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

BackgroundAlzheimer'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).AimThe 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 methodsPatients 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.ResultsA 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.ConclusionTo 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

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.This study was partially funded by an ISABIAL grant (2020-286) to J-AM-A and by the Direcció General de Ciència I Investigació, Generalitat Valenciana to JS-V (AICO/2021/308). M-ÁC-G was supported by a BEFPI fellowship from the Generalitat Valenciana.Peer reviewe

Biomarcadores en líquido cefalorraquídeo de pacientes con enfermedad de Alzheimer prodrómica

Introduction: The prodromal Alzheimer�Ls disease (AD) is a new concept that include an amnesic mild cognitive impairment (MCIa) and alterations in some complementary tests. Objective: To test the presence of alterations in the cerebrospinal fluid (CSF) biomarkers in our MCI-a patients who developed AD in the first year after the lumbar puncture. Method: 24 control subjects and 36 MCI-a patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we quantified CSF A�À1-42, T-tau and P-tau181p proteins, and calculated the ratios T-tau / A�À1-42 y P-tau 181p / A�À1-42. This project was approved by the local Ethical Committee. Results: One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients showed lower A�À1-42 protein levels (285.37 �} 73.36 vs. 365.21 �} 112.53 pg/ml, p < 0.02) and higher T-tau protein (88.3 �} 40.82 vs. 53.21 �} 23.38 pg/ml, p < 0.002), P-tau 181p protein (66.44 �} 23.87 vs. 31.25 �} 13.74 pg/ml, p< 0.02 ), T-tau / A�À1-42 ratio (0.34 �} 0.19 vs. 0.15 �} 0.08, p < 0.001 ) and P-tau 181p / A�À1-42 ratio (0.25 �} 0.12 vs. 0.09 �} 0.06, p < 0.0001) than the control subjects. Conclusion: In our experience, as the recent literature, it exist the very clear alterations of CSF biomarkers in patients with prodromal AD.Introduccion: La enfermedad de Alzheimer (EA) prodromica es un concepto reciente que incluye la presencia de un deterioro cognitivo leve de tipo amnesico (DCL-a) y la alteracion en determinadas pruebas complementarias. Objetivo: Comprobar la existencia de alteraciones en los biomarcadores del liquido cefalorraquideo (LCR) en aquellos de nuestros pacientes con DCL-a que en el primer ano postpuncion lumbar desarrollaron la EA. Materiales y metodos: Inicialmente, incluimos 36 pacientes con DCL-a, procedentes de la consulta de deterioro cognitivo de nuestro hospital (criterios de Petersen, 2006) y 24 sujetos control. Por medio de la tecnologia xMAPR Luminex se obtuvieron los niveles de las proteinas A�À1-42, T-tau y P-tau181p en el LCR, mediante los reactivos INNO-BIA Alz-bio 3 (Innogenetics), y los cocientes T-tau / A�À1-42 y P-tau181p / A�À1-42. Las muestras de 19 pacientes se analizaron por duplicado. Resultados: Los coeficientes de correlacion intraclase para cada uno de los tres biomarcadores tenian valores superiores a 0,95. En los doce meses posteriores a la PL, 14 pacientes (38%) con DCL-a progresaron a EA (criterios NINCDS-ADRDA). Estos ultimos presentaban diferencias estadisticamente significativas con respecto a los sujetos control en todos los parametros estudiados: A�À1-42 (285,37 �} 73,36 frente a 365 pg/ml, p < 0,02), T-tau ( 88,3 �} 40,82 frente a 53,21 �} 23,38 pg/ml, p < 0,002), P-tau181p (66,44 �} 23,87 frente a 31,25 �} 13,74 pg/ml, p < 0,02), cociente T-tau / A�À1-42 (0,34 �} 0,19 frente a 0,15 �} 0,08, p < 0,001) y cociente P-tau181p / A�À1-42 (0,25 �} 0,12 frente a 0,09 �} 0,06, p < 0,0001). Conclusion: Como viene mostrando la bibliografia medica reciente, nuestra experiencia tambien pone de manifiesto unas claras alteraciones en los biomarcadores del LCR en los pacientes con EA prodromica

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.This study was funded in part by the Direcció General d’Universitat, Investigació i Ciència, GVA (AICO/2018/090 to JSV), co‐financed by the Fondo Europeo de Desarrollo Regional, and through CIBERNED, ISCIII (FEDER, ‘Investing in your future’). MSGA is supported by a Miguel Servet II Grant from Instituto de Salud Carlos III (CPII1600011).Peer reviewe

Relation between alpha-synuclein and core CSF biomarkers of Alzheimer’s disease

This article belongs to the Special Issue Alzheimer's Disease and Related Dementias: Current Knowledge, Advances, and Future Direction.[Background]: Alzheimer’s disease (AD) is characterized by the presence of β-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.For the acquisition of the reagents by Novartis Spain, Nutricia Spain, KRKA Spain and Neuraxpharm Spain. “This study was funded in part by the Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL; grant 190258)”.Peer reviewe

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.This study was funded in part by the Direcció General d’Universitat, Investigació i Ciència, GVA (AICO/2018/090 to JSV), co‐financed by the Fondo Europeo de Desarrollo Regional, and through CIBERNED, ISCIII (FEDER, ‘Investing in your future’). MSGA is supported by a Miguel Servet II Grant from Instituto de Salud Carlos III (CPII1600011).Peer reviewe