RESUMEN
Several studies have shown that reduced amyloid-beta 1-42 (Abeta(42)) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. beta-site APP cleaving enzyme (BACE1) is thought to be the major beta-secretase involved in Abeta production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Abeta(40), Abeta(42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) in CSF of control (n=12), mild cognitive impairment (n=18), and AD (n=17) subjects. Patients were classified according to their Abeta(42), t-tau, and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Abeta(42) < 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo
, Enfermedad de Alzheimer/patología
, Secretasas de la Proteína Precursora del Amiloide/líquido cefalorraquídeo
, Ácido Aspártico Endopeptidasas/líquido cefalorraquídeo
, Anciano
, Enfermedad de Alzheimer/genética
, Péptidos beta-Amiloides/líquido cefalorraquídeo
, Apolipoproteínas E/genética
, Trastornos del Conocimiento/líquido cefalorraquídeo
, Trastornos del Conocimiento/genética
, Ensayo de Inmunoadsorción Enzimática/métodos
, Femenino
, Humanos
, Masculino
, Persona de Mediana Edad
, Fragmentos de Péptidos/líquido cefalorraquídeo
, Estadística como Asunto
, Proteínas tau/líquido cefalorraquídeo
RESUMEN
BACKGROUND: To improve ante mortem diagnostic accuracy of Alzheimer disease (AD), measurement of the biomarkers amyloid-beta(1-42) (Abeta42), total tau (Tau), and tau phosphorylated at threonine(181) (pTau) in cerebrospinal fluid (CSF) has been proposed. We have used these markers and evaluated their performance. METHODS: From January 2001 to January 2007, we assessed Abeta42, Tau, and pTau by commercial ELISAs in CSF from 248 consecutive AD patients and 131 patients with subjective memory complaints attending our outpatient memory clinic. Diagnoses were made blind to the results of the biomarker assays. We assessed sensitivity and specificity and analyzed trends over time. RESULTS: Interassay CVs from analysis of pools of surplus CSF specimens were mean 11.3% (SD 4.9%) for Abeta42; 9.3% (1.5%) for Tau, and 9.4% (2.5%) for pTau, respectively (n = 7-18). To achieve 85% sensitivity, cutoff values were 550 (95% CI 531-570) ng/L for Abeta42; 375 (325-405) ng/L for Tau, and 52 (48-56) ng/L for pTau. Corresponding specificities were 83% (95% CI 76%-89%) for Abeta42, 78% (70%-85%) for Tau, and 68% (60%-77%) for pTau. Logistic regression to investigate the simultaneous impact of the 3 CSF biomarkers on the diagnosis yielded a sensitivity of 93.5% and specificity of 82.7%, at a discrimination line of Abeta42 = 373 + 0.82 x Tau. The area under the ROC curves of Tau and pTau showed significant fluctuation over time. CONCLUSIONS: CSF biomarkers Abeta42 and Tau can be used as a diagnostic aid in AD. pTau did not have additional value over these 2 markers. Cutoff values, sensitivities, specificities, and discrimination lines depend on the patient groups studied and laboratory experience.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fosforilación , Curva ROC , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Prostate-specific antigen (PSA) is a serine protease that in serum, is predominantly found complexed to the serine protease inhibitor alpha1-antichymotrypsin (ACT). ACT co-localizes with amyloid plaques in Alzheimer's disease (AD) brain and both PSA and ACT are detectable in cerebrospinal fluid (CSF). Therefore, we aimed to determine whether PSA is produced in the brain and whether PSA and PSA-ACT complex levels in CSF can be used as a biomarker for AD. METHODS: Levels of ACT and PSA-ACT were determined by sandwich enzyme-linked immunosorbent assay in CSF and serum samples of AD (n = 16), frontotemporal lobe dementia (FTLD) (n = 19), mild cognitively impaired (MCI) patients (n = 19) and controls (n = 12). Total PSA was determined in a non-competitive immunoassay. Reverse transcriptase-polymerase chain reaction (RT-PCR) for PSA was performed on postmortem hippocampus and temporal cortex specimens from control and AD cases. RESULTS: PSA is expressed in the brain, as detected by RT-PCR. PSA and PSA-ACT complexes were detectable in CSF of almost all male and only very few female subjects. The levels of PSA and PSA-ACT complexes in CSF did not differ between AD, FTLD, MCI and control groups. PSA CSF/serum quotients highly correlated with albumin CSF/serum quotients. Furthermore, the hydrodynamic radius of PSA was found to be 3 nm and the theoretical PSA quotient, derived from the Felgenhauer plot, corresponded well with the measured PSA quotient. CONCLUSIONS: PSA is locally produced in the human brain; however, brain PSA hardly contributes to the CSF levels of PSA. PSA and PSA-ACT levels in CSF are not suitable as a biomarker for AD.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Antígeno Prostático Específico/líquido cefalorraquídeo , alfa 1-Antiquimotripsina/líquido cefalorraquídeo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Trastornos del Conocimiento/líquido cefalorraquídeo , Demencia/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Lóbulo Frontal/patología , Humanos , Inmunoensayo/métodos , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espectrometría de Fluorescencia/métodos , Lóbulo Temporal/patologíaRESUMEN
BACKGROUND: Serum amyloid P component (SAP), present in amyloid-beta (Abeta) plaques in Alzheimer's disease (AD), may protect Abeta deposits against proteolysis, thereby promoting plaque formation. The aim was to investigate if SAP levels in cerebrospinal fluid (CSF) and serum can be used to discriminate controls, AD and mild cognitive impairment (MCI) patients, and to identify incipient AD among MCI patients. METHODS: SAP levels in CSF and serum were determined in 30 controls, 67 MCI and 144 AD patients. At follow-up, 39 MCI patients had progressed to dementia, while 25 had remained stable (mean follow-up time: 2.6 +/- 1.0 and 2.1 +/- 0.8 years). RESULTS: Cross-sectionally no differences were found in SAP levels in CSF and serum between the groups. MCI patients that had progressed to dementia at follow-up had lower CSF SAP levels (13 microgram/l, range 3.3-199.3 microgram/l) than MCI nonprogressors (20.2 microgram/l, range 7.0-127.7 microgram/l; p < 0.05) [corrected]. A low CSF SAP level was associated with a 2-fold increased risk of progression to AD (hazard ratio = 2.2; 95% confidence interval = 0.9-5.4). CONCLUSION: Our data suggest that measurement of CSF SAP levels can aid in the identification of incipient AD among MCI patients.
Asunto(s)
Enfermedad de Alzheimer/sangre , Trastornos del Conocimiento/sangre , Componente Amiloide P Sérico/metabolismo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores , Trastornos del Conocimiento/líquido cefalorraquídeo , Estudios Transversales , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeo , Factores de Riesgo , Componente Amiloide P Sérico/líquido cefalorraquídeoRESUMEN
BACKGROUND: Frontotemporal dementia (FTD) is pathologically heterogeneous, sometimes revealing intraneuronal inclusions of neurofilaments. We therefore measured CSF neurofilament profiles in patients with FTD, patients with early onset Alzheimer's disease (EAD) and healthy control subjects to explore the discriminative potential of CSF neurofilaments compared with the existing CSF biomarkers amyloid-beta(1-42), tau and tau phosphorylated at threonine-181. METHODS: CSF levels of light chain, heavy chain and hyperphosphorylated heavy chain neurofilaments (NfL, t-NfH and P-NfH) were compared between 17 subjects with FTD, 20 with EAD and 25 cognitively healthy controls. RESULTS: A subgroup of FTD patients had remarkably high CSF levels of both NfL and NfH. The degree of NfH phosphorylation was increased in FTD compared to both other groups. The levels of CSF NfL were significantly higher in EAD compared to controls. CONCLUSION: Differences in CSF biomarker profiles might reflect differential involvement of neurofilaments and tau in FTD and EAD. The subgroup of FTD patients with high CSF neurofilament levels may have a different neuropathological substrate and future studies addressing this specific issue are needed.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Demencia/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Demencia/patología , Femenino , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Proteínas de Neurofilamentos/metabolismo , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/metabolismo , Fosforilación , Valores de Referencia , Proteínas tau/metabolismoRESUMEN
Homocysteine accumulation, frequently observed in plasma of AD patients, may be a sign of a reduced activity of the brain methionine-homocysteine transmethylation cycle. S-Adenosylmethionine (SAM) is the main methyl donor in several transmethylation reactions. The demethylated product of SAM, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine, which can be remethylated to methionine by transfer of a methyl group of 5-methyltetrahydrofolate (5-MTHF). A reduced activity of the transmethylation cycle in the brain may result in hypomethylation of the promoter of the presenilin 1 (PS1) gene, which will lead to overexpression of presenilin 1 and, consequently, to increased Abeta(1-42) (Abeta42) formation. Brain transmethylation was studied in 30 patients with 'probable' AD and 28 age-matched non-demented controls by measuring the cerebrospinal fluid (CSF) levels of SAM, SAH and 5-MTHF. 5-MTHF was determined by HPLC with electrochemical detection, while SAM and SAH were assayed by stable isotope dilution tandem mass spectrometry. We found no statistical differences between AD patients and controls for 5-MTHF, SAM and SAH levels, and the SAM/SAH-ratio in CSF. These findings argue against a possible change in methylation of the promoter and expression of PS1.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Encéfalo/metabolismo , S-Adenosilhomocisteína/líquido cefalorraquídeo , S-Adenosilmetionina/líquido cefalorraquídeo , Tetrahidrofolatos/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/metabolismo , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Espectrometría de Masas , Proteínas de la Membrana/metabolismo , Metilación , Persona de Mediana Edad , Presenilina-1 , Regiones Promotoras Genéticas , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Tetrahidrofolatos/metabolismoRESUMEN
Various C-terminally truncated amyloid beta peptides (Abeta) are linked to Alzheimer's disease (AD) pathogenesis. Cerebrospinal fluid (CSF) concentrations of Abeta38, Abeta40, and Abeta42 were measured by enzyme-linked immunosorbent assay in 30 patients with AD and 26 control subjects. CSF Abeta42 levels was decreased in patients with AD, whereas CSF Abeta38 and Abeta40 levels were similar in patients with AD and control subjects. All three Abeta peptides were interrelated, particularly CSF Abeta38 and Abeta40. Diagnostic accuracy of CSF Abeta42 concentrations was not improved by applying the ratios of CSF Abeta42 to Abeta38 or Abeta40.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadAsunto(s)
Péptidos beta-Amiloides/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Demencia/diagnóstico , Femenino , Humanos , Inmunoensayo/métodos , Masculino , Persona de Mediana Edad , Curva ROC , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Reported concentrations of amyloid beta (1-42) (A beta 42) and tau in cerebrospinal fluid (CSF) differ among reports. We investigated the effects of storage temperature, repeated freeze/thaw cycles, and centrifugation on the concentrations of A beta 42 and tau in CSF. METHODS: Stability of samples stored at -80 degrees C was determined by use of an accelerated stability testing protocol according to the Arrhenius equation. A beta 42 and tau concentrations were measured in CSF samples stored at 4, 18, 37, and -80 degrees C. Relative CSF concentrations (%) of the biomarkers after one freeze/thaw cycle were compared with those after two, three, four, five, and six freeze/thaw cycles. In addition, relative A beta 42 and tau concentrations in samples not centrifuged were compared with samples centrifuged after 1, 4, 48, and 72 h. RESULTS: A beta 42 and tau concentrations were stable in CSF when stored for a long period at -80 degrees C. CSF A beta 42 decreased by 20% during the first 2 days at 4, 18, and 37 degrees C compared with -80 degrees C. CSF tau decreased after storage for 12 days at 37 degrees C. After three freeze/thaw cycles, CSF A beta 42 decreased 20%. CSF tau was stable during six freeze/thaw cycles. Centrifugation did not influence the biomarker concentrations. CONCLUSIONS: Repeated freeze/thaw cycles and storage at 4, 18, and 37 degrees C influence the quantitative result of the A beta 42 test. Preferably, samples should be stored at -80 degrees C immediately after collection.