrine, dysregulations of ketones, deficiency of brand-chain amino acids and polyunsaturated fatty acids were found in a similar prodromal time window and can be witnessed as the last pre-symptomatic conditions before the diagnosis. Our findings present a comprehensive temporal-diagnostic landscape preceding incident dementia, which could improve selection for preventive and early disease-modifying treatment trials.

Vocal and tongue exercise in early to mid-stage Parkinson disease using the Pink1-/- rat

Vocal and swallowing deficits are common in Parkinson disease (PD). Because these impairments are resistant to dopamine replacement therapies, vocal and lingual exercise are the primary treatment, but not all individuals respond to exercise and neural mechanisms of treatment response are unclear. To explore putative mechanisms, we used the progressive Pink1-/- rat model of early to mid-stage PD and employed vocal and lingual exercises at 6- and 10-months of age in male Pink1-/- and wild type (WT) rats. We hypothesized that vocal and lingual exercise would improve vocal and tongue use dynamics and increase serotonin (5HT) immunoreactivity in related brainstem nuclei. Rats were tested at baseline and after 8 weeks of exercise or sham exercise. At early-stage PD (6 months), vocal exercise resulted in increased call complexity, but did not change intensity, while at mid-stage (10 months), vocal exercise no longer influenced vocalization complexity. Lingual exercise increased tongue force generation and reduced relative optical density of 5HT in the hypoglossal nucleus at both time points. The effects of vocal and lingual exercise at these time points are less robust than in prodromal stages observed in previous work, suggesting that early exercise interventions may yield greater benefit. Future work targeting optimization of exercise at later time points may facilitate clinical translation.

Directness of Communication Mediates Sexual Satisfaction: What We Can Learn from a Positive View of BDSM Practice

BDSM practitioners typically report higher sexual satisfaction than the general population (Botta et al., 2019; Joyal & Carpentier, 2017; Strizzi et al., 2022). One possible reason for this is that the BDSM community prioritizes open communication and challenges traditional sexual scripts. In a sample of 376 individuals, we found a positive association between BDSM participation and sexual satisfaction which was fully mediated by direct communication about sex. These results build upon previous literature that emphasizes the vital role of communication in sexual satisfaction, broadening this result to a more sexually diverse population. In addition, the frameworks used by BDSM communities could inspire the use of similar strategies to improve communication and sexual satisfaction in non-BDSM populations.

Meta-Analysis in Transgenic Alzheimer's Disease Mouse Models Reveals Opposite Brain Network Effects of Amyloid-β and Phosphorylated Tau Proteins.

Cognitive deficits observed in Alzheimer's disease (AD) patients have been correlated with altered hippocampal activity. Although the mechanism remains under extensive study, neurofibrillary tangles and amyloid plaques have been proposed as responsible for brain activity alterations. Aiming to unveil the mechanism, researchers have developed several transgenic models of AD. Nevertheless, the variability in hippocampal oscillatory alterations found in different genetic backgrounds and ages remains unclear. To assess the oscillatory alterations in relation to animal developmental age and protein inclusion, amyloid-β (Aβ) load, and abnormally phosphorylated tau (pTau), we reviewed and analyzed the published data on peak power, frequency, and quantification of theta-gamma cross-frequency coupling (modulation index values). To ensure that the search was as current as possible, a systematic review was conducted to locate and abstract all studies published from January 2000 to February 2023 that involved in vivo hippocampal local field potential recording in transgenic mouse models of AD. The presence of Aβ was associated with electrophysiological alterations that are mainly reflected in power increases, frequency decreases, and lower modulation index values. Concomitantly, pTau accumulation was associated with electrophysiological alterations that are mainly reflected in power decreases, frequency decreases, and no significant alterations in modulation index values. In this study, we showed that electrophysiological parameters are altered from prodromal stages to the late stages of pathology. Thus, we found that Aβ deposition is associated with brain network hyperexcitability, whereas pTau deposition mainly leads to brain network hypoexcitability in transgenic models.

Early Support for People Who Hear Voices: Exploratory Research on Family Medicine Physicians' Clinical Practice and Beliefs.

Nowadays the phenomenon of hearing voices represents a very fertile and discussed field of research. In psychological and psychiatric fields, the phenomenon has been described as a normal phenomenon, but also as a prodromal stage and as a symptom of psychosis. Through a qualitative research methodology, the aim was to explore how family medicine physicians configure the phenomenon and its clinical and interactive implications. The present research involved 35 family medicine physicians as figures of primary importance in the approach toward people who start to hear voices. Semi-structured interviews have been used and they have been analyzed by the method of discourse analysis. The results show a remarkable difficulty in understanding the phenomenon in all its complexity and the tendency to consider it a symptom or a prodromal stage of psychopathology. Increasing the knowledge of doctors on the subject is necessary so that their evaluation and choice of intervention match the needs of each patient. We also discuss the importance of promoting the knowledge of the potential meanings taken on by the voices in the context of the personal and family background of the individual hearer, and of collaboration with other relevant professionals and services.

Study of the different sleep disturbances during the prodromal phase of depression and mania in bipolar disorders.

One of the challenges in bipolar disorder (BD) lies in early detection of the illness and its recurrences, to improve prognosis. Sleep disturbances (SD) have been proposed as reliable predictive markers of conversion. While preliminary studies have explored the relationship between SD and the onset of mood episodes, the results remain heterogeneous and a few have specifically examined patients' perception of prodromal symptoms and their progression until the episode occurs. Identifying prodromes represents a crucial clinical challenge, as it enables early intervention, thereby reducing the severity of BD. Therefore, the objective of this study is to better characterize and evaluate the progressive nature of SD as prodromal symptoms of mood episodes, and patients' perception of it. Patients diagnosed with BD, either hospitalized or seeking treatment for a (hypo)manic or depressive episode benefited from standardized questionnaires, structured interviews, and self-report questionnaires to evaluate SD prior to the current episode, as well as sociodemographic and clinical information. Out of the 41 patients included, 59% spontaneously reported SD prior to the episode, appearing 90 days before depression and 35 days before mania (pre-indexed/spontaneous reports: 51.22% insomnia complaints, 4.88% hypersomnolence complaints, 7.32% parasomnias, 2.44% sleep movements). After inquiry about specific SD, the percentage of patients reporting prodromal SD increased significantly to 83%, appearing 210 days before depression and 112.5 days before mania (post-indexed reports: 75.61% presented with insomnia complaints appearing 150 days before depression and 20 days before mania, 46.34% had hypersomnolence complaints appearing 60 days before depression, 43.9% had parasomnias appearing 210 days before depression and 22.5 days before mania, 36.59% had sleep movements appearing 120 days before depression and 150 days before mania). Of note, bruxism appeared in 35% of patients before mania, and restless legs syndrome in 20% of patients before depression. This study highlights the very high prevalence of SD prior to a mood episode in patients with BD with differences between depressive and manic episodes. The more systematic screening of sleep alterations of the prodromal phase improved the recognition and characterization of different symptoms onset by patients. This underscores the need for precise questioning regarding sleep patterns in patients, to better identify the moment of transition toward a mood episode, referred to as "Chronos syndrome". The study emphasizes the importance of educating patients about the disorder and its sleep prodromal symptoms to facilitate early intervention and prevent recurrences.

Using digital tools in the context of female dominance in the real estate market


 
 
 For society, women’s work is an important reserve necessary for the effective development of production. Negative trends related to female employment have a detrimental effect on the country’s demographic situation, as well as on social relations. Statistics show that it is women who experience the most problems in terms of career growth and professional development. The volume of job offers for women is characterized by a much narrower professional range, and the average salary level is lower. In addition, a woman’s chances of losing her job are always higher than those of men. However, the digital economy provides new employment opportunities for women. Working in real estate combined with digital tools increases female employment and equalizes income levels between men and women. The purpose of the article is to study the state of use of digital tools in the field of real estate, as an important component of increasing the efficiency of the work of real estate agency personnel.
 
 

N-3 Polyunsaturated Fatty Acids in Elderly with Mild Cognitive Impairment: A Systemic Review and Meta-Analysis.

Mild cognitive impairment (MCI) is the prodromal stage of dementia. In this stage, reasonable intervention measures can help to delay the decline of cognitive function. Supplementation of n-3 polyunsaturated fatty acids (n-3PUFAs) may be beneficial to delay the decline of cognitive function in the elderly. To investigate the effectiveness of docosapentaenoic acid (DHA) or/and eicosapentaenoic acid (EPA) supplements in the elderly with MCI. Eight electronic databases, PubMed, Cochrane Library, Embase, VIP, SinoMed, Web of Science, CNKI, and WANFANG DATA, were searched for related articles from inception until January 2022. Subgroup analyses and sensitivity analyses were performed to detect confounding variables. Standardized mean differences (SMD) with 95% confidence intervals (CI) were determined. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots. Stata12.0 was used for Begg's and Egger's test to quantify whether publication bias. Linear relationship between global cognition and covariates was examined in meta-regression analysis. Twelve studies (n = 1,124) were included. The methodological quality of research is mostly medium. Compared with placebo, n-3PUFAs supplements have benefits on global cognition [SMD = 0.51, 95% CI(0.12, 0.91), p = 0.01]. No significant differences were observed between intervention group and placebo on language fluency, executive functions, and depression. Our findings indicated DHA and/or EPA supplements have benefits on global cognition, and it may also reduce the level of blood amyloid-β (Aβ)-related biomarkers (e.g., Aβ40, Aβ42) and inflammatory factors (e.g., 1L-6, 1L-10). Since there are only two relative articles, more research is needed in the future to clarify the relationship.

0683 Rest-activity Pattern in Isolated RBD – from Prodromal Stage to Association with Parkinsonism-first Phenoconversion

0683 Rest-activity Pattern in Isolated RBD – from Prodromal Stage to Association with Parkinsonism-first Phenoconversion

Who am I with my Lewy bodies? The insula as a core region of the self-concept networks.

Dementia with Lewy bodies (DLB) is characterized by insular atrophy, which occurs at the early stage of the disease. Damage to the insula has been associated with disorders reflecting impairments of the most fundamental components of the self, such as anosognosia, which is a frequently reported symptom in patients with Lewy bodies (LB). The purpose of this study was to investigate modifications of the self-concept (SC), another component of the self, and to identify neuroanatomical correlates, in prodromal to mild DLB. Twenty patients with prodromal to mild DLB were selected to participate in this exploratory study along with 20 healthy control subjects matched in terms of age, gender, and level of education. The Twenty Statements Test (TST) was used to assess the SC. Behavioral performances were compared between LB patients and control subjects. Three-dimensional magnetic resonance images (MRI) were acquired for all participants and correlational analyses were performed using voxel-based morphometry (VBM) in whole brain and using a mask for the insula. The behavioral results on the TST showed significantly impaired performances in LB patients in comparison with control subjects (p < .0001). Correlational analyses using VBM revealed positive correlations between the TST and grey matter volume within insular cortex, right supplementary motor area, bilateral inferior temporal gyri, right inferior frontal gyrus, and left lingual gyrus, using a threshold of p = .001 uncorrected, including total intracranial volume (TIV), age, and MMSE as nuisance covariates. Additionally, correlational analysis using a mask for the insula revealed positive correlation with grey matter volume within bilateral insular cortex, using a threshold of p = .005. The behavioral results confirm the existence of SC impairments in LB patients from the prodromal stage of the disease, compared to matched healthy controls. As we expected, VBM analyses revealed involvement of the insula, among that of other brain regions, already known to be involved in other self-components. While this study is exploratory, our findings provide important insights regarding the involvement of the insula within the self, confirming the insula as a core region of the self-networks, including for high-order self-representations such as the SC.

Shared and Specific Changes of Cortico-Striatal Functional Connectivity in Stable Mild Cognitive Impairment and Progressive Mild Cognitive Impairment.

Mild cognitive impairment (MCI), the prodromal stage of Alzheimer's disease, has two distinct subtypes: stable MCI (sMCI) and progressive MCI (pMCI). Early identification of the two subtypes has important clinical significance. We aimed to compare the cortico-striatal functional connectivity (FC) differences between the two subtypes of MCI and enhance the accuracy of differential diagnosis between sMCI and pMCI. We collected resting-state fMRI data from 31 pMCI patients, 41 sMCI patients, and 81 healthy controls. We chose six pairs of seed regions, including the ventral striatum inferior, ventral striatum superior, dorsal-caudal putamen, dorsal-rostral putamen, dorsal caudate, and ventral-rostral putamen and analyzed the differences in cortico-striatal FC among the three groups, additionally, the relationship between the altered FC within the MCI subtypes and cognitive function was examined. Compared to sMCI, the pMCI patients exhibited decreased FC between the left dorsal-rostral putamen and right middle temporal gyrus, the right dorsal caudate and right inferior temporal gyrus, and the left dorsal-rostral putamen and left superior frontal gyrus. Additionally, the altered FC between the right inferior temporal gyrus and right putamen was significantly associated with episodic memory and executive function. Our study revealed common and distinct cortico-striatal FC changes in sMCIs and pMCI across different seeds; these changes were associated with cognitive function. These findings can help us understand the underlying pathophysiological mechanisms of MCI and distinguish pMCI and sMCI in the early stage potentially.

Identifying Progression-Specific Alzheimer's Subtypes Using Multimodal Transformer.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet its current treatments are limited to stopping disease progression. Moreover, the effectiveness of these treatments remains uncertain due to the heterogeneity of the disease. Therefore, it is essential to identify disease subtypes at a very early stage. Current data-driven approaches can be used to classify subtypes during later stages of AD or related disorders, but making predictions in the asymptomatic or prodromal stage is challenging. Furthermore, the classifications of most existing models lack explainability, and these models rely solely on a single modality for assessment, limiting the scope of their analysis. Thus, we propose a multimodal framework that utilizes early-stage indicators, including imaging, genetics, and clinical assessments, to classify AD patients into progression-specific subtypes at an early stage. In our framework, we introduce a tri-modal co-attention mechanism (Tri-COAT) to explicitly capture cross-modal feature associations. Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (slow progressing = 177, intermediate = 302, and fast = 15) were used to train and evaluate Tri-COAT using a 10-fold stratified cross-testing approach. Our proposed model outperforms baseline models and sheds light on essential associations across multimodal features supported by known biological mechanisms. The multimodal design behind Tri-COAT allows it to achieve the highest classification area under the receiver operating characteristic curve while simultaneously providing interpretability to the model predictions through the co-attention mechanism.

The role of the brain renin-angiotensin system in Parkinson´s disease.

The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.

Detection of virus-specific T cells via ELISpot corroborates early diagnosis in human Borna disease virus 1 (BoDV-1) encephalitis

BackgroundWithin endemic regions in southern and eastern Germany, Borna disease virus 1 (BoDV-1) causes rare zoonotic spill-over infections in humans, leading to encephalitis with a high case-fatality risk. So far, intra-vitam diagnosis has mainly been based on RT-qPCR from cerebrospinal fluid (CSF) and serology, both being associated with diagnostic challenges. Whilst low RNA copy numbers in CSF limit the sensitivity of RT-qPCR from this material, seroconversion often occurs late during the course of the disease.Case presentationHere, we report the new case of a 40 − 50 year-old patient in whom the detection of virus-specific T cells via ELISpot corroborated the diagnosis of BoDV-1 infection. The patient showed a typical course of the disease with prodromal symptoms like fever and headaches 2.5 weeks prior to hospital admission, required mechanical ventilation from day three after hospitalisation and remained in deep coma until death ten days after admission.ResultsInfection was first detected by positive RT-qPCR from a CSF sample drawn four days after admission (viral load 890 copies/mL). A positive ELISpot result was obtained from peripheral blood collected on day seven, when virus-specific IgG antibodies were not detectable in serum, possibly due to previous immune adsorption for suspected autoimmune-mediated encephalitis.ConclusionThis case demonstrates that BoDV-1 ELISpot serves as additional diagnostic tool even in the first week after hospitalisation of patients with BoDV-1 encephalitis.