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1.
Mol Psychiatry ; 15(2): 138-45, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18663368

RESUMEN

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Trastornos del Conocimiento/líquido cefalorraquídeo , Demencia/líquido cefalorraquídeo , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Sensibilidad y Especificidad , Estadística como Asunto , Proteínas tau/líquido cefalorraquídeo
2.
J Neural Transm (Vienna) ; 114(7): 919-27, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17318305

RESUMEN

To evaluate variations in amyloid beta (Abeta) peptide pattern in cerebrospinal fluid (CSF) in neurodegenerative disorders. A recently established quantitative urea-based Abeta-sodium-dodecylsulfate-polyacrylamide-gel-electrophoresis with western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide (Abeta1-37, 1-38, 1-39, 1-40, 1-42) pattern in CSF. We asked whether the variation might be useful to further elucidate the overlap between or distinctions among neurodegenerative diseases in Abeta-processing. We used the Abeta-SDS-PAGE/immunoblot to investigate CSF for disease-specific Abeta peptide patterns. CSF samples from 96 patients with mainly clinically diagnosed Alzheimer's disease (n = 15), progressive supranuclear palsy (n = 20), corticobasal degeneration (n = 12), Parkinson's disease (n = 11), multiple systems atrophy (n = 18), and dementia with Lewy-bodies (n = 20) were analysed as well a comparison group (n = 19). The Abeta peptide patterns varied between tauopathies and synucleinopathies and between all diseases and the comparison group, possibly due to the influence of tau and alpha-synuclein on Abeta-processing.


Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Tauopatías/etiología , Tauopatías/patología , alfa-Sinucleína/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/biosíntesis , Péptidos beta-Amiloides/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/líquido cefalorraquídeo , Atrofia de Múltiples Sistemas/etiología , Atrofia de Múltiples Sistemas/patología , Procesamiento Proteico-Postraduccional , Tauopatías/líquido cefalorraquídeo , alfa-Sinucleína/fisiología , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/fisiología
5.
Exp Neurol ; 223(2): 366-70, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19664622

RESUMEN

We measured concentrations of Abeta peptides 1-42 and 1-40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3-3.8% for Abeta1-42, and 1.8-4.1% for Abeta1-40, inter-assay imprecision for Abeta1-42, Abeta1-40, and Abeta1-42/Abeta1-40 concentration ratio in the range of 2.3-11.5%, 2.2-10.4% and 4.2-9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n=193) had significantly lower Abeta1-42 plasma concentrations (p<0.007), and Abeta1-42/1-40 ratios (p<0.003) compared to patients with other dementias and MCI of other types (n=64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Inmunoensayo/métodos , Fragmentos de Péptidos/sangre , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Demencia/sangre , Demencia/líquido cefalorraquídeo , Demencia/diagnóstico , Diagnóstico Precoz , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Valor Predictivo de las Pruebas
6.
Nervenarzt ; 79 Suppl 3: 139-46; quiz 147-8, 2008 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-18931988

RESUMEN

Over the past 10 years, the status of laboratory analysis in dementia has increasingly changed from its use for exclusion diagnoses for secondary causes of dementias to determining positive diagnoses of neurodegenerative dementias. This especially applies to the cerebrospinal fluid diagnosis of Alzheimer's disease (AD). Just a few years ago, a lumbar puncture was advised only with sufficiently founded clinical suspicion and with higher priority for the exclusion of inflammatory causes of cognitive dementias. In contrast, pathologically changed biomarkers in the cerebrospinal fluid have already been indexed as supportive attributes of the diagnosis in the 2007 amended research criteria of AD. The lumbar puncture is therefore increasingly becoming part of the clinical routine diagnosis of demential processes and has, to some extent, far-reaching consequences. In this article, we discuss some of the important aspects.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Biomarcadores/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Diagnóstico Diferencial , Humanos , Ovillos Neurofibrilares/patología , Fragmentos de Péptidos/metabolismo , Fosforilación , Placa Amiloide/patología , Valor Predictivo de las Pruebas , Proteínas tau/líquido cefalorraquídeo
7.
J Neural Transm (Vienna) ; 114(5): 621-8, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17245538

RESUMEN

Cerebrospinal fluid (CSF) carboxyterminally truncated amyloid-beta (Abeta) peptides, Abeta1-42 and tau protein were evaluated in 30 patients with frontotemporal lobe degenerations (FTLD), 30 Alzheimer's disease (AD) patients and 30 non-demented disease controls (NDC) by Abeta-SDS-PAGE/immunoblot as well as commercial ELISAs for Abeta1-42 and total tau. FTLD displayed a significant drop of Abeta1-37 (p = 2.7 x 10(-4)), Abeta1-38 (p = 4.2 x 10(-5)) and Abeta1-42 (p = 3.3 x 10(-4)). Abeta1-42 was selectively decreased in AD (p = 8.5 x 10(-10)). Decreased Abeta1-38 enabled contrasts of beyond 85% to distinguish FTLD from AD and NDC patients, alone or in combination. Accordingly, low CSF Abeta1-37 and Abeta1-38 represent a biomarker candidate for FTLD and may reflect disease-specific changes of APP metabolism. Further validation should be carried out on dementias other than AD, diagnostically relevant control groups without dementia and without any evident affection of the central nervous system and subgroups of FTLD. Moreover, independent methods of measurement should be applied to CSF Abeta1-38.


Asunto(s)
Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas del Líquido Cefalorraquídeo/metabolismo , Demencia/líquido cefalorraquídeo , Demencia/diagnóstico , Péptidos/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/química , Biomarcadores/líquido cefalorraquídeo , Proteínas del Líquido Cefalorraquídeo/química , Demencia/fisiopatología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Immunoblotting , Masculino , Fragmentos de Péptidos/líquido cefalorraquídeo , Valor Predictivo de las Pruebas , Estructura Terciaria de Proteína , Proteínas tau/análisis , Proteínas tau/líquido cefalorraquídeo
8.
Mol Psychiatry ; 12(7): 671-80, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17339876

RESUMEN

Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-beta (Abeta) peptide patterns, using the quantitative Abeta-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Abeta1-38. The main outcome measures were a striking decrease of Abeta1-42 in AD (P=7.4 x 10(-19)), and most interestingly a pronounced decrease of Abeta1-38 in FTD (P=9.6 x 10(-7)). Moreover, a novel peptide that most probably represents an oxidized alpha-helical form of Abeta1-40 (Abeta1-40(ox)) displayed a highly significant increase in DLB (P=3.7 x 10(-3)) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Abeta peptide abundances (Abeta1-X%) was clearly superior to absolute CSF Abeta levels. Abeta1-42% and Abeta1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Abeta1-40(ox)% yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Abeta1-38 levels as measured by the Abeta-SDS-PAGE/immunoblot and MSD, respectively. CSF Abeta peptides may reflect disease-specific impact of distinct neurodegenerative processes on Abeta peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Demencia/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Demencia/clasificación , Demencia/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/clasificación , Estudios Prospectivos
9.
J Neural Transm (Vienna) ; 113(11): 1771-8, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16906356

RESUMEN

Differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is often crucial. CSF Tau protein and Amyloid-beta (A beta) peptides have shown diagnostic value for the diagnosis of AD, but discrimination from DLB was poor.Herein, we investigate CSF of 18 patients with probable AD, 25 with probable DLB and 14 non-demented disease controls (NDC) by A beta-SDS-PAGE/immunoblot and commercially available ELISAs for A beta1-42 and tau. CSF A beta peptide patterns and tau exhibited disease specific alterations among AD and DLB. The ratio of A beta1-42 to A beta1-38 and A beta1-42 to A beta1-37, respectively, in combination with absolute tau, yielded a sensitivity and specificity of 100 and 92%, respectively. We conclude that CSF A beta peptide patterns and tau levels reflect disease-specific pathophysiological pathways of these dementias as distinct neurochemical phenotypes. Combined evaluation of these biomarkers provides a reasonable accuracy for differential diagnosis of AD and DLB.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Western Blotting , Diagnóstico Diferencial , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Sensibilidad y Especificidad , Proteínas tau/líquido cefalorraquídeo
10.
J Neural Transm (Vienna) ; 112(7): 933-48, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15937638

RESUMEN

Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimer's disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), Abeta42, Abeta40 and S-100B protein, using a set of commercially available assays. Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. Abeta42 and Abeta40 remained relatively stable during follow-up but we found a slight increase of the median Abeta42 level in DLB, whereas in AD, Abeta42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases. The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD. Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Acetilcolinesterasa/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Diagnóstico Diferencial , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Proteínas tau/metabolismo
11.
J Neurochem ; 81(3): 481-96, 2002 May.
Artículo en Inglés | MEDLINE | ID: mdl-12065657

RESUMEN

Human lumbar CSF patterns of Abeta peptides were analysed by urea-based beta-amyloid sodium dodecyl sulphate polyacrylamide gel electrophoresis with western immunoblot (Abeta-SDS-PAGE/immunoblot). A highly conserved pattern of carboxyterminally truncated Abeta1-37/38/39 was found in addition to Abeta1-40 and Abeta1-42. Remarkably, Abeta1-38 was present at a higher concentration than Abeta1-42, being the second prominent Abeta peptide species in CSF. Patients with Alzheimer's disease (AD, n = 12) and patients with chronic inflammatory CNS disease (CID, n = 10) were differentiated by unique CSF Abeta peptide patterns from patients with other neuropsychiatric diseases (OND, n = 37). This became evident only when we investigated the amount of Abeta peptides relative to their total Abeta peptide concentration (Abeta1-x%, fractional Abeta peptide pattern), which may reflect disease-specific gamma-secretase activities. Remarkably, patients with AD and CID shared elevated Abeta1-38% values, whereas otherwise the patterns were distinct, allowing separation of AD from CID or OND patients without overlap. The presence of one or two ApoE epsilon4 alleles resulted in an overall reduction of CSF Abeta peptides, which was pronounced for Abeta1-42. The severity of dementia was significantly correlated to the fractional Abeta peptide pattern but not to the absolute Abeta peptide concentrations.


Asunto(s)
Péptidos beta-Amiloides/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Adulto , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4 , Apolipoproteínas E/genética , Biomarcadores/análisis , Biomarcadores/líquido cefalorraquídeo , Western Blotting , Sistema Nervioso Central/metabolismo , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedad Crónica , Secuencia Conservada , Electroforesis en Gel de Poliacrilamida , Encefalitis/líquido cefalorraquídeo , Femenino , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/química , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
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