Implementation of an Artificial Neural Network on the Test Barcelona Workstation As a Predictive Model for the Classification of Normal, Mild Cognitive Impairment and Alzheimer’s Disease Subjects Using the Neuronorma Battery

Objective: To develop and implement an online Artificial Neural Network (ANN) that provides the probability of a subject having mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Method: Different ANNs were trained using a sample of 350 controls (CONT), 75 MCI and 93 AD subjects. The ANN structure chosen was the following: (1) an input layer of 33 cognitive variables from the Neuronorma battery plus two sociodemographic variables, age and education. This layer was reduced to a 15 features input vector using Multiple Discriminant Analysis method, (2) one hidden layer with 8 neurons, and (3) three output neurons corresponding to the 3 expected cognitive states. This ANN was defined in a previous study [28]. The ANN was implemented on the web site www.test-barcelona.com (Test Barcelona Workstation) [9]. Results: When comparing CONT, MCI and AD participants, the best ANN correctly classifies up to 94,87% of the study participants. Conclusions: The online implemented ANN, delivers the probabilities (%) of belonging to the CONT, MCI and AD groups of a subject assessed using the 35 characteristics (variables) of the Neuronorma profile. This tool is a good complement for the interpretation of cognitive profiles. This technology improves clinical decision making. Keywords: Artificial Neural Network, Probability, Alzheimer disease, Test Barcelona Workstation

Neuropsychological Test Barcelona-2: Theoretical and Practical Aspects

The Barcelona test (TB) is an instrument of neuropsychological assessment, developed under the influence of Luria’s ideas, and published in 1990 [1]. It explores the main cognitive functions and allows the design of graphic profiles similar to those of the Boston Test for the diagnosis of aphasia. Objective: To present the theoretical and practical characteristics of a new version of the test, the Test Barcelona-2. The new and computerized versions of test structure is described here with six modules established: (1) Language-attention-orientation; (2) Reading and writing; (3) Motorpraxis; (4) Perception-gnosis; (5) Memory; (6) Abstraction-execution. As a novelty, test allows the selection for specific profiles: alpha, beta, abbreviated, aphasia, andecological-forensic approach. The types of variables condition a different statistical approach and a differentiated form of graphic expression. The new test presents a modular structure, which allows determining intra- and inter-module dissociations. Computerization greatly facilitates the work of the clinician. In the case of aphasia the test allows to differentiate easily all its clinical forms. Keywords: Test Barceona-2, neuropsychological test; computerized workstation, modular structur

Altered sleep and neurovascular dysfunction in alpha-synucleinopathies: the perfect storm for glymphatic failure

Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson’s disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-β would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function (for example through control of nocturnal blood pressure) with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies

APOE-ε4 Shapes the Cerebral Organization in Cognitively Intact Individuals as Reflected by Structural Gray Matter Networks

Gray matter networks (GMn) provide essential information on the intrinsic organization of the brain and appear to be disrupted in Alzheimer’s disease (AD). Apolipoprotein E (APOE)-ε4 represents the major genetic risk factor for AD, yet the association between APOE-ε4 and GMn has remained unexplored. Here, we determine the impact of APOE-ε4 on GMn in a large sample of cognitively unimpaired individuals, which was enriched for the genetic risk of AD. We used independent component analysis to retrieve sources of structural covariance and analyzed APOE group differences within and between networks. Analyses were repeated in a subsample of amyloid-negative subjects. Compared with noncarriers and heterozygotes, APOE-ε4 homozygotes showed increased covariance in one network including primarily right-lateralized, parietal, inferior frontal, as well as inferior and middle temporal regions, which mirrored the formerly described AD-signature. This result was confirmed in a subsample of amyloid-negative individuals. APOE-ε4 carriers showed reduced covariance between two networks encompassing frontal and temporal regions, which constitute preferential target of amyloid deposition. Our data indicate that, in asymptomatic individuals, APOE-ε4 shapes the cerebral organization in a way that recapitulates focal morphometric alterations observed in AD patients, even in absence of amyloid pathology. This suggests that structural vulnerability in neuronal networks associated with APOE-ε4 may be an early event in AD pathogenesis, possibly upstream of amyloid deposition

Especialización turística y rendimientos del capital humano de las regiones españolas en el sector de la hostelería

El objetivo de este trabajo es evaluar la existencia y el grado de especialización en la industria turística de las principales regiones españolas desde la perspectiva del stock de capital humano y de los rendimientos de la educación, centrándose en el subsector de la hostelería. Para ello, se ha utilizado una versión extendida de la ecuación de salarios de Mincer (1974) y datos procedentes de la Encuesta de Estructura Salarial para el año 2006. Todas las regiones analizadas muestran rendimientos de la educación más bajos en el sector de la hostelería que los que se presentan en otros servicios privados. Existen también diferencias significativas en los rendimientos de la educación entre regiones, especialmente en Cataluña y en las Islas Canarias.The aim of our study is to evaluate the existence and degree of specialization in tourism of the Spanish regions from the perspective of the human capital stock and the returns of their education, limiting the scope of study to the hospitality subsector. We use an expanded version of the Mincer wage equation (1974) and data from the 2006 Spanish Wage Structure Survey. All the regions under analysis show lower education returns (and other human capital variables) in the hospitality sector when compared to other private services. There are signifi cant differences in education returns between regions, especially in Catalonia and the Canary Islands

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease

BACKGROUND: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults. METHODS: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change. RESULTS: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = - 0.141, p = 0.005), t-tau (β = - 0.147 p = 0.004) and neurogranin levels (β = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only. CONCLUSIONS: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment. TRIAL REGISTRATION: NCT01835717 , NCT02485730 , NCT02685969

The combined expression of the nonstructural protein NS1 and the N-terminal half of NS2 (NS21-180) by ChAdOx1 and MVA confers protection against clinical disease in sheep upon bluetongue virus challenge

26 páginas, 2 tablas, 10 figuras.Bluetongue, caused by bluetongue virus (BTV), is a widespread arthropod-borne disease of ruminants that entails a recurrent threat to the primary sector of developed and developing countries. In this work, we report modified vaccinia virus Ankara (MVA) and ChAdOx1-vectored vaccines designed to simultaneously express the immunogenic NS1 protein and/or NS2-Nt, the N-terminal half of protein NS2 (NS21-180). A single dose of MVA or ChAdOx1 expressing NS1-NS2-Nt improved the protection conferred by NS1 alone in IFNAR(-/-) mice. Moreover, mice immunized with ChAdOx1/MVA-NS1, ChAdOx1/MVA-NS2-Nt, or ChAdOx1/MVA-NS1-NS2-Nt developed strong cytotoxic CD81 T-cell responses against NS1, NS2-Nt, or both proteins and were fully protected against a lethal infection with BTV serotypes 1, 4, and 8. Furthermore, although a single immunization with ChAdOx1-NS1-NS2-Nt partially protected sheep against BTV-4, the administration of a booster dose of MVA-NS1- NS2-Nt promoted a faster viral clearance, reduction of the period and level of viremia and also protected from the pathology produced by BTV infection. IMPORTANCE Current BTV vaccines are effective but they do not allow to distinguish between vaccinated and infected animals (DIVA strategy) and are serotype specific. In this work we have develop a DIVA multiserotype vaccination strategy based on adenoviral (ChAdOx1) and MVA vaccine vectors, the most widely used in current phase I and II clinical trials, and the conserved nonstructural BTV proteins NS1 and NS2. This immunization strategy solves the major drawbacks of the current marketed vaccines.This work was supported by grants AGL2017-82570-R and PID2020-112992RR-I00 from the Spanish Ministry of Science and by the EU Horizon 2020 Program (European Commission grant agreement no. 727393-PALE-Blu). S.U.T. was a recipient of a predoctoral fellowship from the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Centro de Investigación en Sanidad Animal (program FPI-SGIT2018). We declare no competing interests. J.O. conceived the study. S.U.T. and L.J.C. wrote the manuscript with contributions from J.O. and inputs from all other authors. S.U.T., L.J.C., S.G., and A.M.L. designed and developed all the vaccines used in this work. S.U.T., L.J.C., E.C.P., G.L., and S.M. conducted mice experiments and cytometric analysis. J.B. and P.S.C. conducted sheep immunizations, postmortem studies, and histopathological analysis. S.U.T. and L.J.C. analyzed antibodies, viremias, and hematological parameters. A.N. helped revising the articlePeer reviewe

Peripheral and placental immune responses in sheep after experimental infection with "Toxoplasma gondii" at the three terms of gestation

P. 1-9Although it is known that gestation could infuence the clinical course of ovine toxoplasmosis, the precise efect of the term of gestation when sheep are infected are yet mostly unknown. The aim of this study was to evaluate the peripheral and placental immune responses developed in pregnant sheep after experimental infection with Toxoplasma gondiiat diferent times of gestation. Thirty‑six pregnant sheep were allocated in diferent groups, orally inocu‑lated with sporulated oocysts of T. gondiiat early, mid and late gestation and culled within 30 days post‑infection. The peripheral humoral and cytokine responses were evaluated, as well as the transcription of cytokines at the placenta. Serological analysis revealed that, regardless the term of gestation when infected, specifc IgG against T. gondiiwere detected from day 8 post‑infection and there was an early peripheral release of IFN‑γ at the frst week post‑infection followed by a short peak of IL10 and TNF‑α at the second week post‑infection. There were no signifcant diferences in this response between infected groups. At the placenta, a similar increase in transcription of IFN‑γ, and TNF‑α was found at the three terms of gestation, while IL‑4 increased mainly at the frst and second terms and IL‑10 transcription was higher at the last term. While these fndings show that both Th1 and Th2 cytokines play a key role in the patho‑genesis of ovine toxoplasmosis and that placental and peripheral immune responses do not closely correlate, there seems to be no clear modulation of these responses along the gestation.S

Exploring cognitive and biological correlates of sleep quality and their potential links with Alzheimer's disease (ALFASleep project): protocol for an observational study

INTRODUCTION: The growing worldwide prevalence of Alzheimer's disease (AD) and the lack of effective treatments pose a dire medical challenge. Sleep disruption is also prevalent in the ageing population and is increasingly recognised as a risk factor and an early sign of AD. The ALFASleep project aims to characterise sleep with subjective and objective measurements in cognitively unimpaired middle/late middle-aged adults at increased risk of AD who are phenotyped with fluid and neuroimaging AD biomarkers. This will contribute to a better understanding of the pathophysiological mechanisms linking sleep with AD, thereby paving the way for the development of non-invasive biomarkers and preventive strategies targeting sleep. METHODS AND ANALYSIS: We will invite 200 participants enrolled in the ALFA+ (for ALzheimer and FAmilies) prospective observational study to join the ALFASleep study. ALFA+ participants are cognitively unimpaired middle-aged/late middle-aged adults who are followed up every 3 years with a comprehensive set of evaluations including neuropsychological tests, blood and cerebrospinal fluid (CSF) sampling, and MRI and positron emission tomography acquisition. ALFASleep participants will be additionally characterised with actigraphy and CSF-orexin-A measurements, and a subset (n=90) will undergo overnight polysomnography. We will test associations of sleep measurements and CSF-orexin-A with fluid biomarkers of AD and glial activation, neuroimaging outcomes and cognitive performance. In case we found any associations, we will test whether changes in AD and/or glial activation markers mediate the association between sleep and neuroimaging or cognitive outcomes and whether sleep mediates associations between CSF-orexin-A and AD biomarkers. ETHICS AND DISSEMINATION: The ALFASleep study protocol has been approved by the independent Ethics Committee Parc de Salut Mar, Barcelona (2018/8207/I). All participants have signed a written informed consent before their inclusion (approved by the same ethics committee). Study findings will be presented at national and international conferences and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04932473