Asymptomatic Stage Research Articles

Germinal center activity and B cell maturation are associated with protective antibody responses against Plasmodium pre-erythrocytic infection.

Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. However, the lack of well-defined features within vaccine-elicited antibody responses that correlate with protection represents a major roadblock to improving on current generation vaccines. We vaccinated mice (BALB/cJ and C57BL/6J) with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated vaccine-elicited humoral immunity and identified immunological factors associated with protection after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice. In contrast, all C57BL/6J mice were infected similar to controls. Protection was mediated by antibodies and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer CSP-specific germinal center experienced B cells and class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that the development of protective antibody responses in BALB/cJ mice in response to vaccination with PyCSP was associated with increased germinal center activity and somatic mutation compared to C57BL/6J mice, highlighting the key role B cell maturation may have in the development of vaccine-elicited protective antibodies against CSP.

Hierarchical spectral clustering reveals brain size and shape changes in asymptomatic carriers of C9orf72.

Traditional methods for detecting asymptomatic brain changes in neurodegenerative diseases such as Alzheimer’s disease or frontotemporal degeneration typically evaluate changes in volume at a predefined level of granularity, e.g. voxel-wise or in a priori defined cortical volumes of interest. Here, we apply a method based on hierarchical spectral clustering, a graph-based partitioning technique. Our method uses multiple levels of segmentation for detecting changes in a data-driven, unbiased, comprehensive manner within a standard statistical framework. Furthermore, spectral clustering allows for detection of changes in shape along with changes in size. We performed tensor-based morphometry to detect changes in the Genetic Frontotemporal dementia Initiative asymptomatic and symptomatic frontotemporal degeneration mutation carriers using hierarchical spectral clustering and compared the outcome to that obtained with a more conventional voxel-wise tensor- and voxel-based morphometric analysis. In the symptomatic groups, the hierarchical spectral clustering-based method yielded results that were largely in line with those obtained with the voxel-wise approach. In asymptomatic C9orf72 expansion carriers, spectral clustering detected changes in size in medial temporal cortex that voxel-wise methods could only detect in the symptomatic phase. Furthermore, in the asymptomatic and the symptomatic phases, the spectral clustering approach detected changes in shape in the premotor cortex in C9orf72. In summary, the present study shows the merit of hierarchical spectral clustering for data-driven segmentation and detection of structural changes in the symptomatic and asymptomatic stages of monogenic frontotemporal degeneration.

Role of low dose computed tomography on lung cancer detection and mortality - an updated systematic review and meta-analysis.

Chest low dose computed tomography (LDCT) is reported to be a sensitive tool for the detection of lung cancer at asymptomatic stage, thus reducing mortality. The review assesses the effect of LDCT screening on all-cause mortality, lung cancer mortality and incidence rates. We conducted literature searches of PubMed, SCOPUS, and the Cochrane Library from inception through January 2020 to identify relevant studies assessing the diagnostic accuracy of LDCT for lung cancer. We used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for reporting this meta-analysis and review. The inclusion criteria were a) Randomized control trials, b) Comparing LDCT to any other form of screening or standard of care, and (c) Primary outcome studied: all-cause mortality, lung cancer-specific mortality, rate of early detection of lung cancer. A total of 11 studies encompassing 97,248 patients were included. When compared with controls (no screening or CXR), LDCT screening was associated with statistically significant reduction in lung cancer mortality (pooled RR 0.86; 95% CI 0.75-0.98); low heterogeneity was observed (I2= 27.86). However, LDCT screening was not associated with statistically significant reduction in all-cause mortality (RR =0.96; 95% CI: 0.92 -1.01). Notably, the LDCT screening was associated with statistically significant increase in lung cancer detection (RR =1.76; 95% CI: 1.14-2.72). LDCT screening has the potential to reduce mortality due to lung cancer among high-risk individuals. LDCT could be considered as a screening modality after careful assessment of other factors like prevalence of TB, proportion of high-risk population, cost, access and availability of LDCT.

Raman Spectroscopy Enables Confirmatory Diagnostics of Fusarium Wilt in Asymptomatic Banana.

Fusarium oxysporum f. sp. cubense (FOC) causes Fusarium wilt, one of the most concerning diseases in banana (Musa spp.), compromising global banana production. There are limited curative management options after FOC infections, and early Fusarium wilt symptoms are similar with other abiotic stress factors such as drought. Therefore, finding a reliable and timely form of early detection and proper diagnostics is critical for disease management for FOC. In this study, Portable Raman spectroscopy (handheld Raman spectrometer equipped with 830 nm laser source) was applied for developing a confirmatory diagnostic tool for early infection of FOC on asymptomatic banana. Banana plantlets were inoculated with FOC; uninoculated plants exposed to a drier condition were also prepared compared to well-watered uninoculated control plants. Subsequent Raman readings from the plant leaves, without damaging or destroying them, were performed weekly. The conditions of biotic and abiotic stresses on banana were modeled to examine and identify specific Raman spectra suitable for diagnosing FOC infection. Our results showed that Raman spectroscopy could be used to make highly accurate diagnostics of FOC at the asymptomatic stage. Based on specific Raman spectra at vibrational bands 1,155, 1,184, and 1,525 cm−1, Raman spectroscopy demonstrated nearly 100% accuracy of FOC diagnosis at 40 days after inoculation, differentiating FOC-infected plants from uninoculated plants that were well-watered or exposed to water deficit condition. This study first reported that Raman spectroscopy can be used as a rapid and non-destructive tool for banana Fusarium wilt diagnostics.

Osteoprotegerin Gene Polymorphisms Are Associated with Subclinical Atherosclerosis in the Mexican Mestizo Population.

Subclinical atherosclerosis (SA) is the presence of coronary calcification in the absence of cardiovascular symptoms, and it usually progresses to atherosclerotic disease. Studies have shown an association of osteoprotegerin gene (OPG) variants with calcification process in cardiovascular diseases; however, to this day there are no studies that evaluate individuals in the asymptomatic stage of atherosclerotic disease. Therefore, the purpose of this study was to analyze the association of four genetic variants and haplotypes of the OPG gene with the development of SA, through TaqMan genotyping assays. We also aimed to identify potential response elements for transcription factors in these genetic variants. The study included 1413 asymptomatic participants (1041 were controls and 372 were individuals with SA). The rs3102735 polymorphism appeared as a protective marker (OR = 0.693; 95% CI = 0.493–0.974; pheterozygote = 0.035; OR = 0.699; 95% CI = 0.496–0.985; pcodominant 1 = 0.040) and two haplotypes were associated with SA, one as a decreased risk: GACC (OR = 0.641, 95% CI = 0.414–0.990, p = 0.045) and another as an increased risk: GACT (OR = 1.208, 95% CI = 1.020–1.431, p = 0.029). Our data suggest a lower risk of SA in rs3102735 C carriers in a representative sample of Mexican mestizo population.

European Stroke Organisation guidelines on treatment of patients with intracranial atherosclerotic disease.

The aim of the present European Stroke Organisation guideline is to provide clinically useful evidence-based recommendations on the management of patients with intracranial atherosclerotic disease (ICAD). The guidelines were prepared following the Standard Operational Procedure of the European Stroke Organisation guidelines and according to GRADE methodology. ICAD represents a major cause of ischemic stroke worldwide, and patients affected by this condition are exposed to a high risk for future strokes and other major cardiovascular events, despite best medical therapy available. We identified 11 relevant clinical problems affecting ICAD patients and formulated the corresponding Population Intervention Comparator Outcomes (PICO) questions. The first two questions refer to the asymptomatic stage of the disease, which is being increasingly detected thanks to the routine use of noninvasive vascular imaging. We were not able to provide evidence-based recommendations regarding the optimal detection strategy and management of asymptomatic ICAD, and further research in the field is encouraged as subclinical ICAD may represent a big opportunity to improve primary stroke prevention. The second block of PICOs (3-5) is dedicated to the management of acute large vessel occlusion (LVO) ischemic stroke caused by ICAD, a clinical presentation of this disease that is becoming increasingly relevant and problematic, since it is associated with more refractory endovascular reperfusion procedures. An operational definition of probable ICAD-related LVO is proposed in the guideline. Despite the challenging context, no dedicated randomized clinical trials (RCTs) were identified, and therefore the guideline can only provide with suggestions derived from observational studies and our expert consensus, such as the escalated use of glycoprotein IIb-IIIa inhibitors and angioplasty/stenting in cases of refractory thrombectomies due to underlying ICAD. The last block of PICOs is devoted to the secondary prevention of patients with symptomatic ICAD. Moderate-level evidence was found to recommend against the use of oral anticoagulation as preferred antithrombotic drug, in favor of antiplatelets. Low-level evidence based our recommendation in favor of double antiplatelet as the antithrombotic treatment of choice in symptomatic ICAD patients, which we suggest to maintain during 90 days as per our expert consensus. Endovascular therapy with intracranial angioplasty and or stenting is not recommended as a treatment of first choice in high-grade symptomatic ICAD (moderate-level evidence). Regarding neurosurgical interventions, the available evidence does not support their use as front line therapies in patients with high-grade ICAD. There is not enough evidence as to provide any specific recommendation regarding the use of remote ischemic conditioning in ICAD patients, and further RCTs are needed to shed light on the utility of this promising therapy. Finally, we dedicate the last PICO to the importance of aggressive vascular risk factor management in ICAD, although the evidence derived from RCTs specifically addressing this question is still scarce.

Clinical characteristics and CBS gene analysis of 13 cases with classic homocystinuria

Objective: To analyze the clinical features and CBS gene variants of 13 patients with classic homocystinuria, and the strategies of individual treatment and prevention were explored. Methods: The general information, clinical manifestations, laboratory tests, cranial images, CBS gene variants, diagnosis and therapeutic strategies of 13 patients with classic homocystinuria admitted to the Department of Pediatrics of Children's Hospital Affiliated to Zhengzhou University and Peking University First Hospital from November 2013 to June 2021 were analyzed retrospectively. Results: There were 13 patients diagnosed at the age of 10 days to 14 years, 6 were male and 7 were female. There were 3 patients detected by newborn screening and received treatment at the asymptomatic stage. There were 10 patients clinically diagnosed at the age of 5 to 14 years. Their symptoms appeared at age of 1 to 6 years. The major clinical manifestations were marfanoid features, lens dislocation and (or) myopia, developmental delay, osteoporosis, and cardiovascular diseases. Brain magnetic resonance imaging showed asymmetric infarcts in 4 patients and hypomyelination in 1 case. Increased blood methionine, plasma total homocysteine and urinary total homocysteine with normal urinary methylmalonic acid were found in 13 patients. The biochemical features were consistent with classic homocystinuria. Totally 18 variants were identified in CBS gene of 13 patients, 10 variants were novel and 8 were reported. only 1 patient was partially responsive to vitamin B6 treatment, while 12 cases were non-responsive. They were mainly treated with low methionine diet and betaine supplement. Three vitamin B6 non-responsive cases received liver transplantation at age of 3, 8 and 8 years, respectively. Their blood methionine and total homocysteine returned to normal within a week after liver transplantation. One patient died. Prenatal diagnosis was performed for a fetus when the mother was pregnant again. Two pathogenic CBS gene variants were identified from the amniocytes as same as the proband. Conclusions: The clinical manifestations of classic homocystinuria are complex and variable. Blood amino acid analysis, serum or urine total homocysteine assay and gene analysis are critical for its diagnosis. There were 10 novel CBS gene varients were identified expanding the CBS gene varient spectrum. Liver transplantation is an effective treatment. Prenatal diagnosis is important to prevent classic homocysteinuria.

Bruegger's exercises vs deep cervical flexor training in asymptomatic participants with forward head posture: a randomised controlled trial

Background/Aims Forward head posture is the most frequent postural deviation in typically healthy individuals and is associated with rounding of the shoulders. Prevention should be considered when it is at the asymptomatic stage by screening and early exercise intervention. The aim of the study was to examine the effects of Bruegger's exercises compared to deep cervical flexor training in asymptomatic participants with forward head posture. Methods This randomised controlled trial included 51 participants with asymptomatic forward head posture, who were allocated to one of three groups. One group undertook Bruegger's exercises with an elastic resistance band, another group performed deep cervical flexor training with a pressure biofeedback unit and the control group performed isometric neck exercises. Outcomes measured were the craniovertebral angle, the craniocervical flexion endurance test and the Pectoralis Minor Index, which were assessed at baseline on day 1 and at the end of the 3-week intervention. Follow-up assessment was undertaken for craniovertebral angle at 6 and 9 weeks from day 1 of the intervention. Statistical analysis included paired t-tests, the Wilcoxon signed-rank test, analysis of variance and the Kruskal–Wallis test. Results All three groups showed improvements in craniovertebral angle and the craniocervical flexion endurance test when compared between pre- and post-intervention. Only those in the Bruegger's exercises group showed an increase in the length of the pectoralis minor according to the Pectoralis Minor Index. Deep cervical flexor muscle endurance increased significantly (P<0.0002) for those in the Bruegger's exercises group and deep cervical flexor training group. At the end of the intervention (week 3) (P<0.0205) and follow up at week 9 (P<0.0029), individuals in the Bruegger's exercises group had maintained the craniovertebral angle correction for longer than those in the deep cervical flexor training and control group. Conclusions Bruegger's exercises with an elastic resistance band was found to be an effective intervention exercise to correct posture from head to scapula and can be included in the treatment of patients with postural head and neck issues.

Current and Near-Future Treatment of Alzheimer's Disease.

Recent findings have improved our understanding of the multifactorial nature of AD. While in early asymptomatic stages of AD, increased amyloid-β synthesis and tau hyperphosphorylation play a key role, while in the latter stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells, and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-β catenin pathway, which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, combination therapies consisting of drugs that rectify several above-mentioned dysfunctions should be used. It should be noted that many widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover, as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel methods to enhance health and treat AD.

Additional autoimmune diseases associated with type 1 diabetes in children and adolescents: A French single-center study from 2014 to 2021

ContextPatients with type 1 diabetes (T1D) are more likely to develop other autoimmune diseases than the general population. ObjectivesTo describe additional autoimmunity in a cohort of children and adolescents with T1D, as well as to identify factors associated with the presence of additional autoantibodies (AABs) and of additional autoimmune diseases (AADs). SettingThis was a single-center retrospective cohort study of 179 children and adolescents (median age: 9.1 years) diagnosed with T1D between 2014 and 2020 in a specialized center in France. Patients were screened for autoimmune thyroiditis and celiac disease at T1D diagnosis and once every 1–2 years during follow-up. Other AADs and their specific autoantibodies were screened for only if clinical or laboratory signs were present. ResultsAt T1D diagnosis, 15.6% of participants presented with at least one type of AAB including antibodies specific to Hashimoto's disease (TPOAb and/or TGAb) and/or to celiac disease (tTGAb and/or EMAb). Only 2.8% of participants presented with an AAD as early as T1D diagnosis. The median follow-up was 37 months. The cumulative incidence of AABs and AADs at 2 years of follow-up was, respectively, 3.9% and 5.4%, and it doubled at 3 years of follow-up. Only one patient, also affected by Down syndrome, was diagnosed with 2 AADs. Hashimoto's disease was the most frequently diagnosed AAD, followed by celiac disease, both at an asymptomatic stage. Vitiligo and Graves’ disease were also diagnosed in this cohort but affected few patients. Children aged 6–12 years were more likely to present with an AAD at diabetes diagnosis (p = 0.043). Conclusion: The high prevalence and incidence of additional autoimmunity in children and adolescents with T1D justifies regular screening of AABs and AADs.

Ginkgo biloba protects striatal neurodegeneration and gut phagoinflammatory damage in rotenone-induced mice model of Parkinson's disease: Role of executioner caspase-3/Nrf2/ARE signaling.

Asymptomatic and early clinical stages of Parkinson's disease (PD) have been linked with comorbid non-motor symptoms including dysfunction of the gastrointestinal (GI) tract. Notwithstanding, neuroprotective and gastroprotective effects of Ginkgo biloba supplements (GBS) have been investigated independently. Hence, whether GBS-mediated GIT-protective capacity could be helpful in PD via gut-brain anti-inflammatory signaling still remains unknown. Treatment with GBS significantly repressed the motor behavioral and neuromuscular deficits and prevented loss of striatal dopaminergic loss by improving the level of tyrosine hydroxylase enzyme and suppressing synucleinopathy development. Striatal neurons and ileal epithelial injury following intraperitoneal rotenone administration were accompanied with oxidoinflammatory/nitroinflammatory stress and marked inhibition of cholinergic transmission. Moreover, there was increased striatal executioner caspase-3 and decreased nuclear factor erythroid-2-related factor 2 (Nrf2) immunoexpression, loss of striatal pyramidal neuron with a marked decrease in length and width of the dendritic spines as well as significant hyperplasia of cryptal cells in the ileal epithelial tissues, all which were reversed by the pretreatment + concurrent (Pre-CONC) and concurrent (CONC) GBS treatment pattern. In sum, we proved the potential dual effects of GBS in preventing both dopaminergic neural-related impairments and gut wall abnormalities linked with PD.

Gout

Gout is the most common inflammatory arthritis in men with arising incidence worldwide. It is ametabolic disease caused by hyperuricemia. Common causes of hyperuricemia, in addition to hereditary reduced renal excretion of urate, include purine over-nutrition, aging, comorbidities and associated medications, some of which increase serum urate levels. The first gout flare represents the signal for deposited urate crystals. If hyperuricemia remains untreated, crystal deposition proceeds and can cause recurrent gout flares, joint destruction and tophi. There is evidence that silent inflammation is ongoing even during asymptomatic stages. Gout patients often exhibit other metabolic, renal and cardiovascular co-morbidities and have higher (cardiovascular) mortality. Therefore, guidelines call for consequent urate lowering strategies to bring serum urate levels to atarget at least below 360 µmol/l. The following article summarizes the recent state of knowledge regarding the diagnosis and therapy of gout.

Therapy Developments in Alzheimer's Disease

The development of new therapies to treat Alzheimer's disease is a focus of global drug discovery. Research is being conducted into more potent therapies for symptomatic treatment, particularly for behavioral disturbances, but also into drugs that intervene in the pathophysiology of the disease, with the aim of halting or at least slowing the progression of the disease. To this end, the focus of identifying people with Alzheimer's disease is shifting to stages of pre-dementia such as that of Mild Cognitive Impairment (MCI), almost synonymous with prodromal AD, or even to asymptomatic stages. Currently, passive immunization using monoclonal antibodies against Aβ42 has shown the most encouraging results. However, it has not been possible to demonstrate statistically significant differences on the primary target parameters in multiple completed pivotal trials. The anti-amyloid antibody aducanumab received conditional preliminary approval in the U.S. based on amyloid reduction; approval for its use in Europe is an ongoing process. Current pharmacological treatments of Alzheimer's disease offer limited symptomatic benefit. No drugs to delay progression of the disease is yet on the market in Germany. Therefore, it is recommended that patients, especially those in pre-dementia stages or at the onset of Alzheimer's disease, be encouraged to participate in clinical trials in order to help develop new drugs that are more effective in the treatment of this disease and that can then benefit many more patients in the future.

Sensitivity of the Social Behavior Observer Checklist to Early Symptoms of Patients With Frontotemporal Dementia.

Changes in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes. Asymptomatic individuals and patients with neurodegenerative disease were selected from the multisite ALLFTD cohort study. In a sample of participants with at least 1 time point of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy. A total of 1,082 FTLD pathogenic variant carriers and noncarriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 nonfluent variant primary progressive aphasia, 137 progressive supranuclear palsy, and 113 Alzheimer disease syndrome). The Disorganized score increased between asymptomatic to very mild (p = 0.016, estimate = -1.10, 95% CI = -1.99 to -0.22), very mild to mild (p = 0.013, estimate = -1.17, 95% CI = -2.08 to -0.26), and mild to moderate/severe (p < 0.001, estimate = -2.00, 95% CI = -2.55 to -1.45) disease stages in behavioral variant frontotemporal dementia regardless of pathogenic variant status. Asymptomatic GRN pathogenic gene variant carriers showed more reactive behaviors (preoccupation with time: p = 0.001, estimate = 1.11, 95% CI = 1.06 to 1.16; self-consciousness: p = 0.003, estimate = 1.77, 95% CI = 1.52 to 2.01) than asymptomatic noncarriers (estimate = 1.01, 95% CI = 0.98 to 1.03; estimate = 1.31, 95% CI = 1.20 to 1.41). The Insensitive score increased to a clinically abnormal level in advanced stages of behavioral variant frontotemporal dementia (p = 0.003, estimate = -0.73, 95% CI = -1.18 to -0.29). Higher scores on each subscale corresponded with higher caregiver burden (p < 0.001). Greater change over time corresponded to greater fronto-subcortical atrophy in the semantic-appraisal and fronto-parietal intrinsically connected networks. The SBOCL is sensitive to early symptoms and reflects disease severity, with some evidence for progression across asymptomatic and symptomatic stages of FTLD syndromes; thus, it may hold promise for early measurement and monitoring of behavioral symptoms in clinical practice and treatment trials. This study provides Class II evidence that the SBOCL is sensitive to early behavioral changes in FTLD pathogenic variants and early symptomatic individuals in a highly educated patient cohort.

Automatic Classification of Subjects of the PSEN1-E280A Family at Risk of Developing Alzheimer's Disease Using Machine Learning and Resting State Electroencephalography.

The study of genetic variant carriers provides an opportunity to identify neurophysiological changes in preclinical stages. Electroencephalography (EEG) is a low-cost and minimally invasive technique which, together with machine learning, provide the possibility to construct systems that classify subjects that might develop Alzheimer's disease (AD). The aim of this paper is to evaluate the capacity of the machine learning techniques to classify healthy Non-Carriers (NonCr) from Asymptomatic Carriers (ACr) of PSEN1-E280A variant for autosomal dominant Alzheimer's disease (ADAD), using spectral features from EEG channels and brain-related independent components (ICs) obtained using independent component analysis (ICA). EEG was recorded in 27 ACr and 33 NonCr. Statistical significance analysis was applied to spectral information from channels and group ICA (gICA), standardized low-resolution tomography (sLORETA) analysis was applied over the IC as well. Strategies for feature selection and classification like Chi-square, mutual informationm and support vector machines (SVM) were evaluated over the dataset. A test accuracy up to 83% was obtained by implementing a SVM with spectral features derived from gICA. The main findings are related to theta and beta rhythms, generated in the parietal and occipital regions, like the precuneus and superior parietal lobule. Promising models for classification of preclinical AD due to PSEN-1-E280A variant can be trained using spectral features, and the importance of the beta band and precuneus region is highlighted in asymptomatic stages, opening up the possibility of its use as a screening methodology.

Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside

BackgroundTargeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality.MethodsM5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC99 value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study.ResultsDoses of 100 and 200 mg would provide exposures exceeding IC99 in 96 and 100% of the simulated population, respectively.ConclusionsThis approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase.Graphical

Generation of heterozygous PKD1 mutant pigs exhibiting early-onset renal cyst formation

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, manifesting as the progressive development of fluid-filled renal cysts. In approximately half of all patients with ADPKD, end-stage renal disease results in decreased renal function. In this study, we used CRISPR-Cas9 and somatic cell cloning to produce pigs with the unique mutation c.152_153insG (PKD1insG/+). Pathological analysis of founder cloned animals and progeny revealed that PKD1insG/+ pigs developed many pathological conditions similar to those of patients with heterozygous mutations in PKD1. Pathological similarities included the formation of macroscopic renal cysts at the neonatal stage, number and cystogenic dynamics of the renal cysts formed, interstitial fibrosis of the renal tissue, and presence of a premature asymptomatic stage. Our findings demonstrate that PKD1insG/+ pigs recapitulate the characteristic symptoms of ADPKD.Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the formation of cysts within the kidneys. The authors generated PKD1 heterozygous knockout (PKD1insG/+) pigs by CRISPR-Cas9 and somatic cell cloning techniques. The founder cloned animals and progeny showed the renal cyst formation from the neonatal stage, interstitial fibrosis of the renal tissue, and the presence of a premature asymptomatic stage. Their findings demonstrate that PKD1insG/+ pigs recapitulate the characteristic symptoms of ADPKD.

Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort.

Background and ObjectivesDisease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic).MethodsC9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage.ResultsA total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1.DiscussionWe confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.

Long-Term Follow-Up of Three Family Members with a Novel NNT Pathogenic Variant Causing Primary Adrenal Insufficiency.

Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the NNT gene. The patients were followed until the ages of 21.6, 20.2, and 4.2 years. PAI was diagnosed in the eldest two brothers after an Addisonian crisis and the third was diagnosed at the age of 4.5 months in the asymptomatic stage due to the genetic screening of family members. Whole exome sequencing with a targeted interpretation of variants in genes related to PAI was performed in all the patients. The urinary steroid metabolome was determined by gas chromatography–mass spectrometry in the asymptomatic patient. The three patients, who were homozygous for c.1575dup in the NNT gene, developed isolated glucocorticoid deficiency. The urinary steroid metabolome showed normal excretion of cortisol metabolites. The adolescent patients had slow pubertal progression with low–normal testicular volume, while testicular endocrine function was normal. Bone mineral density was in the range for osteopenia in both grown-up siblings. Echocardiography revealed no structural or functional heart abnormalities. This article is among the first with a comprehensive and chronologically-detailed description of patients with NNT deficiency.

Reconfigured metabolism brain network in asymptomatic microtubule-associated protein tau mutation carriers: a graph theoretical analysis

BackgroundStudies exploring topological properties of the metabolic network during the presymptomatic stage of genetic frontotemporal dementia (FTD) are scarce. However, such knowledge is important for understanding brain function and disease pathogenesis. Therefore, we aimed to explore FTD-specific patterns of metabolism topology reconfiguration in microtubule-associated protein tau (MAPT) mutation carriers before the onset of symptoms.MethodsSix asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who all belonged to the same family of FTD. For comparison, we included 32 behavioral variant FTD (bvFTD) patients and 33 unrelated healthy controls. Each participant underwent neuropsychological assessments, genetic testing, and a hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) scan. Voxel-wise gray matter volumes and standardized uptake value ratios were calculated and compared for structural MRI and fluorodeoxyglucose (FDG)-PET, separately. The sparse inverse covariance estimation method (SICE) was applied to topological properties and metabolic connectomes of brain functional networks derived from 18F-FDG PET/MRI data. Independent component analysis was used to explore the metabolic connectivity of the salience (SN) and default mode networks (DMN).ResultsThe asymptomatic MAPT carriers performed normal global parameters of the metabolism network, whereas bvFTD patients did not. However, we revealed lost hubs in the ventromedial prefrontal, orbitofrontal, and anterior cingulate cortices and reconfigured hubs in the anterior insula, precuneus, and posterior cingulate cortex in asymptomatic carriers compared with non-carriers, which overlapped with the comparisons between bvFTD patients and controls. Similarly, significant differences in local parameters of these nodes were present between asymptomatic carriers and non-carriers. The reduction in the connectivity of lost hub regions and the enhancement of connectivity between reconfigured hubs and components of the frontal cortex were marked during the asymptomatic stage. Metabolic connectivity within the SN and DMN was enhanced in asymptomatic carriers compared with non-mutation carriers but reduced in bvFTD patients relative to controls.ConclusionsOur findings showed that metabolism topology reconfiguration, characterized by the earliest involvement of medial prefrontal areas and active compensation in task-related regions, was present in the presymptomatic phase of genetic FTD with MAPT mutation, which may be used as an imaging biomarker of increased risk of FTD.