Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer's disease from cortical dementias

International audienceBackground: Considering that most of semantic dementia (SD) and frontotemporal dementia (FTD) patients show no postmortem Alzheimer's disease (AD) pathology, cerebrospinal fluid (CSF) biomarkers may be of value for distinguishing these patients from those with AD. Additionally, biomarkers may be useful for identifying patients with atypical phenotypic presentations of AD, such as posterior cortical atrophy (PCA) and primary progressive non-fluent or logopenic aphasia (PNFLA). Methods: We investigated CSF biomarkers (beta-amyloid 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau [P-tau]) in 164 patients with AD (n=60), PCA (n=15), behavioral variant FTD (n=27), SD (n=19), (PNFLA) (n=26) and functional cognitive disorders (FCD, n=17). We then examined the diagnostic value of these CSF biomarkers in distinguishing the patients from those with AD. Results: The P-Tau/Aβ42 ratio was found to be the best biomarker for discriminating AD from FTD and SD, with a sensitivity of 91.7% and 98.3%, respectively, and a specificity of 92.6% and 84.2%, respectively. As expected, biomarkers were less effective in differentiating AD from PNFLA and PCA, as significant proportions of PCA and PNFLA patients (60% and 61.5%, respectively) had concurrent alterations of both T-tau/Aβ42 and P-Tau/Aβ42 ratios. None of the FCD patients had a typical AD CSF profile or abnormal T-tau/Aβ42 or P-Tau/Aβ42 ratios. Conclusion: The P-Tau/Aβ42 ratio is a useful tool to discriminate AD from both FTD and SD, which are known to involve pathological processes distinct from AD. Biomarkers could be useful for identifying patients with an atypical AD phenotype that includes PNFLA and PCA

Regional dynamics of the resting brain in amyotrophic lateral sclerosis using fALFF and ReHo analyses

Resting state functional magnetic resonance imaging (rs-fMRI) has been playing an important role in the study of amyotrophic lateral sclerosis (ALS). Although functional connectivity is widely studied, the patterns of spontaneous neural activity of the resting brain are important mechanisms that have been used recently to study a variety of conditions but remain less explored in ALS. Here we have used fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) to study the regional dynamics of the resting brain of non-demented ALS patients compared with healthy controls. As expected, we found the sensorimotor network (SMN) with changes in fALFF and ReHo but also found the default mode (DMN), frontoparietal (FPN), salience (SN) networks altered and the cerebellum, although no structural changes between ALS patients and controls were reported in the regions with fALFF and ReHo changes. We show an altered pattern in the spontaneous low frequency oscillations that is not confined to the motor areas and reveal a more widespread involvement of non-motor regions, including those responsible for cognition

Deficits in emotion recognition as markers of frontal behavioral dysfunction in Amyotrophic Lateral Sclerosis

Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with prominent motor symptoms. Patients with ALS may also manifest frontal behavior symptoms and cognitive decline, including impairment in facial emotion recognition. The authors aimed to investigate whether deficits in emotion recognition were associated with frontal behavior symptoms in ALS. Methods: Participants were patients with probable or definite sporadic ALS (N521; male:female ratio, 11:10; median age, 62 years; median disease duration, 3 years) and agematched and education-matched healthy control subjects (N525; male:female ratio, 14:11; median age, 61 years). The Facial Emotion Recognition Test (FERT) was administered to all participants. Patients with ALS were assessed using the Cambridge Behavior Inventory-Revised and were classified into two groups according to the presence of frontal behavioral symptoms: ALS with no behavioral symptom (ALSns; N59) and ALS with at least one behavioral symptom (ALSbs; N512). Results: Apathy and mood symptoms were the most frequent neuropsychiatric symptoms in the patient group. Patients with ALS performed worse than control subjects in the recognition of sadness (p,0.004). There were no differences between control subjects and patients in the ALSns group in all FERT scores, but the ALSbs group had lower performance than control subjects in sadness (p,0.003). Conclusions: Emotion recognition deficit may be a marker of frontal behavior in ALS

A decomposition resolution approach for a production-inventory-distribution-routing problem

ABSTRACT: The aim of this study is to develop a solution to the problem of distribution of goods proposed by the Mathematical Competitive Game 2017-2018, jointly organized by the French Federation of Mathematical Games and Mathematical Modelling Company. Referred to as a production-inventory-distribution-routing problem (PIDRP), it is an NP-hard combinatorial optimization problem, which received the least attention in the literature. The research is quantitative model-based and combines exact and heuristic methods to propose a multiple-phase resolution approach to PIDRP. The results show that the use of clusters ensures practical operational aspects and provides good feasible solutions for the PIDRP in short and long-term planning. The theoretical contribution of this study liesin the PIDRP modeling strategy, and the practical contribution consists in solving a real-life PIDRP-based using optimization techniques

Mitochondrial DNA-like sequence in the nuclear genome of Saguinus (Callitrichinae, Primates): transfer estimation

Mitochondrial DNA-like sequences have been found in the nuclei of a variety of organisms. These nuclear pseudogenes can be used to estimate relative evolutionary rates of mitochondrial genes, and can be used as outgroups in phylogenetic analyses. In this study, mitochondrial sequences with pseudogene-like characteristics, including deletions and/or insertions and stop codons, were found in tamarins (Saguinus spp., Callitrichinae, Primates). Phylogenetic analysis allowed estimation of the timing of the migration of these sequences to the nuclear genome, and also permitted inferences on the phylogeny of the genus. The choice of an inadequate outgroup (Aotus infulatus) prevented a good phylogenetic resolution of the subfamily Callitrichinae. The relatively ancient divergence of the Cebidae (Callitrichinae, Aotinae and Cebinae) may have favored confounding homoplasies.Seqüências tipo mitocondriais têm comumente sido encontradas no genoma nuclear de diversos organismos. Quando acidentalmente incluídas em estudos de seqüências mitocondriais, diversas conclusões errôneas podem ser obtidas. No entanto, estes pseudogenes nucleares tipo mitocondriais podem ser usados para a estimativa da taxa relativa de evolução de genes mitocondriais e também como grupo externo em análises filogenéticas. No presente trabalho, seqüências mitocondriais com características do tipo de pseudogene, tais como deleções e/ou inserções e códons de parada, foram encontradas em tamarins (Saguinus spp., Callitrichinae, Primates). A análise filogenética permitiu a estimativa do tempo da migração da seqüência mitocondrial para o genoma nuclear e algumas inferências filogenéticas. A escolha de um grupo externo não adequado (Aotus infulatus) não permitiu uma reconstrução filogenética confiável da subfamília Callitrichinae. A divergência bastante antiga de Cebidae (Callitrichinae, Aotinae e Cebinae) pode ter favorecido o aparecimento de homoplasias, obscurecendo a análise

Cost-effectiveness of insulin analogs from the perspective of the Brazilian public health system

Human insulin is provided by the Brazilian Public Health System (BPHS) for the treatment of diabetes, however, legal proceedings to acquire insulin analogs have burdened the BPHS health system. The aim of this study was to perform a cost-effectiveness analysis to compare insulin analogs and human insulins. This is a pharmacoeconomic study of cost-effectiveness. The direct medical cost related to insulin extracted from the Ministry of Health drug price list was considered. The clinical results, i.e. reduction in glycated hemoglobin (HbA1c), were extracted by meta-analysis. Different scenarios were structured to measure the uncertainties regarding the costs and reduction in HbA1c. Decision tree was developed for sensitivity of Incremental Cost Effectiveness Ratio (ICER). A total of fifteen scenarios were structured. Given the best-case scenario for the insulin analogs, the insulins aspart, lispro, glargine and detemir showed an ICER of R$1,768.59; R$ 3,308.54; R$11,718.75 and R$ 2,685.22, respectively. In all scenarios in which the minimum effectiveness was proposed, lispro, glargine and detemir were dominant strategies. Sensitivity analysis showed that the aspart had R$3,066.98 [95$ 6,163.97 [95% CI: 3919.29; 11401.57] for incremental costs. We concluded there was evidence that the insulin aspart is the most cost-effective

Direct and indirect effects of a pH gradient bring insights into the mechanisms driving prokaryotic community structures

Background: pH is frequently reported as the main driver for prokaryotic community structure in soils. However, pH changes are also linked to "spillover effects" on other chemical parameters (e.g., availability of Al, Fe, Mn, Zn, and Cu) and plant growth, but these indirect effects on the microbial communities are rarely investigated. Usually, pH also co-varies with some confounding factors, such as land use, soil management (e.g., tillage and chemical inputs), plant cover, and/or edapho-climatic conditions. So, a more comprehensive analysis of the direct and indirect effects of pH brings a better understanding of the mechanisms driving prokaryotic (archaeal and bacterial) community structures. Results: We evaluated an agricultural soil pH gradient (from 4 to 6, the typical range for tropical farms), in a liming gradient with confounding factors minimized, investigating relationships between prokaryotic communities (16S rRNA) and physical-chemical parameters (indirect effects). Correlations, hierarchical modeling of species communities (HMSC), and random forest (RF) modeling indicated that both direct and indirect effects of the pH gradient affected the prokaryotic communities. Some OTUs were more affected by the pH changes (e.g., some Actinobacteria), while others were more affected by the indirect pH effects (e.g., some Proteobacteria). HMSC detected a phylogenetic signal related to the effects. Both HMSC and RF indicated that the main indirect effect was the pH changes on the availability of some elements (e.g., Al, Fe, and Cu), and secondarily, effects on plant growth and nutrient cycling also affected the OTUs. Additionally, we found that some of the OTUs that responded to pH also correlated with CO2, CH4, and N2O greenhouse gas fluxes. Conclusions: Our results indicate that there are two distinct pH-related mechanisms driving prokaryotic community structures, the direct effect and "spillover effects" of pH (indirect effects). Moreover, the indirect effects are highly relevant for some OTUs and consequently for the community structure; therefore, it is a mechanism that should be further investigated in microbial ecology.Peer reviewe

Direct and indirect effects of a pH gradient bring insights into the mechanisms driving prokaryotic community structures

Background: pH is frequently reported as the main driver for prokaryotic community structure in soils. However, pH changes are also linked to "spillover effects" on other chemical parameters (e.g., availability of Al, Fe, Mn, Zn, and Cu) and plant growth, but these indirect effects on the microbial communities are rarely investigated. Usually, pH also co-varies with some confounding factors, such as land use, soil management (e.g., tillage and chemical inputs), plant cover, and/or edapho-climatic conditions. So, a more comprehensive analysis of the direct and indirect effects of pH brings a better understanding of the mechanisms driving prokaryotic (archaeal and bacterial) community structures. Results: We evaluated an agricultural soil pH gradient (from 4 to 6, the typical range for tropical farms), in a liming gradient with confounding factors minimized, investigating relationships between prokaryotic communities (16S rRNA) and physical-chemical parameters (indirect effects). Correlations, hierarchical modeling of species communities (HMSC), and random forest (RF) modeling indicated that both direct and indirect effects of the pH gradient affected the prokaryotic communities. Some OTUs were more affected by the pH changes (e.g., some Actinobacteria), while others were more affected by the indirect pH effects (e.g., some Proteobacteria). HMSC detected a phylogenetic signal related to the effects. Both HMSC and RF indicated that the main indirect effect was the pH changes on the availability of some elements (e.g., Al, Fe, and Cu), and secondarily, effects on plant growth and nutrient cycling also affected the OTUs. Additionally, we found that some of the OTUs that responded to pH also correlated with CO2, CH4, and N2O greenhouse gas fluxes. Conclusions: Our results indicate that there are two distinct pH-related mechanisms driving prokaryotic community structures, the direct effect and "spillover effects" of pH (indirect effects). Moreover, the indirect effects are highly relevant for some OTUs and consequently for the community structure; therefore, it is a mechanism that should be further investigated in microbial ecology.Peer reviewe

Equine Colic Syndrome Induced by the Ingestion of Sugarcane

Background: Equine colic syndrome comprises numerous conditions associated with abdominal pain in horses. Impaction, a common cause of this manifestation, is strongly related to these animals’ diet. Highly fibrous diets such as sugarcane can predispose horses to colic. The clinical condition can be worsened by fermentative processes, which lead to dysbiosis, circulatory disorders and even endotoxemia. The aim of this study was to report 4 cases of colic syndrome among 8 horses that underwent an experiment to adapt them to a sugarcane-based diet, and to correlate the animals’ clinical conditions to the forage they ingested. Cases: Eight male castrated Mangalarga Marchador horses, between 5.5 and 7 years old, were subjected to an experiment to test the feasibility of sugarcane as forage. Four of these horses were taken to the Large Animal Veterinary Hospital (HVGA) of the Federal Rural University of Rio de Janeiro for treatment of abdominal signs of discomfort a few days after the exclusive consumption of sugarcane, in a proportion of 1.75% of live weight in dry matter. The animals’ symptoms ranged from behavioral signs indicative of pain to changes in vital parameters and structure of the feces, as well as changes revealed by transrectal palpation. Three of the 4 cases presented impaction in the small colon, and 1 of the horses also presented impaction in the right dorsal colon and rostral displacement of the pelvic flexure, with accumulation of contents in the right ventral colon and sternal flexure. Two of the cases were treated medically, while the other 2 required surgical intervention. The clinical condition of all the patients evolved favorably and they were discharged between 2 and 18 days. Discussion: Colic originating in the digestive system is a syndrome strongly associated with management, especially with respect to confinement, nutrition, and parasite control. During the experiment, 4 of the 8 horses fed with sugarcane presented with colic syndrome. The low quality of sugarcane fiber is due to the high degree of lignification of the plant cell wall, which favors accumulation of ingesta. The poor digestibility and sweet taste of this roughage favor increased consumption. Furthermore, its high sucrose content, associated with an increased rate of passage in the small intestine, alters the intestinal microbiome, and hence, the fermentation byproducts and pH of the ingesta. High intestinal content, allied to longer retention times in the colon and activation of the renin-angiotensin-aldosterone system, promote greater dryness of the ingesta, predisposing the occurrence of impactions in the most distal portion of the large intestine. Intestinal distension and mesenteric traction caused by the accumulation of contents and gases trigger pain, which can worsen due to displacement of the large colon. Small colon impaction, which is easily identified by transrectal palpation, evolves gradually and its treatment, both clinical and surgical, tends to have a favorable prognosis. The need for alternative food sources for horses is a growing demand; however, sugarcane as an exclusive roughage has been shown to be unsafe for horses. The low quality of the fiber and the high sucrose content of this forage can alter the digestive physiology of horses through changes in the passage rate, microbiome and motility of digesta, predisposing them to intestinal dysfunction, ingesta compaction and displacement of the large colon. Keywords: horse, acute abdomen, nutrition, diet, forage, digestibility, gastrointestinal disease. Título: Síndrome cólica em equinos induzida por ingestão de cana de açúcar. Descritores: cavalo, abdômen agudo, nutrição, dieta, foragem, digestibilidade, doença gastrointestinal

Papez circuit gray matter and episodic memory in amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia

Amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia are two different diseases recognized to overlap at clinical, pathological and genetic characteristics. Both conditions are traditionally known for relative sparing of episodic memory. However, recent studies have disputed that with the report of patients presenting with marked episodic memory impairment. Besides that, structural and functional changes in temporal lobe regions responsible for episodic memory processing are often detected in neuroimaging studies of both conditions. In this study, we investigated the gray matter features associated with the Papez circuit in amyotrophic lateral sclerosis, behavioural variant frontotemporal dementia and healthy controls to further explore similarities and differences between the two conditions. Our non-demented amyotrophic lateral sclerosis patients showed no episodic memory deficits measured by a short-term delayed recall test while no changes in gray matter of the Papez circuit were found. Compared with the amyotrophic lateral sclerosis group, the behavioural variant frontotemporal dementia group had lower performance on the short-term delayed recall test and marked atrophy in gray matter of the Papez circuit. Bilateral atrophy of entorhinal cortex and mammillary bodies distinguished behavioural variant frontotemporal dementia from amyotrophic lateral sclerosis patients as well as atrophy in left cingulate, left hippocampus and right parahippocampal gyrus. Taken together, our results suggest that sub-regions of the Papez circuit could be differently affected in amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia