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1.
Neurobiol Aging ; 34(1): 338-50, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22727277

ABSTRACT

Transgenic mouse models have been an invaluable resource in elucidating the complex roles of ß-amyloid and tau in Alzheimer's disease. Although many laboratories rely on qualitative or semiquantitative techniques when investigating tau pathology, we have developed 4 Low-Tau, Sandwich enzyme-linked immunosorbent assays (ELISAs) that quantitatively assess different epitopes of tau relevant to Alzheimer's disease: total tau, pSer-202, pThr-231, and pSer-396/404. In this study, after comparing our assays with commercially available ELISAs, we demonstrate our assay's high specificity and quantitative capabilities using brain homogenates from tau transgenic mice, htau, JNPL3, and tau knockout. All 4 ELISAs show excellent specificity for mouse and human tau, with no reactivity to tau knockout animals. An age-dependent increase of serum tau in both tau transgenic models was also seen. Taken together, these assays are valuable methods to quantify tau and phospho-tau levels in transgenic animals, by examining tau levels in brain and measuring tau as a potential serum biomarker.


Subject(s)
Alzheimer Disease/metabolism , tau Proteins/genetics , tau Proteins/metabolism , Animals , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Epitope Mapping , Humans , Mice , Mice, Transgenic , Phosphorylation/genetics , Sensitivity and Specificity , tau Proteins/blood , tau Proteins/deficiency
2.
J Alzheimers Dis ; 16(2): 351-62, 2009.
Article in English | MEDLINE | ID: mdl-19221425

ABSTRACT

Little is known of combined utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers for prediction of Alzheimer's disease (AD) and longitudinal data is scarce. We examined these biomarkers at baseline and longitudinally in incipient AD. Forty-five subjects [21 controls (NL-NL), 16 stable MCI (MCI-MCI), 8 MCI who declined to AD (MCI-AD)] received MRI and lumbar puncture at baseline and after 2 years. CSF measures included total and phosphorylated tau (T-tau, P-tau(231)), amyloid-beta (Abeta(42)/Abeta(40)) and isoprostane. Voxel-based morphometry identified gray matter concentration (GMC) differences best distinguishing study groups and individual GMC values were calculated. Rate of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC-MTL, and for CSF higher CSF T-tau, P-tau(231), IP and lower Abeta(42)/Abeta(40) as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of isoprostane in MCI-AD as compared with NL-NL. Combining baseline CSF-P-tau(231) and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (p(step)<0.05). These results provide support for including multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/pathology , Magnetic Resonance Imaging/methods , Aged , Alzheimer Disease/complications , Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoprotein E4/genetics , Area Under Curve , Cognition Disorders/cerebrospinal fluid , Cognition Disorders/complications , Cognition Disorders/diagnosis , Cognition Disorders/genetics , Female , Functional Laterality , Gas Chromatography-Mass Spectrometry , Humans , Image Processing, Computer-Assisted , Isoprostanes/cerebrospinal fluid , Longitudinal Studies , Male , Middle Aged , Peptide Fragments/cerebrospinal fluid , Sensitivity and Specificity , tau Proteins/cerebrospinal fluid
3.
Neurobiol Aging ; 30(5): 682-90, 2009 May.
Article in English | MEDLINE | ID: mdl-17889968

ABSTRACT

OBJECTIVES: To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau(231)), amyloid beta (Abeta) Abeta(42)/Abeta(40) ratio, isoprostane (IP) as well as P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios. RESULTS: At baseline and at follow-up MCI-AD showed higher levels P-tau(231), T-tau, IP, P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios and lower Abeta(42)/Abeta(40) than MCI-MCI or NL-NL. Baseline P-tau(231) best predicted MCI-AD (80%, p<0.001) followed in accuracy by P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios (both 75%, p's<0.001), T-tau (74%, p<0.001), Abeta(42)/Abeta(40) (69%, p<0.01), and IP (68%, p<0.01). Only IP showed longitudinal effects (p<0.05). CONCLUSIONS: P-tau(231) is the strongest predictor of the decline from MCI to AD. IP levels uniquely show longitudinal progression effects. These results suggest the use of CSF biomarkers in secondary prevention trials.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnosis , Cognition Disorders/cerebrospinal fluid , Cognition Disorders/diagnosis , tau Proteins/cerebrospinal fluid , Aged , Aged, 80 and over , Amyloid beta-Peptides/analysis , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/analysis , Biomarkers/cerebrospinal fluid , Cohort Studies , Disease Progression , Early Diagnosis , Female , Humans , Isoprostanes/analysis , Isoprostanes/cerebrospinal fluid , Longitudinal Studies , Male , Middle Aged , Peptide Fragments/analysis , Peptide Fragments/cerebrospinal fluid , Predictive Value of Tests , Prognosis , tau Proteins/analysis
4.
Biol Psychiatry ; 63(6): 609-18, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-17720148

ABSTRACT

BACKGROUND: We examined whether cerebral metabolic rates for glucose (CMRglc) on 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) are altered in cognitively normal apolipoprotein E (ApoE) E4 carriers with subjective memory complaints (SMC). METHODS: Twenty-eight middle-aged normal subjects (NL) were examined, including 13 E4 carriers (E4+; 6 with SMC [SMC+] and 7 without SMC [SMC-]) and 15 noncarriers (E4-; 7 SMC+ and 8 SMC-). Subjects received an FDG-PET scan and a lumbar puncture to measure CSF total (T-Tau) and hyperphosphorylated tau(231) (P-Tau), 40 and 42 amino acid forms of beta-amyloid (Abeta40 and Abeta42), and F(2)-isoprostane (IP). RESULTS: As compared with E4-, E4+ subjects showed decreased CMRglc in AD-related brain regions and associated higher CSF IP, P-Tau, T-Tau, and P-Tau/Abeta42 levels (p's < .05). As compared with SMC-, SMC+ subjects showed reduced parietotemporal and parahippocampal gyrus (PHG) CMRglc. A significant ApoE by SMC status interaction was found, with the E4+/SMC+ showing the lowest PHG CMRglc and the highest CSF IP, P-Tau, and P-Tau/Abeta42 levels as compared with all other subgroups (p's < or = .05). The combination of CSF and CMRglc measures significantly improved the accuracy of either measures alone in discriminating ApoE groups (86% accuracy, odds ratio [OR] = 4.1, p < .001) and E4+/SMC+ from all other subgroups (86% accuracy, OR = 3.7, p = .005). Parahippocampal gyrus CMRglc was the most accurate discriminator of SMC groups (75% accuracy, OR = 2.4, p < .001). CONCLUSIONS: Normal E4 carriers with SMC show altered AD-related CSF and FDG-PET measures. Longitudinal studies are needed to assess whether these brain abnormalities foreshadow clinical decline.


Subject(s)
Alzheimer Disease/genetics , Apolipoprotein E4/genetics , Biomarkers/cerebrospinal fluid , Blood Glucose/metabolism , Energy Metabolism/genetics , Genetic Carrier Screening , Memory Disorders/genetics , Positron-Emission Tomography , Aged , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Brain/diagnostic imaging , Brain/metabolism , Female , Fluorodeoxyglucose F18 , Humans , Male , Memory Disorders/cerebrospinal fluid , Middle Aged , Peptide Fragments/cerebrospinal fluid , Reference Values , tau Proteins/cerebrospinal fluid
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