Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
Por:
Suarez-Calvet, M, Morenas-Rodriguez, E, Kleinberger, G, Schlepckow, K, Caballero, MAA, Franzmeier, N, Capell, A, Fellerer, K, Nuscher, B, Eren, E, Levin, J, Deming, Y, Piccio, L, Karch, CM, Cruchaga, C, Shaw, LM, Trojanowski, JQ, Weiner, M, Ewers, M, Haass, C, Alzheimers Dis Neuroimaging
Publicada:
10 ene 2019
Resumen:
BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid -peptide (A) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of A(1-42) (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal A pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsA pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, A pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.
Filiaciones:
Suarez-Calvet, M:
Ludwig Maximilians Univ Munchen, Fac Med, Chair Metab Biochem, Biomed Ctr BMC, Munich, Germany
German Ctr Neurodegenerat Dis DZNE Munich, Munich, Germany
Pasqual Maragall Fdn, BBRC, Barcelona, Catalonia, Spain
Morenas-Rodriguez, E:
German Ctr Neurodegenerat Dis DZNE Munich, Munich, Germany
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Inst Invest Biomed, Dept Neurol, Barcelona, Catalonia, Spain
Kleinberger, G:
Ludwig Maximilians Univ Munchen, Fac Med, Chair Metab Biochem, Biomed Ctr BMC, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Schlepckow, K:
German Ctr Neurodegenerat Dis DZNE Munich, Munich, Germany
Caballero, MAA:
Ludwig Maximilians Univ Munchen, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany
Franzmeier, N:
Ludwig Maximilians Univ Munchen, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany
Capell, A:
Ludwig Maximilians Univ Munchen, Fac Med, Chair Metab Biochem, Biomed Ctr BMC, Munich, Germany
Fellerer, K:
Ludwig Maximilians Univ Munchen, Fac Med, Chair Metab Biochem, Biomed Ctr BMC, Munich, Germany
Nuscher, B:
Ludwig Maximilians Univ Munchen, Fac Med, Chair Metab Biochem, Biomed Ctr BMC, Munich, Germany
Eren, E:
Ludwig Maximilians Univ Munchen, Fac Med, Chair Metab Biochem, Biomed Ctr BMC, Munich, Germany
Dokuz Eylul Univ, Izmir Int Biomed & Genome Inst, Izmir, Turkey
Dokuz Eylul Univ, Inst Hlth Sci, Dept Neurosci, Izmir, Turkey
Levin, J:
German Ctr Neurodegenerat Dis DZNE Munich, Munich, Germany
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
Deming, Y:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Piccio, L:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Washington Univ St Louis, Hope Ctr Neurol Disorders, St Louis, MO USA
Karch, CM:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ St Louis, Hope Ctr Neurol Disorders, St Louis, MO USA
Washington Univ St Louis, Knight Alzheimers Dis Res Ctr, St Louis, MO USA
Cruchaga, C:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ St Louis, Hope Ctr Neurol Disorders, St Louis, MO USA
Washington Univ St Louis, Knight Alzheimers Dis Res Ctr, St Louis, MO USA
Shaw, LM:
Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA
Univ Penn, Perelman Sch Med, Inst Aging, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
Trojanowski, JQ:
Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA
Univ Penn, Perelman Sch Med, Inst Aging, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
Weiner, M:
Univ Calif San Francisco, San Francisco, CA 94143 USA
Ewers, M:
Ludwig Maximilians Univ Munchen, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany
Haass, C:
Ludwig Maximilians Univ Munchen, Fac Med, Chair Metab Biochem, Biomed Ctr BMC, Munich, Germany
German Ctr Neurodegenerat Dis DZNE Munich, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Gold, Green Published
|