Influence of Different Diagnostic Criteria on Alzheimer Disease Clinical Research.

BACKGROUND AND OBJECTIVES: Updates in Alzheimer disease (AD) diagnostic guidelines by the National Institute on Aging-Alzheimer's Association (NIA-AA) and the International Working Group (IWG) over the past 11 years may affect clinical diagnoses. We assessed how these guidelines affect clinical AD diagnosis in a cohort of cognitively unimpaired (CU) and cognitively impaired (CI) individuals. METHODS: We applied clinical and biomarker data in algorithms to classify individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort according to the following diagnostic guidelines for AD: 2011 NIA-AA, 2016 IWG-2, 2018 NIA-AA, and 2021 IWG-3, assigning the following generic diagnostic labels: (1) not AD (nAD), (2) increased risk of developing AD (irAD), and (3) AD. Diagnostic labels were compared according to their frequency, convergence across guidelines, biomarker profiles, and prognostic value. We also evaluated the diagnostic discordance among the criteria. RESULTS: A total of 1,195 individuals (mean age 73.2 ± 7.2 years, mean education 16.1 ± 2.7, 44.0% female) presented different repartitions of diagnostic labels according to the 2011 NIA-AA (nAD = 37.8%, irAD = 23.0%, AD = 39.2%), 2016 IWG-2 (nAD = 37.7%, irAD = 28.7%, AD = 33.6%), 2018 NIA-AA (nAD = 40.7%, irAD = 9.3%, AD = 50.0%), and 2021 IWG-3 (nAD = 51.2%, irAD = 8.4%, AD = 48.3%) frameworks. Discordant diagnoses across all guidelines were found in 512 participants (42.8%) (138 [91.4%] occurring in only ß-amyloid [CU 65.4%, CI 34.6%] and 191 [78.6%] in only tau-positive [CU 71.7%, CI 28.3%] individuals). Differences in predicting cognitive impairment between nAD and irAD groups were observed with the 2011 NIA-AA (hazard ratio [HR] 2.21, 95% CI 1.34-3.65, p = 0.002), 2016 IWG-2 (HR 2.81, 95% CI 1.59-4.96, p < 0.000), and 2021 IWG-3 (HR 3.61, 95% CI 2.09-6.23, p < 0.000), but not with 2018 NIA-AA (HR 1.69, 95% CI 0.87-3.28, p = 0.115). DISCUSSION: Over 42% of the studied population presented discordant diagnoses when using the different examined AD criteria, mostly in individuals with a single positive biomarker. Except for 2018 NIA-AA, all guidelines identified asymptomatic individuals at risk of cognitive impairment. Our findings highlight important differences between the guidelines, emphasizing the necessity for updated criteria with enhanced staging metrics, considering clinical, research, therapeutic, and trial design aspects.

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Clinicogenetic characterization of cerebrotendinous xanthomatosis in Brazil.

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype-phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants.

Omics-derived biological modules reflect metabolic brain changes in Alzheimer's disease.

INTRODUCTION: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive. METHODS: Here, we integrated [18F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis. RESULTS: Our results showed that multiple transcriptomic modules are associated with brain [18F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t(223) = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t(223) = 3.90, P value < 0.001). DISCUSSION: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD. HIGHLIGHTS: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [18F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [18F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [18F]FDG-PET metabolism.

15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN.

This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.

Glial reactivity is linked to synaptic dysfunction across the aging and Alzheimer's disease spectrum.

Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease(AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synaptic dysfunction in 478 individuals across the aging and AD spectrum from two cohorts with available CSF measures of amyloid-ß(Aß), phosphorylated tau(pTau181), astrocyte reactivity(GFAP), microglial activation(sTREM2), and synaptic biomarkers(GAP43 and neurogranin). Elevated CSF GFAP levels were linked to presynaptic and postsynaptic dysfunction, regardless of cognitive status or Aß presence. CSF sTREM2 levels were associated with presynaptic biomarkers in cognitively unimpaired and impaired Aß + individuals and postsynaptic biomarkers in cognitively impaired Aß + individuals. Notably, CSF pTau181 levels mediated all associations between GFAP or sTREM2 levels and synaptic dysfunction biomarkers. These results suggest that neuronal-related synaptic biomarkers could be used in clinical trials targeting glial reactivity in AD.

Simplified Method for Kinetic and Thermodynamic Screening of Cardiotonic Steroids Through the K + -Dependent Phosphatase Activity of Na + /K + -ATPase with Chromogenic pNPP Substrate .

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na+/K+-ATPase (NKA, EC 3.6.3.9). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (kon), dissociation rate (koff) and equilibrium (Ki) constants of CTS for structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of Ki of the cardenolides digitoxigenin, essentially due to a reduction of kon In contrast, the Ki of the structurally related bufadienolide bufalin increased much less due to the reduction of its koff partially compensating the decrease of its kon When evaluating the kinetics of 15 natural and semi-synthetic CTS, we observed that both kon and koff correlated with Ki (Spearman test), suggesting that differences in potency depend on variations of both kon and koff A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of koff rather than an increase of kon Rising the temperature did not alter the koff of digitoxin, generating a ∆H‡ (koff) of -10.4 {plus minus} 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of kon, koff, and Ki of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds. Significance Statement We described a fast, simple, and cost-effective method for the measurement of phosphatase pNPPase activity enabling structure-kinetics relationships of Na+/K+-ATPase inhibitors, which are important compounds due to their antitumor effect and endogenous role. Using 15 compounds, some of them original, we were able to delineate the kinetics and/or thermodynamics differences due to the type of sugar and lactone ring present in the steroid structure.

Personalized biomodel of the cervical spine for laboratory laminoplasty training.

OBJECTIVE: The use of biomodels in the laboratory for studying and training cervical laminoplasty has not yet been reported. We propose the use of a cervical spine biomodel for surgical laminoplasty training. METHODS: This is an experimental study. Ten 3D identical cervical spine biomodels were printed based on CT and MRI scans of a patient diagnosed with spondylotic cervical myelopathy. The additive manufacturing method employed fused deposition modeling (FDM) and polylactic acid (PLA) and selected as the raw material. The sample was divided into two groups: control (n = 5; the biomodels were submitted to CT scanning) and open-door (n = 5; the biomodels were submitted to open-door laminoplasty and postoperative CT). The area and anteroposterior diameter of the vertebral canal were measured on CT scans. RESULTS: Printing each piece took twelve hours. During the surgical procedure, there was sufficient support from the biomodels to keep them immobilized. Using the drill was feasible; however continuous irrigation was mandatory to prevent plastic material overheating. The raw material made the biomodel CT study possible. The vertebral canal dimensions increased 24.80% (0.62 cm2) in the area and 24.88% (3.12 mm) in the anteroposterior diameter. CONCLUSIONS: The cervical spine biomodels can be used for laminoplasty training, even by using thermosensitive material such as PLA. The use of continuous irrigation is essential while drilling.

Long-COVID olfactory dysfunction: allele E4 of apolipoprotein E as a possible protective factor.

BACKGROUND: Olfactory dysfunction (OD) represents a frequent manifestation of the coronavirus disease 2019 (COVID-19). Apolipoprotein E (APOE) is a protein that interacts with the angiotensin-converting enzyme receptor, essential for viral entry into the cell. Previous publications have suggested a possible role of APOE in COVID-19 severity. As far as we know, no publications found significant associations between this disease's severity, OD, and APOE polymorphisms (E2, E3, and E4). OBJECTIVE: To analyze the epidemiology of OD and its relationship with APOE polymorphisms in a cohort of Long-COVID patients. METHODS: We conducted a prospective cohort study with patients followed in a post-COVID neurological outpatient clinic, with OD being defined as a subjective reduction of olfactory function after infection, and persistent OD being defined when the complaint lasted more than 3 months after the COVID-19 infection resolution. This cross-sectional study is part of a large research with previously reported data focusing on the cognitive performance of our sample. RESULTS: The final sample comprised 221 patients, among whom 186 collected blood samples for APOE genotyping. The persistent OD group was younger and had a lower hospitalization rate during the acute phase of the disease (p < 0.001). Furthermore, the APOE variant E4 allele frequency was lower in this group (p = 0.035). This study evaluated OD in an outpatient population with COVID-19. In the current literature on this disease, anosmia is associated with better clinical outcomes and the E4 allele is associated with worse outcomes. CONCLUSION: Our study provides new information to these correlations, suggesting APOE E4 as a protective factor for OD.

ANTECEDENTES: A disfunção olfatória (DO) é uma manifestação frequente da doença do coronavírus 2019 (COVID-19). A apolipoproteína E (APOE) é uma proteína que interage com o receptor da enzima conversora de angiotensina, essencial para a entrada viral na célula. Publicações anteriores sugeriram um possível papel da APOE na gravidade da COVID-19. Até onde sabemos, nenhuma publicação encontrou associações significativas entre a gravidade dessa doença, DO e polimorfismos da APOE (E2, E3 e E4). OBJETIVO: Analisar a epidemiologia da DO e sua relação com os polimorfismos do gene APOE em uma coorte de pacientes com COVID longa. MéTODOS: Um estudo de coorte prospectiva com pacientes acompanhados em ambulatório neurológico pós-COVID, com DO sendo definida como uma redução subjetiva da função olfativa após a infecção e a DO persistente sendo definida quando a queixa durou mais de 3 meses após a resolução da infecção por COVID-19. Este estudo transversal é parte de uma pesquisa maior com dados anteriormente relatados, focando na performance cognitiva dos pacientes. RESULTADOS: Foram selecionados 221 pacientes para esse estudo, dos quais 186 haviam coletado amostras de sangue para genotipagem APOE. O grupo DO persistente foi mais jovem e apresentou menor taxa de internação na fase aguda da doença (p < 0,001). Além disso, a frequência do alelo E4 da APOE foi menor nesse grupo (p = 0,035). Este estudo avaliou a DO em uma população com COVID longa. Na literatura atual sobre essa doença, a anosmia está associada a melhores desfechos clínicos e o alelo E4 está associado a piores desfechos. CONCLUSãO: Nosso estudo acrescenta novas informações a essas correlações, sugerindo a APOE E4 como um fator de proteção para DO.

Prediction of future cognitive decline among cognitively unimpaired individuals using measures of soluble phosphorylated tau or tau tangle pathology.

Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R2 PET=0.32 vs R2 PLASMA=0.32, pdifference=0.812) and with progression to mild cognitive impairment (Hazard ratio[HR]PET=1.56[1.43-1.70] vs HRPLASMA=1.63[1.50-1.77], pdifference=0.627). Combined plasma and PET models were superior to the single biomarker models (R2=0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

In vitro probiotic potential of lactic acid bacteria isolated from the intestines of Muscovy ducks.

The current study was conducted to isolate, test and characterize molecularly and physiologically lactic acid bacteria from the intestines of Muscovy ducks to evaluate their probiotic potential for poultry farming. Three hundred lactic acid bacteria from the gastrointestinal tract of Muscovy ducks were isolated. The strains were phenotypically characterized by observing cell morphology, performing Gram staining, catalase production, and testing their ability to grow in MRS broth at different temperatures, pH values, NaCl concentrations, bile concentration, and in compatibility tests between strains. Nine strains were selected based on their resilience. Eight strains were identified using molecular techniques. These strains exhibited significant tolerance to acidic pH, bile salts, and NaCl, essential for probiotic function. All isolates inhibited the growth of Salmonella enterica serotype Typhimurium (DT104) and Enteropathogenic Escherichia coli serotype O86:H34 (EPEC), showcasing their antimicrobial potential. Antibiotic susceptibility testing revealed 100% resistance to clindamycin and erythromycin but high susceptibility to ampicillin and vancomycin. Growth was observed at various temperatures, indicating mesophilic characteristics. Compatibility tests confirmed their suitability for probiotic formulations. Genomic analysis identified the strains primarily as Enterococcus. Conclusively, the study identified eight out of nine selected lactic acid bacteria strains from Muscovy ducks as autochthonous probiotics, showing resilience to treatments and compatibility for consortium formulation. These strains are suitable for in vivo testing for potential poultry farming applications. Further research on their molecular mechanisms and in vivo effects is needed.

Cyclodextrins as a Strategy for Enhancing Solubility of Therapeutic Agents for Neglected Tropical Diseases: A Systematic Review.

BACKGROUND: Neglected Tropical Diseases (NTD) are chronic infectious conditions that primarily affect marginalized populations. The chemotherapeutic arsenal available for treating NTD is limited and outdated, which poses a challenge in controlling and eradicating these diseases. This is exacerbated by the pharmaceutical industry's lack of interest in funding the development of new therapeutic alternatives. In addition, a considerable number of drugs used in NTD therapy have low aqueous solubility. To address this issue, solubility enhancement strategies, such as the use of inclusion complexes with cyclodextrins (CD) can be employed. OBJECTIVE: Therefore, this systematic review aims to present the application of CD in complexing with drugs and chemotherapeutic compounds used in the therapy of some of the most prevalent NTD worldwide and how these complexes can enhance the treatment of these diseases. METHODS: Two bibliographic databases, Science Direct and PubMed, were used to conduct the search. The selection of studies and the writing of this systematic review followed the criteria outlined by the PRISMA guidelines. RESULTS: From a total of 978 articles, 23 were selected after applying the exclusion criteria. All the studies selected were consistent with the use of CD as a strategy to increase the solubility of therapeutic agents used in NTD. CONCLUSION: The results indicate that CD can enhance the solubility of chemotherapeutic agents for the treatment of Neglected Tropical Diseases (NTD). This review presents data that clearly highlights the potential use of CD in the development of new treatments for neglected tropical diseases. It can assist in the formulation of future treatments that are more effective and safer.

Analysis of physical traits, clinical parameters, and energy metabolism of in vivo- and in vitro-derived Flemish newborn calves during the first day of life.

Studies investigating physiological deviations from normality in newborn calves derived from in vitro fertilization procedures remain important for the understanding of factors that reduce calf survival after birth. The aim of this study was to investigate parameters affecting health and welfare of newborn Flemish calves derived from in vitro embryo production (IVP) in the first hours of life in comparison to in vivo-derived calves. Physical traits of newborn calves and fetal membranes (FM) were recorded soon after birth. Newborn venous blood samples were collected at several time points within the first 24 h of life for analyses of energy substrates, electrolytes, blood gases, acid-base balance, blood chemistry, and haematology. A liver biopsy was taken within the first hour after birth for analysis of gene expression of key enzymes of the fructolytic and glycolytic pathways. Newborn IVP calves were heavier and larger at birth, which was associated with heavier FM. At several time points during the first 24 h of life, IVP-derived calves had altered rectal temperature, blood gases, electrolyte concentrations, blood parameters for liver, kidney and muscle function, and acid-base balance, plasma lipid metabolism, and hemogram parameters. The relative mRNA abundances for triokinase and lactate dehydrogenase-B were greater in IVP calves. In summary, IVP-derived newborn calves were at higher risk of clinical problems after birth, which was markedly greater in heavier and larger calves. Such animals take longer to adapt to extrauterine life and should receive a special attention during the immediate neonatal period.

Integrated Design and Fabrication of Pneumatic Soft Robot Actuators in a Single Casting Step.

Bio-inspired soft robots have already shown the ability to handle uncertainty and adapt to unstructured environments. However, their availability is partially restricted by time-consuming, costly, and highly supervised design-fabrication processes, often based on resource-intensive iterative workflows. Here, we propose an integrated approach targeting the design and fabrication of pneumatic soft actuators in a single casting step. Molds and sacrificial water-soluble hollow cores are printed using fused filament fabrication. A heated water circuit accelerates the dissolution of the core's material and guarantees its complete removal from the actuator walls, while the actuator's mechanical operability is defined through finite element analysis. This enables the fabrication of actuators with non-uniform cross-sections under minimal supervision, thereby reducing the number of iterations necessary during the design and fabrication processes. Three actuators capable of bending and linear motion were designed, fabricated, integrated, and demonstrated as 3 different bio-inspired soft robots, an earthworm-inspired robot, a 4-legged robot, and a robotic gripper. We demonstrate the availability, versatility, and effectiveness of the proposed methods, contributing to accelerating the design and fabrication of soft robots. This study represents a step toward increasing the accessibility of soft robots to people at a lower cost.

Hormone therapy is associated with lower Alzheimer's disease tau biomarkers in post-menopausal females -evidence from two independent cohorts.

BACKGROUND: Females represent approximately 70% of the Alzheimer's disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum. METHODS: This cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-ß (Aß) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aß-PET on regional tau-PET. RESULTS: HT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs (P < 0.05, Hedges' g = 0.73), Braak III-IV ROIs (P < 0.0001, Hedges' g = 0.74) and Braak V-VI ROIs (P < 0.0001, Hedges' g = 0.69) compared to HT- females. HT + females also showed significantly lower CSF p-tau181 (P < 0.001) and plasma p-tau181 (P < 0.0001) concentrations. Additionally, results from multivariate linear regression models indicated that HT interacts with cortical Aß and is associated with lower regional NFT load. CONCLUSIONS: Overall, findings from this observational study suggest that HT is associated with lower tau neuroimaging and fluid biomarkers in postmenopausal females. Due to the close link between tau and cognition, this study highlights the need for large randomized controlled trials designed to systemically study the influences of HT on AD biomarkers and disease progression.

In-vivo neuronal dysfunction by Aß and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer's disease.

The molecular mechanisms underlying neuronal dysfunction in Alzheimer's disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aß) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aß- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aß and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant's real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aß-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aß and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aß and tau's synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aß-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.

Ataxias in Brazil: 17 years of experience in an ataxia center.

BACKGROUND: Cerebellar ataxias comprise sporadic and genetic etiologies. Ataxia may also be a presenting feature in hereditary spastic paraplegias (HSPs). OBJECTIVE: To report a descriptive analysis of the frequency of different forms of cerebellar ataxia evaluated over 17 years in the Ataxia Unit of Universidade Federal de São Paulo, Brazil. METHODS: Charts of patients who were being followed from January 2007 to December 2023 were reviewed. We used descriptive statistics to present our results as frequencies and percentages of the overall analysis. Diagnosed patients were classified according to the following 9 groups: sporadic ataxia, spinocerebellar ataxias (SCAs), other autosomal dominant cerebellar ataxias, autosomal recessive cerebellar ataxias (ARCAs), mitochondrial ataxias, congenital ataxias, X-linked ataxias, HSPs, and others. RESULTS: There were 1,332 patients with ataxias or spastic paraplegias. Overall, 744 (55.85%) of all cases were successfully diagnosed: 101 sporadic ataxia, 326 SCAs, 20 of other autosomal dominant cerebellar ataxias, 186 ARCAs, 6 X-linked ataxias, 2 mitochondrial ataxias, 4 congenital ataxias, and 51 HSPs. CONCLUSION: This study describes the frequency of cerebellar ataxias in a large group of patients followed for the past 17 years, of whom 55% obtained a definitive clinical or molecular diagnosis. Future demographic surveys in Brazil or Latin American remain necessary.

ANTECEDENTES: Ataxias cerebelares compreendem as etiologias esporádicas e genéticas. Ataxia também pode ser uma característica das paraplegias espásticas hereditárias (HSPs). OBJETIVO: Relatar uma análise descritiva da frequência das diferentes formas de ataxias cerebelares avaliadas ao longo de 17 anos no Setor da Ataxias da Universidade Federal de São Paulo, Brasil. MéTODOS: Prontuários de pacientes acompanhados de janeiro de 2007 a dezembro de 2023 foram revisados. Usamos análise descritiva para apresentar nossos resultados como frequências e percentuais. Os pacientes foram classificados de acordo com os 9 grupos seguintes: ataxias esporádicas, ataxias espinocerebelares (SCA), outras ataxias cerebelares autossômicas dominantes, ataxias cerebelares autossômicas recessivas (ARCA), ataxias mitocondriais, ataxias congênitas, ataxias ligadas ao X, PEH e outros. RESULTADOS: Foram avaliados 1.332 pacientes. Desse total, 744 tiveram um diagnóstico definitivo: 101 ataxias esporádicas, 326 SCA, 20 outras ataxias cerebelares autossômicas dominantes, 186 (ARCA), 6 ataxias ligadas ao X, 2 ataxias mitocondriais, 4 ataxias congênitas e 51 HSP. CONCLUSãO: Esse estudo descreve a frequência e a etiologia das ataxias em um grande grupo de pacientes acompanhados nos últimos 17 anos, dos quais 55% obtiveram diagnóstico clínico ou molecular definitivos. Estudos demográficos futuros do Brasil ou da América Latina continuam sendo necessários.

HPV Detection in Breast Tumors and Associated Risk Factors in Northeastern Brazil.

Breast cancer risk factors include lifestyle, genetic-hormonal influences, and viral infections. Human papillomavirus (HPV), known primarily as the etiological agent of cervical cancer, also appears active in breast carcinogenesis, as evidenced in our study of 56 patients from northeastern Brazil. We assessed the clinical and sociodemographic characteristics, correlating them with various breast cancer tumor types. HPV detection involved amplifying the L1 region, with viral load measured using the E2/E6 ratio and viral activity indicated by E5 oncogene expression. Predominantly, patients over 56 years of age with healthy lifestyles showed a high incidence of invasive ductal carcinoma and triple-negative breast cancer. HPV was detected in 35.7% of cases, mostly HPV16, which is associated with high viral loads (80 copies per cell) and significant E5 expression. These results hint at a possible link between HPV and breast carcinogenesis, necessitating further studies to explore this association and the underlying viral mechanisms.