Original article
A comparison of early diagnostic utility of Alzheimer disease biomarkers in magnetic resonance and cerebrospinal fluid
Comparación de la capacidad diagnóstica precoz de los biomarcadores de la enfermedad de Alzheimer en resonancia magnética cerebral y líquido cefalorraquídeo
J.A. Monge Argilésa,
, M.A. Blanco Cantóa, C. Leiva Salinasb, L. Florsb, C. Muñoz Ruizc, J. Sánchez Payád, R. Gasparini Berenguera, C. Leiva Santanaa
Corresponding author
a Servicio de Neurología, Hospital General Universitario de Alicante, Alicante, Spain
b Servicio de Radiología, Hospital General Universitario La Fe, Valencia, Spain
c Laboratorio de Inmunología. Hospital General Universitario de Alicante, Alicante, Spain
d Servicio de Medicina Preventiva, 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" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Radiología, Hospital General Universitario La Fe, Valencia, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Laboratorio de Inmunología. Hospital General Universitario de Alicante, Alicante, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Medicina Preventiva, Hospital General Universitario de Alicante, Alicante, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Comparación de la capacidad diagnóstica precoz de los biomarcadores de la enfermedad de Alzheimer en resonancia magnética cerebral y líquido cefalorraquídeo" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Due to the increasing prevalence of Alzheimer disease (AD), early identification of patients with mild cognitive impairment (MCI) who will develop AD is now one of our most important targets.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Dubois et al.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and more recently, Sperling et al.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> who introduced the term MCI due to AD, have published criteria aimed at achieving early diagnosis.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The decrease in peptide Aβ<span class="elsevierStyleInf">1–42</span> levels and the increase in Tau protein levels in CSF have a high predictive ability in patients with MCI.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Today, these features are considered to be associated with the pathophysiology of the disease.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Brain MRI has also demonstrated predictive ability for AD in patients with MCI.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a> However, there is controversy regarding which of these biomarkers has a greater diagnostic accuracy. Some authors consider that biomarkers in CSF<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–10</span></a> have a greater predictive ability, while others support the biomarkers in MRI.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The lack of an optimal biomarker has led different authors to draw from the results of both complementary tests to multiply the predictive ability of each individual test.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–13</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Our objectives are (1) to compare the early diagnostic abilities of AD biomarkers in CSF and brain MRI, and (2) to determine the diagnostic accuracy of the combination of both techniques in normal clinical practice conditions.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0030" class="elsevierStylePara elsevierViewall">Longitudinal study.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Subjects of the study</span><p id="par0035" class="elsevierStylePara elsevierViewall">Between 2008 and 2009, we included 30 patients with amnestic MCI diagnosed according to Petersen criteria of 2006.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> All patients come from the cognitive impairment unit at Hospital General Universitario in Alicante, and some of them had been monitored for several years. Tests included physical and neurological examination, neuropsychological examination, the 15-item geriatric depression scale by Yesavage, blood test, brain MRI scan, and lumbar puncture (LP). These patients attend the outpatient service for check-ups every 6 months. During check-up visits, progression to AD is assessed according to NINCDS-ADRDA criteria<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and results on the GDS scale. Based on status at 2 years after LP, we classified patients as stable (MCI) or progression to AD (AD).</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Inclusion criteria</span><p id="par0040" class="elsevierStylePara elsevierViewall">Patients with amnestic MCI, older than 55 years, Folstein MMSE score of 20 to 27 and score of less than 78 on the informant questionnaire. Participants signed an informed consent form to be included in the study and to undergo LP.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Exclusion criteria</span><p id="par0045" class="elsevierStylePara elsevierViewall">Presence of dementia or any other neurological, psychiatric or systemic condition that could lead to cognitive impairment. Anticoagulant treatment and absence of informed consent were also exclusion criteria. Likewise, patients scoring more than 5 on the Yesavage geriatric depression scale were excluded.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Procedures</span><p id="par0050" class="elsevierStylePara elsevierViewall">The lead neurologist diagnosed pure amnestic or multidomain MCI according to Petersen criteria.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> This step was followed by a neuropsychological study which included an assessment of memory, language, executive functions, attention, and visuoconstructive ability using the Mini Mental State Examination (MMSE), Rey auditory verbal test, Trail Making Test (TMT), and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Altered functions were defined as a <span class="elsevierStyleItalic">Z</span> score of −1.5 or less, meaning at least 1.5 standard deviations below the control subject mean, on at least one of the tests used to analyse that function. Progression from MCI to AD was determined based on fulfilment of NINCDS-ADRDA criteria (significant interference with the subject's activities), as well as a decrease on the MMSE and/or an increase of more than 7 points on the IQCODE.</p><p id="par0055" class="elsevierStylePara elsevierViewall">All patients underwent a brain MRI scan to rule out other cerebral lesions responsible for clinical symptoms and also to assess medial temporal atrophy (MTA).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Extraction and analysis of cerebrospinal fluid</span><p id="par0060" class="elsevierStylePara elsevierViewall">Lumbar punctures were performed between February 2008 and February 2009. Samples were obtained between 10.00 and 14.00. The lead neurologist performed the LP with a 20<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>3½″ spinal needle. CSF was collected in polypropylene tubes and frozen within 1<span class="elsevierStyleHsp" style=""></span>hour at −80<span class="elsevierStyleHsp" style=""></span>°C. Fluid was centrifuged before taking the aliquot to be frozen. Prior to preparing the samples for freezing, we collected the fluid in a tube to run clinical biochemistry tests and perform a cell count. In no cases did the cell count show more than 100 red blood cells.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Measurement of Aß<span class="elsevierStyleInf">1–42</span>, T-tau, and P-tau<span class="elsevierStyleInf">181p</span> levels in cerebrospinal fluid</span><p id="par0065" class="elsevierStylePara elsevierViewall">Biomarkers of AD in CSF were analysed using INNOTEST reagents for Aβ<span class="elsevierStyleInf">1–42</span>, T-tau and P-tau<span class="elsevierStyleInf">181p</span>. Reagents are manufactured by Innogenetics (Ghent, Belgium). We also obtained T-tau/Aβ<span class="elsevierStyleInf">1–42</span> and P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1–42</span> coefficients. These coefficients are frequently used by multiple authors because they seem to show the link between amyloid and Tau pathways of the disease.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">All samples were analysed simultaneously at the end of the recruitment process; researchers were blinded to clinical data.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Analysis of magnetic resonance imaging scans</span><p id="par0075" class="elsevierStylePara elsevierViewall">Brain MRI scans were performed with a 1.5 Tesla MR unit (General Electric) and included a coronal slice in T1-weighted sequences. Two experienced radiologists visually quantified MTA according to the method described by Korf et al.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Radiologists were blinded to clinical data. We analysed the correlation between results delivered by each radiologist; intraclass correlation coefficients were 0.80 and 0.85. We selected the results from the radiologist whose assessment correlated the closest with clinical symptoms for comparison to CSF results.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Statistical analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Abnormal levels of Aβ<span class="elsevierStyleInf">1–42</span> were defined as less than 500<span class="elsevierStyleHsp" style=""></span>pg/mL and the remaining variables were considered abnormal for T-tau values exceeding 450<span class="elsevierStyleHsp" style=""></span>pg/mL, P-tau<span class="elsevierStyleInf">181p</span> in excess of 60<span class="elsevierStyleHsp" style=""></span>pg/mL, T-tau/Aβ<span class="elsevierStyleInf">1–42</span> coefficient above 0.17, and P-tau<span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1–42</span> above 0.05. Overall results were considered abnormal when 3 of the variables were abnormal.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Brain MRI was considered abnormal when the sum of right and left MTA was 3 or more.</p><p id="par0090" class="elsevierStylePara elsevierViewall">We used the Kolmogorov–Smirnov test to analyse distribution type for each variable, and Mann–Whitney to compare the 2 groups.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Association was studied with the chi-square test or Fisher's exact test where necessary. We calculated relative risk (RR) with a confidence interval (CI) of 95% to quantify the magnitude of the association. To analyse predictive ability, we calculated sensitivity, specificity, positive predictive value, and negative predictive value (NPV). Statistical significance was established at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 and statistical testing was completed using SPSS version 19.0.</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ethical considerations</span><p id="par0100" class="elsevierStylePara elsevierViewall">Pharmaceutical laboratories that have funded the project did not intervene in the design, gathering, or interpretation of any data, or in the drafting of this article.</p><p id="par0105" class="elsevierStylePara elsevierViewall">All patients gave their informed consent to undergo LP.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Results</span><p id="par0110" class="elsevierStylePara elsevierViewall">Clinical and demographic variables and results for each of the CSF and MRI variables are reflected in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. We found significant differences for family history of dementia, which is clearly more frequent in the MCI group. There were also significant differences for all variables measured in the CSF analysis.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows that the RR (95% CI) of developing AD given abnormal MRI results was 1.5 (0.7–3.4), but this level is not statistically significant. However, the RR (95% CI) of developing AD when given abnormal results for biomarkers in CSF was 2.7 (1.1–6.7), with a statistical significance level of 0.01.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Predictive ability of AD biomarkers in CSF is always higher than that of biomarkers in brain MRI scans, as shown in <a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a>.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Results for AD biomarkers in CSF and brain MRI scans were combined. It is striking that none of the patients in whom both sets of results were normal developed AD in the 2 years after being included in the study. The RR of developing AD given abnormal biomarkers in the CSF analysis or the brain MRI is clearly statistically significant at 0.01 (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a> shows the predictive ability of combining both biomarkers, the method with the highest sensitivity and NPV (100%).</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0135" class="elsevierStylePara elsevierViewall">According to the evaluation scales used in this study, our results show that for early diagnosis of AD, the predictive ability of biomarkers in CSF is higher than that of brain MRI biomarkers. Our results coincide with those of most authors who make this comparison.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–10</span></a> However, there is no consensus on which variables should be used to obtain the best results. While some authors believe that absolute values of Aβ<span class="elsevierStyleInf">1–42</span> and T-tau <a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–8</span></a> are the best variables, others opt for the P-tau <span class="elsevierStyleInf">181p</span>/Aβ<span class="elsevierStyleInf">1–42</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> or T-tau/Aβ<span class="elsevierStyleInf">1–42</span><a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> coefficients. We believe that requiring 3 abnormal CSF variables in order for the test to be considered abnormal is sufficiently strict. These findings also reflect the simultaneous involvement of amyloid and Tau pathways.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">These results coincide with the recent hypothetical model of biomarker behaviour in AD.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> According to this model, the earliest findings are altered levels of Aβ<span class="elsevierStyleInf">1–42</span> and they reach their maximum concentration during the preclinical phase. Subsequently, but also during the preclinical phase, Tau protein levels also become abnormal. It is only at the end of that phase that abnormal structural MRI findings can be observed.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Some authors believe that biomarkers in brain MRI scans are better predictors than biomarkers in CSF. However, their studies employ MRI volumetric analysis techniques for MRI analysis that are currently beyond our reach.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Based on our results, we can conclude that the predictive ability of either technique used alone is not high enough to be considered satisfactory. However, in our opinion, the pathophysiological data from CSF analysis in MCI patients is what provides the best available information regarding early diagnosis of AD.</p><p id="par0155" class="elsevierStylePara elsevierViewall">Most authors state that combined analysis of both types of biomarkers yields better diagnostic accuracy than using either of the tests alone.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–13</span></a> In our experience, sensitivity and NPV reach maximum values with combined analysis. Relative risk of developing AD when either of the 2 biomarkers was abnormal could not be calculated due to lack of stable patients presenting abnormal results on one of the tests. Nevertheless, the data are clearly statistically significant, and we therefore add our experience to that of the authors cited previously. Our data are the first to be published in Spanish literature.</p><p id="par0160" class="elsevierStylePara elsevierViewall">Our results seem to show a remarkably high rate of conversion to AD in the 2 years after patients were included. However, we should point out that if the mean duration of symptoms prior to the study is added to the duration of the study period itself, our results are comparable with those described the literature (10%–15% yearly conversion rate).</p><p id="par0165" class="elsevierStylePara elsevierViewall">Our study's limitations include the lack of confirmation with anatomical pathology techniques and absence of MRI volumetric analysis. One advantage, however, is our suggestion that doctors use a method including technical means that are now accessible for most cognitive impairment units in our country.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0170" class="elsevierStylePara elsevierViewall">This study was partially funded by <span class="elsevierStyleGrantSponsor" id="gs1">Novartis España</span> and <span class="elsevierStyleGrantSponsor" id="gs2">Grunenthal España</span>.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflicts of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors declare having no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres370406" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec349645" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres370407" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec349644" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study design" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Subjects of the study" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Inclusion criteria" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Exclusion criteria" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Procedures" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Extraction and analysis of cerebrospinal fluid" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Measurement of Aß, T-tau, and P-tau levels in cerebrospinal fluid" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Analysis of magnetic resonance imaging scans" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0060" "titulo" => "Ethical considerations" ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflicts of interest" ] 11 => array:2 [ "identificador" => "xack93084" "titulo" => "Acknowledgements" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-01-28" "fechaAceptado" => "2013-06-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec349645" "palabras" => array:6 [ 0 => "Biomarkers" 1 => "Mild cognitive impairment" 2 => "Early diagnosis" 3 => "Alzheimer disease" 4 => "Cerebrospinal fluid" 5 => "Brain magnetic resonance" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec349644" "palabras" => array:6 [ 0 => "Biomarcadores" 1 => "Deterioro cognitivo leve" 2 => "Diagnóstico precoz" 3 => "Enfermedad de Alzheimer" 4 => "Líquido cefalorraquídeo" 5 => "Resonancia magnética" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The goals of this study were to compare the early diagnostic utility of Alzheimer disease biomarkers in the CSF with those in brain MRI in conditions found in our clinical practice, and to ascertain the diagnostic accuracy of both techniques used together.</p> <span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Between 2008 and 2009, we included 30 patients with mild cognitive impairment (MCI) who were examined using 1.5<span class="elsevierStyleHsp" style=""></span>Tesla brain MRI and AD biomarker analysis in CSF. MRI studies were evaluated by 2 radiologists according to the Korf's visual scale. CSF biomarkers were analysed using INNOTEST reagents for Aβ<span class="elsevierStyleInf">1–42</span>, total-tau and phospho-tau<span class="elsevierStyleInf">181p</span>. We evaluated clinical changes 2 years after inclusion.</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">By 2 years after inclusion, 15 of the original 30 patients (50%) had developed AD (NINCDS-ADRA criteria). The predictive utility of AD biomarkers in CSF (RR 2.7; 95% CI, 1.1–6.7; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.01) was greater than that of MRI (RR 1.5; 95% CI 95%, 0.7–3.4; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.2); using both techniques together yielded sensitivity and a negative predictive value of 100%. Normal results on both complementary tests ruled out progression to AD (100%) within 2 years of inclusion.</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Our results show that the diagnostic accuracy of biomarkers in CSF is higher than that of biomarkers in MRI. Combined use of both techniques is highly accurate for either early diagnosis or exclusion of AD in patients with MCI.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Nuestros objetivos fueron comparar la capacidad de diagnóstico precoz de los biomarcadores (BMC) de enfermedad de Alzheimer (EA) en LCR y RM cerebral, en condiciones posibles de nuestra práctica clínica y, además, conocer la precisión diagnóstica de la combinación de ambas técnicas.</p> <span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Entre 2008 y 2009, estudiamos a 30 pacientes con deterioro cognitivo leve (DCL) mediante RM cerebral de 1.5 teslas y análisis de BMC de EA en el LCR. Las RM fueron valoradas por 2 neurorradiólogos, atendiendo a la escala visual de Korf (2004). Los BMC de EA en LCR se analizaron mediante reactivos INNOTEST para proteínas Aβ<span class="elsevierStyleInf">1-42</span>, total-tau y fosfo-tau. Se evaluó la evolución clínica (según criterios NINCDS-ADRDA) a los 2 años tras la inclusión.</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Entre los 30 pacientes iniciales, 15 evolucionaron a EA (criterios NINCDS-ADRDA) a los 2 años de la inclusión. La capacidad predictiva de los BMC en LCR (RR 2,7; IC del 95%, 1.1-6,7; p<0,01) es superior a los de RM (RR 1,5; IC del 95%, 0,7-3,4; p<0,2), y la combinación de ambas técnicas alcanza una sensibilidad y valor predictivo negativo del 100%. La normalidad de ambas pruebas complementarias descartó al 100% el desarrollo de EA, en los 2 años siguientes a la realización de las mismas.</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Siguiendo nuestra metodología, la precisión diagnóstica de los BMC en LCR es superior a los de la RM para el diagnóstico precoz de EA. La combinación de ambas técnicas consigue una precisión diagnóstica muy alta, tanto para diagnosticar como para excluir precozmente EA, en pacientes con DCL.</p>" ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Monge Argilés JA, Blanco Cantó MA, Leiva Salinas C, Flors L, Muñoz Ruiz C, Sánchez Payá J, et al. Comparación de la capacidad diagnóstica precoz de los biomarcadores de la enfermedad de Alzheimer en resonancia magnética cerebral y líquido cefalorraquídeo. Neurología. 2014;29:397–401.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This study was featured as an oral presentation at the 64th Annual Meeting of the SEN.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "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">MCI \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">Alzheimer dis. \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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of patients (M/W) \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">15 (7/8) \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">15 (5/10) \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="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">Age (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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73.25<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">72.56<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.12 \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="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">Baseline MMSE (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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.4 \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">23<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.2 \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="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">Rey auditory verbal learning 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">4.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.5 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.8 \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">Symptom duration before inclusion (months<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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10.5 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>9.7 \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="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">Years of schooling (mean) \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">4.3 \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">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><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">Family history of dementia \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \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">.01 \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">Aβ<span class="elsevierStyleInf">1–42</span> peptide (mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD), pg/mL \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">970.13<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>372.84 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">551.07<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>138.46 \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">.01 \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">T-tau protein (mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD), pg/mL \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">315<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>132.36 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">511.07<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>182.73 \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">.01 \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">P-tau<span class="elsevierStyleInf">181p</span> protein (mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD), pg/mL \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">49.57<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>36.07 \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">71.57<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>26.57 \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="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">T-tau/Aβ coefficient \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">0.38<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.24 \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">1.01<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.44 \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">.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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P-tau/Aβ coefficient \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">0.06<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.04 \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">0.14<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.07 \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">.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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Right<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>left medial temporal lobe atrophy (Korf) \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">3.27<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.43 \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">4.13<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.67 \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 => "xTab557841.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Clinical and demographical variables and CSF and brain MRI variables for included patients.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">95% CI: confidence interval; RR: relative risk.</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">Alzheimer frequency \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">RR (95% CI) \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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Brain MRI</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>Abnormal \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">58.8% (10/17) \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">1.5 (0.7–3.4) \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="char" 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></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>Normal \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">38.5% (5/13) \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">CSF</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>Abnormal \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">73.3% (11/15) \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">2.7 (1.1–6.7) \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">.01 \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>Normal \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">26.7 (4/15) \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab557839.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Relative risk with a confidence interval of 95% of developing AD.</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="" 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">CSF biomarkers \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">Brain MRI biomarkers \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">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">73 \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">67 \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">73 \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">53 \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">73 \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">59 \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">73 \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">61 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab557840.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Predictive ability of each technique used alone.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "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">Biomarkers \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">AD \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">MCI \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">MRI+/CSF+ \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">6 (75%) \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">2 (25%) \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">MRI+/CSF− \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 (44.4%) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (55.6%) \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">MRI−/CSF+ \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 (71.4%) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (28.6%) \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">MRI−/CSF− \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">0 \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">6 (100%) \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">Total<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>30 \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">15 (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">15 (50%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab557837.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Combination of results from both techniques.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "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">Alzheimer frequency \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">RR (95% CI) \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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">MRI or CSF</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>Abnormal \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">62.5% (15/24) \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">Not calculable \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">.017 \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>Normal \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% (0/6) \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab557836.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Relative risk of developing AD: combination of both techniques.</p>" ] ] 5 => array:7 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "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">MRI+ or CSF+ \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">2nd year \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">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">100 \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">40 \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">63 \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">100 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab557838.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Predictive ability for both techniques combined.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Research criteria for the diagnosis of Alzheimer's disease: Revising the NINCDS-ADRDA criteria" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Dubois" 1 => "H.H. Feldman" 2 => "C. Jacova" 3 => "S.T. Dekosky" 4 => "P. Barberger-Gateau" 5 => "J. Cummings" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1474-4422(07)70178-3" "Revista" => array:6 [ "tituloSerie" => "Lancet Neurol" "fecha" => "2007" "volumen" => "6" "paginaInicial" => "734" "paginaFinal" => "746" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17616482" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.A. Sperling" 1 => "P.S. Aisen" 2 => "L.A. Beckett" 3 => "D.A. Bennett" 4 => "S. Craft" 5 => "A.M. Fagan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jalz.2011.03.003" "Revista" => array:6 [ "tituloSerie" => "Alzheimers Dement" "fecha" => "2011" "volumen" => "7" "paginaInicial" => "280" "paginaFinal" => "292" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21514248" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biomarkers in the cerebrospinal fluid of patients with mild cognitive impairment: a meta-analysis of their predictive capacity for the diagnosis of Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.A. Monge-Argilés" 1 => "J. Sánchez-Payá" 2 => "C. Muñoz-Ruiz" 3 => "A. Pampliega-Pérez" 4 => "J. Montoya-Gutiérrez" 5 => "C. 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We would also like to thank María de los Angeles Miguelsanz (Immunology Laboratory at H.G.U.A.) for her excellent handling of samples.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/21735808/0000002900000007/v1_201409160948/S2173580814000984/v1_201409160948/en/main.assets" "Apartado" => array:4 [ "identificador" => "17109" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "CO1" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735808/0000002900000007/v1_201409160948/S2173580814000984/v1_201409160948/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580814000984?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 0 | 5 |
| 2024 October | 14 | 10 | 24 |
| 2024 September | 34 | 4 | 38 |
| 2024 August | 19 | 6 | 25 |
| 2024 July | 19 | 2 | 21 |
| 2024 June | 14 | 2 | 16 |
| 2024 May | 20 | 9 | 29 |
| 2024 April | 16 | 6 | 22 |
| 2024 March | 25 | 8 | 33 |
| 2024 February | 12 | 4 | 16 |
| 2024 January | 16 | 5 | 21 |
| 2023 December | 19 | 12 | 31 |
| 2023 November | 15 | 5 | 20 |
| 2023 October | 21 | 13 | 34 |
| 2023 September | 18 | 4 | 22 |
| 2023 August | 9 | 7 | 16 |
| 2023 July | 11 | 7 | 18 |
| 2023 June | 17 | 3 | 20 |
| 2023 May | 9 | 10 | 19 |
| 2023 April | 15 | 2 | 17 |
| 2023 March | 13 | 4 | 17 |
| 2023 February | 18 | 5 | 23 |
| 2023 January | 14 | 6 | 20 |
| 2022 December | 21 | 10 | 31 |
| 2022 November | 21 | 7 | 28 |
| 2022 October | 10 | 11 | 21 |
| 2022 September | 18 | 15 | 33 |
| 2022 August | 20 | 22 | 42 |
| 2022 July | 10 | 6 | 16 |
| 2022 June | 13 | 4 | 17 |
| 2022 May | 11 | 7 | 18 |
| 2022 April | 19 | 11 | 30 |
| 2022 March | 19 | 5 | 24 |
| 2022 February | 13 | 4 | 17 |
| 2022 January | 12 | 6 | 18 |
| 2021 December | 21 | 14 | 35 |
| 2021 November | 17 | 10 | 27 |
| 2021 October | 33 | 11 | 44 |
| 2021 September | 20 | 16 | 36 |
| 2021 August | 30 | 6 | 36 |
| 2021 July | 16 | 8 | 24 |
| 2021 June | 18 | 17 | 35 |
| 2021 May | 16 | 9 | 25 |
| 2021 April | 40 | 13 | 53 |
| 2021 March | 20 | 7 | 27 |
| 2021 February | 9 | 7 | 16 |
| 2021 January | 13 | 9 | 22 |
| 2020 December | 10 | 9 | 19 |
| 2020 November | 15 | 9 | 24 |
| 2020 October | 11 | 11 | 22 |
| 2020 September | 11 | 12 | 23 |
| 2020 August | 13 | 9 | 22 |
| 2020 July | 17 | 10 | 27 |
| 2020 June | 15 | 8 | 23 |
| 2020 May | 12 | 11 | 23 |
| 2020 April | 13 | 5 | 18 |
| 2020 March | 34 | 10 | 44 |
| 2020 February | 25 | 9 | 34 |
| 2020 January | 12 | 12 | 24 |
| 2019 December | 25 | 12 | 37 |
| 2019 November | 15 | 10 | 25 |
| 2019 October | 9 | 1 | 10 |
| 2019 September | 9 | 6 | 15 |
| 2019 August | 14 | 1 | 15 |
| 2019 July | 17 | 15 | 32 |
| 2019 June | 18 | 28 | 46 |
| 2019 May | 93 | 57 | 150 |
| 2019 April | 35 | 13 | 48 |
| 2019 March | 7 | 8 | 15 |
| 2019 February | 7 | 4 | 11 |
| 2019 January | 17 | 5 | 22 |
| 2018 December | 4 | 3 | 7 |
| 2018 November | 9 | 5 | 14 |
| 2018 October | 13 | 7 | 20 |
| 2018 September | 7 | 3 | 10 |
| 2018 August | 4 | 1 | 5 |
| 2018 July | 6 | 1 | 7 |
| 2018 June | 8 | 1 | 9 |
| 2018 May | 8 | 6 | 14 |
| 2018 April | 5 | 7 | 12 |
| 2018 March | 2 | 1 | 3 |
| 2018 February | 3 | 3 | 6 |
| 2018 January | 9 | 1 | 10 |
| 2017 December | 6 | 0 | 6 |
| 2017 November | 7 | 2 | 9 |
| 2017 October | 9 | 2 | 11 |
| 2017 September | 7 | 1 | 8 |
| 2017 August | 15 | 3 | 18 |
| 2017 July | 12 | 2 | 14 |
| 2017 June | 15 | 3 | 18 |
| 2017 May | 17 | 6 | 23 |
| 2017 April | 15 | 3 | 18 |
| 2017 March | 8 | 15 | 23 |
| 2017 February | 18 | 2 | 20 |
| 2017 January | 15 | 3 | 18 |
| 2016 December | 18 | 3 | 21 |
| 2016 November | 12 | 4 | 16 |
| 2016 October | 8 | 5 | 13 |
| 2016 September | 6 | 2 | 8 |
| 2016 August | 7 | 4 | 11 |
| 2016 July | 11 | 1 | 12 |
| 2016 June | 15 | 14 | 29 |
| 2016 May | 13 | 6 | 19 |
| 2016 April | 10 | 8 | 18 |
| 2016 March | 18 | 20 | 38 |
| 2016 February | 19 | 11 | 30 |
| 2016 January | 6 | 7 | 13 |
| 2015 December | 7 | 5 | 12 |
| 2015 November | 12 | 8 | 20 |
| 2015 October | 23 | 16 | 39 |
| 2015 September | 16 | 15 | 31 |
| 2015 August | 13 | 5 | 18 |
| 2015 July | 11 | 8 | 19 |
| 2015 June | 11 | 2 | 13 |
| 2015 May | 24 | 10 | 34 |
| 2015 April | 24 | 15 | 39 |
| 2015 March | 19 | 14 | 33 |
| 2015 February | 29 | 19 | 48 |
| 2015 January | 39 | 8 | 47 |
| 2014 December | 43 | 17 | 60 |
| 2014 November | 24 | 9 | 33 |
| 2014 October | 32 | 17 | 49 |
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