Original article
Patients with mild cognitive impairment and a reduced CSF Aβ1-42 protein progress rapidly to Alzheimer's disease
Pacientes con deterioro cognitivo leve y reducción de la proteína Aβ1-42 en LCR evolucionan rápidamente a enfermedad de Alzheimer
J.A. Monge-Argilésa,
, J. Sánchez-Payáb, C. Muñoz-Ruizc, A. Pampliega-Péreza, M.J. Gómez-Lópezd, E. Rodríguez Borjac, J. Montoya-Gutiérreza, C. Leiva-Santanaa
Corresponding author
a Servicio de Neurología, Hospital General Universitario de Alicante, Alicante, Spain
b Servicio de Medicina Preventiva, Hospital General Universitario de Alicante, Alicante, Spain
c Laboratorio de Inmunología, Hospital General Universitario de Alicante, Alicante, Spain
d Clínica Neuropsicóloga, Hospital General Universitario de Alicante, Alicante, Spain
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"apellidos" => "Leiva-Santana" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Neurología, Hospital General Universitario de Alicante, Alicante, Spain" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Medicina Preventiva, Hospital General Universitario de Alicante, Alicante, Spain" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Laboratorio de Inmunología, Hospital General Universitario de Alicante, Alicante, Spain" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Clínica Neuropsicóloga, Hospital General Universitario de Alicante, Alicante, Spain" "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Pacientes con deterioro cognitivo leve y reducción de la proteína Aβ<span class="elsevierStyleInf">1-42</span> en LCR evolucionan rápidamente a enfermedad de Alzheimer" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Many authors consider mild cognitive impairment (MCI) as the most important risk factor for the development of Alzheimer's disease (AD).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Thus, 40–60% of patients with MCI develop AD within the next 5 years,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> while another significant percentage maintain a stable form of cognitive impairment.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Different complementary techniques have been used for several years in an attempt to identify MCI patients who will develop dementia, in order to treat them early or at least to delay and mitigate the devastating effects of the disease. Among the aforementioned complementary techniques the main technique is the analysis of Aβ<span class="elsevierStyleInf">1-42</span>, T-tau and P-tau proteins in cerebrospinal fluid (CSF), as well as the ratios of Aβ<span class="elsevierStyleInf">1-42</span> and both tau proteins, as they reflect the relationship between both AD pathogenic pathways. Their study has led to numerous works being published<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–7</span></a> and also to different meta-analysis of their predictive ability for the diagnosis of AD.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Moreover, recent publications have used these biomarkers to recognise the MCI patients who will progress rapidly to dementia,<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> and even to identify the patients already suffering dementia who will evolve more rapidly.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this work is to verify whether this technique is capable of differentiating our stable MCI patients from those who progressed to AD in the months following the lumbar puncture (LP).</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Study design</span><p id="par0025" class="elsevierStylePara elsevierViewall">This was a cohort study.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Study subjects</span><p id="par0030" class="elsevierStylePara elsevierViewall">The study included 36 patients with amnestic MCI diagnosed according to 2006 Petersen criteria,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> all from the cognitive impairment consultation at Hospital General Universitario in Alicante, some of whom had been monitored for several years. Their study included physical and neurological examinations, a neuropsychological study, Yesavage's geriatric depression scale (15 items), blood tests, brain structural imaging and LP. The patients were monitored in the outpatient clinic with periodic reviews at least every 6 months. These reviews evaluated the development of AD according to the NINCDS-ADRDA criteria<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> and GDS scale. According to the progression at 12 months after LP, we differentiated patients into those who were stable (s-MCI) and those who progressed to AD (p-MCI).</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Inclusion criteria</span><p id="par0035" class="elsevierStylePara elsevierViewall">Amnestic MCI patients over 55 years. They signed informed consent prior to inclusion in the study and performance of LP.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Exclusion criteria</span><p id="par0040" class="elsevierStylePara elsevierViewall">The presence of dementia or any other neurological, psychiatric or systemic disease which could cause cognitive impairment, anticoagulant therapy and lack of informed consent were grounds for exclusion. An evaluation with Yesavage's geriatric depression scale over 5 points was also considered as reason for exclusion.</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Procedures</span><p id="par0045" class="elsevierStylePara elsevierViewall">The neurologist in charge emitted a diagnosis of pure or multi-domain amnestic MCI, according to the Petersen criteria.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Subsequently, a neuropsychological study was conducted that included assessment of memory, language, executive functions, attention and visuo-constructive abilities through the Mini Mental State Examination (MMSE), Rey auditory–verbal learning test, trail making test (TMT) and informer test (INT). Alterations of functions were defined as a result <span class="elsevierStyleItalic">Z</span> of −1.5 or less, which represented at least 1.5 standard deviations below the mean of the control subjects, in at least 1 of the tests used to study each function. The criteria for considering the change from s-MCI to p-MCI was a decline in MMSE over 2 points and/or an in increase in INT over 7 points.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Neuroimaging was performed in all patients with MCI (cerebral MRI in most cases or only cerebral CT scan in 5 of them), in order to rule out other brain lesions which could be responsible for the clinical symptoms.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Obtaining and analysing cerebrospinal fluid</span><p id="par0055" class="elsevierStylePara elsevierViewall">This was conducted between February 2008 and February 2009. The samples were obtained between 10:00 and 14:00<span class="elsevierStyleHsp" style=""></span>h. The LP was conducted by the neurologist responsible using a 20<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>3(1/2) needle. The CSF was collected in standard tubes and was frozen at −80<span class="elsevierStyleHsp" style=""></span>°C in less than 1<span class="elsevierStyleHsp" style=""></span>h. When the CSF contained blood, it was centrifuged prior to freezing. One tube was collected to perform biochemical analysis and cell count prior to obtaining the freezing tubes. In no case did this cell count show over 100 red blood cells.</p><p id="par0060" class="elsevierStylePara elsevierViewall">After the LP, patients were advised to avoid Valsalva manoeuvres for at least 3 days.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Quantifying Aβ<span class="elsevierStyleInf">1-42</span>, T-tau and P-tau<span class="elsevierStyleInf">181p</span> cerebrospinal fluid protein levels</span><p id="par0065" class="elsevierStylePara elsevierViewall">This was performed using Luminex xMAP technology with INNO-BIA AlzBio3 reagents from Innogenetics (Ghent, Belgium). The details of this combination of immunoassay reagents and analytical platform have been published previously.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">All samples were analysed simultaneously at the end of recruitment and in a blind manner for clinical data. The samples from 19 patients were analysed in duplicate.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Study variables</span><p id="par0075" class="elsevierStylePara elsevierViewall">We studied the levels of CSF proteins Aβ<span class="elsevierStyleInf">1-42</span>, T-tau and P-tau<span class="elsevierStyleInf">181p</span>, as well as the ratios T-tau/Aβ<span class="elsevierStyleInf">1-42</span> and P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1-42</span>. These ratios are being used by various authors widely, as they seem to reflect the relationship between the amyloid and tau pathways of the disease.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">The reliability of the technique was calculated using the intraclass correlation coefficient.</p><p id="par0085" class="elsevierStylePara elsevierViewall">We used the Kolmogorov–Smirnov test to analyse the distribution type of each variable.</p><p id="par0090" class="elsevierStylePara elsevierViewall">For comparison between 2 groups, we used the Student's <span class="elsevierStyleItalic">t</span>-test for parametric variables and the Mann–Whitney <span class="elsevierStyleItalic">U</span>-test for nonparametric variables.</p><p id="par0095" class="elsevierStylePara elsevierViewall">In addition, we performed ROC curve analysis to determine the best cut-off values for the measurement of variables. The best cut-off value was defined in response to higher sensitivity above all. We then obtained the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each cut-off point and each variable.</p><p id="par0100" class="elsevierStylePara elsevierViewall">We used a <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 level of statistical significance for all hypothesis contrasts. The statistical analysis was conducted using the SPSS v.10.0 software.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ethical criteria</span><p id="par0105" class="elsevierStylePara elsevierViewall">The pharmaceutical companies that funded this project had no role in its design, data collection or interpretation or in the writing of this work.</p><p id="par0110" class="elsevierStylePara elsevierViewall">This project was approved by the clinical research ethics committee of Hospital General Universitario in Alicante, after obtaining a civil liability insurance policy.</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Reliability of the technique</span><p id="par0115" class="elsevierStylePara elsevierViewall">In the 19 cases analysed in duplicate, the intraclass correlation coefficient was 0.94 for protein Aβ<span class="elsevierStyleInf">1-42</span>, 0.96 for protein T-tau and 0.95 for protein P-tau.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Comparison of s-MCI group vs p-MCI group</span><p id="par0120" class="elsevierStylePara elsevierViewall">By studying the evolution towards dementia of our patients in the first 12 months after the completion of a LP, we observed that 14 (38%) of them had progressed to dementia. When comparing these groups, we observed:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">–</span><p id="par0125" class="elsevierStylePara elsevierViewall">Clinical-demographic characteristics (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>): there were no significant differences among the ages of both groups or among most of the variables studied. However, s-MCI patients had a higher percentage of history of depression (46% vs 18%) and a longer evolution time from the onset of symptoms until the completion of a LP.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">–</span><p id="par0130" class="elsevierStylePara elsevierViewall">Comparison of protein levels and ratios (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>): distinctions between the 2 groups were notable for the protein Aβ<span class="elsevierStyleInf">1-42</span> (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.02) and the ratio P-tau/Aβ<span class="elsevierStyleInf">1-42</span> (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.02). The remaining variables studied did not reach statistical significance.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">–</span><p id="par0135" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the results of the ROC curves for each of the variables studied. The sensitivity and NPV values for the cut-off points selected were above 70% in 4 and 3 variables, respectively.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></li></ul></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0140" class="elsevierStylePara elsevierViewall">Our MCI patients who progressed to AD in the first year after LP presented an average Aβ<span class="elsevierStyleInf">1-42</span> protein level lower than that of the group of patients who were clinically stable. These results seem useful to identify the MCI patients with a worse prognosis and are in line with some studies published recently.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> Landau et al.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> described an increased P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1-42</span> ratio as a predictor of rapid cognitive decline and, in our experience, we observed this fact in MCI patients with poor prognosis. This ratio has been used by different authors as a reflection of the relationship between the amyloid and tau pathways,<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,16</span></a> both altered in AD.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Furthermore, we found a decrease in protein Aβ<span class="elsevierStyleInf">1-42</span> in this same group of patients. This finding is now considered as the first to appear in AD patients, even before they develop MCI, thus giving greater consistency to our results with respect to those obtained by Blom et al.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> These authors reported an increase in the levels of T-tau and P-tau in patients who progressed to AD rapidly.</p><p id="par0150" class="elsevierStylePara elsevierViewall">In our experience, although there are no statistically significant differences in P-tau<span class="elsevierStyleInf">181p</span> protein levels between both groups, we observed that they were higher in the p-MCI group. The elevation of this biomarker in CSF is currently considered the most specific finding of AD, both in clinical studies<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,9</span></a> and in those confirmed by autopsy.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Analysing the results of the ROC curves, we found high sensitivity and NPV for P-tau and the ratio T-tau/Aβ<span class="elsevierStyleInf">1-42</span>. The remaining results were more discreet, but we must not forget that the only difference between these patients may be their rate of progression to AD. In any case, these findings emphasise the importance of quantifying all 3 biomarkers, as well as the ratios used.</p><p id="par0160" class="elsevierStylePara elsevierViewall">The new criteria for research in AD suggest that both MRI, PET and biomarkers in CSF may support the diagnosis of AD in amnestic MCI patients.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> However, CSF analysis has some advantages over the other 2 techniques. On the one hand, it is cheaper and easier to obtain than PET. Furthermore, the latter currently studies only the amyloid pathway and its use is still very restricted. On the other hand, changes in CSF reflect AD pathology before volumetry.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Therefore, this technique seems especially preferable for a very early diagnosis of AD,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> although both methods are complementary and most publications that combine the predictive ability of CSF analysis with other techniques such as MRI agree on this point.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">From a methodological point of view, the use of the Luminex xMAP technique seems to offer some advantages over CSF analysis by ELISA. The simultaneous quantification of the 3 biomarkers improves the technical management and quality control of tests, according to some authors.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In our case, conducting all quantifications simultaneously, obtaining CSF in a reduced time period and the small age range between the groups significantly decreased confusion factors. The results obtained in the intraclass correlation coefficients for the 3 biomarkers reflect the high reliability of the technique used.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Among the limitations of this study, we note:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">–</span><p id="par0175" class="elsevierStylePara elsevierViewall">Short monitoring time. However, the differences obtained between patients who progressed in the first 12 months after the LP speak to a likely pattern of rapid evolution to AD, as described in recent literature.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> This could support the performance of this test not only for diagnosis, but also for prognostic purposes.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">–</span><p id="par0180" class="elsevierStylePara elsevierViewall">Not all patients included in the study had been diagnosed recently. However, we know that these biomarkers, especially protein Aβ<span class="elsevierStyleInf">1-42</span>, become altered very early in the evolution of AD and do not present significant changes when a control test is performed after a few years.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">–</span><p id="par0185" class="elsevierStylePara elsevierViewall">This is an invasive test. However, there have been no adverse effects on the population studied. This is consistent with the data published by other authors<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> when such tests are performed on patients under good conditions and specific efforts are subsequently avoided for a limited time.</p></li></ul></p><p id="par0190" class="elsevierStylePara elsevierViewall">In summary, patients with MCI who have reduced levels of protein Aβ<span class="elsevierStyleInf">1-42</span> progress rapidly to dementia, while those with higher levels remain stable for a longer time.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interests</span><p id="par0195" class="elsevierStylePara elsevierViewall">This work was funded by Novartis Laboratories Spain and Grunenthal Spain.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres169660" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Material and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec157752" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres169661" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec157753" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study design" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study subjects" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Inclusion criteria" ] 3 => array:3 [ "identificador" => "sec0030" "titulo" => "Exclusion criteria" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Procedures" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Obtaining and analysing cerebrospinal fluid" ] ] ] 4 => array:2 [ "identificador" => "sec0045" "titulo" => "Quantifying Aβ, T-tau and P-tau cerebrospinal fluid protein levels" ] 5 => array:2 [ "identificador" => "sec0050" "titulo" => "Study variables" ] 6 => array:2 [ "identificador" => "sec0055" "titulo" => "Statistical analysis" ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Ethical criteria" ] ] ] 6 => array:3 [ "identificador" => "sec0065" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Reliability of the technique" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Comparison of s-MCI group vs p-MCI group" ] ] ] 7 => array:2 [ "identificador" => "sec0080" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of interests" ] 9 => array:2 [ "identificador" => "xack44750" "titulo" => "Acknowledgements" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2010-12-18" "fechaAceptado" => "2011-03-27" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec157752" "palabras" => array:6 [ 0 => "CSF biomarkers" 1 => "Mild cognitive impairment" 2 => "Alzheimer's disease" 3 => "Aβ<span class="elsevierStyleInf">1-42</span> protein" 4 => "T-tau protein" 5 => "P-tau<span class="elsevierStyleInf">181p</span> protein" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec157753" "palabras" => array:6 [ 0 => "Biomarcadores en LCR" 1 => "Deterioro cognitivo leve" 2 => "Enfermedad de Alzheimer" 3 => "Proteína Aβ<span class="elsevierStyleInf">1-42</span>" 4 => "Proteína T-tau" 5 => "Proteína P-tau<span class="elsevierStyleInf">181p</span>" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Some studies have shown that CSF amyloid-beta 1-42 (Aβ<span class="elsevierStyleInf">1-42</span>), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau<span class="elsevierStyleInf">181p</span>) proteins are useful diagnostic markers for distinguishing between clinically stable mild cognitive impairment (MCI) patients and those who will develop Alzheimer's disease (AD).</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Our objective was to test the ability of this technique to discriminate in our cohort of MCI patients, according to the clinical outcome, one year after the lumbar puncture.</p> <span class="elsevierStyleSectionTitle">Material and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 36 MCI patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we measured CSF Aβ<span class="elsevierStyleInf">1-42</span>, T-tau and P-tau<span class="elsevierStyleInf">181p</span> proteins, and calculated the T-tau/Aβ<span class="elsevierStyleInf">1-42</span> and P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1-42</span> ratios. This project was approved by the local ethics committee.</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients had lower Aβ<span class="elsevierStyleInf">1-42</span> protein levels (285.3<span class="elsevierStyleHsp" style=""></span>ng/ml vs 377<span class="elsevierStyleHsp" style=""></span>ng/ml, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.02) and higher P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1-42</span> ratio (0.25 vs 0.16, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.02) than the clinically stable patients.</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Our MCI patients with lower Aβ<span class="elsevierStyleInf">1-42</span> protein levels and an increased P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1-42</span> ratio progressed quickly to AD. These results may help to identify those MCI patients with a poorer prognosis.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle">Introducción</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En muchos artículos recientes, el análisis de las proteínas Aβ<span class="elsevierStyleInf">1-42</span>, tau total (T-tau) y tau fostorilada (P-tau) en LCR puede discriminar entre los pacientes con deterioro cognitivo leve (DCL) estables y aquellos otros que van a progresar a enfermedad de Alzheimer (EA). Nuestro objetivo fue comprobar la capacidad de estas proteínas del LCR para discriminar, entre nuestros pacientes DCL, según la evolución clínica en el año siguiente a la punción lumbar.</p> <span class="elsevierStyleSectionTitle">Material y métodos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyó a 36 pacientes DCL amnésico (criterios de Petersen 2006) procedentes de la consulta de deterioro cognitivo del Hospital General de Alicante. Usando los reactivos INNO-BIA Alzbio-3 (Innogenetics), cuantificamos las proteínas Aβ<span class="elsevierStyleInf">1-42</span>, T-tau, P-tau<span class="elsevierStyleInf">181p</span> en LCR, y calculamos los cocientes T-tau/Aβ<span class="elsevierStyleInf">1-42</span> y P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1-42</span>. El estudio fue aprobado por el comité ético de investigación del Hospital General de Alicante.</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">En los 12 meses posteriores a la punción lumbar, 14 pacientes DCL (38%) evolucionaron a EA. Estos pacientes, presentaron menores niveles de Aβ<span class="elsevierStyleInf">1-42</span> (285,3 vs. 377,7<span class="elsevierStyleHsp" style=""></span>ng/ml, p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0,02), y un aumento en el valor del cociente P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1-42</span> (0,25 vs. 0,16, p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0,02) que los pacientes que se mantuvieron estables. No hubo diferencias significativas en el resto de variables estudiadas.</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Nuestros pacientes DCL que presentaron niveles reducidos de la proteína Aβ<span class="elsevierStyleInf">1-42</span> y elevación del cociente P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1-42</span> en LCR, evolucionaron rápidamente a EA. Estos resultados pueden ayudar a conseguir el objetivo de identificar de forma precoz a los pacientes DCL con peor pronóstico.</p>" ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Monge-Argilés JA, et al. Pacientes con deterioro cognitivo leve y reducción de la proteína Aβ<span class="elsevierStyleInf">1-42</span> en LCR evolucionan rápidamente a enfermedad de Alzheimer. Neurología. 2011;28–33.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara">This work was presented at the Annual Meeting of the Spanish Neurology Society in 2010.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">AHT: arterial hypertension; DM: diabetes mellitus; HPL: hyperlipidemia; INT: informer test; NS: not significant; Rey A–V test: Rey auditory–verbal learning test; TMT: trail making test.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">s-MCI group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">p-MCI group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Number of cases</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Gender (M/F)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9/13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Age (years) Mean</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73.43<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73.86<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">History</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>DM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>AHT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>HPL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Depression \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Toxic habits</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Family history of dementia</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Years of schooling</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Onset of symptoms (months), mean</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38.22<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.71<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.05 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Initial Folstein MMSE</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Type of MCI</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amnestic: 6A/Multi-domain: 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amnestic: 4A/Multi-domain: 10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Other neuropsychological tests</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>INT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>TMT (s) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">68<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Rey A–V test \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab264743.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Clinical and demographic characteristics of the s-MCI and p-MCI groups.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">s-MCI (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>22) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">p-MCI (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Significance level (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Aβ</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1-42</span></span><span class="elsevierStyleItalic">(pg/ml)</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">377.73<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>130.77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">285.37<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>73.36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">T-tau (pg/ml)</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">75.13<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>34.85 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">88.30<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>40.82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">P-tau</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">181p</span></span><span class="elsevierStyleItalic">(pg/ml)</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52.57<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>24.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66.44<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>23.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">T-tau/Aβ</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1-42</span></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.23<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.34<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.07 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">P-tau</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">181p</span></span><span class="elsevierStyleItalic">/Aβ</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1-42</span></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.16<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab264742.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Comparison of the concentrations of the 3 biomarkers and quotients between biomarkers for s-MCI and p-MCI patients.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Parameters \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Aβ<span class="elsevierStyleInf">1-42</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">T-tau \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">P-tau \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">T-tau/Aβ<span class="elsevierStyleInf">1-42</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">P-tau/Aβ<span class="elsevierStyleInf">1-42</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Limit value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">320 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sensitivity (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Specificity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive predictive value (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative predictive value (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab264744.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara 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Rijmen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1212/01.wnl.0000271375.37131.04" "Revista" => array:6 [ "tituloSerie" => "Neurology" "fecha" => "2007" "volumen" => "69" "paginaInicial" => "1006" "paginaFinal" => "1011" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17785669" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Andreasen" 1 => "L. Minthon" 2 => "P. Davidsson" 3 => "E. Vanmechelen" 4 => "H. Vanderstichele" 5 => "B. Winblad" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Neurol" "fecha" => "2001" "volumen" => "58" "paginaInicial" => "373" "paginaFinal" => "379" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11255440" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:3 [ "identificador" => "xack44750" "titulo" => "Acknowledgements" "texto" => "<p id="par0200" class="elsevierStylePara elsevierViewall">The authors wish to thank the Anaesthesia, Urology and Traumatology Services at Hospital General Universitario in Alicante for their help; as well as María de los Ángeles Miguelsanz, from the Immunology Laboratory, for the excellent management of the samples; and Margarita Ruiz Vegara for her generous collaboration (in memoriam).</p>" ] ] ] "idiomaDefecto" => "en" "url" => "/21735808/0000002700000001/v1_201305151316/S2173580812000119/v1_201305151316/en/main.assets" "Apartado" => array:4 [ "identificador" => "9491" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735808/0000002700000001/v1_201305151316/S2173580812000119/v1_201305151316/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580812000119?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 0 | 9 |
| 2024 October | 19 | 2 | 21 |
| 2024 September | 14 | 2 | 16 |
| 2024 August | 20 | 4 | 24 |
| 2024 July | 14 | 4 | 18 |
| 2024 June | 13 | 2 | 15 |
| 2024 May | 11 | 2 | 13 |
| 2024 April | 21 | 3 | 24 |
| 2024 March | 29 | 4 | 33 |
| 2024 February | 22 | 6 | 28 |
| 2024 January | 37 | 3 | 40 |
| 2023 December | 14 | 4 | 18 |
| 2023 November | 25 | 3 | 28 |
| 2023 October | 28 | 4 | 32 |
| 2023 September | 13 | 2 | 15 |
| 2023 August | 19 | 7 | 26 |
| 2023 July | 12 | 5 | 17 |
| 2023 June | 9 | 4 | 13 |
| 2023 May | 48 | 10 | 58 |
| 2023 April | 40 | 2 | 42 |
| 2023 March | 8 | 3 | 11 |
| 2023 February | 14 | 5 | 19 |
| 2023 January | 23 | 25 | 48 |
| 2022 December | 19 | 16 | 35 |
| 2022 November | 14 | 11 | 25 |
| 2022 October | 9 | 10 | 19 |
| 2022 September | 13 | 17 | 30 |
| 2022 August | 25 | 8 | 33 |
| 2022 July | 16 | 11 | 27 |
| 2022 June | 16 | 7 | 23 |
| 2022 May | 12 | 10 | 22 |
| 2022 April | 10 | 17 | 27 |
| 2022 March | 12 | 12 | 24 |
| 2022 February | 12 | 8 | 20 |
| 2022 January | 15 | 9 | 24 |
| 2021 December | 11 | 13 | 24 |
| 2021 November | 13 | 8 | 21 |
| 2021 October | 8 | 6 | 14 |
| 2021 September | 9 | 9 | 18 |
| 2021 August | 20 | 4 | 24 |
| 2021 July | 12 | 8 | 20 |
| 2021 June | 10 | 13 | 23 |
| 2021 May | 17 | 6 | 23 |
| 2021 April | 22 | 9 | 31 |
| 2021 March | 34 | 7 | 41 |
| 2021 February | 24 | 10 | 34 |
| 2021 January | 11 | 10 | 21 |
| 2020 December | 12 | 10 | 22 |
| 2020 November | 13 | 1 | 14 |
| 2020 October | 11 | 7 | 18 |
| 2020 September | 10 | 6 | 16 |
| 2020 August | 19 | 10 | 29 |
| 2020 July | 10 | 8 | 18 |
| 2020 June | 7 | 2 | 9 |
| 2020 May | 13 | 9 | 22 |
| 2020 April | 14 | 4 | 18 |
| 2020 March | 12 | 3 | 15 |
| 2020 February | 23 | 2 | 25 |
| 2020 January | 19 | 5 | 24 |
| 2019 December | 13 | 7 | 20 |
| 2019 November | 10 | 8 | 18 |
| 2019 October | 16 | 3 | 19 |
| 2019 September | 18 | 10 | 28 |
| 2019 August | 12 | 5 | 17 |
| 2019 July | 16 | 7 | 23 |
| 2019 June | 29 | 11 | 40 |
| 2019 May | 108 | 13 | 121 |
| 2019 April | 54 | 21 | 75 |
| 2019 March | 7 | 165 | 172 |
| 2019 February | 9 | 5 | 14 |
| 2019 January | 6 | 8 | 14 |
| 2018 December | 6 | 8 | 14 |
| 2018 November | 6 | 2 | 8 |
| 2018 October | 11 | 5 | 16 |
| 2018 September | 5 | 6 | 11 |
| 2018 August | 5 | 0 | 5 |
| 2018 July | 4 | 3 | 7 |
| 2018 June | 2 | 1 | 3 |
| 2018 May | 5 | 3 | 8 |
| 2018 April | 2 | 1 | 3 |
| 2018 March | 5 | 0 | 5 |
| 2018 February | 2 | 0 | 2 |
| 2018 January | 7 | 1 | 8 |
| 2017 December | 5 | 2 | 7 |
| 2017 November | 7 | 2 | 9 |
| 2017 October | 7 | 1 | 8 |
| 2017 September | 14 | 5 | 19 |
| 2017 August | 13 | 4 | 17 |
| 2017 July | 12 | 4 | 16 |
| 2017 June | 8 | 13 | 21 |
| 2017 May | 7 | 6 | 13 |
| 2017 April | 5 | 7 | 12 |
| 2017 March | 4 | 27 | 31 |
| 2017 February | 13 | 12 | 25 |
| 2017 January | 18 | 10 | 28 |
| 2016 December | 12 | 6 | 18 |
| 2016 November | 5 | 2 | 7 |
| 2016 October | 19 | 9 | 28 |
| 2016 September | 12 | 4 | 16 |
| 2016 August | 6 | 2 | 8 |
| 2016 July | 15 | 2 | 17 |
| 2016 June | 25 | 19 | 44 |
| 2016 May | 14 | 23 | 37 |
| 2016 April | 12 | 13 | 25 |
| 2016 March | 21 | 26 | 47 |
| 2016 February | 21 | 17 | 38 |
| 2016 January | 15 | 18 | 33 |
| 2015 December | 14 | 13 | 27 |
| 2015 November | 9 | 6 | 15 |
| 2015 October | 16 | 6 | 22 |
| 2015 September | 13 | 7 | 20 |
| 2015 August | 14 | 6 | 20 |
| 2015 July | 8 | 3 | 11 |
| 2015 June | 6 | 2 | 8 |
| 2015 May | 8 | 7 | 15 |
| 2015 April | 18 | 9 | 27 |
| 2015 March | 13 | 3 | 16 |
| 2015 February | 16 | 0 | 16 |
| 2015 January | 32 | 6 | 38 |
| 2014 December | 40 | 12 | 52 |
| 2014 November | 20 | 3 | 23 |
| 2014 October | 26 | 4 | 30 |
| 2014 September | 14 | 1 | 15 |
| 2014 August | 25 | 6 | 31 |
| 2014 July | 19 | 2 | 21 |
| 2014 June | 13 | 1 | 14 |
| 2014 May | 14 | 0 | 14 |
| 2014 April | 11 | 2 | 13 |
| 2014 March | 18 | 4 | 22 |
| 2014 February | 18 | 4 | 22 |
| 2014 January | 10 | 2 | 12 |
| 2013 December | 27 | 5 | 32 |
| 2013 November | 34 | 8 | 42 |
| 2013 October | 39 | 6 | 45 |
| 2013 September | 26 | 4 | 30 |
| 2013 August | 31 | 5 | 36 |
| 2013 July | 14 | 10 | 24 |
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