Validity of CSF alpha-synuclein to predict psychosis in prodromal Alzheimer's disease.

Background: Alzheimer's disease (AD) accompanied by psychotic symptoms (PS) has a poor prognosis and may be associated with imbalances in key neural proteins such as alpha-synuclein (AS). Aim: The aim of the study was to evaluate the diagnostic validity of AS levels in the cerebrospinal fluid (CSF) as a predictor of the emergence of PS in patients with prodromal AD. Materials and methods: Patients with mild cognitive impairment were recruited between 2010 and 2018. Core AD biomarkers and AS levels were measured in CSF obtained during the prodromal phase of the illness. All patients who met the NIA-AA 2018 criteria for AD biomarkers received treatment with anticholinesterasic drugs. Follow-up evaluations were conducted to assess patients for the presence of psychosis using current criteria; the use of neuroleptic drugs was required for inclusion in the psychosis group. Several comparisons were made, taking into account the timing of the emergence of PS. Results: A total of 130 patients with prodromal AD were included in this study. Of these, 50 (38.4%) met the criteria for PS within an 8-year follow-up period. AS was found to be a valuable CSF biomarker to differentiate between the psychotic and non-psychotic groups in every comparison made, depending on the onset of PS. Using an AS level of 1,257 pg/mL as the cutoff, this predictor achieved at least 80% sensitivity. Conclusion: To our knowledge, this study represents the first time that a CSF biomarker has shown diagnostic validity for prediction of the emergence of PS in patients with prodromal AD.

Relation between Alpha-Synuclein and Core CSF Biomarkers of Alzheimer's Disease.

Background: Alzheimer's disease (AD) is characterized by the presence of ß-amyloid plaques and neurofibrillary tangles, while Lewy body dementia (LBD) is characterized by α-synuclein (α-syn) inclusions. Some authors examine α-syn protein in the neurodegeneration process of AD and propose to consider cerebrospinal fluid (CSF) α-syn as a possible additional biomarker to the so-called "core" of AD. Objective: To determine whether there is a correlation between α-syn levels and "core" AD biomarkers in patients with mild cognitive impairment (MCI). Materials and methods: In total, 81 patients in the early stages of MCI were selected from the outpatient dementia consultation in Alicante General Hospital. Using a cross-sectional case-control design, patients were analyzed in four groups: stable MCI (MCIs; n = 25), MCI due to AD (MCI-AD; n = 32), MCI due to LBD (MCI-LBD; n = 24) and a control group of patients with acute or chronic headache (Ctrl; n = 18). Correlation between CSF protein levels in the different groups was assessed by the Rho Spearman test. Results: We found positive correlations between T-tau protein and α-syn (ρ = 0.418; p value < 0.05) and p-tau181p and α-syn (ρ = 0.571; p value < 0.05) exclusively in the MCI-AD group. Conclusion: The correlation found between α-syn and tau proteins in the first stages of AD support the involvement of α-syn in the pathogenesis of AD. This result may have clinical and diagnostic implications, as well as help to apply the new concept of "precision medicine" in patients with MCI.

Measurement of CSF α-synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer's disease.

Previous studies have indicated the potential of cerebrospinal fluid (CSF) α-synuclein (α-syn) to be an additional biomarker for improving differential diagnosis of Alzheimer's disease (AD). We evaluated α-syn diagnostic performance across a well-characterized patient cohort with long-term follow-up. For this purpose, CSF α-syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n = 25), 27 MCI cases due to AD (MCI-AD; n = 32), 24 MCI cases due to Lewy body disease (MCI-LBD; n = 24) and control subjects (Ctrl; n = 18). CSF α-syn levels discriminate between the four groups. There were higher α-syn levels in MCI-AD patients and lower levels in MCI-LBD patients. The combination of α-syn and P-tau resulted in a specificity of 99% and a sensitivity of 97% for MCI-AD. MCI-AD patients with early psychotic symptoms (n = 9) displayed a trend towards a decrease in P-tau and α-syn compared to the MCI-AD patients without psychotic symptoms (n = 23). We conclude that adding CSF α-syn to central core AD biomarkers improves an early differential diagnosis of MCI-AD from other forms of MCI. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Comparison of two analytical platforms for CSF biomarkers of Alzheimer's disease.

Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are currently being assessed with two different assays. Our objective was to study if there is a correlation between values obtained by both techniques, to compare their validity and search for conversion factor between values obtained for every protein. We compared the performances of two commonly used platforms, an enzyme-linked immunosorbent assay (ELISA) and a multiplex (xMAP) technology for measurement of CSF Aß 1-42, total tau (T-tau), and phosphorylated tau 181 (P-tau 181p) proteins, in 30 AD patients and 28 control subjects. The relations between the variables of both techniques were evaluated using the Spearman p correlation coefficient (α = 0.05). Receiver operating characteristic and area under the curve (AUC) analyses were calculated for the variables of both techniques. The two assays platforms yielded different absolute values for the various analytes, always higher in ELISA. We found some correction factor between values: 2,1- to 3-fold for Aß 1-42; 4,1- to 4,6-fold for T-tau; and 1,4- to 1,6-fold for P-tau 181p. In addition, those values were highly correlated (Aß 1-42: r = 0.70, P < 0.01; T-tau: r = 0.90, P < 0.01; P-tau 181p: r = 0.85, P < 0.01) and the AUC for the variables showed very similar values. In conclusion, the results obtained with ELISA and xMAP platforms were highly correlated and its validity is very similar. Differences in absolute values point to the need for a clear description of the technique used. Moreover, we found some conversion factor between values of every protein that may be useful for transformation between both techniques.

Alzheimer disease cerebrospinal fluid biomarkers predict cognitive decline in healthy elderly over 2 years.

AIM: : The aim of this study is to check the ability of cerebrospinal fluid biomarkers of Alzheimer disease (CSF-BMK-AD) to make a discrimination checklist within a healthy group, according to their cognitive development at 2 years of obtaining the sample. MATERIALS AND METHODS: Between 2008 and 2010, 67 subjects without cognitive or behavioral disorders were included as a control group in a study on CSF-AD-BMK. Neuropsychological assessment at baseline and at follow-up had been carried out 2 years later. CSF was obtained at the inclusion. It was analyzed by Innotest reagents to measure amyloid-ß (Aß1-42), total-τ (T-τ), and phosphorylated τ181 (P-τ181p) protein levels, as well as T-τ/Aß1-42 and P-τ181p/Aß1-42 ratios. RESULTS: Two years after inclusion, 28 subjects were not able to be checked for cognitive evolution. Of those who were seen for follow-up (n=39), 29 were cognitively stable and 10 showed cognitive impairment. We found significant differences in Aß1-42 protein level (820 vs. 1359 pg/mL, P<0.003), in the T-τ/Aß1-42 ratio (0.40 vs. 0.19, P<0.009), and in the P-τ181p/Aß1-42 ratio (0.09 vs. 0.04, P<0.003) when both groups were compared. CONCLUSIONS: CSF-BMK-AD are able to discriminate between subjects in a group initially asymptomatic depending on their cognitive evolution at the 2 years' follow-up. These results are consistent with the decrease of CSF Aß1-42 protein levels as the first finding in preclinical AD showed.

Análisis Multiplex de citoquinas intratecales en pacientes con deterioro cognitivo leve / Multiplex analysis of intrathecal cytokines in patients with mild cognitive impairment

Introducción. El estudio del papel de las citoquinas en los procesos neuroinmunológicos se ha intensificado en la última década, si bien los resultados han sido contradictorios debido al empleo de tecnologías poco sensibles. La implementación de la tecnología Multiplex en los inmunoensayos puede ser beneficiosa en la evaluación de pacientes con daño cognitivo leve (DCL) que evolucionan a enfermedad de Alzheimer (EA). Materiales y métodos. Treinta y siete pacientes con DCL y 24 sujetos control fueron estudiados mediante análisis Multiplex de citoquinas intratecales y en suero. Las variables del estudio fueron las citoquinas IL1β, IL2, IL5, IL6, IL7, IL8, IL10, IL12p70, IL13, factor necrosis tumoral alfa (TNFα), interferón gamma (IFNγ) y factor de crecimiento de granulocito-macrófago (GM-CSF) y los cocientes pro/antiinflamatorios IL6/IL10, IL6/IL5, IL8/IL10, IL8/IL5, TNFα/IL10 y TNFα/IL5. Se estudió la evolución a EA en los pacientes DCL y en los sujetos control en el período de un año. Resultados. Se encontraron diferencias significativas (p<0,05) para el cociente IL6/IL10 entre el grupo DCL y el grupo control (mediana [rango intercuartílico]): (1,39 [1,18-1,80] vs. 1,91 [2,68-1,18] pg/ml). De 37 pacientes con DCL, 14 evolucionaron a EA (DCL-EA) en el período de un año. De nuevo se encontraron diferencias significativas (p<0,05) en el cociente IL6/IL10 entre el grupo DCL-EA y DCL- S (o estable): (1,29 [0,84-1,56] vs. 1,42 [1,27-2,07] pg/ml). Ninguno de los sujetos control evolucionó a EA. Conclusiones. El descenso en el cociente IL6/IL10 en LCR puede ser un prometedor marcador diagnóstico de DCL y predictor/pronóstico de EA en DCL (AU)

Introduction. There has been an increase in the number of studies on the role of cytokines in neuro-immunological processes, over the last ten years, but some of these results have been contradictory due to a lack of sensitivity in the technology. The new Multiplex immunoassays can be beneficial for monitoring Mild Cognitive Impairment (MCI) patients who progress to Alzheimer Disease (AD). Methods. A study was conducted on 37 MCI patients and 24 control subjects by means of multiplex analysis of CSF cytokines. The variables measured were the following cytokines: IL1β, IL2, IL5, IL6, IL7, IL8, IL10, IL12p70, IL13, tumour necrosis factor alpha (TNFα), interferon gamma (IFNγ) and granulocyte – macrophage growth colony stimulating factor (GM-CSF), as well as the following pro/anti-inflammatory ratios: IL6/IL10, IL6/IL5, IL8/IL10, IL8/IL5, TNFα/IL10 and TNFα/IL5. Progress to AD in MCI patients was studied over a period of one year. Results. Significant differences were found (P<.05) for IL6/IL10 ratio between MCI patients and Control group (median [IR]): (1.39 [1.18-1.80] vs. 1.91 [2.68-1.18] pg/mL). Of the 37 MCI patients, 14 progressed to AD (DCL-EA group) within a year. Significant differences were also found (P<.05) for IL6/IL10 ratio between the DCL-EA group and the rest of MCI patients that did not progress (DCL-S or stable): (1.29 [0.84-1.56] vs. 1.42 [1.27-2.07] pg/mL). None of the control subjects progressed to AD. Conclusions. A decrease in CSF IL6/IL10 ratio could be a promising diagnostic biomarker in MCI and a prognostic biomarker of AD in MCI (AU)